急性肺曲霉菌病动物模型建立及肿块型肺真菌病CT影像学特征研究
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摘要
背景
随着器官移植及造血干细胞移植的广泛开展,化疗药、免疫抑制剂的广泛应用,肺部机遇性感染发病率迅速上升,是导致免疫抑制患者高死亡率的重要原因之一,如骨髓移植患者及机械通气患者肺部感染的死亡率高达90%。降低死亡率的关键是早期及时的正确诊断,以便能及时有效的给予治疗,遗憾的是目前机遇性感染尤其是机遇性真菌感染的早期及正确诊断极具挑战性,误诊漏诊率在各种肺部感染中居高不下。真菌是常见的机遇性感染致病原之一,其中又以曲霉菌最为多见。为了提高对肺部真菌病影像学特点的认识,提高其诊断准确率,本研究动物实验部分探讨急性烟曲霉菌肺部感染的动物模型制作方法并着重研究其肺部CT表现及演变规律。在此基础上,我们回顾性分析肿块或结节型肺真菌病的流行病学特点及CT表现,并与炎症、结核及良性肿瘤相比较,旨在总结肿块或结节型肺真菌病的影像特点,为鉴别诊断提供依据。
第一部分急性肺曲霉菌病动物模型建立及CT征象学研究
目的
通过建立气管源性与血管源性新西兰大白兔急性肺部烟曲霉菌病模型,总结模型建立方法及其CT表现,并比较气管源性与血管源性模型动物生存期和肺外脏器病变出现情况的差异及CT表现的区别。
材料与方法
1.实验动物及分组
健康新西兰大白兔48只,随机编号分为6组,1-4组各9只为免疫抑制组,5、6组各6只为非免疫抑制组,1、3、5组动物经皮穿刺气管法接种菌液,2、4、6组经耳缘静脉注射法接种菌液,1、2组接种菌液浓度为5×10~7cfu/ml,3-6组接种浓度为5×10~8cfu/ml,接种菌液量均为0.2ml。
2.免疫抑制状态建立及菌液接种
接种菌株为烟曲霉菌标准株。
1-4组实验动物,第1-5天每日耳缘静脉注射阿糖胞苷525mg/m~2,第1、2天每天静脉注射甲强龙5mg/kg,第8、9天每天静脉注射阿糖胞苷484mg/m~2。为预防混合感染,第4天起,1-6组动物均给予万古霉素15mg/kg、头孢他啶150mg/kg静脉注射,每日1次;庆大霉素5mg/kg静脉注射,隔日1次。
实验第二天进行菌液接种,麻醉后根据分组情况按照不同方式不同菌液浓度进行接种。
3.CT扫描
分别于接种前1天、接种后1、3、5、7、9、11、13天将所有当时存活的实验动物进行肺部CT扫描。采用Sensation 16层螺旋CT机。使用儿童头部扫描SFOV,螺旋扫描,床进15mm/周,动物俯卧位,头先进;扫描条件:120KV,200mA;DFOV选择100-120mm;扫描模式:1.0mm×16;肺算法(60)和标准算法重建(40);常规层厚:3mm;重建层厚:1mm;
详细记录病变特征,病变出现的时间,及多次检查的病变演变情况。根据病变的形态、密度将病变分为结节状GGO、片状GGO、实性结节和片状实变4种,根据病变部位分为中心型与外围型,按数量分为单发与多发,且记录弥漫性病变出现情况。
4.动物解剖、病理检查及真菌培养
每日观察动物一般状况并及时解剖死亡动物、留取肺标本做真菌培养(SDA斜面培养基培养并做显微镜下鉴定)及病理检查(HE染色)、记录动物存活时间。接种后第13天将所有存活动物进行CT扫描后处死,解剖、留取标本。
5.建模成功判断标准
根据以下标准判定建模情况:(1)成功接种菌液;(2)兔肺标本真菌培养有烟曲霉菌菌落生长,镜下鉴定为烟曲霉菌;(3)观察期内兔胸部CT扫描发现病灶;(4)病灶部位肺标本病理切片HE染色镜下发现病变;满足条件(1)及(3)或(4)者视为建模成功,满足(1)和(2)但不具备(3)和(4)者视为烟曲霉菌肺部定植状态(潜伏感染),仅满足(1)而不满足其他条件者视为建模失败。
结果
1、建模成功率:第1组一只动物接种前死亡,其余动物均成功接种菌液。免疫抑制组的建模成功率高于非免疫抑制组(35只和3只,100% VS 25%,p=0<0.05)。非免疫抑制组只有42号动物于接种后第8天死亡,其余11只动物均为实验截止日(接种后第13天)人工处死。免疫抑制组动物存活时间最短2天,最长12天,平均6.51±2.34天;其中1组动物平均生存期8.5±1.51天;2组动物平均生存期6±1.80天;3组动物平均生存期7.22±2.64天;4组动物平均生存期4.56±1.42天。生存期的差异受接种方式影响(2因素2水平析因设计, F=15.44, P=0.0004<0.05),血管接种组动物生存时间较气管接种组短;4组动物肉眼观肝脏病变出现比率分别为:2/8、8/9、1/9、8/9,肾病变:0/8、5/9、0/9、7/9,血管接种组肝肾病变较气管接种组更易出现(logistic回归分析)。
2、肺部病变出现时间:35只建模成功的免疫抑制组动物肺部CT发现异常的时间最短为接种后1天,最长7天,平均3.057±1.57天。1组动物平均出现病变时间为3.5±2.07天,2组动物平均出现病变时间为3.22±1.20天,3组动物出现病变时间为3.22±1.56天,4组动物出现病变时间为2.33±1.41天。各组病变出现时间无统计学差异(2因素2水平析因设计方差分析)。
3、肺部病变的演变:免疫抑制动物四种征象出现时间顺序为片状GGO、结节状GGO、实性结节、片状实变,平均出现时间分别为:3.12±1.55天、4.69±2.56天、5.33±1.97天、7.31±2.29天。接种后3天片状GGO的新发病数达到高峰,而结节状GGO、实性结节、片状实变的新发病数在第5天达到高峰,7天之后主要新发征象为片状实变,而其他征象的新出现数下降。经方差分析F=14.783,P=0,各征象出现时间有统计学差异。经过多重比较,片状GGO与其他三种征象出现时间有统计学差异(P值分别为0.017、0.000、0.014)。片状实变与其他三种征象出现时间有统计学差异(P值分别为0.001、0.000、0.046)。分别总结各次CT扫描结果,接种后7天内以肺外围片状GGO多见,第5天和第7天结节状GGO和实性结节所占比重增大,而9天之后则以片状实变为主。35只免疫抑制动物终末期(死亡前最后一次CT检查)4只较前次CT图像增加了结节状GGO,4只增加片状GGO,13只增加片状实变,3只增加实性结节,20只出现弥漫性病变,且片状实变与弥漫性病变均为终末期新发病变。
4、肺部病变的组间比较及特征分析:免疫抑制动物最早出现的病变以肺外围片状GGO为主(32/35,91.4%)。两种接种方式及两种菌液浓度对结节状GGO、片状GGO、片状实变、弥漫性病变的出现率及发病部位、病变数量均无影响(logistic回归分析)。免疫抑制动物实验过程中34只(97.1%)动物见片状GGO,13只(38.2%)出现结节状GGO,13只(38.2%)出现片状实变,6只(17.1%)出现实性结节,34只(97.1%)见多发病变,1只(2.9%)单发病变;各组间征象出现率无明显差异(logistic回归分析)。
5、肺部CT表现的病理基础:
共取35个病灶进行病理学检查,HE染色。其中GGO病灶16个,病理上15个见肺泡少量炎性渗出,11个出现间质浸润,9个见到肺泡内出血,8个见到血管栓塞,仅一个出现肺泡实变。实性病灶19个,病理上1个见肺泡仅有少量炎性渗出,16个出现间质浸润,13个见到肺泡内出血,13个见血管栓塞,18个见肺泡实变。GGO病灶较实性病灶病理多见肺泡少量炎性渗出(P<0.05),两种病灶病理上出现肺泡内出血、间质浸润及血管栓塞的概率无统计学差异(P>0.05),实性病灶较GGO病理上多见肺泡实变(P<0.05)。
结论
1、经皮穿刺气管接种法与经耳缘静脉血管接种法均能制作肺部烟曲霉菌感染模型,免疫机能的破坏是建模成功的关键因素。免疫抑制动物感染烟曲霉菌后,病情进展快,存活时间短,平均存活期1周左右。血管接种组免疫抑制动物因易出现多器官的病变,生存期更短。
2、免疫抑制兔接种曲霉菌后3天左右即出现病变,且出现病变时间不受接种方式及菌液浓度的影响。
3、免疫抑制兔急性肺曲霉菌病模型CT表现最早以肺外围片状GGO为主,之后出现结节状GGO、实性结节,病程后期则以片状实变多见。病变可单发或多发。弥漫病变及片状实变的出现预示病情恶化、预后不良。
4、免疫抑制兔急性肺曲霉菌病模型CT表现以片状GGO为主,其他征象有片状实变、结节状GGO及实性结节等。气管源性与血管源性免疫抑制兔急性肺曲霉菌病模型CT表现无明显差异。
5、肺部接种烟曲霉菌的新西兰大白兔的CT表现能反映其病理变化,GGO提示肺泡少量炎性渗出、出血、间质内炎细胞浸润,而肺实变则说明有较严重的肺实变出血、间质浸润,两种病变都可出现血管栓塞。
第二部分肿块型肺真菌病的CT形态学表现及鉴别诊断
目的
回顾性分析肿块型肺真菌病患者的病灶CT形态学特征并与其他肺内良性结节/肿块相比较,旨在探讨肺部真菌感染的CT表现及鉴别诊断依据。
材料与方法
回顾性分析肺内良性结节或肿块病例共173例。其中真菌38例,67个病灶;炎症43例,46个病灶;结核55例,64个病灶;良性肿瘤37例,37个病灶;共214个病灶纳入研究。分析各组患者的年龄、性别及CT表现,包括病灶大小、形态(类圆形、楔形、不规则形)、界面(清楚光整、清楚但不光整、模糊)、边缘特征(浅分叶、深分叶、直边征、毛刺、尖角或棘状突起、晕征)、内部结构(坏死或空洞形成、洞壁厚薄、内壁是否光整,是否有钙化、脂肪、空气半月征、边缘裂隙)及邻近胸膜改变(胸膜牵拉、肥厚)和卫星灶出现情况,并与炎症、结核及良性肿瘤比较,探讨肿块或结节型肺真菌病与其他三类疾病之间的鉴别点。
结果
1、病人一般资料: 173例患者,男99例,女74例,年龄最小18岁,最大79岁,平均49.65±11.92岁。真菌患者,男25例,女13例,年龄最小26岁,最大77岁,平均47.50±11.43岁;炎症患者,男27例,女16例,年龄最小31岁,最大76岁,平均52.14±11.30岁;结核患者,男36例,女19例,年龄最小18岁,最大79岁,平均48.62±12.67岁;良性肿瘤患者,男11例,女26例,平均50.49±11.84岁。4组患者年龄分布无明显差异(方差分析,F=1.240,P=2.297>0.05)。各组性别分布有差异(χ2=14.632,P=0.002<0.05)。用卡方分割法对各组间性别分布进行比较(P界值为0.0071),良性肿瘤较真菌性肉芽肿多见于女性患者(P=0.001<0.0071)。
2、病灶大小: 214个病灶长径最短0.5cm,最长8.1cm,平均3.04±1.62cm。四组病灶长径均值排列顺序为:良性肿瘤(最短0.7cm,最长7.8cm,平均2.14±1.34cm)<结核(最短0.5cm,最长7.6cm,平均2.86±1.54cm)<真菌(最短0.5cm,最长7.3cm,平均3.37±1.50cm)<炎症(最短0.5cm,最长8.1cm平均3.55±1.78cm)。经方差分析,各组病灶长径有差异(F=7.065,P=0.000<0.05),肿块或结节型肺真菌病的病灶长径较良性肿瘤大(P=0.000<0.05),而与炎症及结核病灶比较无统计学差异(P>0.05)。
3、肺部真菌病灶的CT表现: 67个肿块型肺真菌病病灶形态为类圆形37个(55.2%),不规则形30个(44.8%),未见到楔形病灶;界面清楚但不光整57个(85.1%),界面模糊7个(10.4%),界面光整3个(4.5%);边缘出现棘状突起36个(53.7%),浅分叶29个(43.3%),深分叶23个(34.3%),晕征14个(20.9%),毛刺9个(13.4%),直边征6个(9.0%);出现坏死或空洞10个(14.9%),7例为厚壁空洞,5个内壁光整,5个内壁不规则;2个(3.0%)见钙化,9个(13.4%)见空气半月征,7个(10.4%)见边缘裂隙征,均未见脂肪成分。
4、形态学特征对肺部真菌病的鉴别诊断价值:在各组出现概率有统计学差异的征象有形态不规则形、类圆形、楔形,界面光整、清楚但不光整、模糊,边缘出现棘状突起、直边征、浅分叶、深分叶、晕征,内部见空洞、钙化灶,病灶邻近出现卫星灶、胸膜肥厚、胸膜牵拉(P<0.05)。将肿块或结节型肺真菌病CT表现与炎症、结核、良性肿瘤两两比较(用χ2分割法,P界值为0.0071),肿块或结节型肺真菌病较炎症病灶多见清楚界面,少见楔形征、模糊界面、棘状突起、直边征、晕征、空洞;较结核病灶多见深分叶,少见浅分叶、空洞、钙化、少见胸膜肥厚;较良性肿瘤多见形态不规则、清楚但不光整界面、棘状突起、深分叶、晕征、卫星灶、胸膜肥厚、胸膜牵拉,少见光整界面、钙化灶(P<0.0071)。
结论
1、肿块型肺真菌病好发于40-60岁男性患者,与其他肺内良性结节/肿块相似。
2、肿块型肺真菌病病灶长径变异较大,以2-4cm多见,病灶大小不能单独做为鉴别诊断的依据。
3、肿块型肺真菌病常见CT表现为类圆形或不规则形,界面清楚但不光整,病灶边缘易出现棘状突起、浅分叶或深分叶、晕征,空洞不常见但以厚壁空洞为主。空气半月征及边缘裂隙征为肿块型肺真菌病特异性表现。
4、肿块型肺真菌病、结核、良性肿瘤及炎性肿块/结节征象多有相互重叠,但多数征象在不同疾病的出现率存在差异,对各个征象的详细分析和综合判断有助于肿块型肺真菌性的正确诊断。清楚界面、模糊界面、楔形征、棘状突起、直边征、晕征、空洞的出现有助于肿块型肺真菌病与炎症鉴别,深分叶、浅分叶、空洞、钙化、胸膜肥厚的出现有助于肿块型肺真菌病与结核鉴别,形态不规则、光整界面、清楚但不光整界面、棘状突起、深分叶、晕征、卫星灶、胸膜肥厚、胸膜牵拉、钙化灶的出现有助于肿块型肺真菌病与良性肿瘤鉴别。
Background
The development of pulmonary infection in immunosuppressed patients is a particularly ominous sign and remains a diagnostic challenge. Pulmonary complications are a frequent cause of morbidity and mortality in these patients. Mortality rates for bone marrow transplant recipients with pulmonary infiltrates and requiring mechanical ventilation approach 90%. With the expanding use of solid-organ transplantation (SOT) and hematopoietic stem-cell transplantation (HSCT) coupled with increasingly aggressive chemotherapeutic regimens for malignancies, pulmonary and critical care physicians will find themselves more involved in the care of immunosuppressed patients. Fungi are important pathogenic microorganism to result in opportunistic infections, and Aspergillus is one of the most commom fungi to result in opportunistic infections. Therefore,animal experiment part of our study chose Aspergillus fumigatus which is one of the most common opportunistic algogen to establishment animal model of pulmonary infection,and research the CT appearances of them. In the second part, we analyzed the epidemiology characteristics and CT appearance of phymatoid pulmonary mycosis retrospectively, and compared these characteristics with other dieeases (including inflammation, tuberculosis and benign tumor), purpose to summarize the highlights of differential diagnosis of phymatoid pulmonary mycosis.
