ABO血型与静脉血栓栓塞症(VTE)的风险相关,但这一点尚未在汉族人群中证实。我们采用病历对照研究的方式回顾性分析2010年1月到2016年6月期间北京协和医院出院的所有汉族患者资料。在200660名出院的汉族患者中,共有1412名VTE患者,包括600名深静脉血栓患者,441名肺栓塞患者,以及371名同时合并深静脉血栓与肺栓塞的患者。与199248名非VTE患者对比,VTE患者中非O血型所占比例具有统计学意义地升高,比值比(OR)为1.362 (95% CI 1.205-1.540)。亚组分析显示各VTE亚组中非O血型的OR值依然升高。院前VTE患者中比值比(OR = 1.464)高于院内获得的VTE患者(OR = 1.224),而无诱因VTE患者的比值比(OR = 1.859)高于有诱因的VTE患者(OR = 1.227)。亚组分析显示随着年龄增加,非O血型的OR值逐渐降低。这些结果显示,在汉族人群里,非O血型与VTE的风险之间存在具有统计学意义的弱相关性。
此文发表于蔡柏蔷教授主编的《结缔组织疾病的肺部表现》一书,2014年第一节IgG4相关疾病一.概述IgG4相关疾病(IgG4 related disease, IgG4RD)是一种新近认识的、病因尚不明确的疾病,可累及多个脏器或组织,是一种慢性、进行性发展的自身免疫性疾病。IgG4RD具有以下特点:肿瘤样损害,致密的淋巴浆细胞浸润并富含IgG4(+)浆细胞,席纹样纤维化,以及通常伴有血清IgG4水平的升高。IgG4RD几乎可见于任何一个脏器系统:胆道、唾液腺、眼周组织、肾脏、肺、淋巴结、脑膜、主动脉、乳腺、前列腺、甲状腺、心包和皮肤1-5,而不管哪个脏器受累,其组织病理学特点均高度相似。随着对IgG4RD的认识,一些长期被视为单脏器受累的疾病也被归类至IgG4相关疾病谱,比如Mikulicz综合征、Kuttner肿瘤、Riedel甲状腺炎和腹膜后纤维化。临床上IgG4RD最为常见的表现形式有两种:(1)I型自身免疫性胰腺炎(IgG4相关胰腺炎);(2)唾液腺疾病(如Mikulicz综合征、硬化性涎腺炎或Kuttner肿瘤)。事实上,很多有关IgG4RD的经验总结均来自这两类疾病的研究。由于直到2003年才认识到IgG4RD是一种系统性疾病1,且长时间内无统一的诊断标准,因此对其发病率的了解甚少,目前仅日本报道了IgG4RD在日本的发病率约为0.28-1.08/100,0006。二.病理特点活检标本的组织病理学分析是诊断IgG4RD的基石。IgG4RD在组织形态特征上最具特征性的是呈席纹样分布的致密淋巴浆细胞浸润、闭塞性静脉炎和轻中度嗜酸粒细胞浸润(图1)。炎性损害通常在组织内形成肿瘤样团块,从而破坏受累脏器。除一些特殊情况,中性粒细胞与肉芽肿在IgG4RD组织中一般极为少见。 图1.IgG4相关疾病的组织病理特点。 A.淋巴细胞与浆细胞浸润(HE,×200);B.闭塞性静脉炎(EvG,×200);C.免疫组化示IgG4+浆细胞数量增多(IgG4染色,×200)。除了形态学,尚需免疫组化来帮助IgG4RD的诊断。炎性浸润由T淋巴细胞和B淋巴细胞混合构成,T细胞呈散在分布,而B细胞通常聚集在生发中心。受累组织中可见到免疫球蛋白的各个亚型,但IgG4占主要部分。由于许多炎性浸润也可见到少量IgG4(+)细胞,因此还需在数量上对IgG4有所定义。一方面,在绝对数量上,文献确定的IgG4(+)浆细胞数量的阈值在10-50/HPF之间波动;另一方面,在相对数量上,Ig4(+)浆细胞与IgG(+)浆细胞的比值如果大于50%,更有助于诊断IgG4RD。尤其在疾病的晚期阶段,当组织中只有少量浆细胞存在、而纤维化成为主要成分时,IgG4与IgG的比值将对诊断起关键作用。三.脏器受累的临床特点IgG4相关疾病通常亚急性起病,大部分患者不合并全身症状,一般不伴随发热和C反应蛋白的升高,往往在行常规影像学检查或作病理分析时无意中诊断。某些患者局限于单一脏器,另一些除了主要脏累受累外还合并其他脏器受累。只有极少数患者可自发改善或缓解,其他则需药物治疗。IgG4RD通常有两种临床表现:(1)肿瘤样损害:可导致脏器呈肿瘤样肿大,如自身免疫性胰腺炎中胰腺肿大,Mikulicz综合征中涎腺肿大等;(2)过敏性疾病:许多IgG4RD患者具有过敏性特征,如特应性、湿疹、哮喘和血嗜酸粒细胞升高。在IgG4RD患者中,高达40%合并存在过敏性疾病,如支气管哮喘或慢性鼻窦炎7。虽然IgG4RD呈亚急性发展,但如果不予治疗,仍可导致组织损害甚至脏器功能衰竭。四. 血清血特点在正常人群中,IgG4只占总IgG的不到5%,是比重最低的亚型。大部分IgG4相关疾病的患者血清IgG4水平均升高,但仍有大约30%病理证实为IgG4RD的患者血清IgG4水平正常。对血清IgG4水平升高的那部分患者行系列监测发现,虽然绝大多数患者经激素治疗后血清IgG4水平较治疗前降低,但大部分仍在正常值以上8。血清IgG4水平持续升高的患者中约有30%病情复发,而血清IgG4水平恢复正常的患者也有10%左右的复发率;也有研究报道病情复发与否与IgG4恢复水平无明确关系9。此外,血清IgG4水平升高并非IgG4RD特有,也可见于其他一些疾病,包括变应性疾病,细菌、真菌和寄生虫感染,Rosai-Dorfman疾病,ANCA相关血管炎,多发性肌炎/皮肌炎,胰腺癌,肝胆癌和肺癌10。临床一般以1350mg/L作为血清IgG4水平是否升高的阈值,但对其意义的判读需要谨慎。五.治疗与预后并非所有IgG4RD均需要接受治疗,比如IgG4相关淋巴结病可持续存在数十年而无明显进展,这些患者随诊观察即可;但如果重要脏器受累,则应积极治疗。作为首选药物,皮质激素的用法、用量、持续时间仍有争议。日本的共识指南中建议在自身免疫性胰腺炎中初始给予泼尼松龙0.6mg/kg.day,持续2-4周,然后在3-6个月内减量至每天5mg,然后每天2.5-5mg维持至多3年11。也有文献建议在3个月内就将激素减停9, 12。免疫抑制剂如硫唑嘌呤、吗替麦考酚酯和甲氨蝶呤等通常在激素减量时合并使用,或在病情缓解后维持治疗时使用。利妥昔单抗(Rituximab)作为一种CD20单克隆抗体,广泛用于非霍奇金淋巴瘤的治疗,现也尝试用于复发性或难治性IgG4RD。研究发现,IgG4RD在使用利妥昔单抗治疗后,血清IgG4水平迅速降低,在数周内临床症状即有明显改善。IgG4RD患者与正常人群相比,更易患恶性肿瘤,包括肺癌、结肠癌和淋巴瘤等,目前原因不详。因此对于IgG4RD患者,不管是在诊断时还是随诊过程中,始终需警惕合并恶性肿瘤的可能13。第二节IgG4相关肺疾病一.概述IgG4相关肺疾病(IgG4 related lung disease, IgG4RLD)是IgG4相关疾病累及肺或胸膜时的表现。可单发于肺或同时累及肺外组织。Taniguchi等人在2004年首先报道了自身免疫性胰腺炎合并间质性肺炎,这是有关IgG4RLD的最早报道。从2004年到2012年,英文文献中所能查找到的全部IgG4RLD也仅有数十例14。虽然文献报道的病例较少,但随着对IgG4认识的加深,IgG4RLD的发病率可能并不如预想的那样少。事实上,在一个涉及114名IgG4RD的研究中,14%患者合并肺部或胸膜病变15;而另一个对90名自身免疫性胰腺炎的影像研究表明,54%的患者合并存在肺部损害16,胸腔内淋巴结病是最为常见的表现。IgG4相关疾病胸腔内受累的形式如表格1所示。表格1 IgG4相关疾病胸腔内受累的形式肺实质结节或团块间质性肺疾病气道气管支气管狭窄胸膜胸膜结节胸腔积液纵隔淋巴结病纤维化性纵隔炎二.临床特点IgG4RLD患者中大约一半伴随有呼吸道症状,包括咳嗽、胸痛、血痰和活动后气短,而另一半只有影像异常而无呼吸道症状14, 17。与其他脏器的IgG4RD相似,发热、体重减轻、出汗等全身症状较为少见。总体而言,IgG4RLD的临床肺部表现相当不特异,难以借此与其他肺部疾病相区分。三.组织病理对为数不多的IgG4RLD的组织病理的总结发现,肺组织具有以下特点:弥漫性淋巴浆细胞浸润,不规则纤维化,同时累及动静脉的内膜炎症不伴坏死, IgG4(+)浆细胞绝对数量和相对数量的明显增多。在细胞成分上,浆细胞为主要成分,其次为淋巴细胞和组织细胞;在某些患者嗜酸粒细胞可以很明显,但肉芽肿极为少见。可见,IgG4RLD的病理特点基本与其他部位的相似,但也略有不同:与自身免疫性胰腺炎的组织病理相比,肺组织内席纹样改变不太明显,而胶原纤维化与成纤维母细胞增生活跃更为突出;此外,胰腺组织中仅见到静脉炎,而肺组织中往往动脉与静脉同时受累17, 18。在肺实质受累的患者中,组织病理上有时可符合机化性肺炎(OP)或非特异性间质性肺炎(NSIP)的病理特点。当胸膜受累时,病理上表现为硬化性炎症导致的胸膜显著增厚。在壁层胸膜,硬化性炎症可延伸至胸膜下纤维与脂肪组织;而当脏层胸膜损害时可累及胸膜下肺组织17, 18。四.影像特点IgG4RLD的胸腔内受累包括肺实质、气道、胸膜以及纵隔,可以只累及一个部位,或同时累及多个部位。肺实质受累的影像可表现为如下四种形态:(1)实性结节团块型;(2)圆形磨玻璃型;(3)肺泡间质型;(4)支气管血管束型19(图2)。前两者为肺泡腔病变,密度增高,大小不等,可单发或多发,无明确的肺叶倾向。实性结节团块型要与恶性肿瘤相鉴别,而磨玻璃样的样式要与肺泡细胞癌相鉴别。这两种形态临床上往往因为与肿瘤难以区分而行楔形切除或肺叶切除,最终病理证实。后两者为间质病变,可以表现为网格、蜂窝、不规则索条、小叶间隔与支气管血管束的增粗。事实上,单从影像上是无法与某些特发性间质性肺炎相区分的,如特发性肺间质纤维化(IPF)、非特异性间质性肺炎(NSIP)、隐源性机化性肺炎(COP)和结节病。图2.IgG4相关肺疾病肺实质受累的四种CT表现形式。A. 实性结节团块型;B.圆形磨玻璃型;C.肺泡间质型;D.支气管血管束型气道受累的情况很少见。Ito等人描述了一位诊断为自身免疫性胰腺炎的63岁女性,气管镜下见气管支气管狭窄,粘膜充血水肿;而CT上还见到纵隔淋巴结肿大和支气管血管束增粗20。另一种情况是气道受压牵拉之后出现的狭窄,如纵隔纤维化对气道的压迫,以及肺间质病变引起的牵拉性支气管扩张。部分患者以胸膜为主要受累部位,表现为脏层胸膜或壁层胸膜上结节样损害,合并胸腔积液的情况较为少见17。病理特点如前所述。IgG4RD患者中,40-90%可合并存在纵隔或肺门淋巴结肿大,往往通过CT或PET得以证实。纤维化性纵隔炎有一部分最终被证实为IgG4相关疾病21。五.诊断标准在IgG4RD累及脏器中,目前仅IgG4相关Mikulicz病、IgG4相关I型自身免疫性胰腺炎和IgG4相关肾脏疾病具有各自的诊断标准。鉴于此,日本IgG4小组在2011年发布了普适性的IgG4相关疾病的临床诊断标准22,见表格2。由于IgG4RLD目前尚无属于自己的脏器特异性诊断标准,因此可参考此诊断标准进行临床诊断。此诊断标准的核心是结合临床表现、血清IgG4水平以及病理特点,将诊断区分为确诊(临床、血清与病理皆备)、可能(缺少血清)与可疑(缺少病理)。重要的是,一定要与恶性肿瘤与类似疾病相鉴别。表格2. IgG4相关疾病的普适性临床诊断标准,2011221.临床检查显示单脏器或多脏器的局灶/弥漫性肿大或团块2.血液检查显示血清IgG4水平升高(≥1350mg/L) 3.病理检查显示:(1)显著的淋巴细胞与浆细胞浸润和纤维化(2)IgG4浆细胞浸润:IgG4+/IgG+ > 40%,并且IgG4+浆细胞>10个/HPF确定诊断:1)+2)+3)可能诊断:1)+3)可疑诊断:1)+2)六.治疗和预后IgG4RLD通常对激素治疗反应良好,这一点与其他部位的IgG4RD相似。目前尚无激素治疗方案方面的相关研究,但一般给予初始剂量30mg/day到1mg/kg.day,若治疗有效,2周内即可见明显的症状缓解。激素可在后续数月内逐渐减量,密切监测期间症状缓解情况及有无反复23。当激素减量到≤10mg/day后,可考虑维持数月以降低复发率。对于病变局限行手术完全切除的患者,可能不再需要激素治疗,但也有患者在手术切除后再次复发。与其他部位的IgG4RD相似,免疫抑制剂在IgG4RLD中的治疗仍缺少经验。文献中环孢素A和硼替佐米各有一例在IgG4RLD中的应用24, 25,而我们也曾在临床上尝试过合用吗替麦考酚酯用以激素疗效欠佳的IgG4RLD。鉴于认识IgG4RLD的历史较短,因此对此疾病的预后尚缺乏经验。而与其他部位IgG4RD相似,恶性肿瘤的发病率在IgG4RLD中同样增加,需加以重视。(孙雪峰)参考文献1. Kamisawa T, Funata N, Hayashi Y, et al: A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003, 38:982-984.2. Stone JH, Khosroshahi A, Hilgenberg A, et al: IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum 2009, 60:3139-3145.3. 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本文发表于《中国呼吸与危重监护杂志》2014年5月第13卷第3期支气管镜在风湿免疫病伴肺部异常患者中获取微生物的影响因素的研究孙雪峰留永健肖毅许文兵北京协和医院呼吸内科(北京 100730)[摘要] 目的肺部感染在风湿免疫病患者中常见,支气管镜下检查有助于更好获取微生物,但支气管镜检查存在风险。本文通过对风湿免疫病合并肺部异常患者中支气管镜下获取微生物的影响因素进行研究,以期提高检查阳性率。 方法回顾性分析2009年1月至2013年6月期间北京协和医院风湿免疫科收治的风湿免疫病合并肺部异常、并行支气管镜检查以获取微生物的患者。收取患者特征、临床症状、用药史、实验室检查、影像表现和检查所在肺叶等资料。 结果共有87名患者接受91例次支气管镜检查,包括72例肺泡灌洗,21例支气管吸取和72例毛刷。总阳性率为52.7%,支气管吸取物的阳性率最高为71.4%,肺泡灌洗液为38.9%,毛刷阳性率最低为18.1%。伴有发热、咳嗽或咳痰等临床症状的风湿免疫病患者较无此症状的患者在支气管镜下具有更高的微生物检查阳性率(P=0.028);CT上表现为结节、团块或实变的患者较表现为网格、索条或磨玻璃影的患者具有更高的阳性率(P=0.003)。灌洗部位对诊断阳性率无影响(P=0.691)。结论伴有发热、咳嗽或咳痰等临床症状以及CT上表现为结节、团块或实变的风湿免疫病患者支气管镜下获取微生物的阳性率更高。[关键词]支气管镜;微生物;肺部异常;风湿免疫病通讯作者:许文兵,E-mail: xuwenbing60@163.comFactors Affecting Diagnostic Yield of Bronchoscopy in Obtaining Microorganisms in Patients with Rheumatic Autoimmune Disease and Pulmonary Abnormality SUN Xue-feng, LIU Yong-jian, XIAO Yi and XU Wen-bing. Department of Pulmonary Medicine, Peking Union Medical College Hospital, Beijing, 100730, ChinaCorresponding Author: XU Wen-bing, E-mail: xuwenbing60@163.com[Abstract] Objective Pulmonary infection is commonly-seen in patients with Rheumatic autoimmune disease (RAD). Bronchoscopy will help obtain microorganisms, but there is risk. We studied factors affecting diagnostic yield of bronchoscopy in obtaining microorganisms in RAD patients with pulmonary abnormality, in order to improve diagnostic yield. Methods A retrospective study was performed in RAD patients with lung infiltrates who received bronchoscopy for obtaining microorganisms at the department of Rheumatology, Peking Union Medical College Hospital from January 2009 to June 2013. Patients characteristics, clinical symptoms, medication history, laboratory parameters, radiographic findings and locations where microorganisms were obtained were retrieved. Results Eighty-seven patients received 91 bronchoscopy exams, including 72 bronchoalveolar lavages, 21 bronchial aspirates and 72 bronchial brushes. The total diagnostic yield was 52.7%, bronchoalveolar lavage 71.4%, bronchial aspirate 38.9% and bronchial brush 18.1%. Diagnostic yield was significantly improved in patients with clinical symptoms of fever, cough or expectoration compared to patients without either symptom (P=0.028), and patients with CT finding of nodular, massive or consolidation had a higher diagnostic yield compared to that with CT findings of reticular, linear or ground glass opacity (P=0.003). Diagnostic yield was not affected by location of bronchoalveolar lavage (P=0.691). Conclusion RAD patients with symptoms of fever, cough or sputum, and CT findings of nodular, massive or consolidation would get a higher diagnostic yield.[Key words] bronchoscopy; microorganism; pulmonary abnormality; rheumatic autoimmune disease风湿免疫病(rheumatic autoimmune disease, RAD)患者经常合并肺部疾病,可以是肺部感染,也可以是RAD本身累及肺引起的非感染性肺炎,还可能继发于治疗药物的副作用。肺部感染在RAD患者中很常见,但其临床与影像表现与非感染性肺炎类似,因此增加了鉴别诊断的难度。一些常规的获取病原微生物的方法,如痰液检查、咽拭子、血培养等,往往在免疫功能低下的RAD患者中不能获得与在免疫正常人群中一样高的阳性率,这是因为在RAD患者中,有相当一部分患者合并的是机会性感染,较难通过上述检查获得微生物。支气管镜能够直接获得下呼吸道标本,大大提高了肺部感染诊断的可靠性。但由于支气管镜检查为侵入性检查,存在一定风险,也不易被患者接受,因此往往在诊断困难或经验性治疗无效时才予考虑。此文回顾性分析我院收治的因怀疑肺部感染而行支气管镜检查的RAD患者,研究各因素对其阳性率的影响,以期选择此人群中行支气管镜检查的合适对象,用以提高支气管镜下获取微生物的阳性率。方法一、患者选择回顾性分析2009年1月至2013年6月期间北京协和医院风湿免疫科收治的患者,入选标准如下:(1)基础疾病为风湿免疫病;(2)伴肺部影像异常;(3)行支气管镜检查,镜下标本送检微生物。具有以下任何一条的患者被排除在外:(1)最终诊断非RAD;(2)虽然行支气管镜检查,但标本未送微生物检查。二、数据收集收集以下数据以供分析:(1)患者临床特征,包括性别、年龄、疾病、临床表现、支气管镜检查前四周内激素与抗生素用药史;(2)实验室检查,包括白细胞计数、血沉、C反应蛋白和血浆CD4+ T细胞计数;(3)支气管镜检查前的胸部CT;(4)支气管镜检查结果,包括镜下表现和获取标本部位;(5)标本涂片和培养结果三、阳性结果的定义支气管镜下至少行肺泡灌洗、支气管吸取和毛刷三项检查中的一项,标本送检微生物涂片和培养(包括细菌、真菌、结核,部分标本送检卡氏肺孢子虫涂片或PCR)。上述检查中任一项阳性被定义为此患者阳性。四、统计分析所有数据均使用软件SPSS 19.0(美国SPSS公司)进行统计学分析。各分类变量之间按如下规则进行卡方检验:如果n≥40且T≥5,则用Pearson卡方检验;如果n≥40且T<5,则用连续校正检验;如果n<40或者T<1,则用Fisher精确检验。当P<0.05时认为存在显著性差异。结果一、患者特征表1列出了具体的患者特征。共有87名患者接受91例次支气管镜检查,包括72例肺泡灌洗,21例支气管吸取和72例毛刷。为便于分析,此研究中每一次支气管镜检查均被认为是一名独立的患者。共包括30名男性和61名女性患者,中位年龄47岁(12-69岁)。基础的RAD分别为:31例系统性红斑狼疮,12例血管炎,9例肌炎/皮肌炎,5例原发性干燥综合征,14例其他疾病。74例(81.3%)患者的病程超过3个月,65例(71.4%)患者临床有发热、咳嗽或咳痰症状。大多数患者在支气管镜检查前四周内有使用激素(85.7%)或抗生素(65.9%)的病史。获得阳性结果的共有48例(52.7%),肺泡灌洗液和支气管吸取物微生物培养阳性的共有24例(26.4%)。表2列出了此24例培养阳性的微生物结果,最常见的是白色念珠菌和曲霉菌,其实是葡萄球菌、流感嗜血杆菌、肺炎克雷伯杆菌和大肠杆菌。统计分析表明,伴有发热、咳嗽或咳痰症状的患者较无临床症状的患者更易在支气管镜下获得微生物检查阳性的结果,且具有统计学差异(P=0.028)。