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[JAMA诊断试验解读]:曲霉菌半乳甘露聚糖诊断侵袭性曲霉菌病
2017年10月24日 临床话题, 基本知识 暂无评论

JAMA Diagnostic Test Interpretation

September 26, 2017

Aspergillus Galactomannan for Diagnosing Invasive Aspergillosis

Marisa H. Miceli, Carol A. Kauffman

JAMA. 2017;318(12):1175-1176. doi:10.1001/jama.2017.10661

A 67-year-old man with granulomatous polyangiitis (Wegener granulomatosis) complicated by end-stage renal disease requiring hemodialysis and mild pulmonary fibrosis, was hospitalized with a 2-week history of worsening dyspnea and dry cough. He was taking 20 mg prednisone and 150 mg azathioprine daily.

一名67岁肉芽肿性多血管炎(韦格纳肉芽肿)的男性患者因并发终末期肾病需要血液透析治疗,同时患者还罹患轻度肺间质纤维化。患者因呼吸困难及干咳加重2周入院治疗。患者用药包括强的松20 mg qd及硫唑嘌呤150 mg qd。

On examination, he was afebrile and had diffuse rhonchi and expiratory wheezes. A chest computed tomography (CT) scan revealed bilateral nodular infiltrates and a 1.3-cm cavitary nodule in the right upper lobe. Bronchoscopy was performed on day 2. Blood and bronchoalveolar lavage fluid test results are presented in the Table.

体格检查发现,患者不发热,肺部听诊可闻及弥漫性干罗音及呼气相哮鸣音。胸部CT显示双侧结节状侵润影,且右上肺叶有1.3 cm空洞。入院次日行支气管镜检查。血和肺泡支气管灌洗液检查结果见下表。

  

How Would You Interpret This Patient’s Test Results? 你如何解读患者检查结果?

View Results

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Discussion 讨论

Answer 答案

B. The patient has probable invasive pulmonary aspergillosis. 患者为疑似的侵袭性肺曲霉菌病

Test Characteristics 检查特征

Invasive aspergillosis primarily occurs in patients who have specific risk factors, such as prolonged neutropenia, history of allogeneic hematopoietic cell or solid organ transplantation, use of high-dose corticosteroids or inherited severe immunodeficiency. Dense, well-circumscribed nodular lesion(s) on CT scan, with or without surrounding hazy infiltrate (halo sign) and cavitary lesions, are characteristic but not specific for invasive pulmonary aspergillosis.

侵袭性曲霉菌病主要见于具有特异性危险因素的患者,如长期中性粒细胞缺乏,异体造血干细胞或实体器官移植病史,使用大剂量皮质激素或遗传性严重免疫功能缺陷。CT扫描可见致密的边界清晰的结节病变,伴或不伴周围模糊的浸润影(晕征)是侵袭性肺曲霉菌病的特征性表现,但缺乏特异性。

The Aspergillus galactomannan enzyme immunoassay detects polysaccharides that are present in the cell wall of Aspergillus species and that can be found in serum and bronchoalveolar lavage fluid during invasive infection.1,2

曲霉菌半乳甘露聚糖酶联免疫测定能够检测曲霉菌细胞壁上的多糖,在侵袭性感染时患者血清及肺泡支气管灌洗液中均可检测到。

The role of the galactomannan assay in the diagnosis of invasive aspergillosis has been studied most often in neutropenic patients and allogeneic hematopoietic cell transplant recipients.2,3 In these patient groups, the reported sensitivity of the assay in serum is 70% to 82% and specificity is 81% to 92%, and in bronchoalveolar lavage fluid, sensitivity is 73% to 100% and specificity is 68% to 92%.2 In solid organ transplant recipients, sensitivity is 21% to 86% and specificity is 80% to 89% in serum, and in broncholveolar lavage fluid, sensitivity is 60% to 90% and spedificity is 90% to 96%.4,5 The sensitivity of the assay is higher in bronchoalveolar lavage fluid than in serum, especially in lung transplant recipients.6

半乳甘露聚糖检测用于诊断侵袭性曲霉菌病的研究多见于中性粒细胞缺乏患者以及异体造血干细胞移植患者。在这些患者,血清检测的敏感性70-82%,特异性81-92%,肺泡支气管灌洗液的敏感性为73-100%,特异性为68-92%。在实体器官移植患者,血清半乳甘露聚糖检查的敏感性为21-86%,特异性为80-89%,而肺泡支气管灌洗液检测的敏感性为60-90%,特异性为90-96%。肺泡支气管灌洗液检查的敏感性高于血清,尤其是肺移植患者。

False-negative results occur in patients who are receiving antifungal agents other than fluconazole.7False-positive results occur in patients who are colonized but not infected with Aspergillus species and in those who have infection with Fusarium species, Histoplasma capsulatum, and Blastomyces dermatitidis because these fungi have similar galactomannans in their cell walls.