Part I The Animal Model Establishment of Acute Pulmonary Aspergillosis and CT Appears Study
Objective
To research the method of establish the animal model of Aspergillus fumigatus pneumonia in New Zealand rabbits,and analyze the appearances of chest CT scanning , compare the results of the two methods and search the difference of their CT appearances, through establish the the animal model with the method of inoculate conidia through trachea with puncture or inoculate conidia through ear vein.
Materials and methods
1、Experimential animals and their groups: Forty eight New Zealand rabbits which were healthy were divided into 6 groups randomly. Groups 1-4 which were immunosuppression groups there were 9 animals in each group, and groups 5 and 6 which were intact immune groups there were 6 animals in each group. The animals in groups 1, 3, 5 the conidia were inoculated through trachea with puncture, and in groups 2, 4, 6 the conidia were inoculated through ear vein.
2、Establishment of immunosuppression state and inoculation of the strain: Arabinosylcytosin was administered for the first 5 days through vein according to the criteria 525mg/m~2 and Prednisolone was administered for the first 2 days according to the criteria 5mg/kg with the animals in immunosuppression groups. Arabinosylcytosin was given with the other dose 484mg/m~2 the eighth and ninth day to maintain hypo-immune state. Vancocin and ceftazidime intravenous injection were given every day for 15mg/kg and 150mg/kg respectively, and gentamicin intravenous injection was adopted every other day for 5mg/kg with all the animals. On the 2nd day of the experiments, rabbits were inoculated with a defined 200ul inoculum containing 108 (group 3-6) or 107 (group 1 and 2) conidia of Aspergillus fumigatus.
3、CT examination: Lung CT scan was performed one day pre-infection and 1, 3, 5, 7, 9, 11, 13 post-infection. The features and variation of the CT appearances, the time of the changes appeared were recorded in detail. The CT appearances were identified as four types: nodous GGO, schistic GGO, schistic consolidation and nodule of soft tissue according to the shape and density. And the CT appearances were defined as peripheral or central, single, multiple or asystematic.
4、Animal anatomy and pathology examination and fungal culture:The animals which died were dissected at any time, and pathology examination(HE stainning) and fungul culture were performed on each sample. The survival time of the animal and the changes of lung, liver and kidney of each animal were recorded. All of the animals which survived were executed and dissected at the 13th day after inoculated. All the findings of pathological results and fungus cultivation were analysed.
Results
1、The achievement ratio of model establishment: Forty seven animals received strain innoculation successfullly and one animal in group1 died before innoculation. The achievement ratio of model established of immunosuppression groups was higher than that of intact immune groups(35 VS 3,100% VS 25%,p=0<0.05). In intact immune groups, one animal died on the 8th post-infection, and other 11animals were executed artificially on experimental deadline. The shortest survival time of the animals in immunosuppression groups was 2 days and the longest was 12 days, and the mean time was 6.51±2.34days. The mean survival time of the animals of group 1 was 8.5±1.51days. The mean survival time of the animals of group 2 was 6±1.80 days. The mean survival time of the animals of group 3 was 7.22±2.64 days. The mean survival time of the animals of group 4 was 4.56±1.42days. The survival time of the animals which were inoculated through trachea with puncture was longer than these which were inoculated through ear vein (2×2factorial experiment, F=15.44, P=0.0004<0.05). And the changes of the livers and kidneys in the latter were more conspicuous than those in the former(logistic regression).
2、Time of the abnormal CT appearances were detected: Abnormal CT appearances were found in the animals of immunosuppression groups in 1 day to 7 days and the mean time was 3.057 days. And the mean time of group 1 was 3.5 days, group 2 was 3.22 days, group 3 was 3.22 days, group 4 was 2.33 days. And the time of abnormal CT appearances were found in different groups had no statistical discrepancy (2×2 factorial experiment analysis of variance).
3、Variation of the CTappearances: The four types of CT appearances were ordered with the time to appear as schistic GGO, nodous GGO, nodule of soft tissue density and schistic consolidation, and the mean time was 3.12,4.69,5.33,7.31 days respectively(F=14.783,P=0). The time to appear of schistic GGO was shorter than nodous GGO, nodule of soft tissue density and schistic consolidation (P=0.017, 0.000, 0.014 respectively ). The time to appear of schistic consolidation was longer than nodous GGO and nodule of soft tissue(P=0.000,0.046). In the end stage, new schistic GGO was found in 4 animals, new nodous GGO was found in 4 animals, new schistic consolidation was found in 13 animals, new nodule of soft tissue density was found in 3 animals, and diffuse abnormality was found in 20 animals. And schistic consolidation and diffuse abnormality were not appeared in the former CT exam.
4、Features of the CT appearances: The most common initiatory CT appearances of the immunosuppression animals were schistic GGO at the periphery of the lung(32/35,91.4%). And there were no statistical difference among CT appearances of the 4 groups (logistic regression). Schistic GGO was found in 34 animals(97.1%), nodous GGO was found in 13 animals(38.2%), schistic consolidation was found in 13 animals(38.2%) and nodule of soft tissue density was found in 6 animals(17.1%) in the whole course. Moreover there are 34 animals (97.1%) in which multiple abnormalities were found. And there were no statistical difference among the 4 groups (logistic regression).
5、Pathologic foundation of CT appearances: There are 16 GGO and 19 Solid density specimens were selected for pathologic examination. Hemorrhage could be seen in 9 of the 16 GGO specimens, infl.cells exudation could be seen in 15, interstitial hyperplasy could be seen in 11, embolism could be seen in 8, alveolar consolidation could be seen in 1, alveolar hemorrhage could be seen in 9 specimens. Hemorrhage could be seen in 13 of the 19 Solid density specimens. Infl.cells exudation without alveolar consolidation could be seen in 1, interstitial hyperplasy could be seen in 16, embolism could be seen in 13, alveolar consolidation can be seen in 18, alveolar hemorrhage could be seen in 13 specimens. There was relatively high consistency between CT appearances and pathological findings.
Conclusion
1. The animal models of acute Aspergillus fumigatus pneumonia in New Zealand rabbits can be established with the conidia are inoculated through trachea or vein. Immunosuppression is crucial to establish the model. The state of immunosuppressive rabbits with aspergillus pneumonia aggravates rapidly, and the survival time is short, about a week. The survival of the rabbits inoculated through vein is shorter than inoculated through trachea.
2. The CT abnormality of the animal models of acute Aspergillus fumigatus pneumonia in immunosuppressive New Zealand rabbits can be found in about 3 days after infection. There are no significant difference of the time of CT appearences appear between the animals inoculated through trachea and vein.
3. The CT appearances of the animal models of acute Aspergillus fumigatus pneumonia in immunosuppressive New Zealand rabbits are nonspecific, and the most common appearance is schistic GGO at the periphery of the lung.
4. There are no significant difference of the CT appearences between the animals inoculated through trachea and vein. Diffuse abnormality and schistic consolidation are the signals of aggravated and worse prognosis.
5、There was relatively high consistency between CT appearance and pathological findings in the Aspergillus fumigatus pneumonia models of immunosuppressive New Zealand white rabbits. GGO in CT represents hemorrhage, inflammatory cell infiltration, and interstitium hyperplasy. Consolidations in CT represent consolidation, and interstitium hyperplasy. Embolism can be seen in both the two kind of specimen.
Part II The CT morphological appearance and differential diagnosisof phymatoid pulmonary mycosis
Objective
Study the epidemiology and CT morphological features of phymatoid pulmonary mycosis and compare with other benign dieeases (including inflammation, tuberculosis and benign tumor), purpose to summarize the highlights of differential diagnosis of phymatoid pulmonary mycosis.
Materials and methods
The clinical records and CT images of 173 cases with 214 pulmonary benign nodules/masses were studied, including 38 phymatoid mycosises with 67 nodules/masses, 43 inflammation patients with 46 nodules/masses, 55 tuberculosises with 64 nodules/masses and 37 benign tumors with 37 nodules/masses were studied. The age, gender of the patients and the CT appearance of the phymatoid pulmonary mycosis including the long diameter, shape(round or oval, irregular, wedge shaped), interface(smooth, clear, fuzzy), margin(superficial lobulation, prefound lobulation, rectus margin, spike, speculate protuberanc, halo sign), inner structure(cavitation, cavitation with thick wall, cavitation with irregular inner wall, calcification, fat, cresent sign,marginal fissure) and the satellites, changes of pleura nearby the nodules/masses were analyzed. And these features were compared with inflammation, tuberculosis and benign tumor, to summarize the highlights of differential diagnosisof phymatoid pulmonary mycosis.
Results
1、General information in patients : 173 patients, 99 male, 74 female, 18-79 years old, mean age 49.65±11.92 years. Mycosis: 38 patients, 25 male, 13 female, 26-77 years old, mean age 47.50±11.43 years; inflammation: 43 patients, 27 male, 16 female, 31-76 years old, mean age 52.14±11.30 years; tuberculosis: 55 patients, 36 male, 19 female; 18-79 years old, mean age 48.60±12.67 years; benign tumor: 37 patients, 11 male, 26 female, 32-78 years old, mean age 50.49±11.84 years. There were no statistical differences among the age distribution of the four categories diseases(ANOVA, F=1.240,P=2.297>0.05). And there were statistical differences among the gender distribution of the four categories diseases (χ2=14.632,P=0.002<0.05). And benign tumors were more prone to occur in female (P=0.003, 0.001, 0.002).
2、Size: The range if the long diameters of the 214 nodules/masses was 0.5-8.1 cm, the mean long diameter was 3.04±1.62cm. The 4 categories diseases were arrowed by the long diameter as follows: Benign tumor(0.7-7.8cm, mean 2.14±1.34cm) < tuberculosis(0.5-7.6cm, mean 2.86±1.54cm)< phymatoid mycosis(0.5-7.3cm, mean 3.37±1.50cm)< inflammation(0.5-8.1cm, mean 3.55±1.78cm). There were statistical differences among the long diameter of the four categories diseases (ANOVA, F=7.065,P=0.000<0.05). The long diameter of benign tumor was shorter than the others (P=.000,0.000,0.026), and the long diameter of tuberculosis was shorter than inflammation (P=0.023<0.05), and there were no statistical differences between the long diameter of phymatoid mycosis and inflammation or tuberculosis(P>0.05).
3、Features of the Morphology: The CT appearances of phymatoid pulmonary mycosis were round or oval shape(37, 55.2%), irregular shape(30, 44.8%), clear interface(57, 85.1%), fuzzy interface(7, 10.4%), smooth interface(3, 4.5%), speculate protuberanc(36, 53.7%), superficial lobulation(29, 43.3%), prefound lobulation(23, 34.4%), halo sign(14, 20.9%), spike(9,13.4%), rectus margin(6,9.0%); cavitation (10, 14.9%), 7 cavitations with thick wall, 5 with irregular inner wall and 5 with smooth inner wall; calcification(2, 3.0%), cresent sign(9, 13.4%), marginal fissure(7, 10.4%). And there were no fat in phymatoid pulmonary mycosis. Marginal fissure only could be seen in aspergillosis.