其他特征(包括性别、年龄、疾病、病程、激素与抗生素的使用)均对支气管镜检查获取微生物的阳性率无影响。二、实验室检查和影像结果实验室检查和影像的具体结果参见表3。结果显示,白细胞和CD4+ T淋巴细胞对支气管镜下获取微生物的阳性率均无影响。血沉和C反应蛋白是最常用于评价炎性反应的指标,我们使用mESR(mESR = 血沉×红细胞压积/45%)以减少贫血对血沉的影响。统计分析结果显示,血沉和C反应蛋白同样不影响支气管镜下获取微生物的阳性率。所有患者均行胸部CT检查。我们根据CT上的主要表现将结果分为两组:一组主要表现为网格、索条或磨玻璃;另一组主要表现为结节、团块或实变。结果显示,后一组较前一组的阳性率更高(61.8%对比26.1%),且具有显著性差异(P=0.003)。三、肺泡灌洗部位此研究中共有72例肺泡灌洗,根据灌洗部位将其分为5组(左上叶、左下叶、右上叶、右中叶和右下叶)。结果显示,左下叶阳性率最高为60%,右中叶阳性率最低为29.6%,但彼此之间无显著性差异(P=0.691)。如果将其合并为左肺和右肺,或者上叶、中叶和下叶,统计分析表明彼此之间仍无显著性差异(P=0.264和P=0.458)。四、肺泡灌洗、支气管吸取和毛刷我们还比较了这三种不同的标本获取技术之间的阳性率差异。结果显示,支气管吸取物的阳性率最高为71.4%,肺泡灌洗液为38.9%,毛刷阳性率最低为18.1%。统计结果显示三者之间存在显著性差异(P<0.001),每两组之间的比较同样显示存在统计学差异(P<0.05)。讨论免疫病患者由于疾病本身可导致免疫功能低下,或在使用激素与免疫抑制剂后出现免疫功能低下,因此患有RAD的患者较正常人群容易出现肺部感染,并且经常出现机会性感染,如曲霉菌、巨细胞病毒和卡氏肺孢子虫肺炎等。虽然痰液检查能够提供一定信息,但因其特异性差,往往导致抗生素的过度使用。支气管镜检查直接获取下呼吸道标本,因此其标本可靠性远高于痰液。已经有大量研究表明,支气管镜下肺泡灌洗液的微生物检查对合并肺部感染的免疫功能低下患者具有重要价值,阳性率波动于27.7%至64.8%[1-13],但特异性可达86%[11]。虽然支气管吸取物与支气管毛刷因为有可能被上呼吸道污染,因此其可靠性逊于肺泡灌洗液,但同样优于痰液,所以也具有较高价值。尽管支气管镜下获取的标本优于痰液,但因其操作复杂,存在误吸、感染、出血、痉挛等多种风险,并且过程较为痛苦,因此不能广泛应用于微生物诊断。通过选择合适的患者,提高诊断阳性率,具有重要意义。本研究表明,伴有发热、咳嗽或咳痰等临床症状的RAD患者较无此症状的患者在支气管镜下具有更高的微生物检查阳性率,提示发热、咳嗽、咳痰等症状在RAD患者中对于提示可能为肺部感染具有重要价值。同样的发现也见于其他免疫功能低下的患者[13]。此外,本研究还发现,CT上表现为结节、团块或实变的患者较表现为网格、索条或磨玻璃影的患者具有更高的阳性率。网格、索条或磨玻璃的影像表现之所以阳性率低,可能与以下原因相关:首先,网格、索条等改变发生在肺间质,因此不是肺部感染易受累的部位;其次,有相当一部分RAD累及肺时表现为间质性肺炎,在影像上可表现为网格、索条或磨玻璃。相较而言,RAD在累及肺时主要表现为结节、团块或实变的相对少见。因此,影像上表现为结节、团块或实变时更可能提示为肺部感染,此时行支气管镜检查具有更高的阳性率。虽然激素与抗生素的使用有可能增加机会性感染的机率[14],但在本研究中并未发现两者对最后的阳性率产生影响。原因可能有:首先,本研究中未能充分评估机会致病菌;其次,导致RAD患者免疫抑制的因素众多,彼此之间可能存在干扰,导致阴性结果;再次,经验性抗感染治疗有可能降低药物敏感微生物的阳性率。在本研究中,炎性指标如血沉、C反应蛋白、白细胞计数等均未对阳性率产生影响,因此不能用于预测RAD患者支气管镜微生物检查的阳性率。本研究发现,右中叶获取的标本阳性率最低,这可能与在感染部位不明确时经常取右中叶行肺泡灌洗相关,而这部分患者中有相当部分为非感染性肺炎。尽管如此,与文献报道类似[15],我们也发现获取标本部位对微生物检查的阳性率并未产生具有统计学意义的影响。此外,在本研究中,支气管吸取物的阳性率明显高于肺泡灌洗液与毛刷,但不能因此断定支气管吸取物优于肺泡灌洗液。这是因为,虽然支气管吸取物对微生物检查的阳性率高于肺泡灌洗液,但由于支气管吸取物有一定可能为上呼吸道分泌物,因此对诊断肺部感染的特异性较肺泡灌洗液差,阳性预测值较低。虽然如此,因为支气管吸取操作便捷,在临床实践中仍被广泛地应用。综上所述,本研究表明,在RA患者合并肺部异常时,若临床有发热、咳嗽或咳痰等症状,CT上主要表现为结节、团块或实变,则有较大可能是合并肺部感染,这些患者行支气管镜下微生物检查将会有较高的诊断阳性率。
Sun X, Xiao Y: Pulmonary sequestration in adult patients: a retrospective study. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2015, 48(2):279-282.AbstractObjective: Pulmonary sequestration (PS) is a rare congenital malformation. This study presents the characteristics of PS in adult patients, including pulmonary function and concurrent infection, which have not been well documented previously.Methods: Patients > 16 years old with discharge diagnosis of PS from Peking Union Medical College Hospital between January 1990 and December 2013 were retrospectively analyzed. Age, sex, clinical symptoms, chest computed tomography (CT) results, results of pulmonary function tests, diagnostic methods, type and localization of sequestration, origin of arterial supply, complications due to infection, and treatment information were retrieved from hospital records and analyzed.Results: Seventy-two patients were included in this study (mean age 36.6 + 11.8 years). Clinical symptoms included cough, expectoration, hemoptysis, intermittent fever, and chest pain. The most common CT findings were soft tissue opacity, cystic lesion, cavitary lesion, and bronchiectasis. Intralobar and extralobar sequestrations were present in 92.8% and 7.2% of the patients, respectively. PS located in the left lower lobe was 2.1 times more frequent than that in the right lower lobe. PS was diagnosed by computed tomography angiography (CTA) in only 37.5% of patients; the remaining patients were undiagnosed before surgery. Obstructive ventilation dysfunction was found in 8.8% of patients. Pulmonary aspergillosis was detected in 9.7% of patients, and Pseudomonas aeruginosa was the leading pathogen (as determined by tissue cultures). PS was resected via thoracotomy in 87.0% of patients and via video-assisted thoracoscopic surgery (VATS) in 13.0%.(本研究纳入72名患者,平均年龄36.6+11.8岁。临床症状包括咳嗽、咳痰、咯轿、间断发热和胸痛。最常见的CT表现包括软组织影,囊性病变,空洞和支气管扩张。叶内型和叶外型肺隔离症分别见于92.8%和7.2%的患者。肺隔离症位于左下叶者是右下叶的2.1倍。仅有37.5%的患者通过CTA确诊,其他患者在术前均未明确诊断。8.8%的患者存在阻塞性通气功能障碍。肺曲霉菌病见于9.7%的患者,铜绿假单胞菌是最常见的病原菌。87%的患者通过开胸手术切除病灶,而13%的患者通过胸腔镜切除病灶。)Conclusion: PS is a rare disease, and missed diagnosis and misdiagnosis are very common in PS patients. CTA and other angiography techniques should be used when there is suspicion of PS. Some PS patients have mild to moderate derangement of pulmonary ventilation, and PS might be associated with concurrent aspergillosis. VATS and posterolateral thoracotomy are both feasible methods for PS resection.Key words: pulmonary sequestration; computed tomography; pulmonary function test; angiography; aspergillosisIntroductionPulmonary sequestration (PS) is a rare congenital malformation of the lower respiratory tract in which a solitary non-functioning mass of lung tissue receives arterial blood from the systemic circulation rather than from the pulmonary circulation[1]. PS constitutes 1.1–1.8% of all pulmonary resections[2] and 0.15–6.4% of all congenital pulmonary malformations[3]. Many theories of the aetiology of PS have been proposed[4], and the most widely accepted hypothesis suggests that PS results from formation of an accessory lung bud caudal to the normal lung buds[5, 6]. PS is usually divided into intralobar pulmonary sequestration (ILS), which shares the visceral pleura of an otherwise normal pulmonary lobe, and extralobar pulmonary sequestration (ELS), in which an extralobar sequestration is separated from normal lung tissue by its own pleural covering[7]. PS can be present but undiagnosed for many years, so in many cases PS is diagnosed in adult patients[8, 9]. Compared with pediatric patients, adult PS patients have significantly more respiratory infections and more often require a lobectomy[8]. However, concurrent respiratory infections have not been well documented before, and pulmonary functions in PS patients have never been reported in the literature. In this retrospective study, we describe the characteristics of PS in adult patients, including pulmonary function and concurrent infection, in an attempt to better understand this disease.MethodsThe medical records of patients who were hospitalized at Peking Union Medical College Hospital from January 1990 through December 2013 were searched for the discharge diagnosis of “pulmonary sequestration”. Only patients > 16 years old were included in this study. If a patient was hospitalized two or more times during this time period, only the first hospitalization for PS was included. The following data were retrieved for analysis: age, sex, clinical symptoms, chest computed tomography (CT) results, pulmonary function test results, diagnostic methods, type and localization of sequestration, origin of arterial supply, complications due to infection, and treatment. Due to the retrospective nature of the study, informed consent was waived. The study was approved by the Ethical Committee of Peking Union Medical College Hospital.Data were analyzed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA) and SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA). The data are expressed as mean values + SD or percentage. All statistical tests were two-sided. Results were analyzed using the independent-samples t-test between groups of subjects, and parameters such as age and length of postoperative hospital stay were compared. A P value < 0.05 was considered to be significant.ResultsGeneral characteristicsA total of 72 patients with PS were included in this study: 69 cases were from the department of thoracic surgery and 3 cases were from the department of pulmonary medicine. The male : female ratio was 1.12 : 1. Patient age ranged from 16 to 75 years (mean age 36.6 + 11.8 years). There was no difference in age between the ILS and ELS subgroups (P = 0.60). An average of 1.4 cases per year was diagnosed in the 1990s (1990–1999), 3.3 cases per year in the 2000s (2000–2009), and 6.25 cases per year in the 2010s (2010–2013).Types and localization of PSSixty-nine of the 72 patients underwent surgery and could be definitely divided into ILS (64 cases, 92.8%) and ELS (5 cases, 7.2%). Forty-six (66.7%) cases were located in the left lower lobe, 22 (31.9%) cases were located in the right lower lobe, and one case was located bilaterally in the lower lobes.Clinical symptoms of PSCough and expectoration were the most common clinical symptoms, noted in 59 (81.9%) patients, followed by hemoptysis (21 cases, 29.2%), intermittent fever (18 cases, 25.0%), and chest pain (15 cases, 20.8%). Seven (9.7%) patients were asymptomatic and PS was discovered incidentally. The interval time from onset of initial symptoms to diagnosis ranged from 2 weeks to more than 40 years, and the mean interval time was more than 63 months. There were no obvious differences in clinical symptoms and interval time between the ILS and ELS subgroups.Chest CT results for PS patientsA chest CT scan was performed for all patients enrolled in this study. Soft tissue opacity was the most common CT finding (62 cases, 86.1%). Cystic lesion was found in 15 (20.8%) patients, and air-fluid levels were discerned in 8 of them. Cavitary lesion and bronchiectasis were found in 10 (13.9%) and 6 (8.3%) patients, respectively. Calcinosis and pleural effusion were also noted in four and three patients, respectively. It was not unusual for a given patient to exhibit more than one of these findings. CT scans for ILS and ELS were similar and indistinguishable.Pulmonary function test results for PS patientsSpirometry was performed in 57 patients preoperatively, but lung volume and diffusion function were not measured. Pulmonary function test results for the other 15 patients were lacking in the medical records. The results are shown in Table 1. The mean forced expiratory volume in the first second (in