Online Data Supplement. Impulse Oscillometry in Adults with Bronchiectasis

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1 Online Data Supplement Impulse Oscillometry in Adults with Bronchiectasis Wei-jie Guan *1, Ph. D.; Yong-hua Gao *2, Ph. D.; Gang Xu *3, Ph. D.; Zhi-ya Lin 1, Ph. D.; Yan Tang 1, M. D.; Hui-min Li 1, M. T.; Zhi-min Lin 1, M. Med.; Jin-ping Zheng 1, M. D., Rong-chang Chen 1, M. D.; Nan-shan Zhong 1, M. D. 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, Guangzhou Medical University, Guangzhou, Guangdong, China 2. Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 3. Department of Geriatrics, Guangzhou First People s Hospital, Guangzhou, Guangdong, China Corresponding Author 1: Nan-shan Zhong, M. D., 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, Address: 151 Yanjiang Road, Guangzhou, Guangdong, China, Fax: , Phone: , nanshan@vip.163.com Corresponding Author 2: Rong-chang Chen, M. D., 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, Address: 151 Yanjiang Road, Guangzhou, Guangdong, China, Fax: , Phone: , chenrc@vip.163.com *Drs. Wei-jie Guan, Yong-hua Gao and Gang Xu contributed equally to the study. Author Contributions: W. J. G., Y. H. G. and G. X. drafted the manuscript; Z. M. L., Y. T., R. C. C. and N. S. Z. were responsible for patient recruitment; W. J. G., Y. H. G., G. X., H. M. L. and Z. M. L. collected individual data; W. J. G., Y. H. G. and G. X. performed statistical analyses; W. J. G., Y. H. G., G. X., J. P. Z., R. C. C. and N. S. Z. contributed to study conception; R. C. C. and N. S. Z. provided

2 critical review of the manuscript and approved the final submission. Primary Source of Funding: Changjiang Scholars and Innovative Research Team in University ITR0961, The National Key Technology R&D Program of the 12th National Five-year Development Plan 2012BAI05B01 and National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer No. 2013BAI09B09 (to Profs. Zhong and Chen), National Natural Science Foundation No and 2014 Scientific Research Projects for Medical Doctors and Researchers from Overseas, Guangzhou Medical University No. 2014C21 (to Dr. Guan). Conflict of Interest: Profs. Zhong and Chen declared that they had received Changjiang Scholars and Innovative Research Team in University ITR0961, The National Key Technology R&D Program of the 12th National Five-year Development Plan 2012BAI05B01 and National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer No. 2013BAI09B09. Dr. Guan declared that he has received National Natural Science Foundation No and 2014 Scientific Research Projects for Medical Doctors and Researchers from Overseas, Guangzhou Medical University No. 2014C21. All other authors declared no potential conflict of interest. None of the funding sources had any role on the study. E2

3 Methods Sputum Culture and Quantitative Assessment of Bacterial Load Fresh sputum sample was collected during the hospital visit between 9:00 and 11:00 am. Subjects were instructed to fully empty their mouth and remove oral remnants followed by chest physiotherapy for 10 to 15 minutes. This was followed by forced expectoration to collect sputum sample into a 50ml sterile plastic pot. The method for sputum culture has been introduced previously [E1]. Briefly, blood agar (Biomeurix Inc., France) and chocolate agar plates (Biomeurix Inc. France) were employed. The fresh sputum was homogenized using SPUTASOL (Oxoid SR089A) and serially diluted with natural saline (10-4, 10-5 and 10-6 ). This was followed by adding 10μl respective diluent to the agar plates with a micropipette tube and inoculation via a standardized inoculation ring. The culture media were placed in a thermostatic box containing 5% carbon dioxide at 37 for overnight inoculation. Pathogenic bacteria included Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis and other clinically significant bacteria at the investigator s discretion. Non-pathogenic bacteria (commensals) included Neisseria, α-streptococcus hemolyticus, Bacilli diphtheria and coagulase-negative staphylococcus. Prolonged culture was done for the negative plates. Bacterial load was determined on a daily basis, with a maximum of 4 consecutive days. E3