使用氟康唑以外的其他抗真菌药物时可出现假阴性结果。曲霉菌定植而非感染患者,镰刀霉属、荚膜组织胞浆菌及皮炎芽生菌感染患者可呈假阳性结果,因为这些真菌细胞壁具有相似的半乳甘露聚糖。

False-positive reactions with piperacillin-tazobactam have been reported in the past, but manufacturing changes have eliminated this problem. Other reported causes of false-positive results include severe mucositis, severe gastrointestinal graft vs host disease, blood products collected in certain commercially available infusion bags, multiple myeloma (IgG type), and flavored ice pops or frozen desserts containing sodium gluconate.

既往曾有报告哌拉西林-他唑巴坦可呈假阳性反应,但制药厂的工艺改变解决了这一问题。引起假阳性结果的其他原因包括严重的粘膜炎,严重的胃肠道移植物抗宿主病,采用某些输液袋收集的血液制品,多发骨髓瘤(IgG型)以及含有葡萄糖酸钠的冰棒或冰冻甜点等。

The time required to receive galactomannan test results is 2 to 7 days if the test is sent to a reference laboratory. The cost to Medicare is $90.

如果标本送到中心实验室,半乳甘露聚糖检测所需时间为2-7天。Medicare的费用为90美元。

Application of Test Results to This Patient 检查结果在此例患者的应用

This patient was at high risk for invasive pulmonary aspergillosis because of prolonged therapy with prednisone. Based on radiological findings and a positive galactomannan assay in bronchoalveolar lavage fluid, he was diagnosed with probable invasive pulmonary aspergillosis and started on voriconazole (Box).8,9Two days later, Aspergillus fumigatus was recovered in bronchoalveolar lavage fluid culture. Pseudomonas aeruginosa was also present in the culture but was considered to be only colonizing the airways.

此患者长期使用激素治疗,因此具有侵袭性肺曲霉菌病的高危因素。根据影像学发现以及肺泡支气管灌洗液半乳甘露聚糖检查结果阳性,诊断为疑似侵袭性肺曲霉菌病,并开始接受伏立康唑治疗。2天后,肺泡支气管灌洗液培养分离到烟曲霉菌。同时还培养到铜绿假单胞菌,但认为是气道定植菌。

Box. Simplified EORTC-MSG Diagnostic Criteria for Proven, Probable, and Possible Invasive Pulmonary Aspergillosisa

Proven Invasive Pulmonary Aspergillosis

  • Presence of host risk factors and radiological criteria and histopathologic or cytopathologic evidence of septate hyphae suggestive of Aspergillus species and compatible tissue damage in a specimen taken from a sterile site; or

  • Recovery of Aspergillus species by culture from a sterile site

Probable Invasive Pulmonary Aspergillosis

  • Presence of host risk factors and radiological criteria and recovery of Aspergillus species in culture from a nonsterile site; or

  • Evidence of septate hyphae suggestive of Aspergillus species in a specimen from a nonsterile site; or

  • Aspergillus galactomannan detected in serum or bronchoalveolar lavage fluid; or

  • (1,3) β-D-glucan detected in serum

Possible Invasive Pulmonary Aspergillosis

  • Presence of host risk factors and radiological criteria in the absence of microbiological evidence and no alternative diagnosis to explain these findings

Abbreviation: EORTC-MSG, European Organization for Research and Treatment of Cancer-Mycoses Study Group.

a Adapted from De Pauw et al.8

Proven invasive pulmonary aspergillosis requires proof of tissue invasion by histopathological examination or positive culture from a normally sterile site.8 In this patient, the diagnosis of proven invasive pulmonary aspergillosis could not be made because the transbronchial lung biopsy did not show hyphae invading lung tissue. For patients who have hematological malignancies or have received a hematopoietic stem cell transplant, lung biopsy is rarely performed because of thrombocytopenia, and thus, most cases of invasive pulmonary aspergillosis in these patient groups are deemed probable or possible (Box).

确诊侵袭性肺曲霉菌病需要组织病理学检查证实组织侵袭,或无菌部位培养结果阳性。此例患者不能确诊侵袭性肺曲霉菌病,因为经支气管肺活检未发现菌丝侵袭肺组织。对于血液系统恶性肿瘤患者或接受造血干细胞移植的患者,因为血小板缺乏,很少进行肺活检,因此,这些患者中多数侵袭性肺曲霉菌病的诊断为疑似或可能。

What Are Alternative Diagnostic Testing Approaches? 还有哪些其他的诊断检查方法?