percentage, FEV1%) was 87.2% (range, 53.1–117.6%), and FEV1 impairment was found in 15 (26.3%) patients (defined as FEV1% < 80%). Obstructive ventilation dysfunction was found in 5 (8.8%) patients, and all of them were graded as moderate obstructive ventilation dysfunction (defined as the ratio of FEV1 to forced vital capacity (FVC) < 70% and 50% ≤ FEV1% < 80%). Only one of the five patients with obstructive ventilation dysfunction had a smoking history. Two out of nine patients with concurrent pulmonary infection (22.2%) had obstructive ventilation dysfunction, which was approximately 3.5 times greater than that without concurrent pulmonary infection. The three ELS patients who underwent spirometry exhibited normal results.Methods of diagnosing PSTwenty-seven (37.5%) patients were diagnosed as having PS preoperatively by computed tomography angiography (CTA), and three of them underwent digital subtraction angiography (DSA) as well. The other 45 (62.5%) patients were not diagnosed as having PS before surgery, but its presence was confirmed by surgery and postoperative pathology. All five ELS patients were not diagnosed with PS before surgery.Aberrant arterial supply of PSThe presence of an aberrant arterial blood supply for PS was confirmed in all 72 patients in this study. Sixty-two (86.1%) cases originated from the thoracic aorta, five (6.9%) cases originated from the abdominal aorta, four (5.6%) cases originated from the phrenic artery, and one (1.4%) case originated from the intercostal artery. Concurrent infection in patients with PSSeven samples of resected tissues with suspected concurrent infection from ILS patients were sent for microbiological culture. Pseudomonas aeruginosa was present in three patients, Aspergillus fumigatus was present in one patient, and the other three cultures were negative for bacteria, fungi, and mycobacteria. Aspergillus sp. was also discovered during pathological examination of tissues from six other ILS patients. Patients with Pseudomonas aeruginosa were treated with antibiotics postoperatively for 3–7 days, and patients with Aspergillus sp. were not treated with any antifungal medicine postoperatively. All patients with concurrent infection recovered well without any obvious complications. Concurrent pulmonary infection was not diagnosed in any of the ELS patients.TreatmentSixty-nine patients underwent surgery. Lobectomy was performed via thoracotomy in 55 ILS patients and via video-assisted thoracoscopic surgery (VATS) in 9 ILS patients. Mass excision of the sequestered lung tissue was performed via thoracotomy in all five ELS patients. The other three patients were stable and chose not to undergo surgery. All surgeries were successfully performed without severe complications or death. Atelectasis occurred in three ILS patients after surgery, but they recovered well after treatment. Length of postoperative hospital stay in patients with VATS was 6.6 + 1.5 days, which was much shorter than that in patients with thoracotomy (9.1 + 3.2 days, P = 0.001). For ELS patients who underwent thoracotomy, length of postoperative hospital stay was much shorter than that of ILS patients (7.2 + 0.84 days vs. 9.2 + 3.2 days, P = 0.002).DiscussionAs a rare congenital malformation of the lower respiratory tract, PS lacks communication with the tracheobronchial tree and receives an aberrant arterial blood supply from the systemic circulation. The term “sequestration” was first used by Pryce to describe PS in 1946[10]. As shown in our study, more PS patients have been diagnosed in recent years compared to years past, indicating that PS is becoming more widely recognized.PS is characterized as ILS or ELS based on whether the lesion is located inside or outside a normal lobe and whether separate visceral pleura can be distinguished. ILS is the most common form, constituting approximately 75–93% of PS cases in the literature[8, 11, 12] and 92.5% in our study. PS in the left lower lobe is two to three times more common than that in the right lower lobe[8, 11, 12]. Our results showed a propensity for localization in the left lower lobe as well (2.1 times that in the right lower lobe). Clinical symptoms of PS arise from concomitant pulmonary infection and are manifested as recurrent cough, expectoration, hemoptysis, chest pain, and fever[3]. When pulmonary infection is not present, PS is diagnosed incidentally, as was the case for 9.7% of the patients in our study. This study showed that the mean interval between onset of initial symptoms and diagnosis was more than 5 years, which illustrates that missed diagnosis was very common in these PS patients.DSA once was considered to be the gold standard for diagnosis of PS, as it explicitly reveals the aberrant arterial blood supply. However, with the advent of noninvasive techniques, such as CTA and magnetic resonance angiography, DSA has fallen out of favor and is seldom performed except in problematic cases or when preoperative or therapeutic embolization of the supplying artery is necessary[13, 14]. Despite the broad use of these angiography techniques, only 37.5% of patients in this study were diagnosed by CTA and/or DSA; the remaining 62.5% of patients were diagnosed after surgery. This result means that misdiagnosis of PS before surgery is quite common in clinical practice. To our knowledge, evaluation of pulmonary function in PS patients has not been reported previously. In this study, obstructive ventilation dysfunction was found in 8.8% of PS patients. Derangement of pulmonary ventilation can be attributed to smoking, PS itself, and/or concurrent infection. Although FEV1 impairment was found in 26.3% of patients, FEV1% in all patients tested was > 50%, which means that the ventilation dysfunction was mild to moderate, and this level of dysfunction might be explained by the relatively limited distribution of PS. Because pulmonary ventilation function in PS patients is normal or mildly to moderately impaired, PS patients can tolerate intubation and surgery.Pulmonary infection is a common complication of PS, and it causes clinical symptoms. However, the microorganisms that co-occur with PS have not been systemically studied before. Seven samples of resected tissues with suspected concurrent infection were sent for microbiological culture. Pseudomonas aeruginosa was found in three of the seven samples. P. aeruginosa is a pathogen commonly found in bronchiectasis, and PS often is accompanied by bronchiectasis and its structure resembles that of bronchiectasis. Other pathogens have occasionally been reported in PS patients, such as tuberculosis and nocardia[3, 15, 16]. In our study, seven patients were diagnosed with aspergillosis. In 2005, Berna et al.[17] reported four cases of PS in combination with aspergillosis and reviewed 15 cases that were reported in the literature. Since then, three more cases have been reported[18-20]. Among our 7 cases and the 22 cases in the literature, only one case was ELS, and the others were all ILS. Whether or not the association between aspergillosis and PS is specific[21] remains a matter of debate, but the relatively high morbidity (9.7%) of aspergillosis in PS patients in our study indicates that this relationships needs to be studied further.In symptomatic patients or when cancer cannot be excluded, surgical resection is recommended. In asymptomatic ILS patients, elective surgery should be considered to prevent recurrent infection, and serial monitoring is appropriate in asymptomatic ELS patients. Since 2002 when Wan et al.[22] first described VATS lobectomy for treating PS, the use of VATS for PS resection has been practiced widely. A recent study[11] comparing VATS and posterolateral thoracotomy for PS resection showed no difference in many parameters, including duration of the operation, length of postoperative hospital stay, and complications, thereby demonstrating the feasibility of VATS for PS resection. Furthermore, although limited by the small sample size, our study showed that patients undergoing VATS had a statistically significantly shorter length of postoperative hospital stay than patients undergoing thoracotomy, indicating that VATS might be preferable to thoracotomy for PS resection.ConclusionMany PS patients are not diagnosed until they are adults. Clinical presentation associated with PS is nonspecific, and CTA and other methods of angiography are crucially important for the diagnosis of PS. Mild to moderate derangement of pulmonary ventilation occurs in some PS patients, and PS might be associated with concurrent aspergillosis. VATS and posterolateral thoracotomy are both feasible methods for PS resection, and VATS might be preferable to thoracotomy for reducing length of postoperative hospital stay.StatementSome patients included in this study have been described previously by Liu et al.[23].Conflicts of Interests: none declared.
