ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Page 1 of 45
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: +86-20-83062718, Phone: +86-20-83062718, E-mail: [email protected] 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: +86-20-83062719, Phone: +86-20-83062719, E-mail: [email protected]
*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 critical review of the manuscript and approved the final submission.
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Running Title: IOS in bronchiectasis
Abstract Count: 322 words, Full Text Count: 3167 words
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. 81400010 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. 81400010 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.
This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org
Identifier No.: 10.03 Chronic bronchial suppurative diseases
Copyright © 2015 by the American Thoracic Society
Page 2 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Page 3 of 45
Abstract Rationale: The utility of impulse oscillometry (IOS) in bronchiectasis has not been systematically investigated. Objectives: To determine the utility of IOS parameters and their correlation with radiology, disease severity, sputum bacteriology and spirometry, and to compare the changes in IOS parameters during exacerbations and convalescence of bronchiectasis. Methods: We recruited 100 bronchiectasis patients and 28 healthy subjects. Receiver operation characteristic curve was plotted to analyze the diagnostic performance of IOS parameters. Chest high-resolution computed tomography (HRCT), Bronchiectasis Severity Index (BSI) assessment, sputum culture and spirometry were performed. Correlation between IOS parameters and clinical indices was determined using Spearman’s model. Changes in IOS parameters, compared with spirometry, during exacerbation were assessed in 16 bronchiectasis patients. Measurements and Main results: IOS parameters (in particular, resonant frequency) could discriminate bronchiectasis patients from healthy subjects. Higher levels of IOS parameters were associated with Pseudomonas aeruginosa infection, dyshomogeneity, higher BSI and HRCT score, more bronchiectatic lobes and cystic bronchiectasis (all P0.05). Increased frequency dependence (higher Fres or AX) was more likely to be associated with lower HRCT scores (5 or lower) than FEV1. Compared with FEV1, any single IOS parameter being abnormal was more common in mild bronchiectasis, particularly in
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
patients with HRCT score of 5 or lower. IOS parameters were not statistically different from baseline to exacerbations and convalescence (all P>0.05). Conclusion: IOS parameters correlate with clinical indices and could reflect peripheral airway abnormality. An increased number of aberrant IOS parameters signals poorer clinical conditions. Increased frequency dependence might be a sensitive marker of mild bronchiectasis. Any single IOS parameter being abnormal sensitively reflects mild bronchiectasis. IOS parameters do not change significantly during bronchiectasis exacerbations. Clinical Trial Registration: No.: NCT01761214; URL: www.clinicaltrials.gov. Key Words: Bronchiectasis; impulse oscillometry; radiology; bacteriology; acute exacerbation; convalescence
Copyright © 2015 by the American Thoracic Society
Page 4 of 45
Page 5 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Bronchiectasis is a chronic respiratory disease in which the triplet of airway infection, inflammation and destruction is implicated [1]. The pathogenic insults result in intense airway inflammation [2] leading to persistent airway destruction [3]. Apart from high-resolution computed tomography (HRCT) [3], spirometry has constituted the cornerstone of lung function tests which have been applied for assessment of bronchiectasis [4,5]. However, the considerable time lag from onset of bronchiectasis to the radiologic and clinical diagnosis when significant abnormalities are explicitly displayed has restricted the utility of spirometry. The diffusing capacity tests also have limited significance inasmuch that most subjects demonstrated normal gas-exchange capacity [6]. Therefore, new non-invasive techniques are of merit to unravel lung function impairment in bronchiectasis. Impulse oscillometry (IOS) is a non-invasive technique which could, by analyzing the mechanical waves superimposed upon respiratory maneuvers, provide global information regarding the airway resistance [7-9]. It has been reported that IOS may sensitively discriminate small airway disorders in asthma [10-14], chronic obstructive pulmonary disease [15-19], interstitial lung disease [20], spinal muscular atrophy [21] and cystic fibrosis [22]. Furthermore, the fact that IOS could be a surrogate of spirometry in reflecting changes in lung function prior to and following bronchial provocation [8,9,23] or dilation test [24] has rendered it a useful tool to identify changes in the airway caliber. We hypothesized that IOS parameters were abnormal in bronchiectasis and correlated with clinical indices and worsened during exacerbations. To test our hypothesis, we sought to address three-fold objectives: 1) to determine the diagnostic value of IOS parameters to discriminate bronchiectasis patients from healthy subjects; 2) to assess the association between IOS parameters and radiology, sputum bacteriology, disease severity and spirometry; 3) to compare the changes in IOS parameters
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
during steady-state, acute exacerbation and convalescence of bronchiectasis.
