Abstract：
Cystic fibrosis (CF) is characterized by chronic respiratory infections which progressively decrease lung function over time. Affected individuals experience episodes of intensified respiratory symptoms called pulmonary exacerbations (PEx), which in turn accelerate pulmonary function decline and decrease survival rate. An overarching challenge is that there is no standard classification for PEx, which results in treatments that are heterogeneous. Improving PEx classification and management is a significant research priority for people with CF. Previous studies have shown volatile organic compounds (VOCs) in exhaled breath can be used as biomarkers because they are products of metabolic pathways dysregulated by different diseases. To provide insights on PEx classification and other CF clinical factors, exhaled breath samples were collected from 18 subjects with CF, with some experiencing PEx and others serving as a baseline. Exhaled breath was collected in Tedlar bags during tidal breathing and cryotransferred to headspace vials for VOC analysis by solid phase microextraction coupled to gas chromatography-mass spectrometry. Statistical significance testing between quantitative and categorical clinical variables displayed percent-predicted forced expiratory volume in one second (FEV1pp) was decreased in subjects experiencing PEx. VOCs correlating with other clinical variables (body mass index, age, use of highly effective modulator treatment (HEMT), and the need for inhaled tobramycin) were also explored. Two volatile aldehydes (octanal and nonanal) were upregulated in patients not taking the HEMT. VOCs correlating to potential confounding variables were removed and then analyzed by regression for significant correlations with FEV1pp measurements. Interestingly, the VOC with the highest correlation with FEV1pp (3,7-dimethyldecane) also gave the lowestp-value when comparing subjects at baseline and during PEx. Other VOCs that were differentially expressed due to PEx that were identified in this study include durene, 2,4,4-trimethyl-1,3-pentanediol 1-isobutyrate and 5-methyltridecane. Receiver operator characteristic curves were developed and showed 3,7-dimethyldecane had higher ability to classify PEx (area under the curve (AUC) = 0.91) relative to FEV1pp values at collection (AUC = 0.83). However, normalized ΔFEV1pp values had the highest capability to distinguish PEx (AUC = 0.93). These results show that VOCs in exhaled breath may be a rich source of biomarkers for various clinical traits of CF, including PEx, that should be explored in larger sample cohorts and validation studies.
摘要：
囊性纤维化(CF)的特征在于随着时间的推移逐渐降低肺功能的慢性呼吸道感染。受影响的个体经历加剧的呼吸道症状发作，称为肺加重(PEx)。这反过来又加速肺功能下降和降低存活率。一个总体挑战是PEx没有标准分类，这导致治疗是异质的。改善PEx分类和管理是CF患者的重要研究重点。先前的研究表明，呼出气中的挥发性有机化合物（VOC）可以用作生物标志物，因为它们是因不同疾病而失调的代谢途径的产物。提供有关PEx分类和其他CF临床因素的见解，从18名患有CF的受试者中收集呼出气样本，其中一些经历PEx和其他作为基线。在潮气呼吸期间，将呼气收集在Tedlar袋中，并将其冷冻转移到顶空小瓶中，以通过固相微萃取结合气相色谱-质谱法进行VOC分析。定量和分类临床变量之间的统计显著性测试表明，在经历PEx的受试者中，一秒内预测的用力呼气量百分比（FEV1pp）降低。与其他临床变量相关的VOC(体重指数，年龄,使用高效的调节剂治疗（HEMT），以及对吸入妥布霉素的需求)也进行了探索。在未服用HEMT的患者中，两种挥发性醛（辛醛和非肛门）被上调。去除与潜在混杂变量相关的VOC，然后通过回归分析与FEV1pp测量值的显着相关性。有趣的是,在基线和PEx期间比较受试者时,与FEV1pp(3,7-二甲基癸烷)相关性最高的VOC也给出了lowestp值.在这项研究中鉴定的由于PEx而差异表达的其他VOC包括durene，2,4,4-三甲基-1,3-戊二醇1-异丁酸酯和5-甲基十三烷。建立了受试者操作特征曲线，并显示3,7-二甲基癸烷相对于收集时的FEV1pp值（AUC=0.83）具有更高的PEx分类能力（曲线下面积（AUC）=0.91）。然而,归一化的ΔFEV1pp值具有最高的区分PEx的能力(AUC=0.93)。这些结果表明，呼出气中的VOC可能是CF各种临床特征的生物标志物的丰富来源，包括PEX,这应该在更大的样本队列和验证研究中进行探索。
