本文關鍵詞： 慢性阻塞性肺疾病 侵襲性肺曲霉病 臨床特征 動物模型　出處：《吉林大學》2017年碩士論文　論文類型：學位論文

【摘要】：目的:1、通過分析24例COPD合并IPA患者的資料,總結分析其臨床特征,為早期診斷及治療提供幫助。2、為進一步研究COPD合并IPA的發(fā)病機制,探討其動物模型的建立方法。方法:1、收集2010年12月-2016年09月期間就診于吉林大學第二醫(yī)院患者的臨床資料,其中COPD合并IPA患者24例,單純COPD患者24例,包括:(1)一般資料和相關病史:年齡、性別、吸煙指數(shù)、基礎疾病、既往住院次數(shù)及糖皮質激素與廣譜抗生素的應用情況;(2)臨床表現(xiàn)和相關治療:癥狀、體征、胸部影像學表現(xiàn)、氣管鏡結果、實驗室檢查及病原學檢測結果、入院后接受的治療、住院天數(shù)及患者的轉歸�；仡櫺越y(tǒng)計分析兩組患者上述臨床資料。2、COPD合并IPA小鼠模型的建立:選取野生型(WT)C57BL/6小鼠16只,將小鼠進行編號,隨機分為2組,分別為正常對照組(8只)和實驗組(8只)。實驗組小鼠給予口鼻暴露有機玻璃染毒箱熏煙,30min/次,間隔15min,4次/d,持續(xù)16周;其后給予小鼠甲潑尼龍100mg/kg*d,共5d;次日將小鼠經(jīng)氣管穿刺方法給予1×106CFU/ml的孢子混懸液30ul,然后保持小鼠直立狀態(tài)3~5min,縫合頸部皮膚,成功接種后小鼠給予萬古霉素15mg/kg 1/日、頭孢他啶150mg/kg 1/日、慶大霉素5mg/kg隔日1次,預防混合感染。正常對照組不予熏煙,在玻璃箱內(nèi)吸入空氣,相同時間內(nèi)應用等量生理鹽水代替甲潑尼龍及孢子混懸液,其余同實驗組。實驗過程中觀察一般情況包括精神狀態(tài)、活動、進食情況,每2周稱量體重。在成功感染72h后統(tǒng)一處理實驗組及正常對照組小鼠,包括體重測量、小鼠肺功能檢測、肺組織病原學培養(yǎng)及病理學檢查。結果:1、臨床資料分析:(1)兩組患者在年齡、性別上無統(tǒng)計學差異(P0.05)。(2)COPD合并IPA組吸煙指數(shù)、平均住院天數(shù)明顯高于COPD組(P0.05)。(3)分析兩組患者一般資料,在口服或靜脈激素治療≥7d、廣譜抗生素應用≥14d、1年住院次數(shù)≥2次、診斷前入住ICU、白蛋白32g/L、血紅蛋白115g/L的情況上,COPD合并IPA組較COPD組常見(P0.05),而在合并癥方面,存在高血壓、冠心病、糖尿病的情況上兩組之間無明顯差異(P0.05)。(4)兩組患者均存在咳嗽,其他主要臨床癥狀包括咳痰、痰中帶血、發(fā)熱、呼吸困難、胸痛及干濕Up音,兩組臨床表現(xiàn)比較無顯著差異(P0.05)。(5)比較兩組患者白細胞總數(shù)及中性粒細胞百分比,COPD合并IPA組患者(11.072±6.10,78.758±14.77)均明顯高于COPD組(7.829±2.75,65.308±12.34),差異有統(tǒng)計學意義(P=0.0240.05,P=0.0010.05)。(6)COPD合并IPA組相關實驗室及影像學檢查陽性率:GM實驗(54.17%),G實驗(83.33%),痰培養(yǎng)(87.5%);培養(yǎng)出菌株中煙曲霉19例(79.17%),黑曲霉3例(12.5%),黃曲霉2例(8.3%);斑片滲出影(66.67%),結節(jié)影(含“暈輪征”)(34.78%),段葉不張或實變影17.39%),單發(fā)或多發(fā)空洞(17.39%);雙肺磨玻璃樣改變(13.04%),“空氣新月征”(4.34%),胸腔積液(34.78%)。(7)COPD合并IPA組治療方面:聯(lián)合廣譜抗生素同時,分析初始抗真菌治療及療效,結果顯示伊曲康唑、伏立康唑、兩性霉素B、卡泊芬凈和聯(lián)合治療組之間療效無顯著差異(P0.05)。最終17例(70.83%)病情好轉出院(包含擬診患者2例),院內(nèi)確定臨床死亡患者4例,出院后隨訪死亡患者3例,共7例(29.17%)患者死亡。2、COPD合并IPA小鼠模型的建立:(1)體重變化:于第4周開始實驗組小鼠較對照組小鼠體重明顯降低,差異顯著(P0.05)。(2)肺功能:實驗組小鼠氣道總阻力(R)、氣道阻力(Rn)、呼吸系統(tǒng)彈性阻力(E)(2.100±0.310,0.889±0.183,63.070±10.464)較對照組(1.536±0.135,0.636±0.127,48.037±6.092)明顯增加,而呼吸系統(tǒng)順應性(C)較對照組明顯降低(0.016±0.004與0.023±0.003),差異均有統(tǒng)計學意義(P0.05)。(3)肺組織勻漿培養(yǎng):實驗組小鼠肺組織勻漿培養(yǎng)曲霉菌菌落呈藍綠色,正常對照組培養(yǎng)陰性。(4)組織病理學:實驗組小鼠肺組織切片在顯微鏡下可觀察到充血水腫的肺泡組織,炎癥細胞浸潤,肺泡組織結構破壞,肺氣腫形成,肺泡間可見分隔且分叉呈45°夾角真菌菌絲,符合COPD合并IPA的病理特征;對照組未見上述變化。結論:1、COPD合并IPA通常發(fā)生在老年患者,且相對COPD患者吸煙指數(shù)高,住院時間長。2、應用激素、抗生素,反復住院、ICU治療,營養(yǎng)不良在COPD合并IPA患者中存在比例高,一定程度上影響疾病的發(fā)生及進展。3、COPD合并IPA患者癥狀不典型,相關實驗室及影像學檢查結果特異性及敏感性均不高,但反復痰培養(yǎng)對于診斷仍有重要意義。4、對臨床診斷及擬診患者,早期應用標準抗真菌治療方案仍能使患者獲益,同時應結合患者病情進行綜合治療,對于重癥患者的抗真菌治療仍是難點。5、在單純被動吸煙法制作COPD模型的基礎上給予甲潑尼龍引起免疫抑制,其后應用氣管穿刺法接種煙曲霉孢子混懸液的方法可成功建立COPD合并IPA小鼠模型。