Methods
Subjects Subjects were recruited from September 2012 to October 2013. Bronchiectasis was diagnosed based on clinical symptoms (chronic productive coughing, purulent sputum or hemoptysis) and chest HRCT at collimation of 1-2 mm within 12 months. Eligible patients were 18-75 years of age and had to remain clinically stable for at least 4 weeks. (See below for definition of bronchiectasis exacerbations) Patients with severe systemic diseases (i.e. uncontrolled hypertension or coronary heart disease, recent cerebral stroke and malignancy), use of oral or systemic antibiotics 4 weeks previously, poor cooperation or limited understanding were excluded. Healthy subjects were 18 to 75 years of age, had baseline FEV1≥ 80% predicted, had neither upper respiratory tract infection within 3 weeks nor systemic diseases and had normal chest radiography. The study protocol was approved by Ethic Committee of The First Affiliated Hospital of Guangzhou Medical University. All subjects gave written informed consent prior to the study.
Study Design In this cross-sectional study, the diagnostic value of IOS parameters and the association with clinical indices in steady-state bronchiectasis were determined. Longitudinal follow-up visits were scheduled to investigate the changes in IOS parameters during exacerbation and convalescence. Bronchiectasis exacerbation was
Copyright © 2015 by the American Thoracic Society
Page 6 of 45
Page 7 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
defined as significant changes in 3 or more of following symptoms/signs for at least 2 days: cough frequency, 24-hour sputum volume, sputum purulence and (or) emerging fever, dyspnea or chest pain [25-31]. Patient-reported worsening of conditions was verified by the investigators who, based on baseline sputum bacteriology, prescribed antibiotic therapy according to British Thoracic Society guideline [32], with slight modifications. Patients were reassessed during convalescence visit, at one week after the 14-day antibiotic treatment.
Impulse Oscillometry Measurement of IOS (JAEGER MS-IOS, CareFusion Germany GmbH, Hochberg, Germany) was conducted prior to spirometry, as described previously [8,9,23]. The system was calibrated using a 3-L syringe before the measurement. Subjects were seated upright with the head straight and in slight extension. A nose clip was applied and the lips were tightly sealed around mouthpiece to avoid gas-leakage. The cheeks should also be firmly supported by both palms. Subjects were instructed to breathe tidally into the mouthpiece for 20 to 30 seconds per individual maneuver. At least 3 reproducible measurements without artifacts (breath-holding, glottis closure, coughing or swallowing) were evaluated. IOS parameters, including respiratory impedance at 5 Hz (Z5), airway resistance at 5 Hz (R5), airway resistance at 20 Hz (R20), lung resistance at 5 Hz (X5), resonance frequency (Fres) and reactance area (AX), were recorded. The 3 maneuvers with coefficient of variance
Page 1 of 45
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: +86-20-83062718, Phone: +86-20-83062718, E-mail: [email protected] 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: +86-20-83062719, Phone: +86-20-83062719, E-mail: [email protected]
*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 critical review of the manuscript and approved the final submission.
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Running Title: IOS in bronchiectasis
Abstract Count: 322 words, Full Text Count: 3167 words
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. 81400010 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. 81400010 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.
This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org
Identifier No.: 10.03 Chronic bronchial suppurative diseases
Copyright © 2015 by the American Thoracic Society
Page 2 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Page 3 of 45
Abstract Rationale: The utility of impulse oscillometry (IOS) in bronchiectasis has not been systematically investigated. Objectives: To determine the utility of IOS parameters and their correlation with radiology, disease severity, sputum bacteriology and spirometry, and to compare the changes in IOS parameters during exacerbations and convalescence of bronchiectasis. Methods: We recruited 100 bronchiectasis patients and 28 healthy subjects. Receiver operation characteristic curve was plotted to analyze the diagnostic performance of IOS parameters. Chest high-resolution computed tomography (HRCT), Bronchiectasis Severity Index (BSI) assessment, sputum culture and spirometry were performed. Correlation between IOS parameters and clinical indices was determined using Spearman’s model. Changes in IOS parameters, compared with spirometry, during exacerbation were assessed in 16 bronchiectasis patients. Measurements and Main results: IOS parameters (in particular, resonant frequency) could discriminate bronchiectasis patients from healthy subjects. Higher levels of IOS parameters were associated with Pseudomonas aeruginosa infection, dyshomogeneity, higher BSI and HRCT score, more bronchiectatic lobes and cystic bronchiectasis (all P0.05). Increased frequency dependence (higher Fres or AX) was more likely to be associated with lower HRCT scores (5 or lower) than FEV1. Compared with FEV1, any single IOS parameter being abnormal was more common in mild bronchiectasis, particularly in
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
