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慢性阻塞性肺疾病穩(wěn)定期患者小氣道改變及其對吸入劑的治療反應評價

發(fā)布時間:2018-09-08 16:34
【摘要】:慢性阻塞性肺疾病(Chronic obstructive pulmonary disease, COPD,簡稱慢阻肺)是以持續(xù)存在的氣流受限為特征的疾病,氣流受限呈進行性發(fā)展,伴有氣道和肺組織對有害氣體或顆粒的炎癥反應的增加。慢阻肺是呼吸系統的常見病和多發(fā)病,患病率、病死率居高不下,在影響患者的勞動力和生活質量的同時,也將帶來沉重的社會和經濟負擔。預計2020年慢阻肺將占世界疾病經濟負擔的第五位,2030年其病死率將位居第三位,致殘率則升至第七位。小氣道疾病(SAD)和肺實質的破壞(肺氣腫)是慢阻肺重要的發(fā)病機制,也是氣流受限的主要原因。小氣道是指直徑小于2mm,沒有軟骨的氣道,通常位于氣管支氣管樹的第8-23級。在慢阻肺患者,長期的慢性炎癥刺激使小氣道管壁增厚、管腔狹窄阻塞,氣道阻力明顯增加,小氣道成為氣流受限的主要部位。了解小氣道結構和功能變化,對于分析慢阻肺的嚴重程度、了解疾病進展、評價治療療效和預后均有重要意義。肺通氣功能檢查(PFT)是診斷慢阻肺并進行疾病嚴重程度分級的金標準。但是肺功能分級相同的患者肺氣腫和小氣道改變程度存在差異,PFT并不能反映患者的病理改變特征和病變程度。脈沖振蕩檢查(IOS)是近年來研究較多的氣道阻力評價方法,可分析氣道總阻力、中心氣道和外周小氣道阻力。IOS指標比肺通氣功能指標FEV1更敏感,可用于評價慢阻肺患者早期的小氣道改變,并評估吸入治療藥物的療效。高分辨率CT(HRCT)可定量分析氣道和肺組織結構改變,由于中等大小的氣道可以代表小氣道,并反映小氣道組織病理改變程度,因而可通過HRCT分析大中氣道來反映小氣道功能。目前,HRCT已成為臨床研究中遠端肺組織評價的重要的手段。穩(wěn)定期慢阻肺的治療以緩解患者癥狀,提高運動耐量,改善肺功能及降低急性加重的風險為目標。吸入性糖皮質激素和長效的β2受體激動劑聯合治療(ICS/LABA)對改善患者臨床癥狀和生活質量、減少住院次數和降低急性加重風險均有重要意義。小氣道為慢阻肺患者氣流受限的主要部位,以小氣道改變?yōu)橹鞯穆璺位颊邔Χ绦Е?受體激動劑有較大的反應性。因此,治療小氣道或是了解小氣道的治療反應,有望更好地控制疾病。吸入性丙酸倍氯米松/福莫特羅提供的超細顆粒藥物(1.4-1.5um)有較高的肺部沉積,可改善整個氣道的炎癥和支氣管收縮反應。已有研究表明,丙酸倍氯米松/福莫特羅治療可改善慢阻肺患者的氣體限閉,但其對氣道阻力和氣道、肺組織結構的影響尚不明確,同時也很少有研究比較其與傳統治療藥物的療效差異。第一部分慢性阻塞性肺疾病患者小氣道結構和功能評價目的分析小氣道改變在慢阻肺發(fā)生、發(fā)展中的作用,探討高分辨率CT和脈沖振蕩在慢阻肺小氣道評價中的應用價值。方法以2014年9月至2015年12月期間就診于南方醫(yī)科大學珠江醫(yī)院門診的穩(wěn)定期慢阻肺患者為研究對象(慢阻肺組),均符合2013年中華醫(yī)學會呼吸病學分會慢性阻塞性肺疾病學組關于慢阻肺的診斷標準,并排除其它呼吸道急慢性疾病者。以同期門診健康體檢者為對照組,要求經查體、近期胸片和肺通氣功能檢查均未見異常。采用德國耶格公司MasterScreen肺功能儀對所有受試者依次進行IOS和肺通氣功能檢查,分析響應頻率(Fres)、小氣道阻力(R5-R20)與PFT指標相關性。并在同一天內使用Philips Brilliance 256層iCT對慢阻肺患者進行HRCT檢查,測定右肺上葉尖段支氣管第3級分支氣管壁徑線(WT)、伴行肺動脈直徑(BWT),同時予肺氣腫定量(LAA%),分析氣道壁增厚、肺氣腫與PFT、IOS指標相關性。結果1.一般資料:入選慢阻肺患者132例,其中男性117例,女性15例,平均年齡為(67.9±9.7)歲。根據2013版慢阻肺全球防治策略(GOLD)對氣流受限嚴重程度的分級標準,GOLD1級28例,GOLD 2級42例,GOLD3級42例,GOLD4級20例。對照組92名,其中男性78名,女性14名,平均年齡(65.49±9.8)歲。兩組受試者在年齡、性別、身高、體重方面的差別均無統計學意義。慢阻肺組吸煙指數較對照組明顯增高(t=4.960,P0.01)。2.慢阻肺組和對照組肺功能比較:慢阻肺組FEV1%pred和FEV1/FVC明顯低于對照組,肺通氣功能小氣道指標FEF25%-75%pred、FEF50%pred、 FEF75%pred也較對照組明顯降低,組間差別有統計學意義(P0.01)。慢阻肺組Z5、R5、Fres、R5-R20均較對照組增高(P0.01),慢阻肺患者X5絕對值增大(P0.01),兩組間R20差別無統計學意義(P=0.754)。3.慢阻肺GOLD1~4級患者IOS指標比較:慢阻肺患者隨氣流受限程度加重(GOLD1~4級),Z5、R5、Fres、R5-R20均逐漸增大,組間差別有統計學意義(P0.01)。X5絕對值隨阻塞程度加重逐漸增大(P0.01),但中心氣道阻力指標R20的變化不明顯(P=0.662)。4.慢阻肺組IOS與PFT指標相關性分析:Z5、R5、Fres、R5-R20與肺通氣功能各指標均存在負相關(P0.01)。X5與FEV1%pred、FEV1/FVC、 FEF25%-75%pred、FEF50%pred等指標存在正相關(P0.01)。Fres與通氣功能各指標FVC、FEV1、FEV1%pred、FEV1/FVC、FEF25%-75%pred、FEF50%pred的相關性均較強,且與FEV1相關性最強(r=-0.715,P0.01)。R5-R20與FEV1%pred、FEF25%-75%pred、FEF50%pred也有較強的相關性(P0.01)。5.IOS指標ROC曲線及曲線下面積:以132名慢阻肺患者和92名健康對照組為分析人群建立ROC曲線。以IOS各指標各臨界點對應的敏感度(Sensitivity)為縱坐標,以誤判率(1-specificity)為橫坐標繪制曲線。IOS各指標對應的曲線下面積取值大小依次是:FresR5-R20Z5R50.5.同時,以正確診斷指數(Youden指數)最大值對應點為各指標的最佳分界點,Fres、R5-R20診斷慢阻肺的最佳分界點分別為13.93和0.055。6.HRCT結果分析:慢阻肺組GOLD 1~4級HRCT測定指標分析結果:WT:(1.39±0.20)mm;BWT:(4.09±0.76)mm;WT/BWT:(35.1±7.31)%:LAA%: (7.14%±8.49)%。WT隨氣流受限程度加重而增加,但組間差別無統計學意義(P0.05)。隨氣流受限程度增加,WT/BWT逐漸增大(F=4.859,P0.01),LAA%亦增大(F=9.792,P0.01)。WT/BWT與FEV1%pred存在負相關性(r=-0.329,P0.01),與IOS指標Fres、R5-R20存在正相關(P0.05);LAA% 與FEV1%pred、FEF25%-75%pred、FEF50%pred存在負相關,其中與FEV1%pred的相關性最強,相關系數為-0.566(P0.01)。