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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 1
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute 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 Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
ABSTRACT Background and objective: Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries. Methods: Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports. Results: We enrolled 148 patients (44.6 ± 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (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 foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable.
SUMMARY AT A GLANCE This is the first report on bronchiectasis aetiologies in mainland China. Idiopathic, post-infectious and immunodeficiency were the most common aetiologies. No significant differences were found in ethnicity or geography. Our findings will shed light on early diagnosis and management of bronchiectasis in future studies and clinical practice in China.
Conclusions: Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China. Key words: aetiology, bronchiectasis, clinical characteristic, diagnostic test, idiopathic. Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; HRCT, high-resolution computed tomography; MMEF, maximal mid-expiratory flow.
INTRODUCTION Correspondence: Rong-chang Chen, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang 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 January 2015; accepted 19 January 2015 (Associate Editor: Chi Chiu Leung). © 2015 Asian Pacific Society of Respirology
Bronchiectasis is a heterogeneous disease characterized by chronic cough, sputum production, haemoptysis and fever1–4 that results from various aetiologies. Ethnic or geographic variations were shown to contribute to different aetiologic spectra among different studies, for instance, idiopathic bronchiectasis accounted for around 50% in western countries5–9 and 80% in Hong Kong, China.10 Symptoms, signs, disease severity and prognosis of bronchiectasis differ considerably with different Respirology (2015) doi: 10.1111/resp.12528
2
W Guan et al.
aetiologies. Pseudomonas aeruginosa infection elicited worsening of symptoms11 and rapid lung function decline2 in cystic fibrosis. Importantly, aetiologic assessment may shift treatment paradigms.6 Children with bronchiectasis related to primary ciliary dyskinesia, aspiration and immunodeficiency would benefit considerably from aetiology-targeted therapies.7 Global prevalence of bronchiectasis was estimated to be 1.5∼17.8 per 10 000,12 and the morbidity increasing with age.13 China accounts for one fifth of world’s population, yet lacks epidemiologic profiles of bronchiectasis. Comparatively poor hygiene and healthcare conditions could lead to higher prevalence of bronchiectasis and different aetiologic spectra compared with western countries. Guangzhou is a major city in southern China, with a population of over 10 million, with representative characteristics of southeastern Asians. Investigation into bronchiectasis aetiology in this group is urgently indicated, and might improve treatment outcomes and provide insights into future clinical trials. We hypothesized that bronchiectasis aetiologies in mainland Chinese patients differed from those of western countries, with a higher proportion of postinfectious bronchiectasis. We sought to determine the aetiologies and clinical characteristics of bronchiectasis in Guangzhou, and to compare with literature reports, thus unraveling ethnic or geographic differences.
tubular, 2 for varicose and 3 for cystic bronchiectasis. Maximal total score was 18 for six lobes.14 Disease severity was assessed using Bronchiectasis Severity Index.15
METHODS
Serum total and A. fumigatus-specific IgE These measurements were conducted in patients with wheezing and/or brownish sputum, elevated peripheral blood (>0.4 × 109/L) and (or) sputum eosinophil count (>2.5%), and predominantly central airway bronchiectasis. IgE was assayed using ImmunoCAP microplate reader (Phadia AB, Uppsala, Sweden). Compatible history with serum total IgE >170 kU/L5 and aspergillus-specific IgE >0.35 kU/L suggested allergic bronchopulmonary aspergillosis (ABPA) as the aetiology of bronchiectasis.
