Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens
Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens
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DOI：
10.1371/journal.pone.0143165
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发表时间：
2015-11-18
期刊：
影响因子：
3.7
通讯作者：
Wingard, John R.
中科院分区：
文献类型：
--
作者：
Brasier, Allan R.;Zhao, Yingxin;Wingard, John R.
侵袭性肺曲霉菌病（IPA）是一种机会性真菌感染，发生在因血液系统恶性肿瘤、造血干细胞移植或其他形式的免疫抑制而接受化疗的患者中。在这一组中，曲霉菌感染占霉菌病原体所致死亡的大多数。虽然早期发现与改善的结果，目前的诊断方案缺乏敏感性和特异性。接受化疗、干细胞移植和肺移植的患者入组了一项多中心前瞻性观察性试验。使用生物流体分析平台对疑似和可能的IPA病例以及匹配的对照进行发现蛋白质组学分析，将血浆分级分离成可重现的蛋白质和肽池。从2D凝胶电泳鉴定的556个斑点中，仅在白血病亚组中鉴定出66个差异表达的纯化后修饰的血浆蛋白。该蛋白质组富含补体成分、急性时相反应物和凝血因子。鉴定了与丰富血浆蛋白相对应的低分子量肽。通过统计学过滤选择宿主应答（9种血浆蛋白，4种肽）、真菌多糖（半乳甘露聚糖）和细胞壁组分（β-D葡聚糖）的候选标记物组，作为白血病患者的主要基础诊断。开发定量测量以使用选择性反应监测质谱分析来鉴定候选宿主应答蛋白的差异表达，然后应用于57名白血病患者的单独队列。在这个验证队列中，基于机器学习集成的算法，广义路径搜索器（GPS）比单独的半乳甘露聚糖（GM）或宿主蛋白质产生了更高的病例分类准确性。总之，整合宿主反应蛋白与GM提高了对接受血液系统恶性肿瘤治疗的患者中可能IPA的诊断检测。经过进一步验证，在白血病治疗中早期发现可能的IPA将为早期干预和干预性临床试验提供机会。
Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (beta-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials.