The role of muscle flaps in pulmonary aspergillosis

Pulmonary invades the lung parenchyma and vessels, causing necrotizing pneumonia and massive hemoptysis in immunocompromised patients. Medical treatment alone often fails to clear the organism. Early surgical intervention is advocated in localized disease to remove infection near pulmonary vessels. The resection is limited in an attempt to preserve as much lung function as possible. However, preexisting cavitations and lung disease predispose to postoperative space problems, including prolonged air leak, bronchopleural fistula, and empyema. Muscle flaps provide a solution to these problems by obliterating residual space and providing protective coverage to the bronchial stump. The authors present four cases of pulmonary aspergillosis treated by multimodality therapy and extrathoracic muscle flap transposition. Factors that may contribute to successful treatment include underlying condition of the host and history of cancer, radiation therapy, and great vessel involvement. Despite aggressive medical and surgical therapy, pulmonary aspergillosis has a poor prognosis.     

128例侵袭性肺曲霉病临床疗效分析

目的 通过回顾性病例分析,加强对侵袭性肺曲霉病的认识,重视对侵袭性肺曲霉病的分级诊断,从而制定合理治疗方案.方法 对四川大学华西医院201 1年1 ～12月128例诊断为侵袭性肺曲霉病患者的临床资料进行回顾性分析,重点分析基础疾病、临床表现、影像学表现、诊断及治疗方法.结果 确诊17例;依据宿主危险因素、临床表现及反复痰培养阳性拟诊111例.128例患者均伴有基础疾病.治疗方案包括伏立康唑（86例）,两性霉素B脂质体（1例）,伊曲康唑（12例）,米卡芬净（3例）,卡泊芬净（3例）,两性霉素B去氧胆酸盐（10例）,伏立康唑联合米卡芬净（1例）.治愈或好转81例（63.28％）,自动出院24例（18.75％）,死亡23例（17.97％）.结论 侵袭性肺曲霉病患者多数伴有多种感染危险因素,应当重视侵袭性肺曲霉病的分级诊断,据不同情况给予适当抗真菌治疗,以降低患者病死率.     

肝移植术后曲霉的气道定植与侵袭性曲霉病的关系

目的评价肝移植术后曲霉气道的定植及其发生侵袭性感染的风险。方法回顾2003—2004年南京八一医院和上海长征医院56例肝移植患者进行的连续组织学检查和曲霉培养结果。结果24例患者被分离出曲霉,2例发生侵袭性烟曲霉感染。这2例患者在移植后6个月内都有烟曲霉的定植,并且都死亡,占所有移植后死亡的29％。无曲霉定植者都未发生侵袭性曲霉感染。结论肝移植术后的侵袭性曲霉感染较为少见,但常致死,曲霉定植常见但为一过性,由于气管侵袭性曲霉感染只发生在有烟曲霉定植的移植后6个月内的患者,所以在此期间进行预防性的治疗能否有效降低侵袭性曲霉感染值得研究。     

肺部侵袭性曲霉菌感染的诊断思路

侵袭性真菌感染(invasive fungal infection,IFI)是免疫低下患者常见的并发症之一,尤其在血液肿瘤患者和造血干细胞移植后患者中,IFI更是影响患者生存和生活质量的重要因素。随着氟康唑在高危人群中的广泛预防性应用,白念珠菌的感染较前已有所减少,而曲霉菌的感染比例则有所增[1]     

T cell vaccination in mice with invasive pulmonary aspergillosis

Aspergillus fumigatus, an opportunistic fungal pathogen, is responsible for multiple airway diseases of an allergic and a nonallergic nature. In a murine model of invasive pulmonary aspergillosis, resistance is associated with a decreased lung inflammatory pathology and the occurrence of an IL-12-dependent Th1-type reactivity that are both impaired by IL-4. In the present study we assess the ability of Aspergillus crude culture filtrate Ags and the recombinant allergen Asp f 2 to induce protective antifungal responses in mice with invasive pulmonary aspergillosis. Similar to what occurred upon nasal exposure to viable A. fumigatus conidia, treatment of immunocompetent mice with Aspergillus crude culture filtrate Ags resulted in the development of local and peripheral protective Th1 memory responses, mediated by Ag-specific CD4+ T cells producing IFN-gamma and IL-2 capable of conferring protection upon adoptive transfer to naive recipients. Protective Th1 responses could not be observed in mice deficient of IFN-gamma or IL-12 and did not occur in response to Asp f 2, which, on the contrary, elicited high level production of inhibitory IL-4. The results show that Ags of Aspergillus exist with the ability to induce both Th1- and Th2-type reactivity during infection, a finding that suggests a possible mechanism through which potentially protective immune responses are inhibited in mice with the infection. However, the occurrence of Th1-mediated resistance upon vaccination with Aspergillus crude culture filtrate Ags, suggests the existence of fungal Ags useful as a candidate vaccine against invasive pulmonary aspergillosis.     