LAA%與Fres、R5-R20正相關,相關系數分別為0.466(P0.01)、0.340(P0.05)。結論1.慢阻肺患者小氣道管壁增厚,氣道阻力增加,其增加程度可反映疾病的嚴重程度。2.脈沖振蕩檢查可較準確地測定小氣道阻力,反映小氣道功能,并對慢阻肺有一定的診斷價值。3.高分辨率CT圖像直觀,可定性定量分析氣道和肺組織結構改變,并反映疾病的病理基礎和嚴重程度。4.HRCT和IOS與肺通氣檢查結果相關,可更全面評估小氣道結構和功能改變,對慢阻肺的早期診斷和綜合評估有重要意義。第二部分慢性阻塞性肺疾病患者小氣道對吸入劑的治療反應評價目的了解ICS/LABA聯合治療對慢阻肺患者小氣道的影響,探討HRCT和1OS在慢阻肺吸入劑治療中的評價價值,比較兩種吸入治療藥物(丙酸倍氯米松/福莫特羅、布地奈德/福莫特羅)的療效。方法本研究為一項隨機對照研究,以2015年4月至2016年3月期間符合條件的穩(wěn)定期慢阻肺患者為研究對象。受試者經2周的洗脫期之后,隨機分成2組,分別以丙酸倍氯米松/福莫特羅(100/6ug,2吸/次,2/日)、布地奈德/福莫特羅(160/4.5ug,2吸/次,2/日)治療3月。于入組時、2周后(洗脫期結束時)、治療1月、治療3月對受試者進行共4次隨訪。每次隨訪時行脈沖振蕩、肺通氣功能、彌散功能、支氣管舒張試驗、6分鐘步行試驗,并完成呼吸困難評分(mMRC評分)、CAT評分、圣喬治調查問卷(SGRQ)。第2、4次隨診時完成HRCT。評價2組治療后小氣道氣道結構和功能改變的差異,比較2組療效。結果1.一般資料:本研究共篩選出符合條件的穩(wěn)定期慢阻肺患者42例,其中,2例患者在洗脫期失訪,共有40例慢阻肺患者進入隨機分組,其中男性36例,女性4例。分別接受丙酸倍氯米松/福莫特羅和布地奈德/福莫特羅治療,每組20例患者。兩組受試者在性別、年齡、體重指數、吸煙史方面差別無統計學意義(P0.05)。兩組治療前肺通氣功能指標FVC%pred、FEV1%pred、FEV1/FVC、 DLCO%pred及6分鐘步行距離6MWD無差別(P0.05)。2.癥狀評分和6分鐘步行距離:治療前兩組患者癥狀評分、6分鐘步行距離差別無統計學意義(P0.05)。兩種藥物治療3月后,患者的癥狀評分mMRC評分、CAT評分、圣喬治調查問卷評分均較治療前明顯降低(P0.05)。兩組治療后6分鐘步行距離均較治療前增加(P0.05)。各指標治療前后改變量在兩組間差別無統計學意義(P0.05)。3.肺功能檢查結果分析:兩種藥物治療后肺通氣功能指標FVC、FVC%pred、 YEV1、FEV1%pred、FEV1/FVC等較治療前有所增加,但各指標治療前后差別無統計學意義(P0.05)。兩藥治療后氣道阻力指標Z5、R5、20、R5-R20均較治療前降低(P0.01), Fres較治療前明顯降低(P0.01),X5絕對值較治療前減小(P0.01)。FVC、FEV1、Z5、R5、X5等指標治療前后改變量在兩個藥物組間差別無統計學意義(P0.05)。盡管丙酸倍氯米松/福莫特羅組治療前后R5-R20、Fres改變量較布地奈德/福莫特羅組更大,但兩組差別無統計學意義(P=0.506,0.766)。丙酸倍氯米松/福莫特羅組治療后DLCO%pred較治療前增加(P0.01),布地奈德/福莫特羅組治療后DLCO%pred無明顯改變(P=0.152)。4.HRCT檢查結果分析:治療前LAA%與mMRC評分、CAT評分、SGRQ評分均有明顯的相關性,相關系數分別為0.645,0.601,0.596(P0.01)。同時,LAA%與FEV1%pred、DLCO%pred也存在較強的相關性(r=-0.708,-0.664,0.01)。兩組治療前WT、BWT、WT/BWT及LAA%均無差別(P0.05)。盡管兩種藥物治療后WT、WT/BWT指標均較治療前有所降低,但治療前后差別無統計學意義(P0.05)。兩藥治療前后LAA%均無明顯差別(P0.05)。結論1.ICS/LABA吸入治療可降低慢阻肺患者小氣道阻力,改善患者生活質量和呼吸困難癥狀。2.IOS氣道阻力指標較肺通氣功能指標更敏感,能更好地評價慢阻肺患者吸入治療的療效。3.較小劑量的丙酸倍氯米松/福莫特羅的療效并不亞于布地奈德/福莫特羅。4. HRCT對于吸入治療療效的評價作用及小顆粒藥物丙酸倍氯米松/福莫特羅對慢阻肺的治療作用有待進一步研究。
[Abstract]:Chronic obstructive pulmonary disease (COPD) is a chronic obstructive pulmonary disease characterized by persistent airflow restriction. Airflow restriction develops progressively, accompanied by an increase in airway and lung tissue inflammation response to harmful gases or particles. COPD is a common and frequently-occurring disease of the respiratory system, and its prevalence is high. It is expected that COPD will be the fifth largest economic burden in the world by 2020, the third highest in mortality by 2030, and the seventh highest in disability. Small airway disease (SAD) and lung parenchymal destruction (lung qi) Swelling is an important pathogenesis of COPD and a major cause of airflow limitation. Small airways refer to airways less than 2 mm in diameter and without cartilage, usually located in grades 8-23 of the tracheobronchial tree. The main site of airflow limitation. Understanding the structural and functional changes of small airways is of great significance to the analysis of the severity of COPD, the understanding of disease progression, the evaluation of therapeutic efficacy and prognosis. Impulse oscillation