RESPIRATORY CARE Paper in Press. Published on June 09, 2015 as DOI: 10.4187/respcare.04004
Inflammatory Responses, Spirometry, and Quality of Life in Subjects With Bronchiectasis Exacerbations Wei-jie Guan PhD, Yong-hua Gao PhD, Gang Xu PhD, Zhi-ya Lin PhD, Yan Tang MD, Hui-min Li MT, Zhi-min Lin MSc, Mei Jiang MD, Jin-ping Zheng MD, Rong-chang Chen MD, and Nan-shan Zhong MD BACKGROUND: Bronchiectasis exacerbations are critical events characterized by worsened symptoms and signs (ie, cough frequency, sputum volume, malaise). Objectives: Our goal was to examine variations in airway and systemic inflammation, spirometry, and quality of life during steady state, bronchiectasis exacerbations, and convalescence (1 week following a 2-week antibiotic treatment) to determine whether potentially pathogenic microorganisms, including Pseudomonas aeruginosa, were associated with poorer conditions during bronchiectasis exacerbations. METHODS: Peripheral blood and sputum were sampled to detect inflammatory mediators and bacterial densities. Spirometry and quality of life (St George Respiratory Questionnaire [SGRQ]) were assessed during the 3 stages. RESULTS: Forty-eight subjects with bronchiectasis (43.2 ⴞ 14.2 y of age) were analyzed. No notable differences in species and density of potentially pathogenic microorganisms were found during bronchiectasis exacerbations. Except for CXCL8 and tumor necrosis factor alpha (TNF-␣), serum inflammation was heightened during bronchiectasis exacerbations and recovered during convalescence. Even though sputum TNF-␣ was markedly higher during bronchiectasis exacerbations and remained heightened during convalescence, the variations in miscellaneous sputum markers were unremarkable. Bronchiectasis exacerbations were associated with notably higher SGRQ symptom and total scores, which recovered during convalescence. FVC, FEV1, and maximum mid-expiratory flow worsened during bronchiectasis exacerbations (median change from baseline of ⴚ2.2%, ⴚ0.8%, and ⴚ1.3%) and recovered during convalescence (median change from baseline of 0.6%, 0.7%, and ⴚ0.7%). Compared with no bacterial isolation, potentially pathogenic microorganism or P. aeruginosa isolation at baseline did not result in poorer clinical condition during bronchiectasis exacerbations. CONCLUSIONS: Bronchiectasis exacerbations are characterized by heightened inflammatory responses and poorer quality of life and spirometry, but not by increased bacterial density, which applies for subjects with and without potentially pathogenic microorganism isolation when clinically stable. (ClinicalTrials.gov registration NCT01761214.) Key words: bronchiectasis; exacerbation; potentially pathogenic microorganism; inflammation; spirometry; quality of life. [Respir Care 0;0(0):1–•. © 0 Daedalus Enterprises]
Introduction Bronchiectasis is a chronic respiratory disease characterized by repetitive exacerbations1,2 associated with
Drs Guan, Lin, Tang, Jiang, Zheng, Chen, and Zhong, Ms Li, and Mr Lin are affiliated with the 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, Guangdong, China. Dr Gao is affiliated with the Department of Respiratory and Critical
RESPIRATORY CARE • ● ● VOL ● NO ●
significantly worsened clinical symptoms3 that impact daily life. They are common according to previous stud-
Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Dr Xu is affiliated with the Guangzhou First People’s Hospital, Guangzhou, Guangdong, China. Supplementary material related to this paper is available at http:// www.rcjournal.com. Drs Guan and Gao are co-first authors.
