The Small Airways In Stable Patients With Chronic Obstructive Pulmonary Disease And Its Response To Inhalation Therapy

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation which is progressive and related to the enhanced chronic inflammatory response in lung tissue and the airways to noxious gases or particles. As a major component of respiratory diseases, COPD is a leading cause of morbidity and mortality, which will have a bad effect on the patients’ labor force and the quality of life and result in a heavy social and economic burden as well. COPD is predicted to rank the fifth in the world economic burden of disease by 2020, and rank third in mortality rate and its disability rate will rise to the seventh place by 2030.Small airways disease (SAD) and lung parenchyma destruction (emphysema) are important pathogenesis of COPD and the main reasons for airflow limitation. Small airways are conventionally defined as airways less than 2 mm in diameter and without cartilage, and usually locate from the 8th to 23th branches of the tracheobronchial tree. In COPD patients, long-term stimulation of chronic inflammation results in small airways thickening and luminal stenosis, and the resistance of small airways increase significantly, thus the small airways have become the major part of airflow limitation. Understanding the structural and functional changes of small airways is of great significance in evaluating the severity and progression of COPD as well as predicting the risk of acute exacerbations and the prognosis of the disease.Although pulmonary function test is the gold standard to diagnose and evaluate the severity of COPD, the severity of SAD and emphysema in patients with the same FEV1 grade can be significantly different. Thus, PFT alone can’t provide enough information on the pathological basis and disease type. The Impulse Oscillation System (IOS) is widely used to evaluated airway resistance in studies in recent years, which can measure the total resistance, the central and peripheral airway resistance.The IOS parameters are more sensitive than FEV1, thus it can be used to detect the small airway changes in patients with mild COPD and assess the efficacy of inhalation therapy in COPD patients. High resolution computed tomography (HRCT) can qualitatively analysis the changes of the airways and lung tissue. The airways with moderate size can represent the pathological changes of small airways, thus the changes of small airways can be evaluated indirectly by measuring the moderate airways with HRCT. Nowadays, HRCT has become an important test for distal lung tissue evaluation.Treatment for patients with stable COPD is expected to reduce symptoms, improve exercise tolerance and lung function as well as prevent exacerbations. The combination therapy of inhaled corticosteroids and long-acting beta 2 receptor agonist (ICS/LABA) plays an important role in improving clinical symptoms and quality of life, as well as reducing the frequencies of exacerbations and hospitalization. Small airways are the main part of airflow limitation in COPD, and patients mainly with small airway changes have greater response to short-acting beta 2 agonists. Treating the small airways or understanding the treatment response of the small airways is expected to better control COPD. The combination of beclomethasone dipropionate and formoterol(BDP/F) with its ultrafine particles (1.4-1.5um) has greater lung deposition, which can improve the inflammation reaction of the entire airways and relieve bronchoconstriction. Studies have shown that treatment of beclomethasone dipropionate/formoterol can improve air trapping in COPD patients, but its effect on airway resistance and the structure of the airways and lung tissue is not clear, and there are few researches comparing its efficacy with other traditional drugs.Part One Evaluation of Small airways in Patients with Chronic Obstructive Pulmonary DiseaseObjectiveTo evaluate the relationship between small airway disease and the progression of chronic obstructive pulmonary disease (COPD), and explore the application value of HRCT and IOS in assessing small airways in COPD patients.MethodsPatients with stable COPD (COPD group) were recruited at Zhujiang hospital of Southern Medical University from September,2014 to December,2015. COPD was diagnosed according to the diagnostic criteria of chronic obstructive pulmonary disease study group of Respiratory diseases, the Chinese Medical Association. Patients were excluded if they had a history of other acute or chronic respiratory diseases. The healthy