Abstract
Lung function impairments, especially airflow obstruction, are important features during acute exacerbation in patients with bronchiectasis. Recognition of the risk factors associated with airflow obstruction is important in the management of these exacerbations. The medical records of adult patients admitted to the Peking University People’s Hospital, Beijing, China, from 2004 to 2011 with a diagnosis of bronchiectasis were reviewed retrospectively. Univariate and multivariate analyses were used to evaluate the risk factors associated with airflow obstruction. Airflow obstruction was found in 55.6% of 156 patients hospitalized with acute exacerbation of bronchiectasis, and the risk factors associated with airflow obstruction included young age (≤14 years old) at diagnosis (odds ratio (OR) = 3.454, 95% confidence interval (CI) 1.709–6.982, p = 0.001) as well as the presence of chronic obstructive pulmonary disease (COPD; OR = 14.677, 95% CI 5.696–37.819, p = 0.001), asthma (OR = 3.063, 95% CI 1.403–6.690, p = 0.005), and wheezing on auscultation (OR = 3.279, 95% CI 1.495–7.194, p = 0.003). The C-reactive protein (13.9 mg/dl vs. 6.89 mg/dl, p = 0.005), partial pressure of arterial oxygen (66.7 ± 8.57 mmHg vs. 89.56 ± 12.80 mmHg, p < 0.001), and partial pressure of arterial carbon dioxide (40.52 ± 2.77 mmHg vs. 42.87 ± 5.39 mmHg, p = 0.02) profiles were different between patients with or without airflow obstruction. In addition, patients colonized with potential pathogenic microorganisms had a decreased diffusing capacity (56.0% vs. 64.7%, p = 0.04). Abnormal pulmonary function was common in hospitalized patients with bronchiectasis exacerbations. Airflow obstruction was correlated with the patient’s age at diagnosis, as well as the presence of combined COPD and asthma, and wheezing on auscultation, which also resulted in more severe systemic inflammation and hypoxemia.
Introduction
Non-cystic fibrosis (non-CF) bronchiectasis is a persistent disease characterized by dilated thick-walled bronchi 1 and is an important cause of respiratory morbidity in developing countries. 2 Patients with bronchiectasis suffer from recurrent acute exacerbations, which include airway infection and inflammation, often resulting in hospitalization. Recurrent exacerbations can also lead to progressive deterioration of lung function 3,4 and are one of the strongest predictors of a poor quality of life in patients with bronchiectasis. 5 However, the management of patients with exacerbation still focuses on antibiotic therapy and symptomatic improvement. 1 Therefore, understanding pulmonary function abnormalities and related factors during exacerbation is important to improve the management of bronchiectasis exacerbations. Although most studies have focused on the lung function of adult patients with bronchiectasis at a stable stage, the relationships between lung function and other factors during acute exacerbations have not been well documented. In this study, we conducted a retrospective review of acute exacerbations in hospitalized adult patients with non-CF bronchiectasis in order to determine the clinical, investigational, and microbiological factors associated with pulmonary function tests.
Methods
Subjects and selection criteria
This study was conducted at the Peking University People’s Hospital, a tertiary hospital in Beijing, China. The medical records of adult patients admitted from 2004 to 2011 with a diagnosis of bronchiectasis were reviewed retrospectively. Patients were included in the study if they met the following criteria: (i) had a diagnosis of bronchiectasis based on clinical presentation and high-resolution computerized tomography (HRCT) findings; (ii) had a diagnosis of acute exacerbation, which was defined as having a change in one or more of the common symptoms of bronchiectasis (e.g. increased sputum volume or purulence, worsened dyspnea, increased cough, or increased fatigue) or the appearance of new symptoms (fever, pleurisy, hemoptysis, or requirement of antibiotic treatment) 1 ; (iii) had at least one sputum culture result, and the pulmonary function test was obtained within 2 weeks following admission. Patients in a stable phase, pregnant and lactating women, and patients with a history of active tuberculosis or active allergic bronchopulmonary aspergillosis were excluded from the study.
Ethics statement
Because this retrospective study was based on anonymous and publicly accessible data and did not add any risk to the participants, informed consent was not obtained.
Data collection
Clinical data including the demographics, initial symptoms at admission, duration of symptoms, smoking history, predisposing factors for bronchiectasis, and physical examination findings were extracted from the medical records. Investigational data included the results of routine blood testing, erythrocyte sedimentation rate, C-reactive protein (CRP) level, and arterial blood gas analysis.
Sputum specimens were collected from patients early in the morning and were Gram stained. Only specimens with polymorphonuclear leukocytes and squamous epithelial cells of >25 and <10 per low-power field, respectively, were sent for routine culturing.
