Small-Airway Function Variables in Spirometry, Fractional Exhaled Nitric Oxide, and Circulating Eosinophils Predicted Airway Hyperresponsiveness in Patients with Mild Asthma

Wuping Bao,1,* Xue Zhang,1,* Junfeng Yin,2,* Lei Han,1,* Zhixuan Huang,2 Luhong Bao,1 Chengjian Lv,1 Huijuan Hao,1 Yishu Xue,1 Xin Zhou,1 Min Zhang1 1Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2School of Mathematical Sciences, Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min ZhangDepartment of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, People’s Republic of ChinaTel +86 21 63071428Email maggie_zhangmin@163.comPurpose: Patients with variable symptoms suggestive of asthma but with normal forced expiratory volume in 1 second (FEV1) often fail to be diagnosed without a bronchial provocation test, but the test is expensive, time-consuming, risky, and not readily available in all clinical settings.Patients and Methods: A cross-sectional study was performed in 692 patients with FEV1≥ 80% predicted; normal neutrophils and chest high-resolution computed tomography; and recurrent dyspnea, cough, wheeze, and chest tightness.Results: Compared with subjects negative for AHR (n=522), subjects positive for AHR (n=170) showed increased FENO values, peripheral eosinophils (EOS), and R5-R20; decreased FEV1, FEV1/Forced vital capacity (FVC), and forced expiratory flow (FEFs) (P≤ .001 for all). Small-airway dysfunction was identified in 104 AHR+ patients (61.17%), and 132 AHR− patients (25.29%) (P< 0.001). The areas under the curve (AUCs) of variables used singly for an AHR diagnosis were lower than 0.77. Using joint models of FEF50%, FEF75%, or FEF25%-75% with FENO increased the AUCs to 0.845, 0.824, and 0.844, respectively, significantly higher than univariate AUCs (P < 0.001 for all). Patients who reported chest tightness (n=75) had lower FEFs than patients who did not (P< 0.001 for all). In subjects with chest tightness, the combination of FEF50% or FEF25%-75% with EOS also increased the AUCs substantially, to 0.815 and 0.816, respectively (P < 0.001 for all versus the univariate AUCs).Conclusion: FENO combined with FEF50% and FEF25%-75% predict AHR in patients with normal FEV1. FEF25%-75%, FEF50%, or FEF25%-75% together with EOS also can potentially suggest asthma in patients with chest tightness.Keywords: asthma diagnosis, small-airway function, fractional exhaled nitric oxide, bronchial provocation, impulse oscillometry