subjects at the clinic for physical examination during the same time were served as control group. The controls should have no evidence of respiratory diseases based on history, physical examination and chest X-ray, with normal spirometric values. All the participants underwent IOS and spirometry successively with Jaeger MasterScreen pulmonary function testing system, and correlations between resonance frequency (Fres), small airway resistance (R5-R20) and PFTs were analyzed. Patients were also examined by HRCT with Philips Brilliance 256 iCT on the same day to measure the thickness of the third generation of apical bronchus of the right upper lobe (WT), the adjacent pulmonary artery diameter (BWT) and the degree of emphysema (LAA%). The ratio of WT to BWT (WT/BWT) was calculated to estimate bronchial wall thickening. Relationships between WT/BWT, emphysema and PFTs, IOS were also studied.Results1. Clinical features of each group:One-hundred and thirty-two patients with stable COPD were recruited, with an age of 67.9±9.7. Among them,117 were male patients and 15 were females. According to the GOLD classification,28 of the COPD patients were at stage 1,42 were in stage 2,42 at stage 3, and 20 at stage 4. There were ninety-two healthy controls(78 males and 14 females), with an age of 65.4±9.8. There was no significant difference in gender, age, height and weight between the two groups. Compared with the healthy controls, the COPD group had higher smoking index (t=4.960,P<0.01).2. Comparison of pulmonary function indices between the two groups:The COPD group has lower FEV1%pred and FEV1/FVC compared with the controls. The spirometric indices of small airways, MMEF%pred and MEF50%pred were significantly lower in COPD patients. The COPD patients had increased Z5, R5, Fres and R5-R20, and X5 was lower (P< 0.01).The difference of R20 between the two groups was not significant (P=0.754).3. The IOS indices in COPD patients:Z5, R5, Fres and R5-R20 were gradually increasing with the development of airflow limitation, and the difference between the two groups was statistically significant (P< 0.01). And X5 became smaller from GOLD 1 to GOLD 4 (P< 0.01).The difference of R20 between groups were not significant (P=0.662).4. The relationship between IOS and spirometry in COPD patients:Z5, R5, Fres, and R5-R20 were negatively related to indices of pulmonary function tests (P< 0.01). X5 were positively correlated to FEV1%pred, FEV1/FVC, FEF25%-75%pred and FEF50%pred (P< 0.01). Fres had close association with FVC, FEV1, FEV1%pred, FEV1/FVC, FEF25%-75%pred and FEF50%pred, among them, FEV1 was the strongest(r=-0.715, P<0.01). R5-R20 was correlated with FEV1%pred, FEF25%-75%pred, FEF50%pred (P< 0.01).5. The ROC curve of IOS indices and their area under the curve:132 COPD patients and 43 healthy controls were included for the ROC curve analysis, with sensitivity as ordinate and the error rate (1-specificity) curve as the abscissa. The area under the curve of each IOS index were Fres> R5-R20> Z5> R5> 0.5. At the same time, the point corresponded to the maximum point of correct diagnosis index (Youden index) was the optimum cut-off point of each index, and cut-off point of Fres and R5-R20 in the diagnosis of COPD was 13.93 and 0.055, respectively.6. HRCT results in COPD patients:The indices of HRCT test in COPD patients (meand±SD) were as follows:WT:1.39±0.20mm; BWT:4.09±0.76mm; WT/BWT:35.1±7.31; LAA%:7.14± 8.49. Although WT was increasing, there was no significant difference among the four groups (P> 0.05).WT/BWT and LAA% gradually increased with the progression of airflow limitation(F=4.859,9.792, P< 0.01). WT/BWT was negatively correlated with FEV1%pred (r=-0.329, P< 0.01), and positively with IOS index R5-R20 and Fres (P< 0.05); There were negative correlation between LAA% and FEV1%pred MMEF%pred, MEF50%pred, and the strongest correlation coefficient was between LAA% and FEV1%pred(r=-0.566, P< 0.01). LAA% was positively correlated with Fres and R5-R20, with the correlation coefficient of 0.466 and 0.340 (P< 0.05), respectively.Conclusions1. Peripheral airway resistance is increased and bronchial wall thickens in COPD patients, and these changes can reflect the severity of the disease.2. With simple equipment and easy to operate procedures, IOS can fully reflect the patient’s respiratory physiology, and evaluate small airway function in COPD patients.3. With intuitive images, HRCT can analyze the structural changes of small airway and lung tissue qualitatively and quantitatively, thus it will represent the pathological basis and severity