Pulmonary function tests were performed using a Jaeger spirometer (CareFusion, Hochberg, Germany). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), and carbon monoxide transfer factor were expressed as percentages of values predicted for the patient’s age, sex, and height. Bronchodilator tests were only performed in a minority of patients, so the data were not included in the final analysis. Airflow obstruction was defined as an FEV1/FVC value < 70%; the RV/TLC ratio was used as a measure of pulmonary hyperinflation (>45%); and hypoxemia and hypercapnia were defined as partial pressure of arterial oxygen (PaO2) < 60 mmHg and partial pressure of arterial carbon dioxide (PaCO2) > 45 mmHg, respectively.
Statistical analysis
Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) for Windows, Version 19.0 (SPSS, Chicago, Illinois, USA). A normality and homogeneity of variance test was performed on the measurement data. Data showing a normal distribution are summarized as mean ± standard deviation, and data showing a non-normal distribution are summarized as medians (range). Normally distributed data were compared by the Student’s t-test, and non-normal distribution data were compared by the Kruskal–Wallis test. Numeration data were presented as frequency and compared using the χ2 test. The associated relative risk was estimated as an odds ratio with a 95% confidence interval. The risk factors associated with abnormal lung function in bronchiectasis patients were analyzed by multiple logistic regressions using the forward stepwise method. A two-tailed p < 0.05 was considered statistically significant.
Results
Demographic data and clinical features
From 2004 to 2011, 156 patients with acute exacerbation of bronchiectasis were investigated further by culture of sputum samples and pulmonary function tests during the first 2 weeks after admission. No patient had exacerbations more than one time. Patients diagnosed as pneumonia were not excluded because it was difficult to distinguish pneumonia from exacerbation of bronchiectasis exactly according to the result of chest X-ray. The demographic data are shown in Table 1. There was a preponderance of females (54.4%) and the median duration of symptoms was 12 years (range from 2 to 77 years). Approximately two-thirds (64.1%) of the patients were diagnosed with bronchiectasis before 14 years of age. Seventy patients (44.8%) had a history of smoking, with a median smoking index of 30 packs/year (0.5–120 packs/year).
Baseline characteristics of 156 patients with bronchiectasis exacerbation.
FEV1: forced expiratory volume in one second; FVC: forced vital capacity; DLCO: diffusing capacity for carbon monoxide; RV: residual volume; TLC: total lung capacity.
Chronic obstructive pulmonary disease (COPD) was the most common comorbidity disease (n = 50, 32.1%), followed by asthma (n = 42, 26.9%) and rhinosinusitis (n = 14, 9%). Diabetes mellitus (n = 12, 7.7%), hypertension (n = 15, 9.6%), and coronary heart disease (n = 8, 5.1%) were also common. Sixteen patients (10.3%) were diagnosed as having chronic cor pulmonale. Twenty-nine patients (18.6%) had a prior history of tuberculosis, and another 29 (18.6%) had a history of childhood infections, including unspecified pneumonia (n = 10), measles (n = 9), and unidentified/unconfirmed infections (n = 10). Eight patients were suffering from autoimmune diseases, including rheumatoid arthritis (n = 4), Sjogren’s disease (n = 2), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 1), and adult Still’s disease (n = 1). One patient had a history of liver transplantation, and one patient received a thymoma resection.
Cough (91.7%) and expectoration of purulent sputum (71.8%) were the most common symptoms on admission. Fever was present in 80 (51.3%) patients with exacerbations, while dyspnea and hemoptysis were present in 48.7% and 31.4% of patients, respectively. Moreover, rales and wheezing could be detected in 107 (68.6%) and 48 (31.4%) patients on chest auscultation, respectively. In addition, clubbing of the fingers was seen in 11 (7.1%) patients.
Sputum cultures
Culturing of the sputum from 156 patients yielded potential pathogenic microorganisms (PPMs) in 48 (30.7%) individuals (Table 2). Gram-negative pathogens accounted for 81% of these isolates (39/48). The most frequent microorganisms isolated were Pseudomonas aeruginosa from 20 patients (41.7%) and Staphylococcus aureus from 8 patients (14.3%). Of the 108 patients in the non-PPM group, nothing was isolated from sputum of 8 patients, and normal flora such as alpha-Streptococcus were cultured from sputum of other 100 patients.
Microorganisms isolated from sputum cultures of 156 patients with bronchiectasis exacerbation.
Lung function test results
As shown in Table 1, airflow obstruction was the predominant finding (n = 87, 55.6%), although a restrictive functional defect was occasionally seen (n = 4, 2.6%). Pulmonary hyperinflation was also common (n = 109, 69.9%), and diffusing capacity decreased in 107 patients (68.6%). In addition, 14 patients (9.0%) had type 2 respiratory failure, while 9 (5.8%) had type 1 respiratory failure.