4、Differential diagnosis: The incidence of irregular shape, round or oval shape, wedge shape, smooth interface, clear interface, fuzzy interface, speculate protuberanc, superficial lobulation, prefound lobulation, halo sign, cavitation, calcification, rectus margin, satellite, pleural thick and pleural indentation were different among the four categories diseases(p<0.05). The CT appearances of phymatoid pulmonary mycosis were compared with inflammation, tuberculosis and benign tumor separately. The clear interface was more common in phymatoid mycosis than in inflammation (P<0.0071). And the wedge shaped, fuzzy interface, speculate protuberanc, rectus margin, halo sign and cavitation were less commom in phymatoid mycosis than in inflammation (P<0.0071). The prefound lobulation was more common in phymatoid mycosis than in tuberculosis (P<0.0071). And superficial lobulation, cavitation, calcification, pleural thick were less common phymatoid mycosis than in tuberculosis (P<0.0071). The irregular shape, clear interface, speculate protuberanc, halo sign, prefound lobulation, satellite, pleural thick, pleural indentation were more commom in phymatoid mycosis than in benign tumor (P<0.0071). And the smooth interface, calcification were less common in phymatoid mycosis than in benign tumor (P<0.0071).
Conclusion
1. The susceptible crowd of phymatoid pulmonary mycosis is 40-60 years old males.
2. The sizes of long diameter of phymatoid pulmonary mycosis are disparity. And the range of commom size is 2-4cm. The correct diagnosis of phymatoid pulmonary mycosis should not be carried out only according to the size.
3. The common CT appearances of phymatoid pulmonary mycosis are round, oval shape or irregular shape; clear interface; speculate protuberanc, superficial lobulation or prefound lobulation, halo sign. There are usually thick wall with cavitation. The cresent sign and marginal fissure are specific signs of phymatoid pulmonary mycosis.
4. Although overlay of the CT appearance are common, there are difference in the detail features of the signs, which make them an important evidence for the differential diagnosis of these diseases. The value of a single sign in the differential diagnosis is limited and multi-signs analysis in the differential diagnosis process tends to achieve the correct conclusion. The detection of wedge shaped, clear interface, fuzzy interface, speculate protuberanc, rectus margin, halo sign and cavitation conduce to differential diagnosis between phymatoid pulmonary mycosis and inflammation. And the detection of prefound lobulation, superficial lobulation, cavitation, calcification and pleural thick conduce to differential diagnosis between phymatoid pulmonary mycosis and tuberculosis. And the detection of irregular shape, clear interface, speculate protuberanc, halo sign, prefound lobulation, satellite, pleural thick, pleural indentation, smooth interface and calcification conduce to differential diagnosis between phymatoid pulmonary mycosis and benign tumor.
随着器官移植及造血干细胞移植的广泛开展,化疗药、免疫抑制剂的广泛应用,肺部机遇性感染发病率迅速上升,是导致免疫抑制患者高死亡率的重要原因之一,如骨髓移植患者及机械通气患者肺部感染的死亡率高达90%。降低死亡率的关键是早期及时的正确诊断,以便能及时有效的给予治疗,遗憾的是目前机遇性感染尤其是机遇性真菌感染的早期及正确诊断极具挑战性,误诊漏诊率在各种肺部感染中居高不下。真菌是常见的机遇性感染致病原之一,其中又以曲霉菌最为多见。为了提高对肺部真菌病影像学特点的认识,提高其诊断准确率,本研究动物实验部分探讨急性烟曲霉菌肺部感染的动物模型制作方法并着重研究其肺部CT表现及演变规律。在此基础上,我们回顾性分析肿块或结节型肺真菌病的流行病学特点及CT表现,并与炎症、结核及良性肿瘤相比较,旨在总结肿块或结节型肺真菌病的影像特点,为鉴别诊断提供依据。
第一部分急性肺曲霉菌病动物模型建立及CT征象学研究
目的
通过建立气管源性与血管源性新西兰大白兔急性肺部烟曲霉菌病模型,总结模型建立方法及其CT表现,并比较气管源性与血管源性模型动物生存期和肺外脏器病变出现情况的差异及CT表现的区别。
材料与方法
1.实验动物及分组
健康新西兰大白兔48只,随机编号分为6组,1-4组各9只为免疫抑制组,5、6组各6只为非免疫抑制组,1、3、5组动物经皮穿刺气管法接种菌液,2、4、6组经耳缘静脉注射法接种菌液,1、2组接种菌液浓度为5×10~7cfu/ml,3-6组接种浓度为5×10~8cfu/ml,接种菌液量均为0.2ml。
2.免疫抑制状态建立及菌液接种
接种菌株为烟曲霉菌标准株。
1-4组实验动物,第1-5天每日耳缘静脉注射阿糖胞苷525mg/m~2,第1、2天每天静脉注射甲强龙5mg/kg,第8、9天每天静脉注射阿糖胞苷484mg/m~2。为预防混合感染,第4天起,1-6组动物均给予万古霉素15mg/kg、头孢他啶150mg/kg静脉注射,每日1次;庆大霉素5mg/kg静脉注射,隔日1次。
实验第二天进行菌液接种,麻醉后根据分组情况按照不同方式不同菌液浓度进行接种。
3.CT扫描
分别于接种前1天、接种后1、3、5、7、9、11、13天将所有当时存活的实验动物进行肺部CT扫描。采用Sensation 16层螺旋CT机。使用儿童头部扫描SFOV,螺旋扫描,床进15mm/周,动物俯卧位,头先进;扫描条件:120KV,200mA;DFOV选择100-120mm;扫描模式:1.0mm×16;肺算法(60)和标准算法重建(40);常规层厚:3mm;重建层厚:1mm;
详细记录病变特征,病变出现的时间,及多次检查的病变演变情况。根据病变的形态、密度将病变分为结节状GGO、片状GGO、实性结节和片状实变4种,根据病变部位分为中心型与外围型,按数量分为单发与多发,且记录弥漫性病变出现情况。
4.动物解剖、病理检查及真菌培养
每日观察动物一般状况并及时解剖死亡动物、留取肺标本做真菌培养(SDA斜面培养基培养并做显微镜下鉴定)及病理检查(HE染色)、记录动物存活时间。接种后第13天将所有存活动物进行CT扫描后处死,解剖、留取标本。
5.建模成功判断标准
根据以下标准判定建模情况:(1)成功接种菌液;(2)兔肺标本真菌培养有烟曲霉菌菌落生长,镜下鉴定为烟曲霉菌;(3)观察期内兔胸部CT扫描发现病灶;(4)病灶部位肺标本病理切片HE染色镜下发现病变;满足条件(1)及(3)或(4)者视为建模成功,满足(1)和(2)但不具备(3)和(4)者视为烟曲霉菌肺部定植状态(潜伏感染),仅满足(1)而不满足其他条件者视为建模失败。
结果
1、建模成功率:第1组一只动物接种前死亡,其余动物均成功接种菌液。免疫抑制组的建模成功率高于非免疫抑制组(35只和3只,100% VS 25%,p=0<0.05)。非免疫抑制组只有42号动物于接种后第8天死亡,其余11只动物均为实验截止日(接种后第13天)人工处死。免疫抑制组动物存活时间最短2天,最长12天,平均6.51±2.34天;其中1组动物平均生存期8.5±1.51天;2组动物平均生存期6±1.80天;3组动物平均生存期7.22±2.64天;4组动物平均生存期4.56±1.42天。生存期的差异受接种方式影响(2因素2水平析因设计, F=15.44, P=0.0004<0.05),血管接种组动物生存时间较气管接种组短;4组动物肉眼观肝脏病变出现比率分别为:2/8、8/9、1/9、8/9,肾病变:0/8、5/9、0/9、7/9,血管接种组肝肾病变较气管接种组更易出现(logistic回归分析)。
2、肺部病变出现时间:35只建模成功的免疫抑制组动物肺部CT发现异常的时间最短为接种后1天,最长7天,平均3.057±1.57天。1组动物平均出现病变时间为3.5±2.07天,2组动物平均出现病变时间为3.22±1.20天,3组动物出现病变时间为3.22±1.56天,4组动物出现病变时间为2.33±1.41天。各组病变出现时间无统计学差异(2因素2水平析因设计方差分析)。
3、肺部病变的演变:免疫抑制动物四种征象出现时间顺序为片状GGO、结节状GGO、实性结节、片状实变,平均出现时间分别为:3.12±1.55天、4.69±2.56天、5.33±1.97天、7.31±2.29天。接种后3天片状GGO的新发病数达到高峰,而结节状GGO、实性结节、片状实变的新发病数在第5天达到高峰,7天之后主要新发征象为片状实变,而其他征象的新出现数下降。经方差分析F=14.783,P=0,各征象出现时间有统计学差异。经过多重比较,片状GGO与其他三种征象出现时间有统计学差异(P值分别为0.017、0.000、0.014)。片状实变与其他三种征象出现时间有统计学差异(P值分别为0.001、0.000、0.046)。分别总结各次CT扫描结果,接种后7天内以肺外围片状GGO多见,第5天和第7天结节状GGO和实性结节所占比重增大,而9天之后则以片状实变为主。35只免疫抑制动物终末期(死亡前最后一次CT检查)4只较前次CT图像增加了结节状GGO,4只增加片状GGO,13只增加片状实变,3只增加实性结节,20只出现弥漫性病变,且片状实变与弥漫性病变均为终末期新发病变。
4、肺部病变的组间比较及特征分析:免疫抑制动物最早出现的病变以肺外围片状GGO为主(32/35,91.4%)。两种接种方式及两种菌液浓度对结节状GGO、片状GGO、片状实变、弥漫性病变的出现率及发病部位、病变数量均无影响(logistic回归分析)。免疫抑制动物实验过程中34只(97.1%)动物见片状GGO,13只(38.2%)出现结节状GGO,13只(38.2%)出现片状实变,6只(17.1%)出现实性结节,34只(97.1%)见多发病变,1只(2.9%)单发病变;各组间征象出现率无明显差异(logistic回归分析)。
5、肺部CT表现的病理基础:
共取35个病灶进行病理学检查,HE染色。其中GGO病灶16个,病理上15个见肺泡少量炎性渗出,11个出现间质浸润,9个见到肺泡内出血,8个见到血管栓塞,仅一个出现肺泡实变。实性病灶19个,病理上1个见肺泡仅有少量炎性渗出,16个出现间质浸润,13个见到肺泡内出血,13个见血管栓塞,18个见肺泡实变。GGO病灶较实性病灶病理多见肺泡少量炎性渗出(P<0.05),两种病灶病理上出现肺泡内出血、间质浸润及血管栓塞的概率无统计学差异(P>0.05),实性病灶较GGO病理上多见肺泡实变(P<0.05)。
结论
1、经皮穿刺气管接种法与经耳缘静脉血管接种法均能制作肺部烟曲霉菌感染模型,免疫机能的破坏是建模成功的关键因素。免疫抑制动物感染烟曲霉菌后,病情进展快,存活时间短,平均存活期1周左右。血管接种组免疫抑制动物因易出现多器官的病变,生存期更短。
2、免疫抑制兔接种曲霉菌后3天左右即出现病变,且出现病变时间不受接种方式及菌液浓度的影响。
3、免疫抑制兔急性肺曲霉菌病模型CT表现最早以肺外围片状GGO为主,之后出现结节状GGO、实性结节,病程后期则以片状实变多见。病变可单发或多发。弥漫病变及片状实变的出现预示病情恶化、预后不良。
4、免疫抑制兔急性肺曲霉菌病模型CT表现以片状GGO为主,其他征象有片状实变、结节状GGO及实性结节等。气管源性与血管源性免疫抑制兔急性肺曲霉菌病模型CT表现无明显差异。
5、肺部接种烟曲霉菌的新西兰大白兔的CT表现能反映其病理变化,GGO提示肺泡少量炎性渗出、出血、间质内炎细胞浸润,而肺实变则说明有较严重的肺实变出血、间质浸润,两种病变都可出现血管栓塞。
第二部分肿块型肺真菌病的CT形态学表现及鉴别诊断
目的
回顾性分析肿块型肺真菌病患者的病灶CT形态学特征并与其他肺内良性结节/肿块相比较,旨在探讨肺部真菌感染的CT表现及鉴别诊断依据。
材料与方法
回顾性分析肺内良性结节或肿块病例共173例。其中真菌38例,67个病灶;炎症43例,46个病灶;结核55例,64个病灶;良性肿瘤37例,37个病灶;共214个病灶纳入研究。分析各组患者的年龄、性别及CT表现,包括病灶大小、形态(类圆形、楔形、不规则形)、界面(清楚光整、清楚但不光整、模糊)、边缘特征(浅分叶、深分叶、直边征、毛刺、尖角或棘状突起、晕征)、内部结构(坏死或空洞形成、洞壁厚薄、内壁是否光整,是否有钙化、脂肪、空气半月征、边缘裂隙)及邻近胸膜改变(胸膜牵拉、肥厚)和卫星灶出现情况,并与炎症、结核及良性肿瘤比较,探讨肿块或结节型肺真菌病与其他三类疾病之间的鉴别点。
结果
1、病人一般资料: 173例患者,男99例,女74例,年龄最小18岁,最大79岁,平均49.65±11.92岁。真菌患者,男25例,女13例,年龄最小26岁,最大77岁,平均47.50±11.43岁;炎症患者,男27例,女16例,年龄最小31岁,最大76岁,平均52.14±11.30岁;结核患者,男36例,女19例,年龄最小18岁,最大79岁,平均48.62±12.67岁;良性肿瘤患者,男11例,女26例,平均50.49±11.84岁。4组患者年龄分布无明显差异(方差分析,F=1.240,P=2.297>0.05)。各组性别分布有差异(χ2=14.632,P=0.002<0.05)。用卡方分割法对各组间性别分布进行比较(P界值为0.0071),良性肿瘤较真菌性肉芽肿多见于女性患者(P=0.001<0.0071)。
2、病灶大小: 214个病灶长径最短0.5cm,最长8.1cm,平均3.04±1.62cm。四组病灶长径均值排列顺序为:良性肿瘤(最短0.7cm,最长7.8cm,平均2.14±1.34cm)<结核(最短0.5cm,最长7.6cm,平均2.86±1.54cm)<真菌(最短0.5cm,最长7.3cm,平均3.37±1.50cm)<炎症(最短0.5cm,最长8.1cm平均3.55±1.78cm)。经方差分析,各组病灶长径有差异(F=7.065,P=0.000<0.05),肿块或结节型肺真菌病的病灶长径较良性肿瘤大(P=0.000<0.05),而与炎症及结核病灶比较无统计学差异(P>0.05)。
3、肺部真菌病灶的CT表现: 67个肿块型肺真菌病病灶形态为类圆形37个(55.2%),不规则形30个(44.8%),未见到楔形病灶;界面清楚但不光整57个(85.1%),界面模糊7个(10.4%),界面光整3个(4.5%);边缘出现棘状突起36个(53.7%),浅分叶29个(43.3%),深分叶23个(34.3%),晕征14个(20.9%),毛刺9个(13.4%),直边征6个(9.0%);出现坏死或空洞10个(14.9%),7例为厚壁空洞,5个内壁光整,5个内壁不规则;2个(3.0%)见钙化,9个(13.4%)见空气半月征,7个(10.4%)见边缘裂隙征,均未见脂肪成分。
4、形态学特征对肺部真菌病的鉴别诊断价值:在各组出现概率有统计学差异的征象有形态不规则形、类圆形、楔形,界面光整、清楚但不光整、模糊,边缘出现棘状突起、直边征、浅分叶、深分叶、晕征,内部见空洞、钙化灶,病灶邻近出现卫星灶、胸膜肥厚、胸膜牵拉(P<0.05)。将肿块或结节型肺真菌病CT表现与炎症、结核、良性肿瘤两两比较(用χ2分割法,P界值为0.0071),肿块或结节型肺真菌病较炎症病灶多见清楚界面,少见楔形征、模糊界面、棘状突起、直边征、晕征、空洞;较结核病灶多见深分叶,少见浅分叶、空洞、钙化、少见胸膜肥厚;较良性肿瘤多见形态不规则、清楚但不光整界面、棘状突起、深分叶、晕征、卫星灶、胸膜肥厚、胸膜牵拉,少见光整界面、钙化灶(P<0.0071)。
结论
1、肿块型肺真菌病好发于40-60岁男性患者,与其他肺内良性结节/肿块相似。
2、肿块型肺真菌病病灶长径变异较大,以2-4cm多见,病灶大小不能单独做为鉴别诊断的依据。
3、肿块型肺真菌病常见CT表现为类圆形或不规则形,界面清楚但不光整,病灶边缘易出现棘状突起、浅分叶或深分叶、晕征,空洞不常见但以厚壁空洞为主。空气半月征及边缘裂隙征为肿块型肺真菌病特异性表现。
4、肿块型肺真菌病、结核、良性肿瘤及炎性肿块/结节征象多有相互重叠,但多数征象在不同疾病的出现率存在差异,对各个征象的详细分析和综合判断有助于肿块型肺真菌性的正确诊断。清楚界面、模糊界面、楔形征、棘状突起、直边征、晕征、空洞的出现有助于肿块型肺真菌病与炎症鉴别,深分叶、浅分叶、空洞、钙化、胸膜肥厚的出现有助于肿块型肺真菌病与结核鉴别,形态不规则、光整界面、清楚但不光整界面、棘状突起、深分叶、晕征、卫星灶、胸膜肥厚、胸膜牵拉、钙化灶的出现有助于肿块型肺真菌病与良性肿瘤鉴别。
Background