Sun XF, Wang P, Liu HR, Shi JH: A Retrospective Study of Pulmonary Actinomycosis in a Single Institution in China.Chinese medical journal2015, 128(12):1607-1610.ABSTRACTBackground: Actinomycosis is a rare indolent infectious disease caused by Actinomyces. Although pulmonary actinomycosis is thought to be more prevalent in developing countries, data from developing countries are scanty.Methods: Patients fulfilling the inclusion criteria for pulmonary actinomycosis from Peking Union Medical College Hospital in China between January 2003 and December 2014 were retrospectively analyzed. Baseline characteristics, clinical symptoms, underlying diseases, diagnostic methods, pulmonary function test results, chest CT tests, Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) tests, initial diagnosis, treatment and prognosis were retrieved from medical records and analyzed.Results: Twenty-six patients were included in this study (mean age 52.0 + 13.1 years). The ratio of male to female was 1.17 : 1. Most common clinical symptoms were cough (15/26), sputum (12/26) and hemoptysis (12/26). Chest CT findings presented as masses (13/26), nodules (10/26) and infiltrates (3/26). FDG-PET had an increased standardized uptake value and 4/6 patients were misdiagnosed as malignancy. Many kinds of antibiotics were used in the treatment of pulmonary actonomycosis and all got favorable results. Five patients receiving complete resection of the lesion were cured without postoperative use of antibiotic.Conclusions: Pulmonary actinomycosis is a rare disease even in developing countries, and both misdiagnosis and missed diagnosis are common. FDG-PET seems useless in the differential diagnosis, and complete resection of the pulmonary lesion without postoperative antibiotic therapy might be enough to achieve cure.Key words: Actinomycosis: lung; computed tomography; misdiagnosis; treatmentINTRODUCTIONActinomycosis is a rare, indolent and slowly progressing infectious disease caused by filamentous Gram-positive anaerobic bacteria, genus Actinomyces, belonging to the family Actinomycetaceae.1 The human form of actinomycosis was first described in 1857,2 while pulmonary actinomycosis was described 25 years later, accounting for 15-20% of the total burden of actinomycosis.3Actinomyces are commensals of the human oropharynx, gastrointestinal tract, and urogenital tract. Pulmonary actinomycosis probably results from aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract.4 The most common clinical complaints of pulmonary actinomycosis include cough, hemoptysis and sputum production.5 Fever, Dyspnea and chest pain are also often seen. Chest computed tomography (CT) usually reveals pulmonary infiltrates or masses, and misdiagnosis for lung cancer or tuberculosis is common. Pulmonary actinomycosis usually presents a chronic course, and a long duration of therapy is usually needed.The incidence of pulmonary actinomycosis has declined in recent years in developed countries as a result of better oral hygiene and susceptibility to a broad range of antibiotics3. Pulmonary actinomycosis is thought to have a higher incidence in developing countries because of worse oral hygiene and more alcoholics. However, most data of pulmonary actinomycosis come from developed countries. As a matter of fact, data from developing countries are scanty, and only a case series from Thailand including 16 patients6 was reported in English literature. We performed this study in a developing country, China, with comparison with that in developed countries, to reveal the current situation of pulmonary actinomycosis in developing countries and the difference from that in developed countries.METHODSPatientsPatients with the diagnosis of pulmonary actinomycosis at Peking Union Medical College Hospital from January 2003 to December 2014 were searched, and those fulfilling the following inclusion criteria were included in this study: (1) pulmonary parenchymal abnormality on CT; and (2) a. histopathological identification of actinomycosis from the tissues obtained by lung resection, percutaneous transthoracic lung biopsy, or bronchial biopsy; or b. culture of aseptic tissue, including lung tissue or pleural effusion; or c. histopathological identification of actinomycosis from expectorated mucus plug and remission achieved after therapy aiming at actinomycosis.The following data were retrieved for analysis: baseline characteristics, clinical symptoms, underlying diseases, diagnostic methods, pulmonary function test results, chest CT tests, Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) tests, initial diagnosis, treatment and prognosis. The study was approved by the Ethical Committee of Peking Union Medical College Hospital to use patient medical records, and patient confidentiality was ensured to be respected.Identification of actinomycosisActinomycosis was identified with either of the following criteria: (1) Histopathological examination demonstrated a filamentous branching organism with or without sulfur granules by hematoxylineosin staining or Gomori’s methenamine silver staining. Meanwhile, a Gram staining with a positive result and a modified Kinyoun’s acid-fast staining with a negative result were also obtained. (2) Lung tissue or pleural effusion was sent for actinomycosis culture, which isolated Actinomyces.Statistical analysisData were analyzed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA) and SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA). The data were expressed as mean values + SD or percentage. RESULTSBaseline characteristicsA total of 26 patients were included in this study. Men were mildly prevalent, and mean age was 52.0 years (Table 1). All patients were human immunodeficiency virus (HIV) – negative, and did not have any disease compromising body immunity. Smoking history and alcohol abuse were only noted in male patients, and underlying diseases were only occasionally seen (Table 1). Elevated level of inflammatory markers, including white blood cell count, erythrocyte sedimentation rate and C-reactive protein, were only noted in a minority of patients, and only a few patients had obstructive ventilation dysfunction (Table 1).Clinical symptomsCough was the most common presentation, followed by sputum production and hemoptysis. Fever, short of breath and chest pain were also occasionally noted (Table 1). Three patients were asymptomatic and pulmonary actinomycosis was found accidentally on routine health examination. The interval time from onset of initial symptoms to diagnosis ranged from 1 week to more than 6 years, and the mean interval time was around 10 months.Diagnostic modalitiesPathological confirmation of actinomycosis from lung tissue was achieved in 23 patients, in whom 14 patients received wedge resection or lobectomy, 5 patients received percutaneous transthoracic lung biopsy, and 4 patients received bronchial biopsy. Two patients were diagnosed by pathological confirmation from expectorated mucus plug, and the last patient was diagnosed by actinomycosis culture of pleural effusion.Chest CT and FDG-PET resultsChest CT was performed in all patients. According to chest CT scan, pulmonary actinomycosis was bilateral in 2 patients. Among the remaining 24 unilateral patients, 11 cases were right-sided and 13 cases were left-sided.Pulmonary actinomycosis presented as masses (Fig 1A), nodules (Fig 1C) and patchy infiltrates (Fig 1D) in 13, 10 and 3 patients separately. Solitary lesion was observed in 20 (76.9%) patients, while the other 6 patients presented as multiple lesions. Lesion margins in 3 patients with patchy infiltrates were ill-defined with ground glass opacities, and in the remaining patients, 18 patients had an irregular or spiculated edge, while the other 5 patients presented multiple smooth nodules. Mediastinal or hilar lymphadenopathy was seen in 15 (57.7%) patients. As the typical CT features of parenchymal actinomycosis, lesion located peripherally with pleural involvement was noted in 11 (42.3%) patients (Fig 1A, B, C), cavity was seen in 6 (23.1%) patients (Fig 1C), and central low-attenuation was observed in 5 (19.2%) patients (Fig 1B). Air bronchogram was noted in 5 (19.2%) patients. Calcification was noted in 3 (11.5%) patients.Six patients received FDG-PET examination. The maximum standardized uptake value (SUVmax) ranged from 2.1 to 14.3. According to FDG-PET results, 4 patients were considered to have malignancy, while the other 2 patients were considered to have inflammation. Initial diagnosesA misdiagnosis was often made as the initial diagnosis. Lung cancer was the most common initial diagnosis, noted in 13 (50.0%) patients, followed by pulmonary tuberculosis (7 cases, 26.9%). Non-tuberculosis pulmonary infection was suspected only in 6 (23.1%) patients.Treatment and prognosisIn spite of our best effort, 6 patients were still lost to follow-up. In the remaining 20 patients, 5 patients diagnosed by surgery did not take any medicine after surgery in view of the complete resection of the lesion, and all of them were stable and uneventful at 2 to 3-year follow-up. Other 15 patients (diagnosed by surgery in 7 patients and by other methods in the remainder) were treated with antibiotics for 3 to 18 months (2 patients for 3 months, and the others for equal or more than 6 months). Amoxicillin/clavulanic acid was used most commonly (6 patients), then moxifloxacin (4 patients), minocycline (3 patients), and penicillin G (2 patients). Some other antibiotics were also used occasionally, including ampicillin/sulbactam, cefaclor, levofloxacin, clarithromycin and doxycycline (1 patient each). Five patients received combination therapy with 2 kinds of antibiotics. During follow-up ranging from 3 months to 3 years, all these patients were stable and remission was confirmed by chest CT.DISCUSSIONOur present study analyzes the data of pulmonary actinomycosis at a teaching hospital in China during the past 11 years, and as far as we know, this is the largest study of pulmonary actinomycosis in a single institution in China.Pulmonary actinomycosis is seen at all ages, but mainly in adults. Most series described a peak incidence in the 4th and 5th decades.4, 7 All studies published in recent five years showed a mean age in the 5th,5, 8-10 as is seen in our study. Although lower than that reported in literature,4 the prevalent incidence of infection in males is still noted in this study, which has been partly attributed to poorer oral hygiene and/or a higher incidence of facial trauma in males.2, 11With the improvement in oral hygiene, and early use of antibiotics, the presentation of pulmonary actinomycosis