Correlation between lung function test results and clinical features
The patients were divided into two groups according to the FEV1/FVC results. The demographic data and the clinical features of these two groups are compared in Table 3. In patients with airflow obstruction, COPD, asthma, and abnormal chest auscultation were more common. The CRP (13.9 mg/dl vs. 6.89 mg/dl, p = 0.005), PaO2 (66.7 ± 8.57 mmHg vs. 89.56 ± 12.80 mmHg, p < 0.001), and PaCO2 (40.52 ± 2.77 mmHg vs. 42.87 ± 5.39 mmHg, p = 0.02) profiles were different between patients with or without airway obstruction.
Comparison of the clinical features between 156 bronchiectasis patients with normal or abnormal lung function.
PPMs: potential pathogenic microorganisms; non-PPMs: non-potential pathogenic microorganisms; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; OR: odds ratio; CI: confidence interval; CRP: C-reactive protein; PaO2: partial pressure of arterial oxygen; PaCO2: partial pressure of arterial carbon dioxide.
Multiple regression analyses
According to a stepwise regression analysis (Table 4), the risk factors associated with airflow obstruction included young age (<14 years old) at diagnosis as well as the presence of COPD, asthma, and wheezing on auscultation.
Multivariate logistic regression analysis of clinical feature risk factors associated with abnormal lung function in 156 bronchiectasis patients.
COPD: chronic obstructive pulmonary disease; OR: odds ratio; CI: confidence interval.
Correlation between sputum cultures and lung function test results
Patients colonized with PPMs had a decreased diffusing capacity (p < 0.05), but there were no significant differences in FEV1/FVC, FEV1/pred, or RV/TLC (Table 5).
Comparison of lung function between patients with and without PPM airway colonization.
PPMs: potential pathogenic microorganisms; non-PPMs: non-potential pathogenic microorganisms; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; DLCO: diffusing capacity for carbon monoxide; RV: residual volume; TLC: total lung capacity.
Discussion
Being a specialized respiratory and critical care department of a tertiary hospital, our department enrolls patients suffering from relatively severe disease. The 156 patients we analyzed had a median age of 65 years and most of them were diagnosed at an early age (<14 years old) with a median duration of symptoms of 12 years; additionally, fever was more common in our patients than in pediatric patients. 6 Twenty-three patients (14.8%) had respiratory failure, and 16 patients (10.3%) developed chronic cor pulmonale, which is an important complication leading to increased morbidity and the worsening of the individual’s quality of life. Exacerbation in our patient cohort was typically characterized by an increased cough, expectoration of purulent sputum, fever, dyspnea, hemoptysis, rales, and/or wheezing on auscultation as well as airflow obstruction and diffuse dysfunction.
Because of the retrospective nature of our study, we could not determine the underlying etiology of our patients with bronchiectasis. Of our patients, 37.2% could recall a history of infection, with half of them being related to tuberculosis. This prevalence rate was higher than the 14.7% calculated for another recent retrospective study in Beijing 7 but lower than the 49.7% found in a Turkish study. 8 Immune deficiency was rare in our patient cohort as only one patient had a slightly decreased immunoglobulin G concentration of 4.97 g/l (normal range 7.2–16.8 g/l). Ciliary assessment was not performed in our study, which resulted in the under diagnosis of primary ciliary dyskinesia. We did not exclude CF specifically because CF was very rare in Asia. Bronchiectasis in patients with autoimmune disease, especially rheumatoid arthritis, has also been reported. 9 In our patients, 5.1% were diagnosed with autoimmune disease, which supports the importance of autoimmune disease in the etiology of bronchiectasis.
COPD and asthma were the comorbidities in 32.1% and 26.9% of our patients admitted with bronchiectasis, respectively. Many reports have shown the association between bronchiectasis and COPD in recent years. The incidence of bronchiectasis in 75 patients with all of the Global Initiative for Chronic Obstructive Lung Disease stages of disease was 27% in England 10 and as high as 50% in 76 patients with moderate-to-severe COPD in Spain. 3 In addition, patients with COPD combined with bronchiectasis were more likely to have severe exacerbations, chronic airway infection, and increased sputum inflammatory markers. 3 Furthermore, bronchiectasis with asthma is linked strongly, but not exclusively, to those patients with fixed airflow obstruction and severe disease. 11 In our study, the combination of COPD and asthma was also an important factor associated with airflow obstruction. The overlap of COPD and asthma has received more and more attention, but the overlap of COPD, asthma, and bronchiectasis was not well documented. Also combination management may be important to patients with more severe airflow obstruction.