The development of pulmonary infection in immunosuppressed patients is a particularly ominous sign and remains a diagnostic challenge. Pulmonary complications are a frequent cause of morbidity and mortality in these patients. Mortality rates for bone marrow transplant recipients with pulmonary infiltrates and requiring mechanical ventilation approach 90%. With the expanding use of solid-organ transplantation (SOT) and hematopoietic stem-cell transplantation (HSCT) coupled with increasingly aggressive chemotherapeutic regimens for malignancies, pulmonary and critical care physicians will find themselves more involved in the care of immunosuppressed patients. Fungi are important pathogenic microorganism to result in opportunistic infections, and Aspergillus is one of the most commom fungi to result in opportunistic infections. Therefore,animal experiment part of our study chose Aspergillus fumigatus which is one of the most common opportunistic algogen to establishment animal model of pulmonary infection,and research the CT appearances of them. In the second part, we analyzed the epidemiology characteristics and CT appearance of phymatoid pulmonary mycosis retrospectively, and compared these characteristics with other dieeases (including inflammation, tuberculosis and benign tumor), purpose to summarize the highlights of differential diagnosis of phymatoid pulmonary mycosis.
Part I The Animal Model Establishment of Acute Pulmonary Aspergillosis and CT Appears Study
Objective
To research the method of establish the animal model of Aspergillus fumigatus pneumonia in New Zealand rabbits,and analyze the appearances of chest CT scanning , compare the results of the two methods and search the difference of their CT appearances, through establish the the animal model with the method of inoculate conidia through trachea with puncture or inoculate conidia through ear vein.
Materials and methods
1、Experimential animals and their groups: Forty eight New Zealand rabbits which were healthy were divided into 6 groups randomly. Groups 1-4 which were immunosuppression groups there were 9 animals in each group, and groups 5 and 6 which were intact immune groups there were 6 animals in each group. The animals in groups 1, 3, 5 the conidia were inoculated through trachea with puncture, and in groups 2, 4, 6 the conidia were inoculated through ear vein.
2、Establishment of immunosuppression state and inoculation of the strain: Arabinosylcytosin was administered for the first 5 days through vein according to the criteria 525mg/m~2 and Prednisolone was administered for the first 2 days according to the criteria 5mg/kg with the animals in immunosuppression groups. Arabinosylcytosin was given with the other dose 484mg/m~2 the eighth and ninth day to maintain hypo-immune state. Vancocin and ceftazidime intravenous injection were given every day for 15mg/kg and 150mg/kg respectively, and gentamicin intravenous injection was adopted every other day for 5mg/kg with all the animals. On the 2nd day of the experiments, rabbits were inoculated with a defined 200ul inoculum containing 108 (group 3-6) or 107 (group 1 and 2) conidia of Aspergillus fumigatus.
3、CT examination: Lung CT scan was performed one day pre-infection and 1, 3, 5, 7, 9, 11, 13 post-infection. The features and variation of the CT appearances, the time of the changes appeared were recorded in detail. The CT appearances were identified as four types: nodous GGO, schistic GGO, schistic consolidation and nodule of soft tissue according to the shape and density. And the CT appearances were defined as peripheral or central, single, multiple or asystematic.
4、Animal anatomy and pathology examination and fungal culture:The animals which died were dissected at any time, and pathology examination(HE stainning) and fungul culture were performed on each sample. The survival time of the animal and the changes of lung, liver and kidney of each animal were recorded. All of the animals which survived were executed and dissected at the 13th day after inoculated. All the findings of pathological results and fungus cultivation were analysed.
Results
1、The achievement ratio of model establishment: Forty seven animals received strain innoculation successfullly and one animal in group1 died before innoculation. The achievement ratio of model established of immunosuppression groups was higher than that of intact immune groups(35 VS 3,100% VS 25%,p=0<0.05). In intact immune groups, one animal died on the 8th post-infection, and other 11animals were executed artificially on experimental deadline. The shortest survival time of the animals in immunosuppression groups was 2 days and the longest was 12 days, and the mean time was 6.51±2.34days. The mean survival time of the animals of group 1 was 8.5±1.51days. The mean survival time of the animals of group 2 was 6±1.80 days. The mean survival time of the animals of group 3 was 7.22±2.64 days. The mean survival time of the animals of group 4 was 4.56±1.42days. The survival time of the animals which were inoculated through trachea with puncture was longer than these which were inoculated through ear vein (2×2factorial experiment, F=15.44, P=0.0004<0.05). And the changes of the livers and kidneys in the latter were more conspicuous than those in the former(logistic regression).
2、Time of the abnormal CT appearances were detected: Abnormal CT appearances were found in the animals of immunosuppression groups in 1 day to 7 days and the mean time was 3.057 days. And the mean time of group 1 was 3.5 days, group 2 was 3.22 days, group 3 was 3.22 days, group 4 was 2.33 days. And the time of abnormal CT appearances were found in different groups had no statistical discrepancy (2×2 factorial experiment analysis of variance).
3、Variation of the CTappearances: The four types of CT appearances were ordered with the time to appear as schistic GGO, nodous GGO, nodule of soft tissue density and schistic consolidation, and the mean time was 3.12,4.69,5.33,7.31 days respectively(F=14.783,P=0). The time to appear of schistic GGO was shorter than nodous GGO, nodule of soft tissue density and schistic consolidation (P=0.017, 0.000, 0.014 respectively ). The time to appear of schistic consolidation was longer than nodous GGO and nodule of soft tissue(P=0.000,0.046). In the end stage, new schistic GGO was found in 4 animals, new nodous GGO was found in 4 animals, new schistic consolidation was found in 13 animals, new nodule of soft tissue density was found in 3 animals, and diffuse abnormality was found in 20 animals. And schistic consolidation and diffuse abnormality were not appeared in the former CT exam.
4、Features of the CT appearances: The most common initiatory CT appearances of the immunosuppression animals were schistic GGO at the periphery of the lung(32/35,91.4%). And there were no statistical difference among CT appearances of the 4 groups (logistic regression). Schistic GGO was found in 34 animals(97.1%), nodous GGO was found in 13 animals(38.2%), schistic consolidation was found in 13 animals(38.2%) and nodule of soft tissue density was found in 6 animals(17.1%) in the whole course. Moreover there are 34 animals (97.1%) in which multiple abnormalities were found. And there were no statistical difference among the 4 groups (logistic regression).
5、Pathologic foundation of CT appearances: There are 16 GGO and 19 Solid density specimens were selected for pathologic examination. Hemorrhage could be seen in 9 of the 16 GGO specimens, infl.cells exudation could be seen in 15, interstitial hyperplasy could be seen in 11, embolism could be seen in 8, alveolar consolidation could be seen in 1, alveolar hemorrhage could be seen in 9 specimens. Hemorrhage could be seen in 13 of the 19 Solid density specimens. Infl.cells exudation without alveolar consolidation could be seen in 1, interstitial hyperplasy could be seen in 16, embolism could be seen in 13, alveolar consolidation can be seen in 18, alveolar hemorrhage could be seen in 13 specimens. There was relatively high consistency between CT appearances and pathological findings.
Conclusion
1. The animal models of acute Aspergillus fumigatus pneumonia in New Zealand rabbits can be established with the conidia are inoculated through trachea or vein. Immunosuppression is crucial to establish the model. The state of immunosuppressive rabbits with aspergillus pneumonia aggravates rapidly, and the survival time is short, about a week. The survival of the rabbits inoculated through vein is shorter than inoculated through trachea.
2. The CT abnormality of the animal models of acute Aspergillus fumigatus pneumonia in immunosuppressive New Zealand rabbits can be found in about 3 days after infection. There are no significant difference of the time of CT appearences appear between the animals inoculated through trachea and vein.
3. The CT appearances of the animal models of acute Aspergillus fumigatus pneumonia in immunosuppressive New Zealand rabbits are nonspecific, and the most common appearance is schistic GGO at the periphery of the lung.
4. There are no significant difference of the CT appearences between the animals inoculated through trachea and vein. Diffuse abnormality and schistic consolidation are the signals of aggravated and worse prognosis.
5、There was relatively high consistency between CT appearance and pathological findings in the Aspergillus fumigatus pneumonia models of immunosuppressive New Zealand white rabbits. GGO in CT represents hemorrhage, inflammatory cell infiltration, and interstitium hyperplasy. Consolidations in CT represent consolidation, and interstitium hyperplasy. Embolism can be seen in both the two kind of specimen.
Part II The CT morphological appearance and differential diagnosisof phymatoid pulmonary mycosis
Objective
Study the epidemiology and CT morphological features of phymatoid pulmonary mycosis and compare with other benign dieeases (including inflammation, tuberculosis and benign tumor), purpose to summarize the highlights of differential diagnosis of phymatoid pulmonary mycosis.