has changed from aggressive to less aggressive behavior in the past years. Cough, sputum and chest pain were reported to be the most common complaints in some studies undertaken in Europe,8, 12 but hemoptysis was more commonly seen in Asian series.5, 6, 9, 10, 13 Our study also reveals a high incidence of hemoptysis, but only 1 case of chest pain, confirming the different clinical manifestations in different regions. Furthermore, the mean duration of symptoms in this study is much longer than that in recent literature, which might be explained by the fact that patients in developing China still lack consciousness for hospitalizing and/or actinomycosis is still not well recognized by Chinese clinicians.The typical CT feature of parenchymal actinomycosis is a chronic segmental air-space consolidation containing necrotic low-attenuation areas with frequent cavity formation and peripheral enhancement,14, 15 but is only seen in less than 50% of patients in this study. Furthermore, imaging modalities in pulmonary actinomycosis are still nonspecific and undiagnostic. Without microbiological or histological confirmation, misdiagnosis for malignancy, tuberculosis or other infections is still fairly common. As a matter of fact, less than 7% of patients who turned out to have actinomycosis were suspected on admission in one series.16 Similar to the literature, our study shows a high rate of initial misdiagnosis. Furthermore, because only a few case reports have described the use of FDG-PET in patients with pulmonary actinomycosis,17-20 therefore we evaluated the use of FDG-PET in the differential diagnosis of pulmonary actinomycosis. Disappointingly, as high as two thirds of patients are misinterpreted as malignancy with FDG-PET, indicating that FDG-PET might be helpless in diagnosing pulmonary actinomycosis. Actinomycosis has been considered to be a medically treatable disease with good prognosis,16 sensitive to a lot of antibiotics, such as penicillin, tetracycline, erythromycin et al. Presumably due to the drug’s poor penetration, which is caused by avascularity and dense co-aggregations of actinomycosis known as sulphur granules, it is usually necessary to treat actinomycosis for a duration as long as 6 -12 months.2, 21 The thoracic form appears to require longer treatment courses compared to other forms.22 However, a few recent studies showed that a relatively brief course (2 to 3 months) of antibiotic therapy would be successful in pulmonary actinomycosis.12, 23, 24 In our study, 2 patients with mild illness are treated with antibiotics for 3 months and both get favorable outcome. Present data show that the optimal duration of antibiotic therapy for pulmonary actinomycosis still needs more investigation. Surgery is usually performed to rule out lung cancer or to control severe symptoms such as hemoptysis.13, 25 Occasionally, surgery is considered when medical treatment has no effect.5 In this study, all patients receiving surgery are undiagnostic before surgery. What is interesting, 5 patients taking no antibiotic after surgery are all cured and no relapse is observed. It indicates that surgery solely might be sufficient to cure pulmonary actinomycosis if complete resection of the lesion is assured. From another point of view, a more thorough and comprehensive microbiological work up before surgical resection would be important so as to avoid unnecessary surgery. Moreover, although these patients taking no antibiotic after surgery are all cured, the potential danger of relapse should be paid attention to.A few limitations are apparent in this study. First, as a rare disease, only 26 patients with pulmonary actinomycosis are included in this study, which will hamper the reliability of results. Second, some data from these patients are incomplete, such as inflammatory markers and pulmonary function tests. In spite of these defects, this study provides some important information about pulmonary actinomycosis in a developing country, and a comparison with that in developed countries will expedite the understanding for pulmonary actinomycosis.In summary, pulmonary actinomycosis is a rare disease even in developing countries, and both misdiagnosis and missed diagnosis are common. FDG-PET seems useless in the differential diagnosis of pulmonary actinomycosis, and complete resection of the pulmonary lesion without postoperative antibiotic therapy might be enough to achieve cure.REFERENCES1. Valour F, Senechal A, Dupieux C, Karsenty J, Lustig S, Breton Pet al. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infect Drug Resist 2014; 7: 183-197.2. Mabeza GF, Macfarlane J. Pulmonary actinomycosis. Eur Respir J 2003; 21: 545-551.3. Wong VK, Turmezei TD, Weston VC. Actinomycosis. BMJ 2011; 343: d6099.4. Bennhoff DF. Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases. Laryngoscope 1984; 94: 1198-1217.5.Kim SR, Jung LY, Oh IJ, Kim YC, Shin KC, Lee MK et al. Pulmonary actinomycosis during the first decade of 21st century: cases of 94 patients. BMC Infect Dis 2013; 13: 216.6.Dujneungkunakorn T, Riantawan P, Tungsagunwattana S. Pulmonary actinomycosis: a study of 16 cases from Central Chest Hospital. J Med Assoc Thai 1999; 82: 531-535.7.Heffner JE. Pleuropulmonary manifestations of actinomycosis and nocardiosis. Semin Respir Infect 1988; 3: 352-361.8.Kolditz M, Bickhardt J, Matthiessen W, Holotiuk O, Hoffken G, Koschel D. Medical management of pulmonary actinomycosis: data from 49 consecutive cases. J Antimicrob Chemother 2009; 63: 839-841.9.Song JU, Park HY, Jeon K, Um SW, Kwon OJ, Koh WJ. Treatment of thoracic actinomycosis: A retrospective analysis of 40 patients. Ann Thorac Med 2010; 5: 80-85.10.Park JY, Lee T, Lee H, Lim HJ, Lee J, Park JS et al. Multivariate analysis of prognostic factors in patients with pulmonary actinomycosis. BMC Infect Dis 2014; 14: 10.11.Smego RA, Jr., Foglia G. Actinomycosis. Clin Infect Dis 1998; 26: 1255-1261; quiz 1262-1253.12.Kinnear WJ, MacFarlane JT. A survey of thoracic actinomycosis. Respir Med 1990; 84: 57-59.13.Endo S, Murayama F, Yamaguchi T, Yamamoto S, Otani S, Saito N et al. Surgical considerations for pulmonary actinomycosis. Ann Thorac Surg 2002; 74: 185-190.14.Cheon JE, Im JG, Kim MY, Lee JS, Choi GM, Yeon KM. Thoracic actinomycosis: CT findings. Radiology 1998; 209: 229-233.15.Kim TS, Han J, Koh WJ, Choi JC, Chung MJ, Lee JH et al. Thoracic actinomycosis: CT features with histopathologic correlation. AJR Am J Roentgenol 2006; 186: 225-231.16.Weese WC, Smith IM. A study of 57 cases of actinomycosis over a 36-year period. A diagnostic 'failure' with good prognosis after treatment. Arch Intern Med 1975; 135: 1562-1568.17.Watanabe K, Kawai H, Muguruma M, Ohara T. [A case of pulmonary actinomycosis in which differentiation of primary and metastatic lung cancers was difficult]. Nihon Kokyuki Gakkai Zasshi 2009; 47: 682-686.18.Kogure S, Yamamoto N, Watanabe F, Yuasa U, Tokui T, Shomura S. [Pulmonary actinomycosis which was clinically suggested lung cancer; report of a case]. Kyobu Geka 2011; 64: 254-257.19.Kanda H, Nakamura Y, Nagata T, Fukumori K, Imoto Y, Tabata K et al. [Surgery for pulmonary actinomycosis that was difficult to differentiate from lung cancer; report of a case]. Kyobu Geka 2011; 64: 864-867.20.Weisshaupt C, Hitz F, Albrich WC, Omlin A. Pulmonary actinomycosis and Hodgkin's disease: when FDG-PET may be misleading. BMJ Case Rep 2014; 2014.21.Yildiz O, Doganay M. Actinomycoses and Nocardia pulmonary infections. Curr Opin Pulm Med 2006; 12: 228-234.22.Slade PR, Slesser BV, Southgate J. Thoracic actinomycosis. Thorax 1973; 28: 73-85.23.Hsieh MJ, Liu HP, Chang JP, Chang CH. Thoracic actinomycosis. Chest 1993; 104: 366-370.24.Skoutelis A, Petrochilos J, Bassaris H. Successful treatment of thoracic actinomycosis with ceftriaxone. Clin Infect Dis 1994; 19: 161-162.25.Boudaya MS, Smadhi H, Marghli A, Mouna M, Charmiti F, Ismail O et al. Surgery in thoracic actinomycosis. Asian Cardiovasc Thorac Ann 2012; 20: 314-319.Table 1 Baseline characteristics of 26 patients with pulmonary actinomycosisNumber (%) or mean (range)Male : Female1.17 : 1Age (years)52.0 + 13.1 (18-75)History of smoking8/26 (30.8%)History of alcohol abuse5/26 (19.2%)Co-morbidity (Pulmonary) Obstructive pulmonary disease2/26 Healed pulmonary tuberculosis1/26 ABPA1/26 Bronchial foreign body1/26Co-morbidity (Non-pulmonary) Hypertension7/26 Gingival disease3/26 GERD2/26 Diabetes Mellitus2/26 Maxillary sinusitis2/26 Subtotal gastrectomy1/26 Ischemic heart disease1/26 Rheumatoid arthritis1/26 Spontaneous abortion1/26Laboratory findings & PFT White blood cell count > 10×109/L1/20 (5.0%) ESR > 20mm/h5/12 (41.7%) CRP > 5mg/L3/10 (30.0%) FEV1/FVC < 70%2/15 (13.3%)Clinical symptoms Cough15/26 (57.7%) Sputum production12/26 (46.2%) Hemoptysis12/26 (46.2%) Fever5/26 (19.2%) Short of breath2/26 (7.7%) Chest pain1/26 (3.8%)ABPA: allergic bronchopulmonary aspergillosis; GERD: gastroesophageal reflux disease; PFT: pulmonary function test; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; FEV1/FVC: forced expiratory volume in the first second / forced vital capacityFigure Legends:Figure 1. Different manifestations of pulmonary actinomycosis on chest CT. An irregular mass (arrow) is seen on the periphery of left upper lobe with pleural involvement in one patient (A), and central low-attenuation (arrow) is noted with mediastinal window settings (B). Two merged subpleural nodules with a central cavity (arrow) are seen in right upper lobe in another patient (C). D shows an ill-defined pulmonary infiltrate (arrow) in right middle lobe in another patient.