The pattern of pulmonary function in bronchiectasis has been characterized by airflow obstruction and hyperinflation both in pediatric 4 and adult patients 3,12 with stable disease. Airflow obstruction was also found in the majority of our patients in exacerbation (n = 87, 55.6%), with significant pulmonary hyperinflation (n = 109, 69.9%) and diffusing capacity defects (n = 107, 68.6%). Several factors have been identified as being associated with greater airflow obstruction in stable patients with bronchiectasis, such as the radiological extent of bronchiectasis (i.e., the severity of bronchiectasis defined by the CT scoring system), airway colonization with P. aeruginosa, or high levels of inflammation markers both in the airways and serum. 3 As HRCT was not scanned during the exacerbation period in most of our patients, we did not analyze the association between the HRCT score and airway obstruction. However, the wheezing heard on auscultation could reflect a physiological change in the lung with flow limitation caused by the movement of airway secretions and the flutter of airways. Serial observation of pulmonary function indices and CT scans in 48 adult patients with bronchiectasis also have found that variations in mucous plugging on CT correlate with minor fluctuations in pulmonary function tests in bronchiectasis, although the severity of bronchial wall thickness is the primary determinant of subsequent major functional decline. 13 In addition, clearance of secretions by rigorous postural drainage has been associated with significant increases in pulmonary function indices in a small cohort of patients with bronchiectasis. 14 In our study, the age at diagnosis and the presence of airway disease may determine the baseline lung function; but wheezing was not only heard in patients with asthma or COPD, and not all patients with asthma have wheezing on auscultation, so wheezing may represent the reversible part of airway obstruction such as mucus hypersecretion. Therefore, clearance of airway secretions and bronchial dilation are important treatment methods during exacerbation of bronchiectasis.
The extent of airflow obstruction may also influence the severity of exacerbation. The patients with FEV1/FVC < 70% had increased levels of CRP, which is a nonspecific systemic inflammation marker. Patients with airflow obstruction also had decreased levels of PaO2 and PaCO2, indicating that these patients experienced a marked increase in breathing effort. However, we couldn’t speculate the real role of bronchiectasis in the formation of airway obstruction, and a more rigorous case–control study was needed to distinct the effect of coexisting diseases.
Hyperinflation was also a significant characteristic of our patients, with a median RV/TLC of 58.20%. In addition, 69.9% of patients had an elevated ratio of RV/TLC. Hyperinflation is an independent characteristic of the disease state and is not always directly linked to airway obstruction, according to various mechanisms. 15 Roberts et al. have shown that the presence of small airway alterations such as bronchiolectasis, bronchiolar mucus plugging, and, especially, bronchiolitis were more related to lung hyperinflation. 16
Haemophilus influenzae and P. aeruginosa are reported to be the most frequently isolated pathogen. 17,18 The most frequent microorganisms isolated in our patient cohort were P. aeruginosa. H. influenzae was not isolated in our study that may be due to the use of antibiotics before admission. Acinetobacter spp were isolated in four patients, three of which were treated in our emergency department several days before admission. Positive sputum culture results were not associated with airflow obstruction in our patients, as reported elsewhere, 17,18 but related with a more severe decrease of the diffusing capacity for the lungs measured using carbon monoxide. The diffusion dysfunction in patients with bronchiectasis was presumably related to atelectasis, bullae, emphysema, fibrosis, and capillary bed destruction, representing a late, irreversible disease. 19,20 Because no data were generated that focused on the change of diffusing capacity during exacerbation of bronchiectasis, we could not conclude whether the patients with positive sputum culture results had a decreased diffusing capacity at baseline or whether they deteriorated during exacerbations.
As a retrospective study, there are a number of limitations with our present study. Firstly, although it was reported by previous studys, 21 there were small improvements in FEV1 and FVC following 2 weeks of treatment with antibiotics in patients with bronchiectasis, we could not assess the actual impact of exacerbation on the change of pulmonary function because no baseline pulmonary function test data during the stable stage were available. Secondly, most patients did not undergo CT scanning during exacerbation, so we could not evaluate the relationship between the changes of lung morphology and function.
In conclusion, we examined the clinical features and risk factors associated with airflow obstruction during acute exacerbation in 156 hospitalized patients with bronchiectasis. Cough, expectoration of purulent sputum, fever, dyspnea, hemoptysis, rales, and/or wheezing on auscultation were common manifestations of exacerbation. Most patients suffered from airflow obstruction and diffuse dysfunction. Airflow obstruction was correlated with the patient age at diagnosis as well as the combined presence of COPD, asthma, and a wheezing sound on auscultation, which also resulted in more severe systemic inflammation and hypoxemia. Only positive sputum cultures were associated with a decrease of the diffusing capacity.
Footnotes
Authors’ Note
Y.M. and Y.N. contributed equally to this work.
Conflict of interest
The authors declared no conflicts of interest.
Funding
This work was supported by the Chronic Respiratory Disease (RDC) funds of the Chinese Medical Association (grant No. 2009-2-28).