Materials and methods
The clinical records and CT images of 173 cases with 214 pulmonary benign nodules/masses were studied, including 38 phymatoid mycosises with 67 nodules/masses, 43 inflammation patients with 46 nodules/masses, 55 tuberculosises with 64 nodules/masses and 37 benign tumors with 37 nodules/masses were studied. The age, gender of the patients and the CT appearance of the phymatoid pulmonary mycosis including the long diameter, shape(round or oval, irregular, wedge shaped), interface(smooth, clear, fuzzy), margin(superficial lobulation, prefound lobulation, rectus margin, spike, speculate protuberanc, halo sign), inner structure(cavitation, cavitation with thick wall, cavitation with irregular inner wall, calcification, fat, cresent sign,marginal fissure) and the satellites, changes of pleura nearby the nodules/masses were analyzed. And these features were compared with inflammation, tuberculosis and benign tumor, to summarize the highlights of differential diagnosisof phymatoid pulmonary mycosis.
Results
1、General information in patients : 173 patients, 99 male, 74 female, 18-79 years old, mean age 49.65±11.92 years. Mycosis: 38 patients, 25 male, 13 female, 26-77 years old, mean age 47.50±11.43 years; inflammation: 43 patients, 27 male, 16 female, 31-76 years old, mean age 52.14±11.30 years; tuberculosis: 55 patients, 36 male, 19 female; 18-79 years old, mean age 48.60±12.67 years; benign tumor: 37 patients, 11 male, 26 female, 32-78 years old, mean age 50.49±11.84 years. There were no statistical differences among the age distribution of the four categories diseases(ANOVA, F=1.240,P=2.297>0.05). And there were statistical differences among the gender distribution of the four categories diseases (χ2=14.632,P=0.002<0.05). And benign tumors were more prone to occur in female (P=0.003, 0.001, 0.002).
2、Size: The range if the long diameters of the 214 nodules/masses was 0.5-8.1 cm, the mean long diameter was 3.04±1.62cm. The 4 categories diseases were arrowed by the long diameter as follows: Benign tumor(0.7-7.8cm, mean 2.14±1.34cm) < tuberculosis(0.5-7.6cm, mean 2.86±1.54cm)< phymatoid mycosis(0.5-7.3cm, mean 3.37±1.50cm)< inflammation(0.5-8.1cm, mean 3.55±1.78cm). There were statistical differences among the long diameter of the four categories diseases (ANOVA, F=7.065,P=0.000<0.05). The long diameter of benign tumor was shorter than the others (P=.000,0.000,0.026), and the long diameter of tuberculosis was shorter than inflammation (P=0.023<0.05), and there were no statistical differences between the long diameter of phymatoid mycosis and inflammation or tuberculosis(P>0.05).
3、Features of the Morphology: The CT appearances of phymatoid pulmonary mycosis were round or oval shape(37, 55.2%), irregular shape(30, 44.8%), clear interface(57, 85.1%), fuzzy interface(7, 10.4%), smooth interface(3, 4.5%), speculate protuberanc(36, 53.7%), superficial lobulation(29, 43.3%), prefound lobulation(23, 34.4%), halo sign(14, 20.9%), spike(9,13.4%), rectus margin(6,9.0%); cavitation (10, 14.9%), 7 cavitations with thick wall, 5 with irregular inner wall and 5 with smooth inner wall; calcification(2, 3.0%), cresent sign(9, 13.4%), marginal fissure(7, 10.4%). And there were no fat in phymatoid pulmonary mycosis. Marginal fissure only could be seen in aspergillosis.
4、Differential diagnosis: The incidence of irregular shape, round or oval shape, wedge shape, smooth interface, clear interface, fuzzy interface, speculate protuberanc, superficial lobulation, prefound lobulation, halo sign, cavitation, calcification, rectus margin, satellite, pleural thick and pleural indentation were different among the four categories diseases(p<0.05). The CT appearances of phymatoid pulmonary mycosis were compared with inflammation, tuberculosis and benign tumor separately. The clear interface was more common in phymatoid mycosis than in inflammation (P<0.0071). And the wedge shaped, fuzzy interface, speculate protuberanc, rectus margin, halo sign and cavitation were less commom in phymatoid mycosis than in inflammation (P<0.0071). The prefound lobulation was more common in phymatoid mycosis than in tuberculosis (P<0.0071). And superficial lobulation, cavitation, calcification, pleural thick were less common phymatoid mycosis than in tuberculosis (P<0.0071). The irregular shape, clear interface, speculate protuberanc, halo sign, prefound lobulation, satellite, pleural thick, pleural indentation were more commom in phymatoid mycosis than in benign tumor (P<0.0071). And the smooth interface, calcification were less common in phymatoid mycosis than in benign tumor (P<0.0071).
Conclusion
1. The susceptible crowd of phymatoid pulmonary mycosis is 40-60 years old males.
2. The sizes of long diameter of phymatoid pulmonary mycosis are disparity. And the range of commom size is 2-4cm. The correct diagnosis of phymatoid pulmonary mycosis should not be carried out only according to the size.
3. The common CT appearances of phymatoid pulmonary mycosis are round, oval shape or irregular shape; clear interface; speculate protuberanc, superficial lobulation or prefound lobulation, halo sign. There are usually thick wall with cavitation. The cresent sign and marginal fissure are specific signs of phymatoid pulmonary mycosis.
4. Although overlay of the CT appearance are common, there are difference in the detail features of the signs, which make them an important evidence for the differential diagnosis of these diseases. The value of a single sign in the differential diagnosis is limited and multi-signs analysis in the differential diagnosis process tends to achieve the correct conclusion. The detection of wedge shaped, clear interface, fuzzy interface, speculate protuberanc, rectus margin, halo sign and cavitation conduce to differential diagnosis between phymatoid pulmonary mycosis and inflammation. And the detection of prefound lobulation, superficial lobulation, cavitation, calcification and pleural thick conduce to differential diagnosis between phymatoid pulmonary mycosis and tuberculosis. And the detection of irregular shape, clear interface, speculate protuberanc, halo sign, prefound lobulation, satellite, pleural thick, pleural indentation, smooth interface and calcification conduce to differential diagnosis between phymatoid pulmonary mycosis and benign tumor.
引文
[1] Ruchel R. Diagnosis of invasive mycoses in severely immunolsuppressed patients. Ann Hemato1,1993,67(1):1-11.
[2]刘正印,王爱霞.系统性真菌感染的现状.中国临床医生,2005,33(11):26-27.
[3] St Germain G,Laverdiere M,Peletier R,et a1.Prevalence and antifungal susceptibility of 442 Candida isolates from blood and other normally sterile sites:results of a 2-year(1996 to 1998)muhicenter surveilance study in Quebec,Canada.J Clin Microbiol,2001,39(3):949-953.
[4] Losada I, Cuervas-Mons V, Millian I, et al. Eraly infection in liver transplant recipients: incidence, severity, risk factors and antibiotic sensitivity of bacterial isolates[J]. Enferm Infect Microbiol Clin,2002,20(9):419-420.
[5]李新华,张玉珍,高秀华。医院真菌感染高危因素调查分析.中华医院感染学杂志,2005,15(3): 280-281.
[6]中华内科杂志编辑委员会.侵袭性肺部感染的诊断标准与治疗原则(草案).中华内科杂志.2006,45(8):697-670.
[7] Mudge D W, Johnson D W, Isbel N M, etal. Obliterative bronchiolitis or opportunistic infection? Adiagnostic challenge in a renal transplant patient. Nephrol-Dial-Transplant.2005, 20(1):246-247.
[8]Hai H. Kenney, Geoffrey A. Agrons, and Jung S. Shin,Best Cases from the AFIP : Invasive Pulmonary Aspergillosis: Radiologic and Pathologic Findings. RadioGraphics, 2002, 22(6): 1507-1510.
[9] Kim M J, Lee K S, Kim J,et al. Crescent sign in invasive pulmonary aspergillosis: frequency and related CT and clinical factors. J-Comput-Assist-Tomogr, 2001, 25(2): 305-310.
[10] Trullas JC, Cervera C. Invasive pulmonary aspergillosis in solid organ and bone marrow transplant recipients.Transplant Proc, 2005, 37(9): 4091-4093.
[11] Kami M, Kishi Y, Hamaki T,et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis. An autopsy-based retrospective study of 48 patients. Mycoses, 2002 , 45(8): 287-294.
[12] Horger M,Einsele H.Invasive pulmonary aspergillosis: frequency and meaning of the "hypodense sign" on unenhanced CT. Br J Radiol, 2005 ,78(932):697-703.
[13] Reichenberger F, Habicht J.M, Gratwohl A,et al. Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients,Eur Respir J, 2001, 19(4): 743– 755.
[14] Hauggaard A, Ellis M, Ekelund L. Early chest radiography and CT in the diagnosis, management and outcome of invasive pulmonary aspergillosis. Acta-Radiol,2002, 43(3): 292-298.
[15] Caillot D, Couaillier J F, Bernard A. et al. Increasing volume and changing characteristics of invasivepulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol, 2001 , 19(1): 253-259.
[16]李军,庞龙滨,李哲等.经皮气管穿刺发建立家兔白色念珠菌肺炎动物模型.山东医药,2005,45(4):23~24.
[17] Habicht,-J-M, Preiss,-M, Passweg,-J, et al. Invasive pulmonary aspergillosis: effects of early resection in a neutropenic rat model. Eur-J-Cardiothorac-Surg, 2002 Nov; 22(5): 728-32.
[18].Kurup, VP. Immunology of allergic bronchopulmonary aspergillosis. Indian-J-Chest-Dis-Allied-Sci, 2000 Oct-Dec; 42(4): 225-37.
[19]Matsumoto, S, Wakai, Y, Nakai, T. fficacy of FK463, a new lipopeptide antifungal agent, in mouse models of pulmonary aspergillosis. Antimicrob-Agents-Chemother, 2000 Mar; 44(3): 619-21.
[20] Vidmantas P, Ruta P, Jeffrey S,et al. Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary Aspergillosis. 2006, 50(4): 1510-1517.
[21]薛峰,刘士远,刘锴等.免疫抑制兔肺部真菌感染早期薄层CT表现与病理对照研究.中华放射学杂志,2009,43(1):71-77.
[22] singh N,Paterson DL Aspergillus infections in transplant recipients.Clin Mierabiol Rev.2005,18(1):44-69.
[23] Groll AH,Mickiene D,Petraifiene R,et a1.Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin(LY303366):Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(10),2845-2855.
[24] Ruijgrok, E.J., Vulto, A.G., van Etten, E.W.M.. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol. 2000,52(6): 619–627.
[25] Cook, C.H., Zhang, Y., McGuinness, B.J., Lahm, M.C., Sedmak, D.D., Ferguson, R.M.. Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice. J. Infect. Dis. 2002,185(10): 1395-1400.
[26]牛艳坤,陈卫围.原发型肺隐球菌病的临床、病理及影像学诊断.实用医学杂志。2006,22(15):1836-1837.
[27] Shorr AF,Susla GM,O’Grady NP.Pulmonary infiltrates in the Non-HIV-infected immunoeompromised patient: etiologies,diagnostic strategies,and outcomes.Chest,2004,125(1):260-271.
[28] Nisederman MS,Sarasi GA,Glassrath J,et a1.呼吸系统感染.北京:人民军医出版社,2005:42.
[29] Perfect JR,Cox GM,Lee JY,et al. The impact of culture isolation of Asporgitins species:a hospital-based survey of asporgillosis.Clin Infect Dis,2001,33(11):1824-1833.
[30] Ruijgrok, E.J., Vulto, A.G., van Etten, E.W.M.. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol. 2000, 52(6), 619–627.
[31] Buchheidt D, Hummel M, Diehl S, et al. Fatal cerebral involvement in systemic aspergillosis: A rare complication of steroid-treated autoimmune bicytopenia [ J ]. Eur J Haem atol, 2004, 72 (5): 375–376.
[32]顾克菊,马越云,苏明权,等.免疫抑制小鼠侵袭性肺烟曲霉菌病动物模型的建立及病理分析.第四军医大学学报,2005, 26(4):314-317.
[33]王海林,郑一君,王桂华.肺曲菌病的影像学表现与病理联系.中国临床医学, 2004, 11(5):887-889.
[34] McAdams HP, Rosado-de-Christenson ML, Lesar M, et al. Thoracic Mycoses from Endemic Fungi: Radiologic–Pathologic Correlation. Radiographics. 1995, 15(2):255-70.
[35]楼慧玲,张溪林,陈于荣等.侵袭性肺曲霉菌病25例的CT诊断.中华结核和呼吸杂志,2004, 27(7):495-497.
[36] Kami M, Kishi Y, Hamaki T, et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis: An autopsy-based retrospective study of 48 patients. Mycoses, 2002 ,45(8): 287-294.
[37] Horger M,Einsele H, Schumacher U, et al. Invasive pulmonary aspergillosis: frequency and meaning of the "hypodense sign" on unenhanced CT. Br J Radiol, 2005 ,78(932):697-703
[38] Reichenberger F, Habicht J.M, Gratwohl A,et al. Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients. Eur Respir J, 2002, 19(4): 743-755.
[39] Aquino SL,Kee ST,Warnock ML,et al. Pulmonary aspergillosis:imaging findings with pathologic correlation.AJR,1994,163(4):811-815.
[40] Rizzi EB,Schinina V,Befiusm A。et al. Pulmonary mycosis in AIDS.Eur J Radiol,2001,37(1):42-46.
[41]陈绿娇,夏俊,陈义雄.肺曲菌球的影像检查技术及影像学表现.实用放射学杂志.2005,21(5):487-489
[42]王晓华,马大庆,周新华.孤立性肺结节的临床与CT计量诊断.中国医学影像技术,2005,21(10):1512-1515.
[43] Devouassoux-Shisheboran M,Hayashi T。Linnoila R 1。et a1.A clinicpathologic study of 100 cases of pulmonary sclerosing hemangioma with immunohistochemical studies: TTF-1 is expressed in bothround and surface cells, suggesting an origin from primitive respiratory epithelium. Am J Surg Pathol,2000,24(7):906-916.
[44]司徒冬荣,龙浩,马国伟,等. 24例肺硬化性血管瘤的诊疗分析.癌症,2008,27(8):861-865.
[45] Qiang JW ,Zhou KR,Lu G,et a1.The Relationship between Solitary Pulmonary Nodules and Bronchi:Multi-slice CT-Pathologieal correlation.Clin Radiol,2004,59(12):1121-1127.
[46] Mueden RF,Pugatch RD,Liptay MJ,et al. Small pulmonary lesions detected at CT, clinical importance. Radiology,1997,202(1):105-110.
[47] Cerfolio RJ,Alien MS, Nascimento AG, et a1. Inflammatory pseudotomours of the lung.Ann Thorac Surg,1999,67:933-936.
[48] Libby DM,Smith JP,Altorki NK,et a1.Managing The small Pulmonary Nodule Diseovered by CT.Chest,2004,125(4):1522-1529.
[49]周旭辉,李子平,谭国胜,等.高分辨率CT正向概率判别法在肺结节鉴别诊断中的应用研究.中华放射学杂志,2005,39(1):29-33.
[50]周永飞,陈正英.肺炎性假瘤的CT表现(附12例分析).实用放射学杂志,2001,17(2):140-141.
[51]. Siegelman SS,Khouri NF,Leo FP,et al. Solitary pulmonary noduler: CT assessment. Radiology, 1986, 160: 307-312.
[55]张燕群.曹丹庆,高育傲.深分叶征在周围型小肺癌CT诊断中的价值.中华放射学杂志,1992,26(3):154-156.
[56] Takashima S,Maruyama Y,Hasegawa M,et a1.CT findings and progression of small peripheral lung neoplasms having a replacement growth pattern[J].AJR。2003,180(3):817-826.
[57]王东听,孙淑敏,张燕群.周围型肺腺癌的CT分析.实用放射学杂志,2004,20(4):306-309.
[58]肖湘生,董伟华.肺癌肿块分叶状形态的病理基础-病理与x线对照研究.中国医学影像学杂志l999,7(1):16-18.
[59]田芳,周燕发.肺内孤立结节周边结构CT征象对良、恶性病变的诊断价值.放射学实践,1999;14(1):57-59.
[60]陈广,马大庆,李铁一.多层螺旋CT多平面重建对小肺癌的基本征象检出.临床放射学杂志,2004,23(2):109-112.
[61] Kuhlman JE, Fishman EK,Siegelman SS.Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology, 1985,157(3): 611-614.
[62] Gaete M, Blandino A, Scribano E, et al. computed tomography halo sign in pulmonary nodules: frequency and diagnostic value. J Thorac Imaging, 1999, 14(2): 109-113.
[63]李春平,周燕发.肺良性结节HRCT病理对照研究.临床放射学杂志,1996,15(3): 156-159.
[64] Nakajima R,Yokose T,Kakinuma R,et a1.Localized pure ground-glass opacity on high-resolution CT:histologic characteristics.J Comput Assist Tomogr,2002,26(3):323-329.
[65] Sabloff BS,Wistuba II,Erasmus JJ.Cystic bronchioloalveolar cell carcinoma.J Thorac Imaging,2005,20(2):ll0-114.
[66] Osamu H, Mitsuko T, Atsuo I, et al. Pulmonary Cavitary Nodules on Computed Tomography: Differentiation of Malignancy and Benignancy. J Comput Assist Tomogr, 2007, 31, (6): 943-949.
[67]. Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: focal and diffuse. Mayo Clin Proc, 2003;78:744Y752.
[68]. Im JG, Itoh H, Lee KS, et al. CT-Pathology correlation of pulmonary tuberculosis. Crit Rev Diagn Imaging, 1995,36:227-285.
[69] Naidich DP, Zerhouni EA.Siegelman SS. Computed Tomography and Magnetic Resonance of the Thorax,2ad.NewYork:Raven press.199l:303-319.
[70]马大庆周围型肺癌钙化征象的CT表现及诊断意义.中华放射学杂志,1993,27(6):370-372.
[71] Seemann M D ,Staebler A,Beinert T,et a1. Usefulness of morphological characteristics for the differentiation of benign from malignant solitary pulmonary lesions using HRCT. Eur Radio1.1999,9(3):409-417.
[72]肖湘生.胸膜凹陷征形成的病理基础.中华放射学杂志,1988,22(2):85-88.
[73] Wormanns D,Diederieh S.Charaeterization of Small Pulmonary Nodules By CT.Eur Radiol,2004,43(4):1380-1391.
[74]伍建林,王圆圆,沈慧聪等.肺孤立良性结节的HRCT表现及病理基础研究.中国医学影像技术.,2003,19(10):1348-1350.
[75] Akira M,Sakatani M,Ishikawa H.Transient radiographic progression during initial treatment of pulmonary tuberculosis:CT findings.J Comput Assist Tomogr,2000,24(3):426-431.
[76]袁新平,张国民,严信.侵袭性肺曲菌病的CT表现.中华放射学杂志,1999,33(9):639-640.
[77] Takatani H,Ashizawa K,Kawai K,et a1.Pulmonary sclerosing hemangioma manifesting as a nodule with irregular air clefts on high-resolution CT.Am J Roentgenol,2007,189(1):W26-W28.
[78] May, K.M. The Collison nebulizer: description, performance and application. Aerosol Sci, 1973,4, 235-243.
[79] Yang, Z.P., Kuo, C.C., Grayston, J.T. A mouse model of Chlamydia pneumoniae strain TWAR pneumonitis. Infect. Immun, 1993, 61(5), 2037–2040.
[80] Becker, M.J., de Marie, S., Fens, M.H.A.M.,et al. Enhanced antifungal efficacy in experimental invasive pulmonary aspergillosis by combination of AmBisome with Fungizone as assessed by several parameters of antifungal response. J. Antimicrob. Chemother, 2002,49(5), 813-820.
[81] Leenders, A.C., de Marie, S., ten Kate, M.T., et al. Liposomal amphotericin B (Am-Bisome) reduces dissemination of infection as compared with amphotericin B deoxycholate (Fungizone) in a rat model of pulmonary aspergillosis. J. Antimicrob. Chemother, 1996, 38(2), 215-225.
[82] Mehrad, B., Moore, T.A., Standiford, T.J. Macrophage inflammatory protein-1 alpha is a critical mediator of host defense against invasive pulmonary aspergillosis in neutropenic hosts. J. Immunol, 2000, 165(2): 962–968.
[83] Allende, M.C., Lee, J.W., Francis, P.,et al. Dose-dependent antifungal activity and nephrotoxicity of amphotericin B colloidal dispersion in experimental pulmonary aspergillosis. Antimicrob. Agents Chemother, 1994, 38(3):518–522.
[84] Roberts, J., Schock, K., Marino, S.,et al. Efficacies of two new antifungal agents, the triazole raviconazole and the echinocandin LY-303366, in an experimental model of invasive aspergillosis. Antimicrob. Agents Chemother, 2000,44(12): 3381– 3388.
[85] Lionakis, M.S. et al. A non-vertebrate in vivo model to study invasive aspergillosis and its treatment with oral antifungals: early experience with Drosphophila. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 14–17 September 2003, Chicago, IL USA (Abstract M-477).
[86] Kurtz, M.B., Bernard, E.M., Edwards, F.F., et al. Aerosol and parenteral pneumocandins are effective in a rat model of pulmonaryaspergillosis. Antimicrob. Agents Chemother. 1995, 39(8), 1784–1789.
[87] Turner, K.J., Hackshaw, R., Papadimitriou, et al., Thepathogenesis of experimental pulmonary aspergillosis in normaland cortisone-treated rats. J. Pathol, 1976, 118, 65–73.
[88] Andrews, C.P., Weiner, M.H.. Immunodiagnosis of invasive pulmonary aspergillosis in rabbits. Fungal antigen detected by radioimmunoassay in bronchoalveolar lavage fluid. Am. Rev. Respir. Dis, 1981,124(1), 60-64.
[89] Chiller, T.M. Development of a murine model of cerebral aspergillosis. J. Infect. Dis, 2002, 186(4), 574–577.
[90] Shibuya, K. Histopathology of experimental invasive pulmonary aspergillosis in rats: pathological comparison of pulmonary lesions induced by specific virulent factor deficient mutants. Microb. Pathogen,1999, 27(3), 23–131.
[91] Merkow, L.P. The pathogenesis of experimental pulmonary aspergillosis. an ultrastructural study of alveolar macrophages after phagocytosis of A. flavus spores in vivo. Am. J. Pathol,1971, 62(1), 57–74.
[92] Sheppard, D.C. et al. Development of a clinically relevant, reproducible inhalational model of invasive aspergillosis. 43rd annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 14–17 September 2003, Chicago, IL USA (Abstract M-372).
[93] May KM. The Collison nebulizer: description, performance and application. Aerosol Sc,1973, 4,235-243.
[94] Yang ZP, Kuo CC., Grayston JT. A mouse model of Chlamydia pneumoniae strain TWAR pneumonitis. Infect. Immun,1993, 61(5), 2037–2040.
[95] Ruijgrok, E.J., Vulto, A.G., Etten, E.W.M. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol, 2000, 52(6), 619–627.
[96] Cook, C.H., Zhang, Y., McGuinness, B.J., et al. Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice. J. Infect. Dis, 2002, 185(10), 1395-1400.
[97] Wheat, L.J. Combination therapy for aspergillosis: is it needed, and which combination? J. Infect. Dis,2003, 187(12), 1831–1833.
[98] Alicia GL, Mayte. MG, Pilar MD, et al. Detection of fungal DNA by real-time polymerase chain reaction: evaluation of 2 methodologies in experimental pulmonary aspergillosis. Diagnostic Microbiology and Infectious Disease, 2006, 56(4):387–393.
[99] Bowman, J.C. Quantitative PCR assay to measure Aspergillus fumigatus burden in a murine model of disseminated aspergillosis: demonstration of efficacy of caspofungin acetate. Antimicrob. Agents Chemother, 2001, 45(12), 3474–3481.
[100] Gavalda, J. Efficacy of nebulized liposomal amphotericin B in the treatment of experimental pulmonary aspergillosis. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 14–17 September 2003, Chicago, IL USA (Abstract M-356).
[101] Bozza, S. Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes. Infect, 2002, 4(13), 1281–1290.
[102] Midthun DE, Swensen SJ, Jett JR.Approach to the Solitary Pulmonary Nodule.Mayo Clin Proc,1993,68(4):37-385.
[103] Katharina M,Eekhardt G.The Challenge of the Solitary Pulmonary Nodule:Diagnostic Assessment with Muhislice Spiral CT.Clin Imaging,2003,27(3):156-161.
[104] Lwano S,Makino N,Ikeda M,et a1.Solitary Pulmonary Nodules:Optimal Slice Thickness of High resolution CT in Differentiating Malignant From benign[J].Clin Imaging,2004,28(5):322-328.
[105]李惠民,肖湘生.肺结节CT影像评价.中国医学计算机成像杂志, 2001, 7(1):30-41.
[106] HartmanTE. Radiologic Evaluation of the Solitary Pulmonary Nodule. Radiol Clin North Anl, 2005, 43(3): 459-465.
[107] Gaeta M,Barone M,Bussi EG,et aL Carcinomatous solitary pulmonary nodules:evaluation of the tumor-bronchi relationship with thin-section CT.Radiology,1993,187(2):535-539.
[108] Geeta M, Barone M, Caruso R. CT-pathologic correlation in nodular bronchioloaveolar carcinoma,JCAT,1994,18(2):229-223.
[109] Yankelevitz DF,Reeves AP,Kostis WJ,et a1.Small Pulmonary Nodules:Volumetrically Determined Growth Rates Based on CT Evaluation.Radiology,2000,217(1):251-256.
[110] Kim JH,Kim HJ,Lee KH,et a1.Solitary Pulmonary Nodules:a Comparative Study Evaluated with Contrast～enhanced Dynamic MR Imaging and CT.Comput Assist Tomogr,2004,28(6):766-775.
[111]慕祖龙,郝敬明,郭天舜.球形肺炎的CT诊断.中华放射学杂志,1996,30(8):528-531.
[112] Naidich DP, Zerhouni EA.Siegelman SS. Computed Tomography and Magnetic Resonance of the Thorax,2nd.NewYork:Raven press.199l:303-319
[113] Zerhouni EA,Stitik FP,Siegelman SS. CT of the pulmonary nodule:A cooperative study. Radiology,1986,160(2):319-327.
[114] Wormanns D,Diederieh S.Charaeterization of Small Pulmonary Nodules By CT[J].Eur Radiol,2004,43(4):1380-1391.
[115]强金伟。周康荣,蒋亚平.等.多层螺旋CT与病理对照研究孤立性肺结节与支气管的关系.中华放射学杂志,2003,37(11):992--996.
[116]张娟.支气管征对周围型肺癌的诊断价值.实用放射学杂志,2002,18(3):239-240.
[117]强金伟,周康荣,蒋亚平,等.多排螺旋CT显示支气管与外周肺癌关系的价值.中华肿瘤杂志,2004,26(1):45-48.
[118]陈广,马大庆.CT多平面重建对胸膜凹陷相关结节切迹检出的价值.中华放射学杂志,2004,38(3):259-262.