4 Results IOS Parameters Significantly Correlated with Clinical Indices and Spirometry in Steady-state Bronchiectasis All IOS parameters but X 5 were positively correlated with the duration of having bronchiectasis symptoms, number of bronchiectatic lobes, HRCT total scores and BSI (all P<0.05). In contrast, all IOS parameters but X 5 were negatively correlated with spirometric indices (all P<0.05). The number of exacerbations was positively correlated with Z 5, R 5, Fres and AX (all P<0.05). However, there were no remarkable correlation between IOS parameters and sputum bacterial density (all P>0.05). (Table E4) Comparison on IOS Parameters between Bronchiectasis Patients and COPD Patients We have reviewed the profiles of 20 patients with clinically stable COPD who were recruited from the out-patient clinics between 2011 and As shown in Table E8, higher GOLD stage was associated with higher levels of frequency dependence (AX), which has been the consequence of small airway dysfunction. Changes in other IOS parameters did not reach statistical significance, possibly because of our small sample sizes. Changes in MMEF were notable because the GOLD stage was classified based on FEV 1 % predicted. We have further selected the profiles of 20 bronchiectasis patients matched with FEV 1 % predicted. Our results showed that IOS parameters did not differ substantially between bronchiectasis patients and COPD patients matched with FEV 1 % predicted. This suggested that, given a similar magnitude of FEV 1 reduction, one would be less likely to anticipate varying IOS E4

5 parameters in different disease entities. (Table E9) References E1. Tsang KW, Chan KN, Ho PL, et al. Sputum Elastase in Steady-State Bronchiectasis. Chest 2000; 117:420 6 E5

6 Table E1: Baseline characteristics of patients enrolled in longitudinal exacerbation cohort Anthropometry Disease characteristics Parameter Exacerbation (n=16) Age (years) 44.7±18.2 Height (cm) 161.3±7.0 Weight (kg) 51.7±6.0 BMI (kg/m 2 ) 19.8±2.0 Never-smokers (No., %) 14 (87.5) Duration of symptom onset (years) 10 (14.0) Duration of diagnosis (years) 7.1±8.2 No. of exacerbations within 2 years 3.0 (3.0) Bronchiectasis etiology Sputum bacteriology No. of bronchiectatic lobes 4.3±1.4 HRCT total score 8.2±3.7 Bronchiectasis severity index 8.5±4.4 Idiopathic 6 (37.5) Post-infectious 2 (12.5) Immunodeficiency 1 (6.3) Asthma 2 (12.5) Gastroesophageal reflux 2 (12.5) Other known etiologies 1 (6.3) Pseudomonas aeruginosa 9 (56.3) Haemophilus parainfluenzae 1 (6.3) Haemophilus influenzae 0 (0.0) Medications ever used within 6 months Other PPMs 1 (6.3) Commensals 5 (31.3) Mucolytics 10 (62.7) Theophylline 11 (68.8) Macrolides 7 (43.8) Inhaled corticosteroids 5 (31.3) Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). Categorical data were expressed as number (percentage). E6

7 Table E2: Spirometry Baseline spirometric and IOS parameters in bronchiectasis patients and healthy subjects Parameter Bronchiectasis patients (n=100) Healthy subjects (n=28) P value FVC pred% 82.3 (28.2) 98.9±10.6 <0.01 FEV 1 pred% 69.0± ±11.1 <0.01 FEV 1 /FVC (%) 72.1± ±5.8 <0.01 MMEF pred% 54.7± ±26.2 <0.01 MEF 50% pred% 45.8± ±26.5 <0.01 MEF 25% pred% 38.5 (36.0) 76.3±23.3 <0.01 Impulse oscillometry Z 5 (kpa/l/s) 0.43 (0.23) 0.30±0.08 <0.01 R 5 (kpa/l/s) 0.35 (0.09) 0.29±0.08 <0.01 R 20 (kpa/l/s) 0.29 (0.07) 0.26±0.07 <0.01 X 5 (kpa/l/s) (0.12) (0.06) <0.01 Fres (kpa/l/s) (12.03) 8.86±1.46 <0.01 AX (kpa/l) 0.37 (1.44) 0.17±0.10 <0.01 Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). Categorical data were expressed as number (percentage). E7

8 Table E3: subjects Diagnostic value of IOS parameters and FEV 1 to discriminate bronchiectasis patients from healthy Area under 95% confidence interval IOS parameters P value Sensitivity Specificity curve Lower limit Upper limit Z 5 (kpa/l/s) < R 5 (kpa/l/s) < R 20 (kpa/l/s) < X 5 (kpa/l/s) < Fres (kpa/l/s) < AX (kpa/l) < FEV 1 pred% < E8