The Fungitell assay detects (1,3) β-D-glucan, another cell wall component of many different fungi. A positive Fungitell result supports the diagnosis of an invasive fungal infection but is not specific for aspergillosis.10

Fungitell检测可检测到(1,3) β-D-葡聚糖,这是很多不同的真菌细胞壁上的另一种成分。Fungitell检查结果阳性支持侵袭性真菌感染的诊断,但对于曲霉菌病缺乏特异性。

Patient Outcome 患者预后

The patient was discharged home to continue therapy with voriconazole. Eight weeks later, a chest CT showed marked improvement. He completed 16 weeks of antifungal therapy with voriconazole. Three months later, he remained asymptomatic.

这名患者最终出院回家时仍继续接受伏立康唑治疗。8周后,胸部CT显示病变明显好转。患者完成了16周的伏立康唑抗真菌治疗。3个月后,患者没有任何临床症状。

Clinical Bottom Line 临床概要

  • When invasive pulmonary aspergillosis is suspected, the following tests should be ordered immediately: a high-resolution CT scan of the thorax, serum galactomannan, and consultation for bronchoscopy with bronchoalveolar lavage for galactomannan assay, fungal stain, and culture. 怀疑侵袭性肺曲霉菌病时,应立即进行以下检查:胸部高分辨CT扫描,血清半乳甘露聚糖,请专科会诊进行支气管镜检查,留取肺泡支气管灌洗液检查半乳甘露聚糖、真菌涂片和培养

  • The sensitivity of the galactomannan assay for invasive pulmonary aspergillosis is higher in bronchoalveolar lavage fluid than in serum. 肺泡支气管灌洗液半乳甘露聚糖检查对于诊断侵袭性肺曲霉菌病的敏感性高于血清

  • In patients who have risk factors and radiologic findings suggesting invasive aspergillosis, a positive galactomannan in serum or bronchoalveolar lavage fluid confirms a diagnosis of probable invasive pulmonary aspergillosis. 具有危险因素且影像学提示侵袭性曲霉菌病的患者,血清或肺泡支气管灌洗液半乳甘露聚糖检查结果阳性,可以诊断疑似侵袭性肺曲霉菌病

  • In patients with risk factors for invasive aspergillosis and radiologic findings consistent with invasive pulmonary aspergillosis, antifungal therapy should be started while awaiting cultures and galactomannan test results. 具有危险因素且影像学符合侵袭性曲霉菌病的患者,在等待培养及半乳甘露聚糖检查结果时,应当开始抗真菌治疗

References

1. Hope WW, Kruhlak MJ, Lyman CA,  et al.  Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis.  J Infect Dis. 2007;195(3):455-466.PubMedArticle

2. Miceli MH, Maertens J.  Role of non-culture-based tests, with an emphasis on galactomannan testing for the diagnosis of invasive aspergillosis.  Semin Respir Crit Care Med. 2015;36(5):650-661.PubMedArticle

3. Maertens JA, Klont R, Masson C,  et al.  Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay.  Clin Infect Dis. 2007;44(10):1329-1336.PubMedArticle

4. Pfeiffer CD, Fine JP, Safdar N.  Diagnosis of invasive aspergillosis using a galactomannan assay.  Clin Infect Dis. 2006;42(10):1417-1427.PubMedArticle

5. Husain S, Clancy CJ, Nguyen MH,  et al.  Performance characteristics of the platelia Aspergillus enzyme immunoassay for detection of Aspergillus galactomannan antigen in bronchoalveolar lavage fluid.  Clin Vaccine Immunol. 2008;15(12):1760-1763.PubMedArticle

6. Zou M, Tang L, Zhao S,  et al.  Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis.  PLoS One. 2012;7(8):e43347.PubMedArticle

7. Duarte RF, Sánchez-Ortega I, Cuesta I,  et al.  Serum galactomannan-based early detection of invasive aspergillosis in hematology patients receiving effective antimold prophylaxis.  Clin Infect Dis. 2014;59(12):1696-1702.PubMedArticle

8. De Pauw B, Walsh TJ, Donnelly JP,  et al.  Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.  Clin Infect Dis. 2008;46(12):1813-1821.PubMedArticle

9. Patterson TF, Thompson GR III, Denning DW, et al.  Practice guidelines for the diagnosis and management of aspergillosis.  Clin Infect Dis. 2016;63(4):e1-e60.PubMedArticle

10. Karageorgopoulos DE, Vouloumanou EK, Ntziora F,  et al.  β-D-glucan assay for the diagnosis of invasive fungal infections.  Clin Infect Dis. 2011;52(6):750-770.PubMedArticle

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