test (IOS) is a widely studied method of airway resistance evaluation in recent years. It can analyze total airway resistance, central airway resistance and peripheral airway resistance. IOS is more sensitive than lung ventilation function index FEV1 and can be used for evaluation. High resolution computed tomography (HRCT) can quantitatively analyze the changes of airway and pulmonary tissue. Since the medium-sized airway can represent the small airway and reflect the degree of pathological changes of small airway tissue, the large and medium airway can be analyzed by HRCT to reflect the function of small airway. At present, HRCT has become an important means of evaluating the distal lung tissue in clinical research. The treatment of stable COPD aims to relieve symptoms, improve exercise tolerance, improve lung function and reduce the risk of acute exacerbation. Inhaled glucocorticoids combined with effective beta 2 receptor agonists (ICS/LABA) can improve the clinical symptoms of patients. Small airways are the main site of airflow restriction in patients with COPD, and patients with small airway changes are more responsive to short-acting beta-2 receptor agonists. Previous studies have shown that beclomethasone propionate/formoterol therapy can improve airway obstruction and airway resistance in patients with COPD. The effect of airway and pulmonary tissue structure on COPD is not clear, and there are few studies comparing it with traditional treatment. Part I: Evaluation of small airway structure and function in patients with COPD Objective To analyze the role of small airway changes in the occurrence and development of COPD, and to explore the role of high resolution CT and pulse oscillation in COPD. Methods Patients with chronic obstructive pulmonary disease (COPD) in the outpatient clinic of Zhujiang Hospital of Southern Medical University from September 2014 to December 2015 were selected as the study subjects. All patients met the diagnostic criteria of COPD in the Society of Respiratory Diseases, Chinese Medical Association, in 2013, and were excluded. Patients with acute or chronic respiratory diseases were examined with Master Screen Pulmonary Function Instrument (Master Screen), a German company, to analyze the response frequency (Fres), small airway resistance (R5-R20) and pulmonary ventilation function. In the same day, Philips Brilliance 256-slice iCT was used to examine the tracheal wall diameter (WT) of the third-grade branch of the right upper lobe apical bronchus, accompanied by pulmonary artery diameter (BWT), and quantitative pulmonary emphysema (LAA%). The correlation between the airway wall thickening, emphysema and PFT, IOS was analyzed. General data: 132 patients with COPD were enrolled, including 117 males and 15 females, with an average age of (67.9 The smoking index in COPD group was significantly higher than that in control group (t = 4.960, P 0.01). 