Patients Between September 2012 and November 2013, bronchiectasis patients aged 18–75 years were consecutively recruited from outpatient respiratory clinics, for performing serial studies on steady-state bronchiectasis (Guangzhou Bronchiectasis Study). Patients with bronchiectasis exacerbations upon physician’s referral were scheduled for inclusion at least 4 weeks post-exacerbation. Bronchiectasis was diagnosed based on chest high-resolution computed tomography (HRCT)2,5,6,10 and symptoms (chronic coughing, sputum production and/or haemoptysis). Patients with asymptomatic bronchiectasis and malignancy were excluded. This study was approved by Ethic Committee of First Affiliated Hospital of Guangzhou Medical University. Patients gave written informed consent. Chest HRCT scoring Chest HRCT at 2 mm collimation within 12 months, when clinically stable, was evaluated. A specialist radiologist with at least 10 years of experience of HRCT review who was blinded to patient’s conditions performed systematic evaluation, including modified Reiff score, predominantly middle lobe bronchiectasis, dyshomogeneity, atelectasis, aspergilloma, cystic bronchiectasis and pulmonary infiltration. Consultancy of a second radiologist was sought if appropriate. Lingular was deemed a separate lobe. For individual lobes, bronchiectasis was scored: 0 for no, 1 for Respirology (2015)
Summarized methods for determining aetiologies Patients were meticulously questioned about their past and present medical history, followed by physical examination, chest (and nasal, if indicated) HRCT, spirometry, diffusing capacity measurement, venous blood sampling (blood routine test and immunoglobins), sputum culture, saccharine test and simplified reflux questionnaire interview. Patients susceptible of having gastroesophageal reflux disease (GERD), aspergillosis, asthma or chronic obstructive pulmonary disease (COPD) underwent 24-h oesophageal pH monitoring, serum total and Aspergillus fumigatus-specific IgE test, and bronchial dilation test, respectively. Hemagglutinin and auto-antibodies were tested for susceptible diffuse panbronchiolitis and connective tissue diseases, respectively. Other diagnostic tests (i.e. bronchoscopy, gastroscopy) could be performed if appropriate (Table 1, Figure S1). See Supplementary Appendix S1 for humoral immunity assessment, nasal saccharine test, sputum culture, diffusing capacity measurement and spirometry.
Gastroesophageal reflux GERD questionnaire was employed for screening (Table S1), with the total score of 12 or greater indicating high probability of GERD,17 which warranted 24-h oesophageal pH monitoring (see Supplementary Appendix S1). History of reflux was meticulously extracted. In patients with confirmed history (gastroscopy, gastrectomy for physician-diagnosed reflux, oesophageal resistance tested positive), GERD was deemed the aetiology if onset of reflux-associated events were chronologically followed by chronic cough and sputum production. Otherwise, GERD was considered as a mere concomitant disease. Post-infectious bronchiectasis During hospital visits, we meticulously inquired past histories of infectious diseases associated with bronchiectasis pathogenesis, including measles, © 2015 Asian Pacific Society of Respirology
3
Aetiology of bronchiectasis in Guangzhou Table 1 Summarized methods for determining the main aetiologies of bronchiectasis Aetiology Post-infectious Immunodeficiency Gastroesophageal reflux disease
Aspergillosis
Kartagener syndrome
Young’s syndrome
Yellow nail syndrome
Connective tissue diseases
Asthma
Chronic obstructive pulmonary disease Lung maldevelopment
Idiopathic
Methods History inquiry History inquiry Serum immunoglobin titres assay History inquiry Simplified reflux questionnaire 24-h pH monitoring (if indicated) History inquiry Symptoms Chest HRCT characters Serum IgE (if indicated) Aspergillosis fumigatus-specific IgE titres (if indicated) Chest HRCT History inquiry Physical examination Saccharine test Nasal CT Physical examination History inquiry Sperm examination (if indicated) Chest HRCT Physical examination History inquiry Consultation of dermatologists (if indicated) Chest HRCT Physical examination History inquiry Serum auto-immune antibodies History inquiry Physical examination Bronchial dilation/provocation test Aspergillosis fumigatus-specific IgE titres for exclusion of aspergillosis) History inquiry Physical examination Bronchial dilation test History inquiry Physical examination Chest HRCT Exclusion of all known aetiologies
Screening of all subjects
References 6,16
Yes Yes
6,7,16
Yes
16,17
No
5,6,16
Yes
6,16
No
6,16
No
6,16
No
6,16
No
16
No
16
Yes
NA
NA
5,6,16
CT, computed tomography; HRCT, high-resolution computed tomography; NA, not applicable.
pertussis, tuberculosis, childhood and adulthood pneumonia. We meticulously determined the sequence of symptoms onset and bronchiectasis, prognosis and relevant treatments. To minimize recall bias, we inquired patients regarding the characteristics of infectious diseases or any of their past history, and verified this via detailed medical charts and chest HRCT review. Patient’s replies were systematically recorded in medical records during interviews. If bronchiectasis symptoms developed after infection,16,18 post-infectious bronchiectasis was deemed the aetiology. History of childhood infection was ascertained by detailed inquiry of patient’s relatives. © 2015 Asian Pacific Society of Respirology
Diagnostic criteria of miscellaneous aetiologies16 See Supplementary Appendix S1. Statistical analysis Statistical analysis was performed using SPSS 16.0 version package (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov test was conducted to determine normality of distribution for continuous variables, which were expressed as mean ± standard deviation or median (interquartile range) as appropriate. Two-sided independent t-test was adopted for normal distribution, otherwise non-parametric test. Respirology (2015)
4
W Guan et al.
Figure 1 Recruitment flowchart. *Saccharine tested positive denoted a nasal mucociliary clearance time being 60 min or greater. Sinus computed tomography (CT) was performed following saccharine test because sinus disease was considered the cause of prolonged nasal mucociliary clearance time (NMCC) in a subgroup of patients. The male patient with Young’s syndrome was not tested for primary ciliary dyskinesia because of the unavailability of measuring tools. NTM, non-tuberculous mycobacteria; DPB, diffuse panbronchiolitis.
Categorical data were expressed as number (percentage) and analysed using chi-square tests. P < 0.05 was deemed statistically significant.
RESULTS Subject recruitment and comparison of clinical characteristics between male and female patients The recruitment process is outlined in Figure 1. Two patients were twin sisters and five had family history of bronchiectasis. Age of onset was normally distributed (Figure S2) and culminated between 30 and 60 years. Most patients were females (62.2%), with a higher proportion of never-smokers compared with males (P < 0.01). Most patients had ventilatory dysfunction (obstructive, restrictive or mixed type). Gender differences in the past history, bronchiectasis exacerbations, HRCT scores and concomitant medications were unremarkable (all P > 0.05) (Table 2). Socioeconomic status For a description of the information on the socioeconomic status of the study participants, see the Supplementary Appendix S1. Respirology (2015)
Sputum bacteriology Four patients failed to produce sputum. Of 144 patients, 57 (39.58%) isolated commensals. Of 97 culture-positive patients, 44 (29.7%) isolated P. aeruginosa, 15 (10.1%) Haemophilus parainfluenzae and 14 (9.5%) Haemophilus influenzae. Overall positive rate for non-tuberculosis Mycobacteria was 3.5% (n = 5). Nine patients (seven females) with predominantly middle/lingular lobe bronchiectasis tested negative for non-tuberculosis Mycobacteria (data not shown). Aetiologic spectra Aetiologic spectra are shown in Figure 2. Of known aetiologies, post-infectious accounted for 27.0% (n = 40), of which post-measles (n = 14, 9.5%) and post-tuberculous (n = 16, 10.8%) were most common, followed by immunodeficiency (n = 13, 8.8%) and asthma (n = 8, 5.4%). Miscellaneous known aetiologies accounted for 8.8%. Patients with Kartagener syndrome, lung maldevelopment, foreign body and Young’s syndrome were comparatively younger upon enrolment. Patients with post-measles, aspergillosis, rheumatoid arthritis and diffuse panbronchiolitis harboured more bronchiectatic lobes leading to higher HRCT scores. Idiopathic (48.91%), post© 2015 Asian Pacific Society of Respirology