[119] Wormanns D,Kohl G,Klotz E,et a1.Volumetric Measurements of Pulmonary Nodules at Multi-row Detector CT :in Vivo Reproducibility.Eur Radiol,2004,14(1):86-92.
[120]宋伟,金征宇,严洪珍,等.初步评估16层螺旋TC的Lungcarer软件在肺结节研究中的辅助价值.中华放射学杂志,2005,39(1):11-16.
[121] Kim JH,Kim HJ,Lee KH,et a1.Solitary Pulmonary Nodules:a Comparative Study Evaluated with Contrast～enhanced Dynamic MR Imaging and CT.Comput Assist Tomogr,2004,28(6):766-775.
[122]李慎江,刘士远,肖湘生,等.CT、MR动态增强在评价孤立性肺结节血流模式中的作用.中华放射学杂志,2005,39(1):9-10.
[123] Swensen SJ,Brown LR,Colby TV,et a1.Lung Nodule Enhancement at CT:Perspective Findings.Radiology,1996,201(2):447-455.
[124] Yamashita K,Matsunobe S,Tsuda T,et a1.Solitary Pulmonary Nodules:Preliminary Study of Evaluation with Incremental Dynamic CT.Radiology,1995,194(2):399-405.
[125] Zhang M,Kono M.Solitary Pulmonary Nodules:Evaluation of Blood Patterns with Dynamic CT[J].Radiology,1997,205(2):471-478.
[126]伍建林,李光军,王克礼,等.多层螺旋CT灌注成像对肺肿瘤的诊断价值[J].中国医学影像技术,2005,21(4):551-555.
[127] Kiessling F,Boese J,corvinus C,et a1.Perfusion CT in Patients with Advanced Bronehial Carcinomas:a Novel Chance for Characterization and Treatment Monitoring[J].Eur Radiol,2004,14(7):1226-l233.
[128]张金娥,粱长虹,赵振军,等.CT肺灌注在肺结节诊断中的应用研究.中华放射学杂志,2005,39(10):1041-1045.
[129] Jeong YJ,Lee KS,Jeong SY,et a1.Solitary Pulmonary Nodule:Characterization with Combined Wash-in and Wash-out Features at Dynamic Multi-etector Row CT.Radiology,2005,237(2):675-683.
[130] Eun JC,Jae WS,Joon BS,et a1.Clinic Utility of Dual-energy CT in the Evaluation of Solitary Pulmonary Nodules:Initial Experience.Radiology,2008,249(2):67l-681.
[131]黄光亮,唐秉航.宽探测器CT多层CT技术新进展.放射学实践,2009,24(2):215-217.
[132] Zinck SE, Leung AN, Frost M, et al, Pulmonary cryptococcosis: CT and pathologic findings. J Comput Assist Tomogr, 2002,26(3): 330-343.
[133]施裕新,张志勇,王月波.肺部真菌病感染的放射学诊断.诊断学理论与实践, 2010,9(2):116-119.
[2]刘正印,王爱霞.系统性真菌感染的现状.中国临床医生,2005,33(11):26-27.
[3] St Germain G,Laverdiere M,Peletier R,et a1.Prevalence and antifungal susceptibility of 442 Candida isolates from blood and other normally sterile sites:results of a 2-year(1996 to 1998)muhicenter surveilance study in Quebec,Canada.J Clin Microbiol,2001,39(3):949-953.
[4] Losada I, Cuervas-Mons V, Millian I, et al. Eraly infection in liver transplant recipients: incidence, severity, risk factors and antibiotic sensitivity of bacterial isolates[J]. Enferm Infect Microbiol Clin,2002,20(9):419-420.
[5]李新华,张玉珍,高秀华。医院真菌感染高危因素调查分析.中华医院感染学杂志,2005,15(3): 280-281.
[6]中华内科杂志编辑委员会.侵袭性肺部感染的诊断标准与治疗原则(草案).中华内科杂志.2006,45(8):697-670.
[7] Mudge D W, Johnson D W, Isbel N M, etal. Obliterative bronchiolitis or opportunistic infection? Adiagnostic challenge in a renal transplant patient. Nephrol-Dial-Transplant.2005, 20(1):246-247.
[8]Hai H. Kenney, Geoffrey A. Agrons, and Jung S. Shin,Best Cases from the AFIP : Invasive Pulmonary Aspergillosis: Radiologic and Pathologic Findings. RadioGraphics, 2002, 22(6): 1507-1510.
[9] Kim M J, Lee K S, Kim J,et al. Crescent sign in invasive pulmonary aspergillosis: frequency and related CT and clinical factors. J-Comput-Assist-Tomogr, 2001, 25(2): 305-310.
[10] Trullas JC, Cervera C. Invasive pulmonary aspergillosis in solid organ and bone marrow transplant recipients.Transplant Proc, 2005, 37(9): 4091-4093.
[11] Kami M, Kishi Y, Hamaki T,et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis. An autopsy-based retrospective study of 48 patients. Mycoses, 2002 , 45(8): 287-294.
[12] Horger M,Einsele H.Invasive pulmonary aspergillosis: frequency and meaning of the "hypodense sign" on unenhanced CT. Br J Radiol, 2005 ,78(932):697-703.
[13] Reichenberger F, Habicht J.M, Gratwohl A,et al. Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients,Eur Respir J, 2001, 19(4): 743– 755.
[14] Hauggaard A, Ellis M, Ekelund L. Early chest radiography and CT in the diagnosis, management and outcome of invasive pulmonary aspergillosis. Acta-Radiol,2002, 43(3): 292-298.
[15] Caillot D, Couaillier J F, Bernard A. et al. Increasing volume and changing characteristics of invasivepulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol, 2001 , 19(1): 253-259.
[16]李军,庞龙滨,李哲等.经皮气管穿刺发建立家兔白色念珠菌肺炎动物模型.山东医药,2005,45(4):23~24.
[17] Habicht,-J-M, Preiss,-M, Passweg,-J, et al. Invasive pulmonary aspergillosis: effects of early resection in a neutropenic rat model. Eur-J-Cardiothorac-Surg, 2002 Nov; 22(5): 728-32.
[18].Kurup, VP. Immunology of allergic bronchopulmonary aspergillosis. Indian-J-Chest-Dis-Allied-Sci, 2000 Oct-Dec; 42(4): 225-37.
[19]Matsumoto, S, Wakai, Y, Nakai, T. fficacy of FK463, a new lipopeptide antifungal agent, in mouse models of pulmonary aspergillosis. Antimicrob-Agents-Chemother, 2000 Mar; 44(3): 619-21.
[20] Vidmantas P, Ruta P, Jeffrey S,et al. Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary Aspergillosis. 2006, 50(4): 1510-1517.
[21]薛峰,刘士远,刘锴等.免疫抑制兔肺部真菌感染早期薄层CT表现与病理对照研究.中华放射学杂志,2009,43(1):71-77.
[22] singh N,Paterson DL Aspergillus infections in transplant recipients.Clin Mierabiol Rev.2005,18(1):44-69.
[23] Groll AH,Mickiene D,Petraifiene R,et a1.Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin(LY303366):Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(10),2845-2855.
[24] Ruijgrok, E.J., Vulto, A.G., van Etten, E.W.M.. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol. 2000,52(6): 619–627.
[25] Cook, C.H., Zhang, Y., McGuinness, B.J., Lahm, M.C., Sedmak, D.D., Ferguson, R.M.. Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice. J. Infect. Dis. 2002,185(10): 1395-1400.
[26]牛艳坤,陈卫围.原发型肺隐球菌病的临床、病理及影像学诊断.实用医学杂志。2006,22(15):1836-1837.
[27] Shorr AF,Susla GM,O’Grady NP.Pulmonary infiltrates in the Non-HIV-infected immunoeompromised patient: etiologies,diagnostic strategies,and outcomes.Chest,2004,125(1):260-271.
[28] Nisederman MS,Sarasi GA,Glassrath J,et a1.呼吸系统感染.北京:人民军医出版社,2005:42.
[29] Perfect JR,Cox GM,Lee JY,et al. The impact of culture isolation of Asporgitins species:a hospital-based survey of asporgillosis.Clin Infect Dis,2001,33(11):1824-1833.
[30] Ruijgrok, E.J., Vulto, A.G., van Etten, E.W.M.. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol. 2000, 52(6), 619–627.
[31] Buchheidt D, Hummel M, Diehl S, et al. Fatal cerebral involvement in systemic aspergillosis: A rare complication of steroid-treated autoimmune bicytopenia [ J ]. Eur J Haem atol, 2004, 72 (5): 375–376.
[32]顾克菊,马越云,苏明权,等.免疫抑制小鼠侵袭性肺烟曲霉菌病动物模型的建立及病理分析.第四军医大学学报,2005, 26(4):314-317.
[33]王海林,郑一君,王桂华.肺曲菌病的影像学表现与病理联系.中国临床医学, 2004, 11(5):887-889.
[34] McAdams HP, Rosado-de-Christenson ML, Lesar M, et al. Thoracic Mycoses from Endemic Fungi: Radiologic–Pathologic Correlation. Radiographics. 1995, 15(2):255-70.
[35]楼慧玲,张溪林,陈于荣等.侵袭性肺曲霉菌病25例的CT诊断.中华结核和呼吸杂志,2004, 27(7):495-497.
[36] Kami M, Kishi Y, Hamaki T, et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis: An autopsy-based retrospective study of 48 patients. Mycoses, 2002 ,45(8): 287-294.
[37] Horger M,Einsele H, Schumacher U, et al. Invasive pulmonary aspergillosis: frequency and meaning of the "hypodense sign" on unenhanced CT. Br J Radiol, 2005 ,78(932):697-703
[38] Reichenberger F, Habicht J.M, Gratwohl A,et al. Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients. Eur Respir J, 2002, 19(4): 743-755.
[39] Aquino SL,Kee ST,Warnock ML,et al. Pulmonary aspergillosis:imaging findings with pathologic correlation.AJR,1994,163(4):811-815.
[40] Rizzi EB,Schinina V,Befiusm A。et al. Pulmonary mycosis in AIDS.Eur J Radiol,2001,37(1):42-46.
[41]陈绿娇,夏俊,陈义雄.肺曲菌球的影像检查技术及影像学表现.实用放射学杂志.2005,21(5):487-489
[42]王晓华,马大庆,周新华.孤立性肺结节的临床与CT计量诊断.中国医学影像技术,2005,21(10):1512-1515.
[43] Devouassoux-Shisheboran M,Hayashi T。Linnoila R 1。et a1.A clinicpathologic study of 100 cases of pulmonary sclerosing hemangioma with immunohistochemical studies: TTF-1 is expressed in bothround and surface cells, suggesting an origin from primitive respiratory epithelium. Am J Surg Pathol,2000,24(7):906-916.
[44]司徒冬荣,龙浩,马国伟,等. 24例肺硬化性血管瘤的诊疗分析.癌症,2008,27(8):861-865.
[45] Qiang JW ,Zhou KR,Lu G,et a1.The Relationship between Solitary Pulmonary Nodules and Bronchi:Multi-slice CT-Pathologieal correlation.Clin Radiol,2004,59(12):1121-1127.
[46] Mueden RF,Pugatch RD,Liptay MJ,et al. Small pulmonary lesions detected at CT, clinical importance. Radiology,1997,202(1):105-110.
[47] Cerfolio RJ,Alien MS, Nascimento AG, et a1. Inflammatory pseudotomours of the lung.Ann Thorac Surg,1999,67:933-936.
[48] Libby DM,Smith JP,Altorki NK,et a1.Managing The small Pulmonary Nodule Diseovered by CT.Chest,2004,125(4):1522-1529.
[49]周旭辉,李子平,谭国胜,等.高分辨率CT正向概率判别法在肺结节鉴别诊断中的应用研究.中华放射学杂志,2005,39(1):29-33.
[50]周永飞,陈正英.肺炎性假瘤的CT表现(附12例分析).实用放射学杂志,2001,17(2):140-141.
[51]. Siegelman SS,Khouri NF,Leo FP,et al. Solitary pulmonary noduler: CT assessment. Radiology, 1986, 160: 307-312.
[55]张燕群.曹丹庆,高育傲.深分叶征在周围型小肺癌CT诊断中的价值.中华放射学杂志,1992,26(3):154-156.
[56] Takashima S,Maruyama Y,Hasegawa M,et a1.CT findings and progression of small peripheral lung neoplasms having a replacement growth pattern[J].AJR。2003,180(3):817-826.
[57]王东听,孙淑敏,张燕群.周围型肺腺癌的CT分析.实用放射学杂志,2004,20(4):306-309.
[58]肖湘生,董伟华.肺癌肿块分叶状形态的病理基础-病理与x线对照研究.中国医学影像学杂志l999,7(1):16-18.
[59]田芳,周燕发.肺内孤立结节周边结构CT征象对良、恶性病变的诊断价值.放射学实践,1999;14(1):57-59.
[60]陈广,马大庆,李铁一.多层螺旋CT多平面重建对小肺癌的基本征象检出.临床放射学杂志,2004,23(2):109-112.
[61] Kuhlman JE, Fishman EK,Siegelman SS.Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology, 1985,157(3): 611-614.
[62] Gaete M, Blandino A, Scribano E, et al. computed tomography halo sign in pulmonary nodules: frequency and diagnostic value. J Thorac Imaging, 1999, 14(2): 109-113.
[63]李春平,周燕发.肺良性结节HRCT病理对照研究.临床放射学杂志,1996,15(3): 156-159.