此文发表于《临床风湿病学杂志》Sun XF, Liu YJ, Xiao Y, Xu WB. Role of bronchoalveolar lavage for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 2014;20:369-72.Abstract Objectives: To evaluate the effectiveness of bronchoalveolar lavage (BAL) for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates, and to evaluate factors that affect the diagnostic yield. Methods: A retrospective study was performed in patients with rheumatic autoimmune diseases and lung infiltrates whose BALs were sent for microbial assays at Peking Union Medical College Hospital from January 2009 to June 2013. Patient characteristics, clinical symptoms, medication history, laboratory parameters, radiographic findings, lung lobe lavaged, and diagnostic yield were retrieved. Results: Seventy BALs were performed in 69 patients. The overall diagnostic yield of BAL for pulmonary infection was 17.1% (12/70), sensitivity was 35.5%, and specificity was 97.4%. Twelve microorganisms were isolated from 12 different BALs conforming to diagnostic criteria, including 4 aspergillus, 3 pneumocystis jirovecii , 3 gram-negative bacilli, 1 gram-positive coccus and 1 mycobacteria. Patients with clinical symptoms of fever, cough or expectoration had a higher diagnostic yield than patients without either symptom (25.6% versus 3.7%, P = 0.042). Patients with ground glass opacity, mass or consolidation radiographically had a higher yield than patients with reticular or nodular infiltrates (20.3% versus 0, P < 0.001). Conclusion: BAL is a useful tool for patients with rheumatic autoimmune diseases and lung infiltrates, especially in cases where initial antimicrobial therapy is ineffective. Opportunistic pathogens are important in patients with rheumatic autoimmune diseases and lung infiltrates, and should be considered when antibacterial treatment is ineffective. Keywords: Bronchoscopy; bronchoalveolar lavage; pulmonary infection; rheumatic autoimmune disease; computed tomographyINTRODUCTIONPulmonary complications are frequent in patients with rheumatic autoimmune diseases, and are usually caused by pulmonary infection or non-infectious pneumonia related to rheumatic autoimmune disease itself or associated treatment. As a commonly-seen event, pulmonary infection is sometimes similar to non-infectious pneumonia symptomatically and radiographically in patients with rheumatic autoimmune diseases, but the treatment is completely different. Routine microbiological procedures, such as sputum examination, throat swab and blood culture, are usually applied in immunosuppressed patients, but often fail to identify pneumonia agents1. Bronchoalveolar lavage (BAL) has been suggested to be an excellent and safe tool for the diagnosis of pulmonary infection in immunocompromised patients, especially in cases where initial empirical antimicrobial treatment is ineffective. However, the role of BAL in patients with rheumatic autoimmune diseases for diagnosing pneumonia has never been systemically studied in the prior literature. The aim of this study is to evaluate the effectiveness of BAL in obtaining diagnostic microorganisms in patients with rheumatic autoimmune diseases and lung infiltrates, and also to evaluate factors that affect the diagnostic yield.MATERIALS AND METHODSPatientsA retrospective review was performed in patients who were admitted to the Department of Rheumatology and underwent fiberoptic bronchoscopy (FOB) at Peking Union Medical College Hospital from January 2009 to June 2013. Eligibility criteria included the following: (1) diagnosis of rheumatic autoimmune disease; (2) presence of pulmonary abnormality on chest computed tomography (CT) scan; (3) performance of bronchoalveolar lavage (BAL) via FOB, and (4) specimen of BAL sent for microbial smear and culture.Data collectionThe following data were extracted from medical records for analysis: (1) clinical characteristics, including gender, age, diagnosis, disease course, clinical manifestation, medication history of corticosteroids and antibiotics before FOB; (2) laboratory parameters, including white blood cell count, erythrocyte sedimentation rate, C-reactive protein and plasma CD4+ T cell count; (3) chest computed tomography before bronchoscopy; (4) FOB results, including gross appearance under bronchoscopy and location of lung lobes lavaged; (5) pathogen results of specimen smear and culture for bacteria, fungus, mycobacteria and pneumocystis jirovecii.Diagnostic criteriaFor each patient, etiology was established according to BAL and other diagnostic procedures, clinical course and final outcome. The following diagnostic criteria were applied to determine whether an identified microorganism from BAL was a true pathogen: (1) Bacteria: quantitative BAL culture ≥ 104 CFU/ml or semi-quantitative culture ≥ 2+ was diagnostic; (2) Fungus: any aspergillus spp. identified by smear or culture was thought to be diagnostic, and all candida species isolated from BAL were thought to be due to contamination or colonization; (3) mycobacteria: positive acid-fast staining or culture was thought to be diagnostic; (4) pneumocystis jirovecii: positive PCR or Gomori’s methenamine silver staining was thought to be diagnostic.Statistical analysisStatistical analysis was performed with SPSS 19.0 software (SPSS Inc., USA). Classified variables were compared using Pearson χ2 test if n ≥ 40 and T ≥ 5, continuity correction test if n ≥ 40 and 1≤ T<5, or Fisher’s exact test if n << span="">40 or T < 1. Statistical significance was set at P < 0.05.RESULTSPatient CharacteristicsIn this study, 70 BAL procedures were performed in 69 patients. Since the interval was longer than two months in the patient who received twice bronchoscopy procedures, it was reasonable to regard the two procedures as separate ones. Therefore, each BAL was regarded as an individual patient in this study. This population had a mean age of 42.7±13.7 years (range from 12 to 63 years). Ratio of male to female was 1:2.5. Of these patients, 27 had systemic lupus erythematosus, 15 had polymyositis or dermatomyositis, 13 had vasculitis, 7 had primary Sjogren syndrome, 5 had arthritis, and the remaining 3 patients had unclassified connective tissue disease, adult still’s disease and spondyloarthropathy separately. Fifty-six (80%) patients had a duration of rheumatic autoimmune disease more than 3 months, and 44 (62.9%) patients manifested fever, obvious cough or expectoration. 85.7% and 67.1% patients were taking corticosteroids and antibiotics separately within two weeks before BAL. Characteristics of this population are presented in Table 1.Microorganisms Isolated from BALsTwelve microorganisms were isolated from 12 different BALs conforming to diagnostic criteria. Table 2 shows the distribution of these infectious diagnoses. Aspergillus (4/12) and pneumocystis jirovecii (3/12) were the most common etiologies, and Gram-negative bacilli also accounted for 3/12 diagnoses. Gram-positive coccus and mycobacteria were only found in one patient separately. Nine patients of the 12 microorganisms had treatment altered after BAL according to drug-susceptibility test.Diagnostic accuracyEtiology was finally contributed to pulmonary infection in 31 patients, in whom 11 BALs were diagnostic, and the others were diagnosed by the means of sputum examination, blood culture, serum antigen assay or treatment response to antibiotics. In the remaining 49 patients finally diagnosed as noninfectious diseases, only one patient’s BAL conformed to diagnostic criteria of infection. Therefore, the overall diagnostic yield of BAL for pulmonary infection was 17.1% (9.6-27.3%), sensitivity was 35.5% (20.3-53.3%), specificity was 97.4% (88.0-99.9%), positive predictive value was 91.7% (65.3-99.6%), negative predictive value was 65.5% (52.7-76.9%), and accuracy was 70.0% (58.5-79.9%).Factors affecting diagnostic yieldWe compared factors that might be associated with diagnostic yield, including age, gender, disease classification, disease course, clinical symptoms, medication history, white blood cell count, CD4+ T lymphocytes, modified erythrocyte sedimentation rate, C-reactive protein, chest CT scan and lobe of BAL (Table1, 3). Diagnostic yield was significantly improved in patients with clinical symptoms of fever, cough or expectoration compared to patients without either symptom (25.6% versus 3.7%, P = 0.042). Statistical difference was also significant between patients with radiographic findings of ground glass opacity, mass or consolidation and patients with reticular or nodular infiltrates (20.3% versus 0, P < 0.001). Statistical analyses of other factors did not reach a significant difference.DISCUSSIONIn this retrospective study, we aimed to evaluate the role of BAL for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates, and also to evaluate relevant factors. The main findings are as follows: (1) Opportunistic organisms, including aspergillus and pneumocystis jirovecii, are predominant in patients with rheumatic autoimmune diseases and BAL-confirmed pneumonia; (2) Diagnostic yield of BAL for pulmonary infection in patients with rheumatic autoimmune diseases is only 17.1%, and the sensitivity was 35.5%, but it has a high specificity and positive predictive value (>90%); (3) Patients with fever and pulmonary symptoms are more likely to have pulmonary infection than patients without symptoms. CT findings of ground glass opacity, mass or consolidation portend a better diagnostic yield than that of reticular or nodular infiltrates. The role of BAL for diagnosing pneumonia has never been systemically studied in patients with rheumatic autoimmune diseases before, but there are a lot of similar studies in immunocompromised patients, especially HIV patients, patients with transplantation, and patients with malignancy following antineoplastic treatment. Microbial yield of BAL in immunocompromised patients with lung infiltrates has varied from 27.7% to 64.8% in previous studies2-14. In this