5
Aetiology of bronchiectasis in Guangzhou Table 2 Clinical characteristics Parameter Anthropometry
Spirometry
Disease-related parameters
Concomitant medications within 6 months
Age (years) Height (cm) Weight (kg) BMI (cm/kg2) Never-smoker (No., %) FVC (L) FVC pred% FEV1 (L) FEV1 pred% FEV1/FVC (%) MMEF (L) MMEF pred% Duration of symptoms (years) Duration of diagnosis (years) No. of acute exacerbations in 2 years No. of severe acute exacerbations in 2 years† No. of hospitalizations in 2 years No. of bronchiectatic lobes HRCT total score Bronchiectasis Severity Index 24-h sputum volume (mL) Inhaled corticosteroids (No., %) Mucolytics (No., %) Macrolides (No., %) Theophylline (No., %)
All patients (n = 148)
Male (n = 56)
Female (n = 92)
P value*
44.6 ± 13.8 160.0 (10.0) 52.0 (10.5) 20.0 (3.9) 131 (88.52) 2.58 ± 0.87 81.79 (26.34) 1.91 ± 0.75 70.37 ± 23.76 75.70 (16.40) 1.68 ± 0.98 56.79 ± 30.53 10.0 (16.0) 3.0 (9.0) 3.0 (4.0) 1.0 (3.0)
43.4 ± 13.0 167.4 ± 5.8 58.9 ± 9.3 21.0 ± 3.2 40 (71.43) 3.28 (1.17) 78.73 ± 19.03 2.26 ± 0.80 68.68 ± 22.52 70.58 ± 13.40 1.88 ± 1.15 55.53 ± 32.14 10.0 (17.0) 3.0 (6.0) 3.0 (3.0) 1.0 (2.0)
44.6 ± 14.2 157.1 ± 5.7 49.5 ± 7.3 20.1 ± 3.0 91 (98.91) 2.23 ± 0.68 78.49 ± 21.08 1.70 ± 0.64 71.41 ± 24.56 76.65 (14.75) 1.55 ± 0.85 57.58 ± 29.65 10.0 (15.0) 3.0 (9.0) 3.0 (3.0) 1.0 (3.0)
0.78
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 1
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute 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 Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
ABSTRACT Background and objective: Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries. Methods: Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports. Results: We enrolled 148 patients (44.6 ± 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (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 foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable.
SUMMARY AT A GLANCE This is the first report on bronchiectasis aetiologies in mainland China. Idiopathic, post-infectious and immunodeficiency were the most common aetiologies. No significant differences were found in ethnicity or geography. Our findings will shed light on early diagnosis and management of bronchiectasis in future studies and clinical practice in China.
Conclusions: Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China. Key words: aetiology, bronchiectasis, clinical characteristic, diagnostic test, idiopathic. Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; HRCT, high-resolution computed tomography; MMEF, maximal mid-expiratory flow.
INTRODUCTION Correspondence: Rong-chang Chen, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang 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 January 2015; accepted 19 January 2015 (Associate Editor: Chi Chiu Leung). © 2015 Asian Pacific Society of Respirology
Bronchiectasis is a heterogeneous disease characterized by chronic cough, sputum production, haemoptysis and fever1–4 that results from various aetiologies. Ethnic or geographic variations were shown to contribute to different aetiologic spectra among different studies, for instance, idiopathic bronchiectasis accounted for around 50% in western countries5–9 and 80% in Hong Kong, China.10 Symptoms, signs, disease severity and prognosis of bronchiectasis differ considerably with different Respirology (2015) doi: 10.1111/resp.12528
2
W Guan et al.
