血浆微小RNA-21表达水平对侵袭性肺曲霉病的诊断价值

Expression and differential diagnostic value of serum microRNA for invasive pulmonary aspergiliosis

目的探讨血浆微小RNA（miR-21）表达水平对侵袭性肺曲霉病（IPA）的诊断价值。方法收集2014年6月至2015年9月广西医科大学附属第四医院门诊和住院的40例IPA患者，男22例，女18例，年龄55-68岁，平均60岁；50例肺结核患者，男23例，女27例，年龄50-62岁，平均55岁；50例肺癌患者，男30例，女20例，年龄55-70岁，平均62岁；同时选取同期门诊健康体检者50名作为对照组，男25名，女25名，年龄50-67岁，平均60岁。检测血浆中miR-21表达水平并单独或联合进行半乳甘露聚糖试验（GM试验）和真菌（1，3）-β-D葡聚糖试验（G试验）。本研究为病例对照研究。采用logistic回归和受试者工作特征曲线（ROC曲线）分析研究结果。结果IPA及肺癌患者miR-21高表达，中位数（最，，氏）分别为0．42（0．31，0．62）和0．80（0．65，0．94），与对照组的0．09（0．04，0．15）和肺结核组的0．08（0．03，0．16）比较，差异均有统计学意义（均P〈0．001）；IPA组分别与对照组、肺结核组及肺癌组鉴别诊断时，miR-21受试者工作曲线下面积（AUC）分别为0．914、0．897和0．863，约登指数分别为0．780、0．700和0．605。血浆中miR-21表达水平在0．198-0．723时，鉴别诊断IPA的准确性较好。IPA与对照组miR-21联合G试验或GM试验的AUC值分别为0．992和0．966，敏感度分别为95％（38／40）和93％（37／40），特异度分别为98％（49／50）和96％（48／50），约登指数分别为0．930和0．885，当三者联合检测时AUC值为0．994，敏感度和特异度分别为98％（39／40）和96％（48／50），约登指数可达0．935。IPA与肺结核组的3个指标联合检测时AUC值可达0．984，敏感度和特异度分别为98％（39／40）和90％（45／50），约登指数为0．875。IPA与肺癌组miR-21联合G试验或GM试验的AUC值分别为0．948和0．979，约登指数分别为0．725和0．895，3个指标联合检测时AUC值可达0．998，敏感度和特异度分别为100％（40／40）和98％（49／50），约登指数可达0．980。结论IPA患者血浆miR-21高表达，当血浆miR-21表达水平为0．198-0．723时，对IPA具有较好的诊断价值。miR-21检测、G试验及GM试验3个指标联合检测的诊断效能优于各单项或双项指标检测的诊断效能。miR-21检测联合G试验及GM试验可提高IPA患者与肺结核、肺癌患者的鉴别诊断能力。

Objective To explore the expression and the clinical diagnostic value of serum miR-21 for invasive pulmonary aspergillosis （IPA）. Methods Outpatients and inpatients from the Fourth Affiliated Hospital of Guangxi Medical University were included in the study during June 2014 to September 2015. The IPA group had 40 patients, male 22, female 18, aged 55-68 years （mean 60 ）, while the control groups included 50 patients with pulmonary tuberculosis [ male 23, female 27, aged 50 - 62 years （ mean 55 ） ] , 50 patients with lung cancer [ male 30, female 20, aged 55 - 70 years （ mean 62 ） ], and 50 healthy controls [ male 25, female 25, aged 50 - 67 years （ mean 60） ]. Serum were obtained and the levels of miR-21 and galactomannan （GM test） and （1, 3 ）-beta-D-glucan （G test） were measured. The related indexes wereanalyzed by logistic regression and ROC curves. Results The serum miR-21 expression in IPA and lung cancer patients were increased, the median values （P25 and P75 ） being 0. 42 （0. 31,0. 62） and 0. 80 （0. 65, 0. 94） respectively, both of which were significantly higher than those of the healthy controls [ 0. 09 （0. 04, 0. 15）] and the tuberculosis cases [ 0. 08（0. 03,0. 16）], P 〈0. 001. The AUCs of miR-21 in IPA group, when compared to healthy controls, tuberculosis cases and lung cancer cases were 0. 914, 0. 897 and 0. 863 respectively, with the Youden index being 0. 780, 0. 700 and 0. 605 respectively. The serum levels of miR-21 in between 0. 198 and 0. 723 had preferable diagnostic accuracy. ROC analysis for miR-21 in IPA compared to healthy controls showed that the AUCs of miR-21 combined with G test or GM test were 0. 992 and 0. 966 respectively, the sensitivity being 95 % （38/40） and 93 % （37/40） respectively, the specificity being98% （49/50） and 96% （48/50） respectively, and the Youden index being 0. 930 and 0. 885 respectively. If miR-21 was combined with G test and GM test, the AUC was 0. 994, the sensitivity and the specificity being 98% （38/40） and 96% （48/50） respectively, and the Youden index increased to 0. 935. ROC analysis for miR-21 in IPA compared to tuberculosis cases showed that when miR-21, G test and GM test were combined, the AUC was 0. 984, the sensitivity and the specificity being 98% （38/40） and 90% （45/50） respectively, and the Youden index being 0. 875. ROC analysis for miR-21 in IPA compared to lung cancer cases showed that the AUC for miR-21 with G test and miR-21 with GM test were 0.948 and 0. 979 respectively, the Youden index being 0. 725 and 0. 895 respectively. When miR-21, G test and GM test were combined, the AUC was 0. 998, the sensitivity and the specificity being 100% （40/40） and 98% （49/50） respectively, and the Youden index increased to 0. 980. Conclusions The serum level of miR-21 in IPA and lung cancer patients were significantly elevated. The serum level of miR-21 between 0. 198 and 0. 723 had preferable differential diagnostic accuracy, and therefore miR-21 may be regarded as an independent potential diagnostic serum marker of IPA. The diagnostic efficiency of miR-21 combined with G test and GM test may be more preferable, and remarkably increase the differential diagnosis of IPA from tuberculosis and lung cancer.