study, only 17.1% of BALs had microbial yield in patients with rheumatic autoimmune diseases, much lower than that in immunocompromised patients other than rheumatic autoimmune diseases. The most possible explanation might attribute to the fact that BALs in this study sent only for bacterial, fungal, mycobacterial assays and some for pneumocystis jirovecii assay, but assays of other pathogens such as virus, cryptococcosis and Legionella were lacking. In addition, heterogeneity of patient population and disease spectrum also contributed to the wide variation of diagnostic yield. Despite the low diagnostic yield and sensitivity, this study had a high specificity and positive predictive value, which meant a positive result of BAL was quite credible. In this study, aspergillus and pneumocystis jirovecii were the leading opportunistic pathogens of pulmonary infection in patients with rheumatic autoimmune diseases. It has been known that pulmonary aspergillosis is associated with neutrophil dysfunction, including neutropenia and impaired neutrophil phagocytic and bactericidal capacity caused by steroid use15. In this study, three cases of aspergillosis were neutropenic, and all four patients were using corticosteroid before BAL, confirming the association of aspergillosis with neutrophil dysfunction. As a matter of fact, pulmonary aspergillosis should be suspected first in neutropenic patients, especially when empiric antibacterial treatment is ineffective.Pneumocystis jirovecii in HIV-negative patients is associated with corticosteroid therapy in up to 75% of cases16, 17, and the morbidity in autoimmune inflammatory diseases has been reported to be as high as 28.5%18. The three cases of patients with Pneumocystis jirovecii pneumonia in this study were all in a large-dose corticosteroid therapy (methylprednisolone 30 mg to 1000 mg per day) when BAL was performed. The low morbidity of Pneumocystis jirovecii pneumonia in this study might be explained by the fact that only part of BALs sent for Pneumocystis jirovecii assay, and many patients were already in trimethoprim-sulfamethoxazole therapy when BAL was performed. Another important opportunistic pathogen with high morbidity in autoimmune diseases19-22, cytomegalovirus (CMV) in BAL, was not evaluated in this study. However, considering the fact that CMV antigenemia assay is usually enough for the diagnosis of CMV infection, invasive BAL procedure in CMV pneumonia was not as necessary as in other pathogens. This study showed that patients with rheumatic autoimmune diseases presenting with fever and pulmonary symptoms were more likely to have pulmonary infection than patients without symptoms, which was easy to be understood, and the correlation was also confirmed in immunocompromised patients other than rheumatic autoimmune diseases14. Radiographic characteristics on chest CT scan can be divided into two patterns: (1) bronchial or alveolar pattern including ground glass opacity, mass or consolidation, and (2) extra-alveolar pattern including reticular infiltrate. Nodules could be located in bronchiole or interstitium which was difficult to be distinguished on common CT, and here we grouped nodules with reticular pattern. Since non-viral pulmonary infection was related to bronchial obstruction or alveolar packing by pus or fluid, it was a reasonable deduction that pulmonary infection was more commonly-seen in alveolar pattern than in extra-alveolar pattern. The deduction was confirmed by this study and other studies in immunocompromised patients14.There were two main limitations in this study. First, as previously mentioned, BAL assays for microorganisms were incomplete, especially the lack of respiratory virus assay and/or atypical pathogen assay led to a low diagnostic yield. Second, etiology of each patient did not have a gold standard. However, we tried our best to make a final diagnosis based upon BAL and other diagnostic procedures, clinical course and final outcome, which was also applied in other studies. Upon strict criteria, diagnostic accuracy would be credible.In conclusion, for the first time, this study evaluated the role of BAL for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates. Although diagnostic yield was low after excluding virus and atypical pathogens, BAL was still an excellent procedure for patients with rheumatic autoimmune diseases and lung infiltrates, especially in cases where initial antimicrobial therapy was ineffective and it would guide correct antibiotic use. Opportunistic pathogens were important in patients with rheumatic autoimmune diseases and lung infiltrates, and should be considered when antibacterial treatment was ineffective.REFERENCES1 Cordani S, Manna A, Vignali M, et al. Bronchoalveolar lavage as a diagnostic tool in patients with hematological malignancies and pneumonia. Infez Med. 2008; 16: 209-13.2 Martin WJ, 2nd, Smith TF, Sanderson DR, et al. Role of bronchoalveolar lavage in the assessment of opportunistic pulmonary infections: utility and complications. Mayo Clinic proceedings Mayo Clinic. 1987; 62: 549-57.3 White P, Bonacum JT, Miller CB. Utility of fiberoptic bronchoscopy in bone marrow transplant patients. Bone marrow transplantation. 1997; 20: 681-7.4 Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005; 127: 1388-96.5 Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Annals of internal medicine. 1984; 101: 1-7.6 Feinstein MB, Mokhtari M, Ferreiro R, et al. Fiberoptic bronchoscopy in allogeneic bone marrow transplantation: findings in the era of serum cytomegalovirus antigen surveillance. Chest. 2001; 120: 1094-100.7 Hummel M, Rudert S, Hof H, et al. Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic malignancies and pulmonary infiltrates. Annals of hematology. 2008; 87: 291-7.8 Rano A, Agusti C, Jimenez P, et al. Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax. 2001; 56: 379-87.9 Eriksson BM, Dahl H, Wang FZ, et al. Diagnosis of pulmonary infections in immunocompromised patients by fiber-optic bronchoscopy with bronchoalveolar lavage and serology. Scandinavian journal of infectious diseases. 1996; 28: 479-85.10 Dunagan DP, Baker AM, Hurd DD, et al. Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest. 1997; 111: 135-41.11 Huaringa AJ, Leyva FJ, Signes-Costa J, et al. Bronchoalveolar lavage in the diagnosis of pulmonary complications of bone marrow transplant patients. Bone marrow transplantation. 2000; 25: 975-9.12 Velez L, Correa LT, Maya MA, et al. Diagnostic accuracy of bronchoalveolar lavage samples in immunosuppressed patients with suspected pneumonia: analysis of a protocol. Respiratory medicine. 2007; 101: 2160-7.13 Jain P, Sandur S, Meli Y, et al. Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates. Chest. 2004; 125: 712-22.14 Brownback KR, Simpson SQ. Association of bronchoalveolar lavage yield with chest computed tomography findings and symptoms in immunocompromised patients. Annals of thoracic medicine. 2013; 8: 153-9.15 Pneumonia in immunocompromised patients. Respirology. 2009; 14 Suppl 2: S44-50.16 Mori S, Cho I, Ichiyasu H, et al. Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthritis in Japan: a possible association between colonization and development of Pneumocystis jiroveci pneumonia during low-dose MTX therapy. Modern rheumatology / the Japan Rheumatism Association. 2008; 18: 240-6.17 Helweg-Larsen J, Jensen JS, Dohn B, et al. Detection of Pneumocystis DNA in samples from patients suspected of bacterial pneumonia--a case-control study. BMC infectious diseases. 2002; 2: 28.18 Fritzsche C, Riebold D, Munk-Hartig A, et al. High prevalence of Pneumocystis jirovecii colonization among patients with autoimmune inflammatory diseases and corticosteroid therapy. Scandinavian journal of rheumatology. 2012; 41: 208-13.19 Tsai WP, Chen MH, Lee MH, et al. Cytomegalovirus infection causes morbidity and mortality in patients with autoimmune diseases, particularly systemic lupus: in a Chinese population in Taiwan. Rheumatology international. 2012; 32: 2901-8.20 Mori T, Kameda H, Ogawa H, et al. Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy. The Journal of rheumatology. 2004; 31: 1349-51.21 Takizawa Y, Inokuma S, Tanaka Y, et al. Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population. Rheumatology (Oxford). 2008; 47: 1373-8.22 Hrycek A, Kusmierz D, Mazurek U, et al. Human cytomegalovirus in patients with systemic lupus erythematosus. Autoimmunity. 2005; 38: 487-91.