aetiologies. Pseudomonas aeruginosa infection elicited worsening of symptoms11 and rapid lung function decline2 in cystic fibrosis. Importantly, aetiologic assessment may shift treatment paradigms.6 Children with bronchiectasis related to primary ciliary dyskinesia, aspiration and immunodeficiency would benefit considerably from aetiology-targeted therapies.7 Global prevalence of bronchiectasis was estimated to be 1.5∼17.8 per 10 000,12 and the morbidity increasing with age.13 China accounts for one fifth of world’s population, yet lacks epidemiologic profiles of bronchiectasis. Comparatively poor hygiene and healthcare conditions could lead to higher prevalence of bronchiectasis and different aetiologic spectra compared with western countries. Guangzhou is a major city in southern China, with a population of over 10 million, with representative characteristics of southeastern Asians. Investigation into bronchiectasis aetiology in this group is urgently indicated, and might improve treatment outcomes and provide insights into future clinical trials. We hypothesized that bronchiectasis aetiologies in mainland Chinese patients differed from those of western countries, with a higher proportion of postinfectious bronchiectasis. We sought to determine the aetiologies and clinical characteristics of bronchiectasis in Guangzhou, and to compare with literature reports, thus unraveling ethnic or geographic differences.
tubular, 2 for varicose and 3 for cystic bronchiectasis. Maximal total score was 18 for six lobes.14 Disease severity was assessed using Bronchiectasis Severity Index.15
METHODS
Serum total and A. fumigatus-specific IgE These measurements were conducted in patients with wheezing and/or brownish sputum, elevated peripheral blood (>0.4 × 109/L) and (or) sputum eosinophil count (>2.5%), and predominantly central airway bronchiectasis. IgE was assayed using ImmunoCAP microplate reader (Phadia AB, Uppsala, Sweden). Compatible history with serum total IgE >170 kU/L5 and aspergillus-specific IgE >0.35 kU/L suggested allergic bronchopulmonary aspergillosis (ABPA) as the aetiology of bronchiectasis.
Patients Between September 2012 and November 2013, bronchiectasis patients aged 18–75 years were consecutively recruited from outpatient respiratory clinics, for performing serial studies on steady-state bronchiectasis (Guangzhou Bronchiectasis Study). Patients with bronchiectasis exacerbations upon physician’s referral were scheduled for inclusion at least 4 weeks post-exacerbation. Bronchiectasis was diagnosed based on chest high-resolution computed tomography (HRCT)2,5,6,10 and symptoms (chronic coughing, sputum production and/or haemoptysis). Patients with asymptomatic bronchiectasis and malignancy were excluded. This study was approved by Ethic Committee of First Affiliated Hospital of Guangzhou Medical University. Patients gave written informed consent. Chest HRCT scoring Chest HRCT at 2 mm collimation within 12 months, when clinically stable, was evaluated. A specialist radiologist with at least 10 years of experience of HRCT review who was blinded to patient’s conditions performed systematic evaluation, including modified Reiff score, predominantly middle lobe bronchiectasis, dyshomogeneity, atelectasis, aspergilloma, cystic bronchiectasis and pulmonary infiltration. Consultancy of a second radiologist was sought if appropriate. Lingular was deemed a separate lobe. For individual lobes, bronchiectasis was scored: 0 for no, 1 for Respirology (2015)
Summarized methods for determining aetiologies Patients were meticulously questioned about their past and present medical history, followed by physical examination, chest (and nasal, if indicated) HRCT, spirometry, diffusing capacity measurement, venous blood sampling (blood routine test and immunoglobins), sputum culture, saccharine test and simplified reflux questionnaire interview. Patients susceptible of having gastroesophageal reflux disease (GERD), aspergillosis, asthma or chronic obstructive pulmonary disease (COPD) underwent 24-h oesophageal pH monitoring, serum total and Aspergillus fumigatus-specific IgE test, and bronchial dilation test, respectively. Hemagglutinin and auto-antibodies were tested for susceptible diffuse panbronchiolitis and connective tissue diseases, respectively. Other diagnostic tests (i.e. bronchoscopy, gastroscopy) could be performed if appropriate (Table 1, Figure S1). See Supplementary Appendix S1 for humoral immunity assessment, nasal saccharine test, sputum culture, diffusing capacity measurement and spirometry.