9 Table E4: Correlation between IOS parameters and clinical and spirometric indices in clinically stable bronchiectasis Clinical indices Z 5 (kpa/l/s) R 5 (kpa/l/s) R 20 (kpa/l/s) X 5 (kpa/l/s) Fres (kpa/l/s) AX (kpa/l) r P r P r P r P r P r P Disease duration (yrs) 0.28 < < < <0.01 No. of bronchiectatic lobes 0.35 < < < < <0.01 HRCT score 0.48 < < < < <0.01 No. of exacerbations within 2 years Sputum bacterial density (cfu/ml) Bronchiectasis Severity Index 0.37 < < < < <0.01 FVC (L) < < < < < <0.01 FEV 1 (L) < < < < < <0.01 MMEF (L/s) < < < < < <0.01 MEF 50% (L/s) < < < < < <0.01 MEF 25% (L/s) < < < < < <0.01 Data in boldface indicated the correlation with statistical significance. All r values denoted the Spearman s correlation coefficients. E9

10 Table E5: Anthropometry Disease characteristics Clinical characteristics in bronchiectasis patients with normal and increased airway resistance Parameter Normal resistance (n=27) 1-2 abnormal IOS indices (n=37) 3-4 abnormal IOS indices (n=12) 5-6 abnormal IOS indices (n=24) P value* Age (years) 46.5± ± ± ± Height (cm) (7.0) 159.3± ± ±6.8 <0.01 Weight (kg) 54.9± (8.0) 49.8 (22.0) 49.1± Duration of symptom onset (years) 5.0 (8.0) 10.0 (15.0) 10.0 (10.0) 20.5±14.4 <0.01 Duration of diagnosis (years) 1.0 (4.0) 4.0 (9.0) 5.6± (12.0) 0.06 No. of exacerbations within 2 years 3.4± (3.0) 4.4± ± No. of bronchiectatic lobes 3.0 (2.0) 4.0 (3.0) 4.0± (2.0) <0.01 HRCT total score 4.0 (4.0) 6.6± ± (7.0) <0.01 Bronchiectasis severity index 5.0± (5.0) 6.2± ±4.1 <0.01 Predominantly lower lobe bronchiectasis (No., %) 17 (63.0) 26 (70.3) 9 (75.0) 19 (79.2) 0.63 Bilateral bronchiectasis (No., %) 22 (81.5) 30 (81.1) 6 (50.0) 24 (100.0) <0.01 Sputum bacteriology Cystic bronchiectasis (No., %) 10 (37.0) 20 (54.1) 6 (50.0) 19 (79.2) 0.03 Dyshomogeneity (No., %) 13 (48.1) 21 (56.8) 6 (50.0) 23 (95.8) <0.01 Pseudomonas aeruginosa (No., %) 7 (25.9) 10 (27.0) 4 (33.3) 14 (58.3) 0.05 Haemophilus parainfluenzae (No., %) 3 (11.1) 3 (8.1) 1 (8.3) 1 (4.2) 0.84 Haemophilus influenzae (No., %) 1 (3.7) 4 (10.8) 1 (8.3) 1 (4.2) 0.66 Other PPMs (No., %) 2 (7.4) 2 (5.4) 1 (8.3) 3 (12.5) 0.80 Commensals (No., %) 15 (55.6) 18 (48.6) 5 (41.7) 5 (20.8) 0.07 The normative ranges for individual IOS parameters were as follows: measured Z5 being lower than 0.5 kpa/l/s; R5 and R20 being lower than 150% of their respective predicted value; X5 being higher than the predicted value minus 0.2 kpa/l/s; Fres and AX being less than their cut-off values (11.87 kpa/l/s and kpa/l). Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). Categorical data were expressed as number (percentage). Data in boldface indicated the comparisons with statistical significance. * P value denoted the comparison on individual clinical parameters, among the four groups. E10