Early diagnosis of invasive pulmonary aspergillosis in a young immunocompetent patient

A 22-year-old insulin-dependent diabetic male was admitted for diabetic ketoacidosis. He developed hospital-acquired pneumonia (HAP) for which empirical antibiotic and antifungal therapy was started on the ward. On day 6, clinical and laboratory findings worsened, and bronchoalveolar lavage (BAL) was performed. Serum real time-polymerase chain reaction (RT-PCR) indicated invasive pulmonary aspergillosis (IPA) and led to antifungal therapy being initiated 48 hours before the results of the BAL culture were available. Despite early appropriate antifungal therapy, however, the patient died on day 22 while being supported by venovenous extracorporeal membrane oxygenation.     

Bronchoalveolar lavage in an immunosuppressed rabbit model of invasive pulmonary aspergillosis

A rabbit model of invasive aspergillosis has been used to investigate the pathogenesis of Aspergillus infection in the immunosuppressed host. The animals received hydrocortisone daily and a single dose of cyclophosphamide 2 days prior to intratracheal instillation of conidia from Aspergillus fumigatus. Bronchoalveolar lavage (BAL) was performed in 3 infected and 2 control saline treated animals sacrificed on days 1, 2, 4, 7 and 10 following inoculation. Infective load within the lung was quantified using an assay for chitin which is an important component of fungal cell walls (in particular the hyphal cell wall) and is not present in vertebrate tissue. The total BAL white cell count did not discriminate between infected and saline treated animals and Aspergillus was cultured from one lavage specimen only. Infected animals developed a marked neutrophil alveolitis by day 2 in contrast to a near total absence of neutrophils in the lavages of the control animals. Phagocytosis of conidia by alveolar macrophages was prominent but did not prevent progressive infection as confirmed by measurement of lung chitin. This pattern of cellular response within the alveolar airspace reflects the complex nature of the response to Aspergillus infection in the immunosuppressed host.     

胞浆识别受体NODs及其信号通路在侵袭性肺曲霉病中的作用

【目的】研究天然免疫系统中胞浆识别受体NODs及其信号通路在小鼠侵袭性肺曲霉病(IPA)中的作用。【方法】小鼠随机分为正常对照组、正常+接种烟曲霉菌组(正常感染组)和免疫抑制+接种烟曲霉菌组(IPA组),经鼻吸入烟曲霉孢子后在不同时相点处死小鼠,无菌取肺组织分别进行病理切片,烟曲霉菌落计数,RT-PCR法、Western blot法动态检测小鼠感染烟曲霉菌过程中肺组织NOD1、NOD2、RIP2 mRNA表达,促炎细胞因子TNF-α含量的变化规律。【结果】鼻吸入烟曲霉菌后72 h时,IPA组肺组织出现严重炎症反应,并有大量的菌丝生成,同时各时相点的烟曲霉菌负荷均高于正常感染组;与正常感染组比较,IPA组NOD1、RIP2 mRNA持续低表达,而NOD2 mRNA则在感染最早期(24 h)异常高表达,而在随后的感染过程中一直处于低表达状态;正常小鼠感染烟曲霉菌后,肺组织中促炎细胞因子TNF-α在感染前期皆呈高表达,且最高表达量均出现在48 h或72 h,之后下降并恢复至正常水平。而IPA小鼠促炎症细胞因子TNF-α缓慢且低水平释放。【结论】NOD1、RIP2的表达受到长期抑制,NOD2在感染最早期的过度激活以及随后的抑制表达,引起促炎细胞因子低表达,可能导致了侵袭性肺曲霉的发生发展。     

黄曲霉致鼻-眼-耳-脑侵袭性曲霉病的抗真菌治疗

报告1例抗真菌治疗有效的重症鼻、眼、耳、脑侵袭性曲霉病。患者男,37岁,因右眼眶肿物11a,右眼视力下降8a,失明伴头痛、头晕进行性加重1a就诊。11a前曾行右上颌窦根治术。临床表现为右眼球突出眼眶,角膜混浊,球结膜充血,眼球内可见白色絮状团块,并有大量透亮稀薄液态分泌物流出。右眼球不能自主活动,完全无光感。右眼眶下方、右上颌窦骨质缺损,塌陷。右侧外耳道骨壁、乳突均受累及。右侧鼻道及外耳道亦见较多透亮稀薄液态分泌物。右眼、右鼻腔、右耳分泌物真菌涂片均见菌丝及孢子,培养结果均为同一黄曲霉。经两性霉素B及伊曲康唑、氟胞嘧啶联合抗真菌治疗6周后,予口服伊曲康唑维持治疗近18个月,目前病变区显著缩小,头痛、头晕症状消失。     

Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC₅₀ of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation.     