[64] Nakajima R,Yokose T,Kakinuma R,et a1.Localized pure ground-glass opacity on high-resolution CT:histologic characteristics.J Comput Assist Tomogr,2002,26(3):323-329.
[65] Sabloff BS,Wistuba II,Erasmus JJ.Cystic bronchioloalveolar cell carcinoma.J Thorac Imaging,2005,20(2):ll0-114.
[66] Osamu H, Mitsuko T, Atsuo I, et al. Pulmonary Cavitary Nodules on Computed Tomography: Differentiation of Malignancy and Benignancy. J Comput Assist Tomogr, 2007, 31, (6): 943-949.
[67]. Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: focal and diffuse. Mayo Clin Proc, 2003;78:744Y752.
[68]. Im JG, Itoh H, Lee KS, et al. CT-Pathology correlation of pulmonary tuberculosis. Crit Rev Diagn Imaging, 1995,36:227-285.
[69] Naidich DP, Zerhouni EA.Siegelman SS. Computed Tomography and Magnetic Resonance of the Thorax,2ad.NewYork:Raven press.199l:303-319.
[70]马大庆周围型肺癌钙化征象的CT表现及诊断意义.中华放射学杂志,1993,27(6):370-372.
[71] Seemann M D ,Staebler A,Beinert T,et a1. Usefulness of morphological characteristics for the differentiation of benign from malignant solitary pulmonary lesions using HRCT. Eur Radio1.1999,9(3):409-417.
[72]肖湘生.胸膜凹陷征形成的病理基础.中华放射学杂志,1988,22(2):85-88.
[73] Wormanns D,Diederieh S.Charaeterization of Small Pulmonary Nodules By CT.Eur Radiol,2004,43(4):1380-1391.
[74]伍建林,王圆圆,沈慧聪等.肺孤立良性结节的HRCT表现及病理基础研究.中国医学影像技术.,2003,19(10):1348-1350.
[75] Akira M,Sakatani M,Ishikawa H.Transient radiographic progression during initial treatment of pulmonary tuberculosis:CT findings.J Comput Assist Tomogr,2000,24(3):426-431.
[76]袁新平,张国民,严信.侵袭性肺曲菌病的CT表现.中华放射学杂志,1999,33(9):639-640.
[77] Takatani H,Ashizawa K,Kawai K,et a1.Pulmonary sclerosing hemangioma manifesting as a nodule with irregular air clefts on high-resolution CT.Am J Roentgenol,2007,189(1):W26-W28.
[78] May, K.M. The Collison nebulizer: description, performance and application. Aerosol Sci, 1973,4, 235-243.
[79] Yang, Z.P., Kuo, C.C., Grayston, J.T. A mouse model of Chlamydia pneumoniae strain TWAR pneumonitis. Infect. Immun, 1993, 61(5), 2037–2040.
[80] Becker, M.J., de Marie, S., Fens, M.H.A.M.,et al. Enhanced antifungal efficacy in experimental invasive pulmonary aspergillosis by combination of AmBisome with Fungizone as assessed by several parameters of antifungal response. J. Antimicrob. Chemother, 2002,49(5), 813-820.
[81] Leenders, A.C., de Marie, S., ten Kate, M.T., et al. Liposomal amphotericin B (Am-Bisome) reduces dissemination of infection as compared with amphotericin B deoxycholate (Fungizone) in a rat model of pulmonary aspergillosis. J. Antimicrob. Chemother, 1996, 38(2), 215-225.
[82] Mehrad, B., Moore, T.A., Standiford, T.J. Macrophage inflammatory protein-1 alpha is a critical mediator of host defense against invasive pulmonary aspergillosis in neutropenic hosts. J. Immunol, 2000, 165(2): 962–968.
[83] Allende, M.C., Lee, J.W., Francis, P.,et al. Dose-dependent antifungal activity and nephrotoxicity of amphotericin B colloidal dispersion in experimental pulmonary aspergillosis. Antimicrob. Agents Chemother, 1994, 38(3):518–522.
[84] Roberts, J., Schock, K., Marino, S.,et al. Efficacies of two new antifungal agents, the triazole raviconazole and the echinocandin LY-303366, in an experimental model of invasive aspergillosis. Antimicrob. Agents Chemother, 2000,44(12): 3381– 3388.
[85] Lionakis, M.S. et al. A non-vertebrate in vivo model to study invasive aspergillosis and its treatment with oral antifungals: early experience with Drosphophila. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 14–17 September 2003, Chicago, IL USA (Abstract M-477).
[86] Kurtz, M.B., Bernard, E.M., Edwards, F.F., et al. Aerosol and parenteral pneumocandins are effective in a rat model of pulmonaryaspergillosis. Antimicrob. Agents Chemother. 1995, 39(8), 1784–1789.
[87] Turner, K.J., Hackshaw, R., Papadimitriou, et al., Thepathogenesis of experimental pulmonary aspergillosis in normaland cortisone-treated rats. J. Pathol, 1976, 118, 65–73.
[88] Andrews, C.P., Weiner, M.H.. Immunodiagnosis of invasive pulmonary aspergillosis in rabbits. Fungal antigen detected by radioimmunoassay in bronchoalveolar lavage fluid. Am. Rev. Respir. Dis, 1981,124(1), 60-64.
[89] Chiller, T.M. Development of a murine model of cerebral aspergillosis. J. Infect. Dis, 2002, 186(4), 574–577.
[90] Shibuya, K. Histopathology of experimental invasive pulmonary aspergillosis in rats: pathological comparison of pulmonary lesions induced by specific virulent factor deficient mutants. Microb. Pathogen,1999, 27(3), 23–131.
[91] Merkow, L.P. The pathogenesis of experimental pulmonary aspergillosis. an ultrastructural study of alveolar macrophages after phagocytosis of A. flavus spores in vivo. Am. J. Pathol,1971, 62(1), 57–74.
[92] Sheppard, D.C. et al. Development of a clinically relevant, reproducible inhalational model of invasive aspergillosis. 43rd annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 14–17 September 2003, Chicago, IL USA (Abstract M-372).
[93] May KM. The Collison nebulizer: description, performance and application. Aerosol Sc,1973, 4,235-243.
[94] Yang ZP, Kuo CC., Grayston JT. A mouse model of Chlamydia pneumoniae strain TWAR pneumonitis. Infect. Immun,1993, 61(5), 2037–2040.
[95] Ruijgrok, E.J., Vulto, A.G., Etten, E.W.M. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in vivo amphotericin B deposition in rats. J. Pharm. Pharmacol, 2000, 52(6), 619–627.
[96] Cook, C.H., Zhang, Y., McGuinness, B.J., et al. Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice. J. Infect. Dis, 2002, 185(10), 1395-1400.
[97] Wheat, L.J. Combination therapy for aspergillosis: is it needed, and which combination? J. Infect. Dis,2003, 187(12), 1831–1833.
[98] Alicia GL, Mayte. MG, Pilar MD, et al. Detection of fungal DNA by real-time polymerase chain reaction: evaluation of 2 methodologies in experimental pulmonary aspergillosis. Diagnostic Microbiology and Infectious Disease, 2006, 56(4):387–393.
[99] Bowman, J.C. Quantitative PCR assay to measure Aspergillus fumigatus burden in a murine model of disseminated aspergillosis: demonstration of efficacy of caspofungin acetate. Antimicrob. Agents Chemother, 2001, 45(12), 3474–3481.
[100] Gavalda, J. Efficacy of nebulized liposomal amphotericin B in the treatment of experimental pulmonary aspergillosis. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 14–17 September 2003, Chicago, IL USA (Abstract M-356).
[101] Bozza, S. Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes. Infect, 2002, 4(13), 1281–1290.
[102] Midthun DE, Swensen SJ, Jett JR.Approach to the Solitary Pulmonary Nodule.Mayo Clin Proc,1993,68(4):37-385.
[103] Katharina M,Eekhardt G.The Challenge of the Solitary Pulmonary Nodule:Diagnostic Assessment with Muhislice Spiral CT.Clin Imaging,2003,27(3):156-161.
[104] Lwano S,Makino N,Ikeda M,et a1.Solitary Pulmonary Nodules:Optimal Slice Thickness of High resolution CT in Differentiating Malignant From benign[J].Clin Imaging,2004,28(5):322-328.
[105]李惠民,肖湘生.肺结节CT影像评价.中国医学计算机成像杂志, 2001, 7(1):30-41.
[106] HartmanTE. Radiologic Evaluation of the Solitary Pulmonary Nodule. Radiol Clin North Anl, 2005, 43(3): 459-465.
[107] Gaeta M,Barone M,Bussi EG,et aL Carcinomatous solitary pulmonary nodules:evaluation of the tumor-bronchi relationship with thin-section CT.Radiology,1993,187(2):535-539.
[108] Geeta M, Barone M, Caruso R. CT-pathologic correlation in nodular bronchioloaveolar carcinoma,JCAT,1994,18(2):229-223.
[109] Yankelevitz DF,Reeves AP,Kostis WJ,et a1.Small Pulmonary Nodules:Volumetrically Determined Growth Rates Based on CT Evaluation.Radiology,2000,217(1):251-256.
[110] Kim JH,Kim HJ,Lee KH,et a1.Solitary Pulmonary Nodules:a Comparative Study Evaluated with Contrast～enhanced Dynamic MR Imaging and CT.Comput Assist Tomogr,2004,28(6):766-775.
[111]慕祖龙,郝敬明,郭天舜.球形肺炎的CT诊断.中华放射学杂志,1996,30(8):528-531.
[112] Naidich DP, Zerhouni EA.Siegelman SS. Computed Tomography and Magnetic Resonance of the Thorax,2nd.NewYork:Raven press.199l:303-319
[113] Zerhouni EA,Stitik FP,Siegelman SS. CT of the pulmonary nodule:A cooperative study. Radiology,1986,160(2):319-327.
[114] Wormanns D,Diederieh S.Charaeterization of Small Pulmonary Nodules By CT[J].Eur Radiol,2004,43(4):1380-1391.
[115]强金伟。周康荣,蒋亚平.等.多层螺旋CT与病理对照研究孤立性肺结节与支气管的关系.中华放射学杂志,2003,37(11):992--996.
[116]张娟.支气管征对周围型肺癌的诊断价值.实用放射学杂志,2002,18(3):239-240.
[117]强金伟,周康荣,蒋亚平,等.多排螺旋CT显示支气管与外周肺癌关系的价值.中华肿瘤杂志,2004,26(1):45-48.
[118]陈广,马大庆.CT多平面重建对胸膜凹陷相关结节切迹检出的价值.中华放射学杂志,2004,38(3):259-262.
[119] Wormanns D,Kohl G,Klotz E,et a1.Volumetric Measurements of Pulmonary Nodules at Multi-row Detector CT :in Vivo Reproducibility.Eur Radiol,2004,14(1):86-92.
[120]宋伟,金征宇,严洪珍,等.初步评估16层螺旋TC的Lungcarer软件在肺结节研究中的辅助价值.中华放射学杂志,2005,39(1):11-16.
[121] Kim JH,Kim HJ,Lee KH,et a1.Solitary Pulmonary Nodules:a Comparative Study Evaluated with Contrast～enhanced Dynamic MR Imaging and CT.Comput Assist Tomogr,2004,28(6):766-775.
[122]李慎江,刘士远,肖湘生,等.CT、MR动态增强在评价孤立性肺结节血流模式中的作用.中华放射学杂志,2005,39(1):9-10.
[123] Swensen SJ,Brown LR,Colby TV,et a1.Lung Nodule Enhancement at CT:Perspective Findings.Radiology,1996,201(2):447-455.
[124] Yamashita K,Matsunobe S,Tsuda T,et a1.Solitary Pulmonary Nodules:Preliminary Study of Evaluation with Incremental Dynamic CT.Radiology,1995,194(2):399-405.
[125] Zhang M,Kono M.Solitary Pulmonary Nodules:Evaluation of Blood Patterns with Dynamic CT[J].Radiology,1997,205(2):471-478.
[126]伍建林,李光军,王克礼,等.多层螺旋CT灌注成像对肺肿瘤的诊断价值[J].中国医学影像技术,2005,21(4):551-555.
[127] Kiessling F,Boese J,corvinus C,et a1.Perfusion CT in Patients with Advanced Bronehial Carcinomas:a Novel Chance for Characterization and Treatment Monitoring[J].Eur Radiol,2004,14(7):1226-l233.
[128]张金娥,粱长虹,赵振军,等.CT肺灌注在肺结节诊断中的应用研究.中华放射学杂志,2005,39(10):1041-1045.
[129] Jeong YJ,Lee KS,Jeong SY,et a1.Solitary Pulmonary Nodule:Characterization with Combined Wash-in and Wash-out Features at Dynamic Multi-etector Row CT.Radiology,2005,237(2):675-683.
[130] Eun JC,Jae WS,Joon BS,et a1.Clinic Utility of Dual-energy CT in the Evaluation of Solitary Pulmonary Nodules:Initial Experience.Radiology,2008,249(2):67l-681.
[131]黄光亮,唐秉航.宽探测器CT多层CT技术新进展.放射学实践,2009,24(2):215-217.
[132] Zinck SE, Leung AN, Frost M, et al, Pulmonary cryptococcosis: CT and pathologic findings. J Comput Assist Tomogr, 2002,26(3): 330-343.
[133]施裕新,张志勇,王月波.肺部真菌病感染的放射学诊断.诊断学理论与实践, 2010,9(2):116-119.