11 Table E6: Comparison on clinical characteristics in bronchiectasis patients with different magnitude of FEV 1 reduction FEV 1 predicted% P Parameter 80% 51%-79% 31%-50% 30% value* (n=37) (n=39) (n=17) (n=7) Anthropometry Age (years) 46.0± ± ± ± Height (cm) 160.3± (8.0) 159.6± ± Weight (kg) 52.5± (10.0) 52.9± ± BMI (kg/m 2 ) 20.5± ± ± ± Disease characteristics Duration of symptom onset (years) 6.0 (13.0) 10.0 (15.0) 20.0 (19.0) 19.0±16.3 <0.01 Duration of diagnosis (years) 1.5 (8.0) 4.0 (8.0) 3.0 (14.0) 5.3± No. of acute exacerbations within 2 years 3.0 (4.0) 3.5± (6.0) 5.0 (2.0) 0.16 No. of bronchiectatic lobes 3.0 (2.0) 4.0± (2.0) 6.0 (0.0) <0.01 HRCT total score 4.0 (3.0) 7.1± ± ±3.3 <0.01 Bronchiectasis severity index 4.0 (6.0) 5.0 (6.0) 8.8± ±3.3 <0.01 Predominantly lower lobe bronchiectasis (No., %) 24 (64.9%) 29 (74.4%) 13 (76.5%) 5 (71.4%) 0.77 Cystic bronchiectasis (No., %) 12 (32.4%) 21 (53.8%) 15 (88.2%) 7 (100.0%) <0.01 Dyshomogeneity (No., %) 16 (43.2%) 25 (64.1%) 15 (88.2%) 7 (100.0%) <0.01 Sputum bacteriology Pseudomonas aeruginosa (No., %) 10 (27.0%) 10 (25.6%) 9 (52.9%) 5 (71.4%) 0.03 Haemophilus parainfluenzae (No., %) 4 (10.8%) 3 (7.7%) 2 (11.8%) 0 (0.0) 0.78 Haemophilus influenzae (No., %) 2 (5.4%) 4 (10.3%) 2 (11.8%) 0 (0.0) 0.67 Other PPMs (No., %) 2 (5.4%) 4 (10.3%) 2 (11.8%) 0 (0.0) 0.67 Commensals (No., %) 19 (51.4%) 18 (46.2%) 3 (17.6%) 2 (28.6%) 0.10 Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). Categorical data were expressed as number (percentage). * P value denoted the comparison on individual clinical parameters, among the four groups. E11

12 Table E7: Comparison on IOS parameters and FEV 1 reduction when stratified by chest HRCT scores in patients with mild bronchiectasis Chest HRCT scores Parameter (n=17) (n=23) (n=18) P value* IOS parameters Z 5 (kpa/l/s) 0.35± (0.12) 0.46 (0.26) 0.03 R 5 (kpa/l/s) 0.34± ± (0.25) 0.03 R 20 (kpa/l/s) 0.30± ± ± X 5 (kpa/l/s) -0.08± (0.05) (0.13) 0.02 Fres (kpa/l/s) 9.10 (3.25) 9.92 (5.51) (13.37) 0.04 AX (kpa/l) 0.21± (0.25) 0.34 (1.06) 0.03 Spirometry FEV 1 pred% 89.65± ± ± IOS parameters being abnormal Z 5 (No., %) 0 (0.0) 1 (4.3) 7 (38.9) <0.01 R 5 (No., %) 0 (0.0) 3 (13.0) 5 (27.8) <0.01 R 20 (No., %) 1 (5.9) 4 (17.4) 3 (16.7) 0.53 X 5 (No., %) 0 (0.0) 2 (8.7) 3 (16.7) 0.21 Fres (No., %) 4 (23.5) 8 (34.8) 10 (55.6) 0.14 AX (No., %) 6 (35.3) 13 (56.5) 13 (72.2) 0.09 Any single IOS parameter being abnormal 8 (47.1) 14 (60.9) 14 (77.8) 0.09 Spirometry being abnormal FEV 1 pred% (No., %) 4 (23.5) 9 (39.1) 12 (66.7) 0.03 Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). Categorical data were expressed as number (percentage). Since the lowest chest HRCT score was 2, we sought to perform comparisons by stratifying chest HRCT scores into 2-3, 4-5 and 6-7, respectively. The normative ranges for individual IOS parameters were as follows: measured Z5 being lower than 0.5 kpa/l/s; R5 and R20 being lower than 150% of their respective predicted value; X5 being higher than the predicted value minus 0.2 kpa/l/s; Fres and AX being less than their cut-off values (11.87 kpa/l/s and kpa/l). * P value denoted the comparison on individual clinical parameters, among the four groups. E12

13 Table E8: Spirometric parameters and IOS parameters in different GOLD stages of COPD GOLD stage (n=9) (n=4) (n=7) P IOS parameter R5 0.48± ± ± R ± ± ± X (0.05) -0.19± ± AX 1.32± ± ± Spirometry FVC pred% 91.79± ± ±8.27 <0.01 FEV 1 pred% 63.52± ± ±4.94 <0.01 MMEF pred% 26.16± ± ±2.81 <0.01 Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). E13

14 Table E9: Comparison on IOS parameters between bronchiectasis patients and COPD patients matched with FEV 1 % predicted Group IOS parameter Bronchiectasis (n=20) COPD (n=20) P R (0.35) 0.56± R ± ± X (0.28) -0.23± AX 1.42 (3.60) 2.14± Numerical data were presented as mean ± standard deviation for normal distribution or otherwise median (interquartile range). E14