of the disease.4. Small airway disease measured by HRCT and IOS are related to the spirometric indices, and represent the structural and functional changes of small airways. Combinations of these two tests with PFT will be possible to make early diagnosis and control the disease better.Part Two The response of small airways to inhalation therapy in COPD patientsObjectiveTo understand the effect of ICS/LABA combination therapy on small airways in patients with COPD, and to explore the application value of HRCT and IOS in the evaluation of inhalation therapy, and to compare the efficacy of two inhalation drugs (Budesonide/formoterol, Beclomethasone dipropionate/formoterol).MethodsThis study was a randomized controlled study. From April 2015 to March 2016 the stable COPD patients who met the inclusion criteria were recruited. After the two week run-in period, the patients were randomly assigned to a 12-week treatment period with either Budesonide/formoterol(BUD/F) or Beclomethasone dipropionate/formoterol(BDP/F) two inhalations twice daily. A total of four clinic visits were performed at screening,the end of run-in period,and after 4 and 12weeks of treatment. At each visit, the patients were arranged to take IOS, PFT, carbon monoxide diffusion function, bronchodilation test,6 minute walking test, and completed the dyspnea score (mMRC score), CAT score, St George’s Respiratory Questionnaire (SGRQ). At the second and fourth visit, the patients took the HRCT test. Evaluating the changes of the small airway structural and functional parameters after treatment, and comparing the efficacy between the two groups.Results1. General information:A total of 42 patients met the inclusion criteria. Two of them were lost to follow up during the run-in period for bad compliance of treatment. 40 patients with COPD were randomly divided into two groups(M/F:36/4) to accept either Budesonide/formoterol (BUD/F) or Beclomethasone dipropionate/formoterol(BDP/F), and each group had 20 cases. There was no significant difference in gender, age, BMI, smoking history between the two groups (P> 0.05). FVC%pred, FEVl%pred, FEV1/FVC, DLCO%pred and 6MWD were not change significantly in both group (P> 0.05).2. Symptom scores and 6 minutes walking distance:The symptom scores, 6WMD before treatment had no significant difference between the two groups (P> 0.05). After treatment by BUD/F or BDP/F for 3 months, the symptom scores of mMRC, CAT, SGRQ decreased significantly (P< 0.05). Both groups had a higher 6WMD after treatment than the baseline (P< 0.05). The changes after treatment of each indice had no significant difference between the two groups (P> 0.05).3. Pulmonary function tests:Although FVC, FVC, FEV1, FEV1%pred, FEV1/ FVC increased after treatment, but the differences before and after treatment were not statistically significant (P> 0.05). The airway resistance indices of Z5, R5, R20, R5-R20 were lower than those before treatment (P< 0.01). After treatment, Fres and the absolute value of X5 was significantly decreased (P< 0.01). The changes of FVC, FEV1, Z5, R5 and X5 were not significant between the two group(P> 0.05). Changes of R5-R20 and Fres were greater in the BDP/F group but not significant between the two groups (P=0.506,0.766). DLCO%pred was increased in the BDP/F group (P< 0.01), while there was not significant change in the BUD/F group (P=0.152).4. HRCT results; LAA% before treatment were correlated with MMRC, CAT and SGRQ scores, and the correlation coefficients were 0.645,0.601,0.596, respectively (P< 0.01). At the same time, There were strong correlations between LAA% and FEV1%pred, DLCO%pred (r=-0.708,-0.664, P< 0.01). There were no difference in baseline of BWT, WT, WT/BWT and LAA% between the two groups (P> 0.05). Although WT and WT/BWT after treatment were lower in both groups, the difference was not significant (P> 0.05).The changes of LAA% were not significant (P> 0.05).Conclusions1. ICS/LABA combination therapy can reduce the small airway resistance in patients with COPD, and relieve the symptom of dyspnea as well as improve their quality of life.2. The airway resistance indices of IOS are more sensitive than the pulmonary function test, thus they can better evaluate the effect of inhalation therapy in COPD patients.3. The efficacy of Beclomethasone dipropionate/formoterol with smaller dose is not inferior to that of Budesonide/formoterol.4. The role of HRCT in assessing the effect of inhalation therapy and the efficay of beclomethasone dipropionate/formoterol with its small particles in COPD should be investigated further.