向编辑:
结节病是特发性肺病的最常见原因之一。国际诊断标准的结节病是基于三个标准:1)兼容临床和/或放射性介绍;2)非加入肉芽肿的组织学证据;3)排除产生类似组织学或临床图的其他疾病[1]。结节病的诊断得到了升高的CD4 + / CD8 + T细胞比率,支气管肺泡灌洗(BAL)淋巴细胞增分和升高的血清血管紧张素转换酶(S-ACE)。但是,这些参数在结节八病变中是可变的[2–4]。
整联蛋白CD103在BAL的CD4 + T细胞上表达。由于循环T细胞的高流入结节病变,已经提出了BAL CD103 + CD4 + T细胞的级分的降低作为结节病的标志物,与淋巴细胞增多和CD4 + / CD8 +比例相结合[5]。In selected groups of patients, decreases in the fraction of CD103+CD4+ T-cells are significantly associated with sarcoidosis [6,7]。本研究的目的是评估这些参数作为第三级医院环境中连续患者的结节病的诊断标志。
这项研究包括病人落下帷幕subsequent flow cytometric analyses at the Dept of Respiratory Medicine, Aarhus University Hospital (Aarhus, Denmark) from August 2007 until April 2009 (n=107). The descriptive parameters and paraclinical findings, including s-ACE (U·L−1), BAL lymphocytosis (determined by differential count), and CD4+/CD8+ and CD103+CD4+/CD4+ T-cell ratios (determined using flow cytometry), were retrieved from case records. The analysis of CD4+/CD8+ ratio was not performed for five controls. The analysis of CD103+CD4+/CD4+ ratio was not performed for six controls. The lymphocyte count was not performed for 10 controls and two cases. The level of s-ACE was not measured for 34 controls. Two patients in the case group were treated with ACE inhibitors, and measurements of their s-ACE levels were not included in the analyses.
所有包含在案例组中的患者都有活组织检查证实的结节病,其中包含在跨刻度或纵隔淋巴结活组织检查中发现的非加以颗粒组织。11名患者具有结节病放射学阶段0 / I,8名患者有阶段II / III。我们没有根据临床特征,放射学或BAL调查结果诊断患有结节病的患者。
对照组的患者被诊断为其他肺部疾病(n = 88):外部过敏性肺泡(n = 12),特异性间质性肺炎(n = 6),非特异性间质性肺炎(n = 6),脱脂性间质肺炎(n =2),淋巴细胞间质肺炎(n = 1),胶原蛋白血管疾病与间质性肺病(n = 10),未分类的间质肺病(n = 26),结核(n = 2),曲霉病(n = 1)和其他非胰酸痛疾病(n = 18)。
BAL fluid was passed through a 40-μm nylon mesh and centrifuged. Subsequently, 100 μL BAL fluid was stained with the following titrated antibodies: allophycocyanin-conjugated CD45 antibody (BD 55485; Becton Dickinson, Brondby, Denmark), AmCyan-conjugated CD3 antibody (BD 339186; Becton Dickinson), peridinin–chlorophyll protein complex-conjugated CD4 antibody (BD 332772; Becton Dickinson), phycoerythrin-conjugated CD8 antibody (R0806; Dako, Glostrup, Denmark) and fluorescein isothiocyanate-conjugated CD103 antibody (BD 550259; Becton Dickinson). 1×106使用FACScanto™II系统(Becton Dickinson)进行分析事件。淋巴细胞和CD3 +,CD3 + CD4 +和CD3 + CD8 + T细胞被表示为CD45 +白细胞的级分。CD3 + CD4 + T细胞的数量除以CD3 + CD8 + T细胞的数量,以计算CD4 + / CD8 +比率。CD3 + CD4 + CD103 +细胞的数量除以CD3 + CD4 + T细胞的数量,以计算CD103 + CD4 + / CD4 +比。
The mean values of the diagnostic markers were compared using unpaired t-tests and p<0.05 was considered statistically significant. For each parameter, the optimal cut-off point was defined as the point on a two-parameter receiver operating characteristic plot where sensitivity = specificity. Sensitivity, specificity, positive predictive value and negative predictive value were subsequently calculated.