此文发表于《中国实用内科杂志》孙雪峰,柳涛,蔡柏蔷. 膈肌麻痹35例临床特点及相关文献复习. 中国实用内科杂志 2011; 31(11): 851-853摘要:目的提高膈肌麻痹的诊治水平。方法回顾性分析1995年1月至2010年3月北京协和医院就诊的14例及1980—2009年中国医院知识仓库(CHKD)中的21例非心脏手术非分娩相关膈肌麻痹患者的临床资料。结果本院资料男女比为2:5,中位年龄60岁。病变累及右侧、左侧和双侧之比为4:2:1。发病至确诊的平均时间为9.8个月。11例(78.6%)主诉胸闷气短,尤以活动或平卧加重。透视下sniff试验在双侧膈肌麻痹患者中均为阴性,在单侧8例(100%)可见受累侧膈肌运动减弱,1例(12.5%)可见膈肌矛盾运动。所有患者PO2均明显下降,较预计值平均降低11.8 mmHg(1 mmHg=0.133 kPa),卧位PO2较立位又平均降低11.0 mmHg,单侧与双侧膈肌麻痹各项血气指标比较差异无统计学意义。肺功能检查为典型限制性通气功能障碍,第1秒用力呼气容积占预计值百分比(FEV1%)由立位59.0%下降至卧位25.5%,平均降低50.3%。14例患者感染6例、特发性3例、肿瘤和手术相关各2例和重症肌无力1例;单纯对因治疗有效率为66.7%。文献统计结果我院结果大致相同。结论膈肌麻痹主要临床特点为卧位明显的呼吸困难,影像表现具有特征性。卧立位血气、卧立位肺功能检查有助诊断,膈神经刺激、跨膈压测定以及超声检查具有重要意义。治疗疗效取决于原发病的治疗,机械通气作为辅助治疗可以缓解病情。关键词:膈肌麻痹;临床特点;治疗缩写:FEV1%=1秒钟用力呼气容积占预计值百分比;FVC%=用力肺活量占预计值百分比;FEV1/FVC=1秒钟用力呼气容积/用力肺活量膈肌麻痹由膈神经病变引起,临床表现为呼吸困难,尤以平卧时明显。单侧膈肌麻痹(UDP)症状较轻,而双侧膈肌麻痹(BDP)往往伴有较重的气短症状,常被误诊为急慢性心力衰竭或冠心病,甚至因此行冠脉造影。目前国内普遍对膈肌麻痹重视不足,误诊和漏诊率极高。迄今为止,国内有关非心脏手术非分娩相关的膈肌麻痹局限于个案报道,尚未见此方面的统计分析。本研究统计分析了近15年内我院诊断的14例非心脏手术非分娩相关的膈肌麻痹病例,同时复习了1980年以来CHKD期刊全文数据库中的21例非心脏手术非分娩相关膈肌麻痹患者的临床资料,以期阐明膈肌麻痹的临床特点、诊断方法和治疗预后。1 对象与方法1.1 研究对象 1995年1月至2010年3月在北京协和医院住院治疗的14例膈肌麻痹患者,除外心脏直视术相关膈肌麻痹和新生儿分娩相关膈肌麻痹。使用CHKD期刊全文数据库进行文献搜索从1980—2009年题名包含“膈肌麻痹”,除外心脏直视术相关膈肌麻痹和新生儿分娩相关膈肌麻痹。共找到符合要求并提供全文的文献15篇,包含21例非心脏手术非分娩相关膈肌麻痹患者。膈肌麻痹目前尚无权威的诊断标准,本研究将同时符合以下2条的患者诊断为膈肌麻痹:(1)X线胸片示单侧或双侧膈肌抬高;(2)透视下sniff试验阳性,或膈神经刺激/跨膈压测定支持膈肌麻痹,或有症状和明确病因且去除病因后症状缓解。1.2 方法回顾性分析符合诊断标准的14例患者的住院病历及门诊病历资料,分析(1)肺部体征;(2)影像:包括X线胸片、胸部CT及胸部透视下sniff试验;(3)自然状态血气;(4)肺功能检查;(5)病因分析;(6)治疗及预后分析。同时复习符合要求的相关文献。1.3 统计分析数据处理采用SPSS 17.0软件处理,计量资料统计采用t检验,P<0.05为差异有统计学意义。2 结果2.1 一般情况本院资料组14例膈肌麻痹患者,4男10女,右侧、左侧与双侧膈肌麻痹者分别为8人、4人与2人,发病中位年龄为60岁(38岁-75岁),从发病至诊断平均间隔时间为9.8个月(2周-72个月)。国内文献组符合要求的21例膈肌麻痹患者[1-15],11男9女,另有1人性别不详,右侧、左侧与双侧膈肌麻痹者分别为10人、6人与5人,发病中位年龄为51岁(14个月-71岁),从发病至诊断平均间隔时间为4个月(3天-12个月)。2.3 症状与体征本院资料组14例患者中,2例BDP与9例UDP患者均因胸闷气短入院,活动后及平卧后加重;1例BDP患者可见呼吸时腹部矛盾运动,其余患者均未见描述。11例患者有异常的肺部体征,表现为患侧呼吸音减低、肺下界上移或湿啰音,其余3例患者肺部查体未见异常。国内文献组患者21例患者中,17例患者均有轻重不一的呼吸困难;除3例未描述外其余18例均有异常肺部体征,主要为三凹征、患侧呼吸音减低和矛盾呼吸。2.4 影像本院资料组全部患者在X线胸片上均可见单侧(与对侧比较)或双侧(与之前比较)膈肌抬高。12例接受胸部CT检查,其中4例描述病变侧下肺膨胀不全,6例描述膈肌抬高,其余无相关描述。10例接受胸部透视检查,2例BDP患者透视下sniff试验均为阴性;其余8例UDP患者透视下均可见单侧膈肌运动较对侧减弱,其中有1例可见膈肌矛盾运动。国内文献组X线胸片同样均见受累侧膈肌抬高。6例患者行胸部CT,4例描述患侧膈肌抬高。9例接受胸部透视检查,均可见患侧膈肌运动减弱和/或矛盾运动。2.5 血气分析本院资料组12例患者行自然状态立位血气测定,实测PO2为(70.7±11.3)mmHg,实测PCO2 为(40.7±4.1)mmHg,根据以下公式计算:预计PO2(mmHg)=102-(0.33×年龄),ΔPO2(预计-实测)为(11.8±10.7)mmHg。有6例患者同时行自然状态卧立位血气测定,其PO2由立位的(73.6±7.5)mmHg降至卧位的(62.6±8.6)mmHg,ΔPO2(立位-卧位)为(11.0±3.8)mmHg。UDP与BDP分组比较无显著性差异。国内文献组仅4例提供自然状态立位血气结果,实测PO2为(83.5±8.3)mmHg;其中有3例患者同时行自然状态卧立位血气测定,ΔPO2(立位-卧位)为(25.3±9.8)mmHg。2.6 肺功能本院资料组12例患者行立位肺功能检查,均为限制性通气功能障碍。立位FEV1%为(59.0±17.5)%,立位FVC%为(61.6±16.1)%,立位FEV1/FVC为(80.0±14.6)%。有4例患者同时行卧立位肺功能检查,卧位FEV1%为(25.5±9.2)%,卧位FVC%为(24.8±10.4)mmHg,ΔFEV1(立位-卧位)/FEV1立位为(50.3±23.3)%。国内文献组仅5例行立位肺功能检查,均为限制性通气功能障碍,无一例行卧立位肺功能比较。2.7 其他检查本院资料组及国内文献组各有2例行膈神经刺激检查,均支持膈肌麻痹诊断。本院资料组尚有1例患者行跨膈压测定,较正常降低。此外,本院资料组有2例患者因气短、不能平卧在外院误诊为冠心病并行冠脉造影,造影结果均正常。2.8 病因分析本院资料组2例BDP中,1例为乳腺癌纵隔转移压迫膈神经所致,另1例为特发性。12例UDP中,6例为感染,重症肌无力、肺腺癌、壁层心包切除术后和右肺切除术后各有1例,另2例为特发性。国内文献组中,5例为感染,8例为肿瘤,脑挫伤、II型糖元累积病、Weber-Christian氏病、脊髓前角病变、胸腺瘤手术后和射频消融术后各有1例,另2例为特发性。2.9 治疗及预后本院资料组14例均接受治疗,6例感染患者均予抗感染治疗,其中2例予BiPAP辅助治疗,3例抗感染后、2例同时予BiPAP治疗后好转,1例感染未控制自动出院;2例肿瘤与1例重症肌无力患者均予针对原发病治疗后好转;2例手术相关患者有1例接受BiPAP辅助治疗,均病情稳定或好转;3例特发性患者未接受任何治疗,均病情稳定。国内文献组报道有17例接受治疗,5例感染患者抗感染后好转;6例肿瘤患者治疗肿瘤后,4例肿瘤控制而好转,1例肿瘤控制但未恢复,1例肿瘤未控制未恢复;1例脑挫伤患者予体外膈肌起搏后好转;1例II型糖元累积病患者予有创呼吸机辅助通气后存活3个月,后因放弃治疗死亡;2例手术相关患者有1例予有创通气,后均稳定或好转;2例特发性患者未接受任何治疗,均病情稳定。对于可治疗病因,单纯对因治疗有效率在本院组为66.7%(6/9),在文献组为69.2%(9/13)。3 讨论膈肌麻痹与膈膨升同属膈肌无力类疾病,两者在临床上经常混淆。狭义的膈膨升仅指膈肌先天缺陷引起的膈肌膨出,广义的膈膨升指膈肌纤维因发育不良、萎缩而异常的抬高,包括膈神经的不明病因、不明部位的损伤造成的膈肌抬高;而膈肌麻痹系指由于一侧或两侧的膈神经受损,神经冲动传导被阻断而产生的膈肌麻痹,导致膈肌异常上升和运动障碍。可见两者存在区别,但也存在一定的重叠。膈肌麻痹最多见于心脏直视术后并发症,而新生儿分娩时损伤膈神经也是引起膈肌麻痹的一个常见原因。非心脏手术非分娩相关的膈肌麻痹多呈散发,目前国内尚无有关的统计分析。本院及国内文献资料均显示非心脏手术非分娩相关膈肌麻痹以右侧居多,约为左侧2倍,而双侧同时受累最为少见。从临床出现症状至明确诊断时间普遍偏长,平均半年左右,这也提示临床对膈肌麻痹重视不足。UDP临床症状普遍较轻,而BDP往往引起较重的呼吸困难,活动及平卧后加重,表现为端坐呼吸。本研究中全部BDP与75%UDP均有呼吸困难主诉,与文献类似。X线胸片是最简便也是最早提示膈肌麻痹的影像检查,但X线胸片上发现膈肌抬高并不一定诊断膈肌麻痹。相较之下,本研究中胸部CT检查提示膈肌抬高的敏感性反较X线胸片为低,考虑与阅片不仔细以及对膈肌抬高不重视相关。胸部透视在膈肌麻痹中具有重要意义,文献报道胸透下sniff试验在单侧膈肌麻痹中敏感性大于90%[16],也往往以此作为单侧膈肌麻痹的诊断标准。BDP患者由于在sniff试验中缺乏健侧膈肌对照,往往得出阴性结果,如本研究中所示。因此,对临床怀疑双侧膈肌麻痹的患者,不建议行sniff试验,而建议膈神经刺激或跨膈压测定。本研究表明,所有膈肌麻痹患者均有低氧血症或I型呼吸衰竭,PO2较预计值降低约10mmHg,而卧位PO2较立位再降低约 10mmHg。受限于病例数量,UDP与BDP在低氧严重程度上未发现区别,这也可能与住院诊治的单侧膈肌麻痹患者症状较重有关。典型的膈肌麻痹表现为限制性通气功能障碍,这一点在本研究中同样得到证实,FEV1与FVC在立位时约为预计值60%,而卧位时进一步降低至25%。有研究显示,单纯限制性通气功能障碍的患者卧位FVC较立位平均下降8.2%,当此值大于25%时需考虑膈肌功能障碍[17];本研究中FEV1与FVC平均下降约50%,是诊断膈肌麻痹的重要依据,我们也因此推荐临床怀疑膈肌麻痹的患者常规行卧立位肺功能检查。跨膈压测定和膈肌肌电图在膈肌麻痹的诊断中具有重要意义,尤其对于双侧膈肌麻痹的诊断。但本研究中仅有1例行跨膈压测定,2例行膈神经刺激检查,其重要性尚未被充分认识。膈肌运动的超声测定因其便捷、无创在近年被推荐应用于膈肌麻痹的诊断与评估恢复,但其与传统检测方法比较的优越性与可靠性尚需进一步评估证实,也希望国内今后能有此方面的研究。膈肌麻痹的病因可分为创伤性,压迫相关性,炎症性,肿瘤性和特发性。通过汇总国内文献及本院资料显示,感染、肿瘤与特发性为导致非手术相关非分娩相关膈肌麻痹最主要的病因,其余见于手术损伤膈神经、各种原因所致膈神经受压和系统性肌病等。文献报道颈椎病也是引起膈肌麻痹的一个重要病因,但本研究中未发现此两者相关性。一般单侧膈肌麻痹患者临床症状往往较轻,若呼吸功能稳定,观察即可;但若患者为双侧膈肌麻痹或患者呼吸困难症状较重影响生活,则需要临床治疗[18]。继发性膈肌麻痹的疗效取决于原发病治疗,若原发病无法去除,或对因治疗后效果不佳,可进行辅助治疗以缓解症状。无创呼吸机辅助通气可以缓解症状,但是不能阻止疾病的进展,部分患者可能需要气管插管或气管切开进行有创呼吸机辅助通气。综合本院组与文献组的研究显示:对于病因可治疗的膈肌麻痹,单纯治疗原发病即可使68%的膈肌麻痹好转,若再结合辅助治疗,此有效率将达到82%。这一结果进一步强调了在治疗膈肌麻痹时治疗原发病的重要性。膈肌折叠术适用于单侧膈肌麻痹患者,其疗效已经被多个小规模的研究所证实[18,19]。由于担心折叠的膈肌出现自发恢复反而影响通气,故双侧膈肌麻痹需慎用膈肌折叠术。国内也有报道在先心病术后出现膈肌麻痹的患儿中行膈肌折叠术获得了满意的疗效,但尚无在成人中应用膈肌折叠术的报道。膈神经起搏通过放置在胸颈部的电极刺激无损的膈神经而引起膈肌运动,也可通过将电极直接放置在膈肌内以达到起搏目的。国内仅少数文献涉及体外膈肌起搏[3],而体内膈肌起搏对术者要求较高,国内尚无相关研究报道。膈肌麻痹在症状轻时易被漏诊,症状重时又易被误诊。不管是漏诊还是误诊,均与临床医生对本疾病的认识不够相关,未能选择合适的检查以明确诊断。本研究的缺点在于未能将更多临床被忽视了的膈肌麻痹包括进来,导致统计资料时不可避免地出现偏移。尽管如此,通过对这14例的统计分析以及对相关文献的复习,能够帮助我们更好地认识膈肌麻痹,以减少误诊与漏诊。
此文发表于呼吸学科最优秀的杂志《美国呼吸与危重监护医学杂志》Sun X, Peng M, Hou X, et al. Refractory IgG4-related lung disease with constitutional symptoms and severe inflammation. Am J Respir Crit Care Med. 2014; 189: 374-5.To the editor:Rishi Raj summarized the characteristics of IgG4-related lung disease in the column of Editorial(1). What he did not discuss, but might be important is: although respiratory symptoms have been described in approximately one-half of patients with IgG4-related lung disease, constitutional symptoms have been uncommon(2, 3). We present here three cases of IgG4-related lung disease with apparent constitutional symptoms and severe inflammation. All of them were refractory to usual dose of prednisone.First is a 47-year old woman with a history of cough and expectoration for four years. There were also intermittent fever and urticaria. Chest CT scan showed a mass with spiculated margins in the right lower lobe, which was surgically resected in suspicion of lung cancer. Post-operative pathology coincided with IgG4-related lung disease, characterized by lymphoplasmocytic proliferation, active fibrois, obstructive vasculitis, and IgG4+ plasmocytes > 50/HPF. Two similar masses, one in right upper lobe and the other in left lower lobe, occurred four months after operation, with elevated erythrocyte sedimentation rate (ESR, 67 mm/hr) and C-reactive protein (CRP, 14.8 mg/L), but normal serum IgG4 concentration. FDG-PET showed high standardized uptake values (SUV, SUVmax 11.8) in the two masses and in hilar and mediastinal lymph nodes. She was treated with prednisone 40 mg/day, and the masses became larger during treatment. Methylprednisolone 80 mg/day was then given for five days, and then tapered to prednisolone 60 mg/day. Meanwhile, mycophenolate mofetil 500 mg Tid was added simultaneously. The masses shrank soon. However, during one year follow-up, when prednisolone was tapered to less than 15mg/day, or mycophenolat mofetil was reduced, the masses would enlarge in a short time.Second is a 36-year old man with a history of cough for ten months and intermittent hemoptysis for four months. There was also occasional fever, and the patient had a smoking history of 16 pack-years. Laboratory tests showed elevated white blood cell count (12.62 × 109/L), elevated ESR (106 mm/hr) and CRP (114.3 mg/L). IgG4 was also elevated to 7490 mg/L. Chest CT scan showed multiple nodules and masses in all sizes and densities, which had high SUVs in FDG-PET. Percutaneous lung biopsy got an nonspecific result, and biopsy from Video-assisted thoracoscopic surgery showed characteristics of IgG4-related lung disease (lymphoplasmocytic proliferation, IgG4+ plasmocytes > 50/HPF, and IgG4+ / IgG+ = 46%). He was treated with prednisone 45 mg/day, but there was no improvement in imaging at one month follow-up.Third is 45-year old woman with a history of fever, cough and chest pain for seven months. Inflammatory markers were apparently elevated (WBC 22.44 × 109/L, PLT 592 × 109/L, ESR 124 mm/hr, CRP 237 mg/L). IgG4 was also elevated to 3970 mg/L. Chest CT scan showed an irregular mass in upper right lobe with air bronchogram, and SUVmax reached 9.9 in FDG-PET. Similar to case 2, percutaneous lung biopsy was nonspecific, and biopsy from VATS coincided with IgG4-related lung disease. The patient was initially treated with prednisone 40mg/day. At one time clinical symptoms and imaging improved. However, when prednisone was tapered to 15 mg/day, the mass enlarged again.As a newly recognized disease, IgG4-related lung disease has not been well understood yet. Up to now, only limited cases have been reported in literature. Inoue D et al. have summarized four patterns of CT findings of IgG4-related lung disease: solid nodular, round-shaped GGO, alveolar interstitial and bronchoalveolar(4). However, it is still poorly understood about the difference between these patterns, especially the difference of clinical symptoms and treatment. We present here three cases of IgG4-related lung disease with CT findings of multiple nodules and masses, and all of them have constitutional symptoms and severe inflammation. Furthermore, all these patients are refractory to usual dose of prednisone treatment. Since pulmonary lesions are large in all these three patients, we would like to postulate that severe inflammation and constitutional symptoms would be parallel to the range of lesions. In spite of the fact that constitutional symptoms have also been occasionally reported in patients with other CT patterns(4), patients with multiple nodules and masses might be more prone to have constitutional symptoms and severe inflammation(5, 6). Increased dose of prednisone, and combination of other pharmacological agents, would be necessary in these patients.References1. Raj R. Igg4-related lung disease. American journal of respiratory and critical care medicine 2013;188:527-529.2. Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin g4-related sclerosing disease. The European respiratory journal 2012;39:180-186.3. Stone JH, Zen Y, Deshpande V. Igg4-related disease. The New England journal of medicine 2012;366:539-551.4. Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Kobayashi T, Yoshikawa J, Miyayama S, Yasui M, Nakanuma Y, Matsui O. Immunoglobulin g4-related lung disease: Ct findings with pathologic correlations. Radiology 2009;251:260-270.5. Sprangers B, Lioen P, Meijers B, Lerut E, Meersschaert J, Blockmans D, Claes K. The many faces of merlin: Igg4-associated pulmonary-renal disease. Chest 2011;140:791-794.6. Kobayashi H, Shimokawaji T, Kanoh S, Motoyoshi K, Aida S. Igg4-positive pulmonary disease. Journal of thoracic imaging 2007;22:360-362.