patients with HRCT score of 5 or lower. IOS parameters were not statistically different from baseline to exacerbations and convalescence (all P>0.05). Conclusion: IOS parameters correlate with clinical indices and could reflect peripheral airway abnormality. An increased number of aberrant IOS parameters signals poorer clinical conditions. Increased frequency dependence might be a sensitive marker of mild bronchiectasis. Any single IOS parameter being abnormal sensitively reflects mild bronchiectasis. IOS parameters do not change significantly during bronchiectasis exacerbations. Clinical Trial Registration: No.: NCT01761214; URL: www.clinicaltrials.gov. Key Words: Bronchiectasis; impulse oscillometry; radiology; bacteriology; acute exacerbation; convalescence
Copyright © 2015 by the American Thoracic Society
Page 4 of 45
Page 5 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
Bronchiectasis is a chronic respiratory disease in which the triplet of airway infection, inflammation and destruction is implicated [1]. The pathogenic insults result in intense airway inflammation [2] leading to persistent airway destruction [3]. Apart from high-resolution computed tomography (HRCT) [3], spirometry has constituted the cornerstone of lung function tests which have been applied for assessment of bronchiectasis [4,5]. However, the considerable time lag from onset of bronchiectasis to the radiologic and clinical diagnosis when significant abnormalities are explicitly displayed has restricted the utility of spirometry. The diffusing capacity tests also have limited significance inasmuch that most subjects demonstrated normal gas-exchange capacity [6]. Therefore, new non-invasive techniques are of merit to unravel lung function impairment in bronchiectasis. Impulse oscillometry (IOS) is a non-invasive technique which could, by analyzing the mechanical waves superimposed upon respiratory maneuvers, provide global information regarding the airway resistance [7-9]. It has been reported that IOS may sensitively discriminate small airway disorders in asthma [10-14], chronic obstructive pulmonary disease [15-19], interstitial lung disease [20], spinal muscular atrophy [21] and cystic fibrosis [22]. Furthermore, the fact that IOS could be a surrogate of spirometry in reflecting changes in lung function prior to and following bronchial provocation [8,9,23] or dilation test [24] has rendered it a useful tool to identify changes in the airway caliber. We hypothesized that IOS parameters were abnormal in bronchiectasis and correlated with clinical indices and worsened during exacerbations. To test our hypothesis, we sought to address three-fold objectives: 1) to determine the diagnostic value of IOS parameters to discriminate bronchiectasis patients from healthy subjects; 2) to assess the association between IOS parameters and radiology, sputum bacteriology, disease severity and spirometry; 3) to compare the changes in IOS parameters
Copyright © 2015 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
during steady-state, acute exacerbation and convalescence of bronchiectasis.
Methods
Subjects Subjects were recruited from September 2012 to October 2013. Bronchiectasis was diagnosed based on clinical symptoms (chronic productive coughing, purulent sputum or hemoptysis) and chest HRCT at collimation of 1-2 mm within 12 months. Eligible patients were 18-75 years of age and had to remain clinically stable for at least 4 weeks. (See below for definition of bronchiectasis exacerbations) Patients with severe systemic diseases (i.e. uncontrolled hypertension or coronary heart disease, recent cerebral stroke and malignancy), use of oral or systemic antibiotics 4 weeks previously, poor cooperation or limited understanding were excluded. Healthy subjects were 18 to 75 years of age, had baseline FEV1≥ 80% predicted, had neither upper respiratory tract infection within 3 weeks nor systemic diseases and had normal chest radiography. The study protocol was approved by Ethic Committee of The First Affiliated Hospital of Guangzhou Medical University. All subjects gave written informed consent prior to the study.
Study Design In this cross-sectional study, the diagnostic value of IOS parameters and the association with clinical indices in steady-state bronchiectasis were determined. Longitudinal follow-up visits were scheduled to investigate the changes in IOS parameters during exacerbation and convalescence. Bronchiectasis exacerbation was
Copyright © 2015 by the American Thoracic Society
Page 6 of 45
Page 7 of 45
ANNALSATS Articles in Press. Published on 05-February-2015 as 10.1513/AnnalsATS.201406-280OC
defined as significant changes in 3 or more of following symptoms/signs for at least 2 days: cough frequency, 24-hour sputum volume, sputum purulence and (or) emerging fever, dyspnea or chest pain [25-31]. Patient-reported worsening of conditions was verified by the investigators who, based on baseline sputum bacteriology, prescribed antibiotic therapy according to British Thoracic Society guideline [32], with slight modifications. Patients were reassessed during convalescence visit, at one week after the 14-day antibiotic treatment.
Impulse Oscillometry Measurement of IOS (JAEGER MS-IOS, CareFusion Germany GmbH, Hochberg, Germany) was conducted prior to spirometry, as described previously [8,9,23]. The system was calibrated using a 3-L syringe before the measurement. Subjects were seated upright with the head straight and in slight extension. A nose clip was applied and the lips were tightly sealed around mouthpiece to avoid gas-leakage. The cheeks should also be firmly supported by both palms. Subjects were instructed to breathe tidally into the mouthpiece for 20 to 30 seconds per individual maneuver. At least 3 reproducible measurements without artifacts (breath-holding, glottis closure, coughing or swallowing) were evaluated. IOS parameters, including respiratory impedance at 5 Hz (Z5), airway resistance at 5 Hz (R5), airway resistance at 20 Hz (R20), lung resistance at 5 Hz (X5), resonance frequency (Fres) and reactance area (AX), were recorded. The 3 maneuvers with coefficient of variance