Gastroesophageal reflux GERD questionnaire was employed for screening (Table S1), with the total score of 12 or greater indicating high probability of GERD,17 which warranted 24-h oesophageal pH monitoring (see Supplementary Appendix S1). History of reflux was meticulously extracted. In patients with confirmed history (gastroscopy, gastrectomy for physician-diagnosed reflux, oesophageal resistance tested positive), GERD was deemed the aetiology if onset of reflux-associated events were chronologically followed by chronic cough and sputum production. Otherwise, GERD was considered as a mere concomitant disease. Post-infectious bronchiectasis During hospital visits, we meticulously inquired past histories of infectious diseases associated with bronchiectasis pathogenesis, including measles, © 2015 Asian Pacific Society of Respirology
3
Aetiology of bronchiectasis in Guangzhou Table 1 Summarized methods for determining the main aetiologies of bronchiectasis Aetiology Post-infectious Immunodeficiency Gastroesophageal reflux disease
Aspergillosis
Kartagener syndrome
Young’s syndrome
Yellow nail syndrome
Connective tissue diseases
Asthma
Chronic obstructive pulmonary disease Lung maldevelopment
Idiopathic
Methods History inquiry History inquiry Serum immunoglobin titres assay History inquiry Simplified reflux questionnaire 24-h pH monitoring (if indicated) History inquiry Symptoms Chest HRCT characters Serum IgE (if indicated) Aspergillosis fumigatus-specific IgE titres (if indicated) Chest HRCT History inquiry Physical examination Saccharine test Nasal CT Physical examination History inquiry Sperm examination (if indicated) Chest HRCT Physical examination History inquiry Consultation of dermatologists (if indicated) Chest HRCT Physical examination History inquiry Serum auto-immune antibodies History inquiry Physical examination Bronchial dilation/provocation test Aspergillosis fumigatus-specific IgE titres for exclusion of aspergillosis) History inquiry Physical examination Bronchial dilation test History inquiry Physical examination Chest HRCT Exclusion of all known aetiologies
Screening of all subjects
References 6,16
Yes Yes
6,7,16
Yes
16,17
No
5,6,16
Yes
6,16
No
6,16
No
6,16
No
6,16
No
16
No
16
Yes
NA
NA
5,6,16
CT, computed tomography; HRCT, high-resolution computed tomography; NA, not applicable.
pertussis, tuberculosis, childhood and adulthood pneumonia. We meticulously determined the sequence of symptoms onset and bronchiectasis, prognosis and relevant treatments. To minimize recall bias, we inquired patients regarding the characteristics of infectious diseases or any of their past history, and verified this via detailed medical charts and chest HRCT review. Patient’s replies were systematically recorded in medical records during interviews. If bronchiectasis symptoms developed after infection,16,18 post-infectious bronchiectasis was deemed the aetiology. History of childhood infection was ascertained by detailed inquiry of patient’s relatives. © 2015 Asian Pacific Society of Respirology
Diagnostic criteria of miscellaneous aetiologies16 See Supplementary Appendix S1. Statistical analysis Statistical analysis was performed using SPSS 16.0 version package (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov test was conducted to determine normality of distribution for continuous variables, which were expressed as mean ± standard deviation or median (interquartile range) as appropriate. Two-sided independent t-test was adopted for normal distribution, otherwise non-parametric test. Respirology (2015)
4
W Guan et al.
Figure 1 Recruitment flowchart. *Saccharine tested positive denoted a nasal mucociliary clearance time being 60 min or greater. Sinus computed tomography (CT) was performed following saccharine test because sinus disease was considered the cause of prolonged nasal mucociliary clearance time (NMCC) in a subgroup of patients. The male patient with Young’s syndrome was not tested for primary ciliary dyskinesia because of the unavailability of measuring tools. NTM, non-tuberculous mycobacteria; DPB, diffuse panbronchiolitis.
Categorical data were expressed as number (percentage) and analysed using chi-square tests. P < 0.05 was deemed statistically significant.