2. Comparison of lung function between COPD group and control group: FEV1% PRED and FEV1 / FVC in COPD group were significantly lower than those in control group, and the small airway index FEF in pulmonary ventilation function was significantly lower than those in COPD group. The levels of Z5, R5, Fres and R5-R20 in COPD group were higher than those in control group (P 0.01). The absolute value of X5 in COPD patients increased (P 0.01). There was no significant difference in R20 between the two groups (P = 0.754). 3. COPD patients with GOLD grade 1-4 had no significant difference in IOS index: COPD patients with COPD grade 1-4: COPD The absolute value of X5 increased with the degree of obstruction (P 0.01), but the change of central airway resistance index R20 was not significant (P = 0.662). 4. Correlation analysis of IOS and PFT in COPD group: Z5, R5, Fres, R5-R20 and PFT All indexes of pulmonary ventilation function were negatively correlated (P 0.01). X5 was positively correlated with FEV1% pred, FEV1 / FVC, FEF25% - 75% pred, FEF50% pred, etc. (P 0.01). Fres was strongly correlated with FVC, FEV1, FEV1% pred, FEV1 / FVC, FEF 25% - 75% pred, FEF 50% pred, and had the strongest correlation with FEV1 (r = - 0.715, P 0.01). The ROC curve and area under the curve of IOS index were established in 132 COPD patients and 92 healthy controls. The sensitivity of each critical point of IOS index was used as ordinate, and the error rate was used as abscissa. The best dividing points for each index were FresR5-R20Z5R50.5. The best dividing points for Fres and R5-R20 were 13.93 and 0.055.6 respectively. HRCT results analysis: GOLD 1-4 HRCT analysis in COPD group Results:WT:(1.39+0.20)mm; BWT:(4.09+0.76)mm; WT/BWT:(35.1+7.31)%:LAA%:7.14%+8.49%. WT increased with the severity of airflow limitation, but there was no significant difference between groups (P 0.05). WT/BWT gradually increased with the degree of airflow limitation (F=4.859, P 0.01), LAA% increased (F=9.792, P 0.01). WT was negatively correlated with TFEV1%. LAA% was negatively correlated with FEV 1% pred, FEF 25% - 75% pred, FEF 50% pred, and the correlation coefficient with FEV 1% PRED was the strongest, and the correlation coefficient was - 0.566 (P 0.01). LAA% was positively correlated with Fres and R5-R20, and the correlation coefficients were 0.466 (P 0.01), 0.340 (P 0). Pulse oscillation test can accurately determine the small airway resistance, reflect the small airway function, and has a certain diagnostic value for COPD. 3. High resolution CT image is intuitive, can qualitative and quantitative analysis of airway and lung tissue structure changes, and reflect the disease. Pathological basis and severity. 4. HRCT and IOS are correlated with the results of pulmonary ventilation, and can be used to evaluate the changes of small airway structure and function more comprehensively. It is important for early diagnosis and comprehensive evaluation of COPD. To investigate the effect of HRCT and 1OS on small airway in patients with COPD and to compare the efficacy of two inhalation therapies (beclomethasone propionate/formoterol, budesonide/formoterol). Methods A randomized