Invasive pulmonary aspergillosis due to a mixed infection caused by Aspergillus flavus and Aspergillus fumigatus

Invasive pulmonary aspergillosis is typically caused by a single Aspergillus species, most frequently Aspergillus fumigatus. Here we report that a lung transplant recipient developed invasive aspergillosis due to a mixed infection caused by Aspergillus flavus and A. fumigatus. The implications for this unusual finding are discussed.     

Value of Aspergillus galactomannan antigen detection in the diagnosis and follow-up of invasive aspergillosis in hematological patients

Serum galactomannan detection is considered to be a useful test for early diagnosis and follow-up of invasive aspergillosis. From February to September 2002, adult patients hospitalized in our Hematology Unit for receiving intensive chemotherapy and/or hematopoietic stem cell transplant were prospectively studied. We analyzed a total of 760 samples obtained from 100 patients. Eleven patients (11%) having a positive result (OD index >1.5 ng/ml) in two consecutive Platelia Aspergillus tests were considered galactomannan-positive cases. On the other hand, 12 patients (12%) were diagnosed of proven or probable invasive aspergillosis. Sensitivity (66.6%), specificity (95.5%), positive predictive value (72.7%) and negative predictive value (96.7%) were comparable to those of larger series. Galactomannan positivity allowed also to anticipate invasive aspergillosis diagnosis (from two to 17 days before radiographic findings and from two to 15 days before mycological culture). Moreover, kinetics of antigenemia could be useful for assessing therapeutic response. Once accepted galactomannan test as a diagnostic criterium for invasive aspergillosis knowing potential causes of false positive results is of paramount importance.     

慢性阻塞性肺疾病急性加重期合并侵袭性肺曲霉菌病23例临床分析

目的探讨慢性阻塞性肺疾病急性加重期(AECOPD)合并侵袭性肺曲霉菌病(IPA)的危险因素及临床特点。方法回顾分析2008年5月至2010年6月浙江大学医学院附属第一医院收治的慢性阻塞性肺疾病急性加重期合并侵袭性肺曲霉菌病患者的临床资料。结果 23例患者中,确诊7例,临床诊断16例。平均年龄(68.3±4.32)岁。其中22例使用广谱抗生素和15例长期使用激素,12例1年内住院>3次,11例年龄>70岁。病灶出现在双上肺占52.1%,双肺多发占21.7%,双下肺占13.0%,位于右中叶和左舌叶共占13.0%;其中5例(21.7%)出现晕征,4例(17.3%)出现"新月"征。结论使用广谱抗生素、长期激素治疗、频繁住院等是慢性阻塞性肺疾病合并肺曲霉菌的危险因素,患者临床表现缺乏特异性,胸部CT表现有一定特征性,结合患者有危险因素及实验室检查,有助于早期诊断和早期治疗,改善患者预后。     

侵袭性曲霉菌病13例临床特点分析

目的分析侵袭性肺曲霉病(IPA)的临床特点,提高对本病的认识。方法对13例确诊的IPA患者的临床资料进行回顾性分析。结果 IPA患者中存在基础疾病或危险因素者占69.2%(9/13);临床表现包括咳嗽、黄痰(13/13)、高热(11/13)、胸闷或呼吸困难(7/13)和咯血(2/13)等;92.3%(12/13)患者有高白细胞血症,WBC大多为(15~30)×109;10例G试验检测的患者中有9例出现阳性;影像学检查:肺内多发空洞及"空气新月征"9例(69.2%),"晕轮征"2例(15.4%),支气管炎表现6例(46.2%),胸腔积液3例(23.1%),颅内播散病灶1例;气管镜检查以粘膜水肿、脓痰、管腔坏死物为主;9例患者痰培养或肺泡灌洗液培养阳性(占69.2%),所有患者病理检查均见曲霉菌丝。所有患者均接受抗真菌药物治疗,4例好转出院,9例恶化放弃治疗或死亡。结论 IPA是临床严峻挑战;掌握该病的临床特点、实验室检查和胸部影像特征,及时的气管镜、组织病理检查有助于IPA确诊。临床医师应高度重视曲霉病。