RESULTS Subject recruitment and comparison of clinical characteristics between male and female patients The recruitment process is outlined in Figure 1. Two patients were twin sisters and five had family history of bronchiectasis. Age of onset was normally distributed (Figure S2) and culminated between 30 and 60 years. Most patients were females (62.2%), with a higher proportion of never-smokers compared with males (P < 0.01). Most patients had ventilatory dysfunction (obstructive, restrictive or mixed type). Gender differences in the past history, bronchiectasis exacerbations, HRCT scores and concomitant medications were unremarkable (all P > 0.05) (Table 2). Socioeconomic status For a description of the information on the socioeconomic status of the study participants, see the Supplementary Appendix S1. Respirology (2015)
Sputum bacteriology Four patients failed to produce sputum. Of 144 patients, 57 (39.58%) isolated commensals. Of 97 culture-positive patients, 44 (29.7%) isolated P. aeruginosa, 15 (10.1%) Haemophilus parainfluenzae and 14 (9.5%) Haemophilus influenzae. Overall positive rate for non-tuberculosis Mycobacteria was 3.5% (n = 5). Nine patients (seven females) with predominantly middle/lingular lobe bronchiectasis tested negative for non-tuberculosis Mycobacteria (data not shown). Aetiologic spectra Aetiologic spectra are shown in Figure 2. Of known aetiologies, post-infectious accounted for 27.0% (n = 40), of which post-measles (n = 14, 9.5%) and post-tuberculous (n = 16, 10.8%) were most common, followed by immunodeficiency (n = 13, 8.8%) and asthma (n = 8, 5.4%). Miscellaneous known aetiologies accounted for 8.8%. Patients with Kartagener syndrome, lung maldevelopment, foreign body and Young’s syndrome were comparatively younger upon enrolment. Patients with post-measles, aspergillosis, rheumatoid arthritis and diffuse panbronchiolitis harboured more bronchiectatic lobes leading to higher HRCT scores. Idiopathic (48.91%), post© 2015 Asian Pacific Society of Respirology
5
Aetiology of bronchiectasis in Guangzhou Table 2 Clinical characteristics Parameter Anthropometry
Spirometry
Disease-related parameters
Concomitant medications within 6 months
Age (years) Height (cm) Weight (kg) BMI (cm/kg2) Never-smoker (No., %) FVC (L) FVC pred% FEV1 (L) FEV1 pred% FEV1/FVC (%) MMEF (L) MMEF pred% Duration of symptoms (years) Duration of diagnosis (years) No. of acute exacerbations in 2 years No. of severe acute exacerbations in 2 years† No. of hospitalizations in 2 years No. of bronchiectatic lobes HRCT total score Bronchiectasis Severity Index 24-h sputum volume (mL) Inhaled corticosteroids (No., %) Mucolytics (No., %) Macrolides (No., %) Theophylline (No., %)
All patients (n = 148)
Male (n = 56)
Female (n = 92)
P value*
44.6 ± 13.8 160.0 (10.0) 52.0 (10.5) 20.0 (3.9) 131 (88.52) 2.58 ± 0.87 81.79 (26.34) 1.91 ± 0.75 70.37 ± 23.76 75.70 (16.40) 1.68 ± 0.98 56.79 ± 30.53 10.0 (16.0) 3.0 (9.0) 3.0 (4.0) 1.0 (3.0)
43.4 ± 13.0 167.4 ± 5.8 58.9 ± 9.3 21.0 ± 3.2 40 (71.43) 3.28 (1.17) 78.73 ± 19.03 2.26 ± 0.80 68.68 ± 22.52 70.58 ± 13.40 1.88 ± 1.15 55.53 ± 32.14 10.0 (17.0) 3.0 (6.0) 3.0 (3.0) 1.0 (2.0)
44.6 ± 14.2 157.1 ± 5.7 49.5 ± 7.3 20.1 ± 3.0 91 (98.91) 2.23 ± 0.68 78.49 ± 21.08 1.70 ± 0.64 71.41 ± 24.56 76.65 (14.75) 1.55 ± 0.85 57.58 ± 29.65 10.0 (15.0) 3.0 (9.0) 3.0 (3.0) 1.0 (3.0)
0.78