1
Copyright (C) 2015 Daedalus Enterprises ePub ahead of print papers have been peer-reviewed, accepted for publication, copy edited and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
RESPIRATORY CARE Paper in Press. Published on June 09, 2015 as DOI: 10.4187/respcare.04004 CLINICAL PARAMETERS AND BRONCHIECTASIS EXACERBATION
ies,4 and variation in bacterial species and/or density may play a role, as bacterial infection triggers airway inflammation5-7 and induces epithelial biofilm formation,8 leading to inflammatory mediator release1 and oxidative stress.9,10 Subjects with stable bronchiectasis who had higher bacterial density reportedly yielded higher serum intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Short- and long-term antibiotics effectively diminish airway inflammation and have been effective in reducing bacterial load. Murray et al11 reported high bacterial clearance rates and improved quality of life following intravenous antibiotic therapy. Courtney et al12 documented substantial reduction in C-reactive protein, sputum inflammatory cell count, sputum inflammatory mediators (eg, tumor necrosis factor- ␣ [TNF- ␣ ] and interleukin-8 [CXCL8]), and quality of life after antibiotic treatment. However, previous findings suffered from limited sample sizes (N ⬍ 20) and failure to monitor changes from steady state to exacerbations. This warranted elucidation of the changes in clinical parameters at different stages. We hypothesized that bronchiectasis exacerbations in clinically stable subjects with potentially pathogenic microorganisms compared with those without would be associated with higher bacterial density and inflammatory biomarker levels, poorer lung function, and impaired quality of life. Because serum C-reactive protein has been shown to sensitively reflect the efficacy of antibiotic therapy, sample size was calculated based on
QUICK LOOK Current knowledge Bronchiectasis is a chronic respiratory disease characterized by repetitive exacerbations and worsening quality of life. Bacterial infection is associated with airway inflammation, biofilm formation, and worsening clinical symptoms. Antibiotic treatment is associated with a reduction in inflammation and improved respiratory function. What this paper contributes to our knowledge Bronchiectasis exacerbations were characterized by markedly heightened inflammatory responses and poorer quality of life and spirometry, but not greater bacterial density. There was no relationship between changes in biomarkers and quality of life from baseline to exacerbations or convalescence regardless of bacterial infection status.
C-reactive protein, the primary end point in our study. Our objectives were 2-fold: (1) to compare airway bacterial density, systemic and airway inflammation, spirometry, and quality of life when clinically stable and during bronchiectasis exacerbation and convalescence and (2) to compare the variations in these parameters between clinically stable subjects with and without potentially pathogenic microorganisms (in particular, P. aeruginosa). Methods
Drs Zhong and Chen were supported by the 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 the National Key Scientific & Technology Support Program: Collaborative Innovation of Clinical Research for Chronic Obstructive Pulmonary Disease and Lung Cancer 2013BAI09B09. Dr Guan was supported by National Natural Science Foundation Grant 81400010 and 2014 Scientific Research Projects for Medical Doctors and Researchers from Overseas, Guangzhou Medical University Grant 2014C21. The other authors have disclosed no conflicts of interest. Correspondence: Nan-shan Zhong MD, 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 510120, China. E-mail: [email protected]. Rong-chang Chen MD, 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 510120, China. E-mail: [email protected]. DOI: 10.4187/respcare.04004
Subjects Between September 2012 and October 2013, adults with clinically stable bronchiectasis (see bronchiectasis etiology in Table 1) were recruited from the First Affiliated Hospital of Guangzhou Medical University in Guangdong, China. Diagnosis of bronchiectasis was based on chest high-resolution computed tomography at 2-mm collimation within 12 months, compatible with typical symptoms.13 Subjects with severe systemic diseases (ie, malignancy), antibiotic use within 4 weeks, or limited understanding were excluded. Approval was obtained from the ethics committee of the First Affiliated Hospital of Guangzhou Medical University, and all subjects provided written informed consent. Study Design This study consisted of 3 stages. At stage 1, subjects with clinically stable bronchiectasis (respiratory symp-
RESPIRATORY CARE • ● ● VOL ● NO ● Copyright (C) 2015 Daedalus Enterprises ePub ahead of print papers have been peer-reviewed, accepted for publication, copy edited and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
2
RESPIRATORY CARE Paper in Press. Published on June 09, 2015 as DOI: 10.4187/respcare.04004 CLINICAL PARAMETERS AND BRONCHIECTASIS EXACERBATION
Table 1.