controlled study was conducted to compare the eligible stable phase between April 2015 and March 2016. Patients with obstructive pulmonary disease were randomly divided into two groups after 2 weeks of elution. They were treated with beclomethasone propionate/formoterol (100/6 ug, 2 inhalation/time, 2/day), budesonide/formoterol (160/4.5 ug, 2 inhalation/time, 2/day) for 3 months. Interview. Pulse oscillation, pulmonary ventilation, diffusion function, bronchodilation test, 6-minute walking test, dyspnea score (mMRC score), CAT score and St. George's Questionnaire (SGRQ) were performed at each follow-up. HRCT was performed at the 2nd and 4th follow-up. The differences of airway structure and function between the two groups were evaluated, and the effects of the two groups were compared. General data: 42 patients with stable COPD were selected in this study. Among them, 2 patients were lost in elution phase and 40 patients were randomly divided into two groups, 36 males and 4 females. They were treated with beclomethasone propionate / formoterol and budesonide / formoterol respectively, 20 patients in each group. There was no significant difference in gender, age, body mass index, smoking history between the two groups (P 0.05). Before treatment, the lung ventilation function index FVC% pred, FEV1% pred, FEV1 / FVC, DLCO% PRED and 6-minute walking distance 6MWD had no difference between the two groups (P 0.05). 2. Symptom score and 6-minute walking distance: Symptom score before treatment, 6-minute walking distance difference between the two groups. There was no significant difference between the two groups (P 0.05). After 3 months of treatment, the symptoms scores of the patients, such as mMRC score, CAT score and St. George's questionnaire score, were significantly lower than those before treatment (P 0.05). The 6-minute walking distance of the two groups increased after treatment (P 0.05). The results of pulmonary function test showed that FVC, FVC% pred, YEV1, FEV1% PRED and FEV1 / FVC were increased after treatment, but there was no significant difference between before and after treatment (P 0.05). FVC, FEV1, Z5, R5, X5 and other indicators before and after treatment had no significant difference between the two drug groups (P 0.05). 766). DLCO% PRED in beclomethasone propionate / formoterol group increased after treatment (P 0.01). There was no significant change in DLCO% PRED in budesonide / formoterol group after treatment (P = 0.152). 4. HRCT analysis showed that LAA% was significantly correlated with mMRC score, CAT score and SGRQ score before treatment, and the correlation coefficients were 0.645, 0.601, 0.596 (P 0.01). There was no significant difference in WT, BWT, WT / BWT and LAA% between the two groups before and after treatment (P Conclusion 1. ICS / LABA inhalation therapy can reduce the small airway resistance and improve the quality of life and dyspnea symptoms in COPD patients. 2.
【學位授予單位】:南方醫(yī)科大學
【學位級別】:碩士
【學位授予年份】:2016
【分類號】:R563.9

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