[Abstract]:Objective: 1. By analyzing the data of 24 cases of COPD patients with IPA, analyze the clinical characters of summary, provide help for the early diagnosis and treatment of.2, to further study the pathogenesis of COPD with IPA, to explore the methods to establish the animal model. Methods: 1, December 2010 -2016 during 09 months of treatment in patients with clinical data the second hospital of Jilin University, including 24 cases of COPD patients with IPA, patients with COPD of 24 cases, including: (1) general information and History: age, gender, smoking index, basic disease, previous hospitalizations and glucocorticoid application of hormone and antibiotics; (2) the clinical manifestations and treatment. The symptoms, signs, chest X-ray manifestation, bronchoscopy results, results of laboratory examination and treatment of pathogens, after accepting admission, hospitalization days and the prognosis of patients. Retrospective statistical analysis of two groups of patients with the clinical data of.2, COPD And the establishment of IPA mice model: selection of wild type (WT) 16 C57BL/6 mice, then the mice were numbered, randomly divided into 2 groups: normal control group (8 rats) and experimental group (8 rats). The mice in experimental group were given oral nasal exposure of organic glass box smoke exposure, 30min/, interval 15min /d, 4, 16 weeks after mice were given methylprednisolone; 100mg/kg*d, 5D; the next day the mice were given 1 methods of tracheal puncture * 106CFU/ml spore suspension of 30ul, and then stay upright mouse 3~5min, neck skin suture, successfully inoculated mice were given vancomycin 15mg/kg 1/, ceftazidime 150mg/kg 1/ the next day, gentamicin 5mg/kg 1 times, the prevention of mixed infection. The control group was given fumigation, inhalation of air in the glass box, the same time the application of normal saline instead of methylprednisolone and spore suspension, the rest of the experimental group were observed during the experiment. Including the mental status, activity, eating, weight every 2 weeks. After successful infection after 72h unified treatment of the experimental group and normal control group of mice, including weight measurement, mouse pulmonary function testing, culture and pathological examination of lung tissue pathogen. Results: 1. Clinical data analysis: (1) patients in the two groups there was no significant difference in age, gender (P0.05). (2) COPD combined with IPA group smoking index, average hospitalization days was significantly higher than COPD group (P0.05). (3) analysis of the general data of the two groups of patients, in the oral or intravenous steroid therapy than 7d, broad-spectrum antibiotics 14d more than 1 years, more than 2 times of hospitalization the diagnosis, before ICU admission, albumin 32g/L, hemoglobin 115g/L cases, compared with the COPD group COPD combined with IPA group (P0.05), and the complications, hypertension, coronary heart disease, diabetes cases no significant difference between the two groups (P0.05). (4) there were two patients with cough and other major 涓村簥鐥囩姸鍖呮嫭鍜崇棸,鐥頒腑甯﹁,鍙戠儹,鍛煎惛鍥伴毦,鑳哥棝鍙婂共婀縐p闊，

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