Baseline Levels
Parameter Anthropometry Age, y Height, cm Weight, kg BMI, kg/m2 Males Never-smoker Spirometry FVC, % predicted FEV1, % predicted FEV1/FVC Maximum mid-expiratory flow, % predicted Disease-related clinical parameters No. of exacerbations within 2 y, Chest HRCT score Leukocytes, ⫻109/L Neutrophils, % C-reactive protein, mg/dL Medications used within 6 mo† Mucolytics Theophylline Macrolides Inhaled corticosteroids Comorbid conditions‡ Post-infection Immunodeficiency Asthma Gastroesophageal reflux Miscellaneous Idiopathic
All Subjects (N ⫽ 49)
Baseline Culture P*
Positive (n ⫽ 28)
Negative (n ⫽ 21)
43.2 ⫾ 14.2 161.1 ⫾ 7.2 51.6 ⫾ 8.6 19.8 ⫾ 3.1 19 (38.8) 41 (83.7)
44.2 ⫾ 15.6 160.4 ⫾ 6.9 49.7 ⫾ 8.2 19.3 ⫾ 2.6 9 (32.1) 25 (89.3)
41.9 ⫾ 12.4 162.1 ⫾ 7.6 54.3 ⫾ 8.7 20.7 ⫾ 3.5 10 (47.4) 16 (76.2)
.71 .70 .81 .70 .27 .22
79.5 ⫾ 25.2 66.0 ⫾ 25.0 0.69 ⫾ 0.13 46.6 ⫾ 29.6
72.5 ⫾ 25.6 58.9 ⫾ 24.2 0.68 ⫾ 0.13 31.8 (27.9)
88.7 ⫾ 21.9 75.4 ⫾ 23.3 0.71 ⫾ 0.13 54.2 ⫾ 30.9
.02 .02 .40 .09
3.0 (3.0) 8.3 ⫾ 4.1 8.0 ⫾ 2.4 61.7 ⫾ 10.3 0.3 (0.5)
3.6 ⫾ 2.4 9.6 ⫾ 4.3 8.3 ⫾ 2.0 61.4 ⫾ 10.7 0.3 (0.8)
3.0 (4.0) 6.6 ⫾ 3.1 7.6 ⫾ 2.8 62.1 ⫾ 10.0 0.3 (0.4)
.96
Inflammatory Responses, Spirometry, and Quality of Life in Subjects With Bronchiectasis Exacerbations Wei-jie Guan PhD, Yong-hua Gao PhD, Gang Xu PhD, Zhi-ya Lin PhD, Yan Tang MD, Hui-min Li MT, Zhi-min Lin MSc, Mei Jiang MD, Jin-ping Zheng MD, Rong-chang Chen MD, and Nan-shan Zhong MD BACKGROUND: Bronchiectasis exacerbations are critical events characterized by worsened symptoms and signs (ie, cough frequency, sputum volume, malaise). Objectives: Our goal was to examine variations in airway and systemic inflammation, spirometry, and quality of life during steady state, bronchiectasis exacerbations, and convalescence (1 week following a 2-week antibiotic treatment) to determine whether potentially pathogenic microorganisms, including Pseudomonas aeruginosa, were associated with poorer conditions during bronchiectasis exacerbations. METHODS: Peripheral blood and sputum were sampled to detect inflammatory mediators and bacterial densities. Spirometry and quality of life (St George Respiratory Questionnaire [SGRQ]) were assessed during the 3 stages. RESULTS: Forty-eight subjects with bronchiectasis (43.2 ⴞ 14.2 y of age) were analyzed. No notable differences in species and density of potentially pathogenic microorganisms were found during bronchiectasis exacerbations. Except for CXCL8 and tumor necrosis factor alpha (TNF-␣), serum inflammation was heightened during bronchiectasis exacerbations and recovered during convalescence. Even though sputum TNF-␣ was markedly higher during bronchiectasis exacerbations and remained heightened during convalescence, the variations in miscellaneous sputum markers were unremarkable. Bronchiectasis exacerbations were associated with notably higher SGRQ symptom and total scores, which recovered during convalescence. FVC, FEV1, and maximum mid-expiratory flow worsened during bronchiectasis exacerbations (median change from baseline of ⴚ2.2%, ⴚ0.8%, and ⴚ1.3%) and recovered during convalescence (median change from baseline of 0.6%, 0.7%, and ⴚ0.7%). Compared with no bacterial isolation, potentially pathogenic microorganism or P. aeruginosa isolation at baseline did not result in poorer clinical condition during bronchiectasis exacerbations. CONCLUSIONS: Bronchiectasis exacerbations are characterized by heightened inflammatory responses and poorer quality of life and spirometry, but not by increased bacterial density, which applies for subjects with and without potentially pathogenic microorganism isolation when clinically stable. (ClinicalTrials.gov registration NCT01761214.) Key words: bronchiectasis; exacerbation; potentially pathogenic microorganism; inflammation; spirometry; quality of life. [Respir Care 0;0(0):1–•. © 0 Daedalus Enterprises]