与其他肺病患者相比,我们在BAL流体中检测到明显升高的淋巴细胞百分比和CD4 + / CD8 +比率,对于患者的患者而言,S-ACE显着升高。但是,我们没有检测患者组之间的BAL流体中CD103 + CD4 + / CD4 +的任何显着差异(表格1)。两种或三个诊断标记的组合降低了灵敏度(35-59%)并增加了特异性(> 90%)(表2.)。CD103+CD4+/CD4+ did not correlate with radiographic staging.
Kolopp.-arda等。[7] reported a sensitivity of 96% for the combination of CD103+CD4+/CD4+ <0.31 and CD4+/CD8+ ≥2.5. In their study, all sarcoidosis patients (n=18) had biopsy-confirmed diagnoses, >10% lymphocytes and CD4+/CD8+ ≥2.5. H厄伦等。[6] reported a sensitivity of 66% and a specificity of 89% for the combined use of CD103+CD4+/CD4+ <0.2 with BAL CD4+/CD8+ >3 or BAL/peripheral blood CD4+/CD8+ >2 in 56 patients with biopsy-confirmed sarcoidosis.
Although BAL lymphocytosis is not a universal finding in sarcoidosis [2], the aforementioned studies included only patients with alveolar lymphocytosis. Among our sarcoidosis patients, five (29%) out of 17 patients had a lymphocyte percentage <10%. Using our optimised cut-off levels of 0.22 and 3.8 for CD103+CD4+/CD4+ and CD4+/CD8+, respectively, the sensitivity was 42% and the specificity was 91%.
Addition of CD103+CD4+/CD4+ to the combination of s-ACE and CD4+/CD8+ decreased sensitivity (表2.)。
当我们应用H报告的阈值时厄伦等。[6]对于我们的数据的BAL CD103 + CD4 + / CD4 +和CD4 + / CD8 +和CD4 + / CD8 +,我们发现39%的敏感性为39%(18名患者中的7例),特异性为87%(78名患者中有68例)。由于我们的研究未测量BAL /外周血CD4 + / CD8 +,因此排除了一种具有BAL CD4 + / CD8 + 3和CD103 + CD4 + / CD4 + <0.20的患者以允许比较研究。我们数据集中较低灵敏度的解释之一可能是患者未预先选择淋巴细胞症的事实。
使用k提出的标准olopp.-arda等。[7],我们发现敏感性为68%,特异性为79%。
早期的研究表明,射线摄影阶段I术中CD103 + CD4 + / CD4 +水平显着降低,与健康对照相比,射线照相阶段II / III结节病的显着升高[5]。We found no significant differences in CD103+CD4+/CD4+ levels between the two radiographically staged groups in our study.
S-ACE是具有高敏感性但低特异性的顺节病的重要标志物。ACE基因中的多态性影响正常的S-ACE浓度[8]。启动子的纯合缺失导致高水平的S-ACE(59.8相对32.2 U·L−1对于纯合的插入等位基因;P <0.0001)在德国人口中[8]。Screening for this polymorphism is not common practice; however, the use of genotype-corrected normal ranges may increase the value of this parameter in the diagnosis and follow-up of sarcoidosis.
The combinations of CD103+CD4+/CD4+, CD4+/CD8+ and lymphocyte percentages that were tested in this study showed limited diagnostic value in this unselected group of sarcoidosis patients. Previously proposed criteria based on combinations of CD103+CD4+/CD4+ and CD4+/CD8+ had a lower sensitivity in this study than previously reported. s-ACE is an established marker of sarcoidosis and is the most useful of the markers that were investigated in this study.
结节病是一种患有若干表型的疾病,其对有用的诊断标志物复杂化。在怀疑结节病时,新改进方法仍有一个未满足的需求,以支持诊断。
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