Introduction Bronchiectasis is a chronic respiratory disease characterized by repetitive exacerbations1,2 associated with
Drs Guan, Lin, Tang, Jiang, Zheng, Chen, and Zhong, Ms Li, and Mr Lin are affiliated with the 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, Guangdong, China. Dr Gao is affiliated with the Department of Respiratory and Critical
RESPIRATORY CARE • ● ● VOL ● NO ●
significantly worsened clinical symptoms3 that impact daily life. They are common according to previous stud-
Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Dr Xu is affiliated with the Guangzhou First People’s Hospital, Guangzhou, Guangdong, China. Supplementary material related to this paper is available at http:// www.rcjournal.com. Drs Guan and Gao are co-first authors.
1
Copyright (C) 2015 Daedalus Enterprises ePub ahead of print papers have been peer-reviewed, accepted for publication, copy edited and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
RESPIRATORY CARE Paper in Press. Published on June 09, 2015 as DOI: 10.4187/respcare.04004 CLINICAL PARAMETERS AND BRONCHIECTASIS EXACERBATION
ies,4 and variation in bacterial species and/or density may play a role, as bacterial infection triggers airway inflammation5-7 and induces epithelial biofilm formation,8 leading to inflammatory mediator release1 and oxidative stress.9,10 Subjects with stable bronchiectasis who had higher bacterial density reportedly yielded higher serum intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Short- and long-term antibiotics effectively diminish airway inflammation and have been effective in reducing bacterial load. Murray et al11 reported high bacterial clearance rates and improved quality of life following intravenous antibiotic therapy. Courtney et al12 documented substantial reduction in C-reactive protein, sputum inflammatory cell count, sputum inflammatory mediators (eg, tumor necrosis factor- ␣ [TNF- ␣ ] and interleukin-8 [CXCL8]), and quality of life after antibiotic treatment. However, previous findings suffered from limited sample sizes (N ⬍ 20) and failure to monitor changes from steady state to exacerbations. This warranted elucidation of the changes in clinical parameters at different stages. We hypothesized that bronchiectasis exacerbations in clinically stable subjects with potentially pathogenic microorganisms compared with those without would be associated with higher bacterial density and inflammatory biomarker levels, poorer lung function, and impaired quality of life. Because serum C-reactive protein has been shown to sensitively reflect the efficacy of antibiotic therapy, sample size was calculated based on
QUICK LOOK Current knowledge Bronchiectasis is a chronic respiratory disease characterized by repetitive exacerbations and worsening quality of life. Bacterial infection is associated with airway inflammation, biofilm formation, and worsening clinical symptoms. Antibiotic treatment is associated with a reduction in inflammation and improved respiratory function. What this paper contributes to our knowledge Bronchiectasis exacerbations were characterized by markedly heightened inflammatory responses and poorer quality of life and spirometry, but not greater bacterial density. There was no relationship between changes in biomarkers and quality of life from baseline to exacerbations or convalescence regardless of bacterial infection status.
C-reactive protein, the primary end point in our study. Our objectives were 2-fold: (1) to compare airway bacterial density, systemic and airway inflammation, spirometry, and quality of life when clinically stable and during bronchiectasis exacerbation and convalescence and (2) to compare the variations in these parameters between clinically stable subjects with and without potentially pathogenic microorganisms (in particular, P. aeruginosa). Methods
Drs Zhong and Chen were supported by the 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 the National Key Scientific & Technology Support Program: Collaborative Innovation of Clinical Research for Chronic Obstructive Pulmonary Disease and Lung Cancer 2013BAI09B09. Dr Guan was supported by National Natural Science Foundation Grant 81400010 and 2014 Scientific Research Projects for Medical Doctors and Researchers from Overseas, Guangzhou Medical University Grant 2014C21. The other authors have disclosed no conflicts of interest. Correspondence: Nan-shan Zhong MD, 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 510120, China. E-mail: [email protected]. Rong-chang Chen MD, 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 510120, China. E-mail: [email protected]. DOI: 10.4187/respcare.04004
Subjects Between September 2012 and October 2013, adults with clinically stable bronchiectasis (see bronchiectasis etiology in Table 1) were recruited from the First Affiliated Hospital of Guangzhou Medical University in Guangdong, China. Diagnosis of bronchiectasis was based on chest high-resolution computed tomography at 2-mm collimation within 12 months, compatible with typical symptoms.13 Subjects with severe systemic diseases (ie, malignancy), antibiotic use within 4 weeks, or limited understanding were excluded. Approval was obtained from the ethics committee of the First Affiliated Hospital of Guangzhou Medical University, and all subjects provided written informed consent. Study Design This study consisted of 3 stages. At stage 1, subjects with clinically stable bronchiectasis (respiratory symp-
RESPIRATORY CARE • ● ● VOL ● NO ● Copyright (C) 2015 Daedalus Enterprises ePub ahead of print papers have been peer-reviewed, accepted for publication, copy edited and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
2
RESPIRATORY CARE Paper in Press. Published on June 09, 2015 as DOI: 10.4187/respcare.04004 CLINICAL PARAMETERS AND BRONCHIECTASIS EXACERBATION
Table 1.
Baseline Levels
Parameter Anthropometry Age, y Height, cm Weight, kg BMI, kg/m2 Males Never-smoker Spirometry FVC, % predicted FEV1, % predicted FEV1/FVC Maximum mid-expiratory flow, % predicted Disease-related clinical parameters No. of exacerbations within 2 y, Chest HRCT score Leukocytes, ⫻109/L Neutrophils, % C-reactive protein, mg/dL Medications used within 6 mo† Mucolytics Theophylline Macrolides Inhaled corticosteroids Comorbid conditions‡ Post-infection Immunodeficiency Asthma Gastroesophageal reflux Miscellaneous Idiopathic
All Subjects (N ⫽ 49)
Baseline Culture P*
Positive (n ⫽ 28)
Negative (n ⫽ 21)
43.2 ⫾ 14.2 161.1 ⫾ 7.2 51.6 ⫾ 8.6 19.8 ⫾ 3.1 19 (38.8) 41 (83.7)
44.2 ⫾ 15.6 160.4 ⫾ 6.9 49.7 ⫾ 8.2 19.3 ⫾ 2.6 9 (32.1) 25 (89.3)
41.9 ⫾ 12.4 162.1 ⫾ 7.6 54.3 ⫾ 8.7 20.7 ⫾ 3.5 10 (47.4) 16 (76.2)
.71 .70 .81 .70 .27 .22
79.5 ⫾ 25.2 66.0 ⫾ 25.0 0.69 ⫾ 0.13 46.6 ⫾ 29.6
72.5 ⫾ 25.6 58.9 ⫾ 24.2 0.68 ⫾ 0.13 31.8 (27.9)
88.7 ⫾ 21.9 75.4 ⫾ 23.3 0.71 ⫾ 0.13 54.2 ⫾ 30.9
.02 .02 .40 .09
3.0 (3.0) 8.3 ⫾ 4.1 8.0 ⫾ 2.4 61.7 ⫾ 10.3 0.3 (0.5)
3.6 ⫾ 2.4 9.6 ⫾ 4.3 8.3 ⫾ 2.0 61.4 ⫾ 10.7 0.3 (0.8)
3.0 (4.0) 6.6 ⫾ 3.1 7.6 ⫾ 2.8 62.1 ⫾ 10.0 0.3 (0.4)
.96
