Relationship between exhaled nitric oxide and atopy in Asian young adults

OBJECTIVES: The relationship between exhaled nitric oxide and atopy is controversial. The aim of this study was to determine the relationship between exhaled nitric oxide (FE(NO)) and atopy in Asian young adults. METHODOLOGY: Subjects were assessed by: (i) the International Study of Asthma and Allergies in Childhood questionnaire to differentiate asthmatic from nonasthmatic and rhinitis from non-rhinitis subjects; (ii) skin prick testing to 10 allergens; and (iii) FE(NO) measurements performed online at a flow rate of 50 mL/s. RESULTS: Complete results were available for 84 subjects. FE(NO) values were highest in atopic asthmatics (n = 34; median FE(NO), 59.8 p.p.b.; interquartile range, 30.4-85.5 p.p.b), followed by atopic nonasthmatics (n = 34; median, 38.4 p.p.b.; range, 16.7-49.3 p.p.b), nonatopic asthmatics (n = 5; median, 19.1 p.p.b.; range, 17.9-33.4 p.p.b), and lowest in nonatopic nonasthmatics (n = 11; median, 15.7 p.p.b.; range, 11.5-21.7 p.p.b). FE(NO) values were significantly higher in atopic (n = 68; median, 44.7 p.p.b.; range, 27.3-75.2 p.p.b) compared to nonatopic subjects (n = 16; median, 17.0 p.p.b.; range, 11.7-23.8 p.p.b.; P < 0.0001), regardless of asthma and rhinitis status. FE(NO) levels correlated with the severity of atopy (wheal size) for both asthmatic (r = 0.44, P = 0.005) and nonasthmatic subjects (r = 0.48, P = 0.001). There was no significant difference in FE(NO) levels between nonatopic asthmatics and nonatopic nonasthmatic subjects (P = 0.25). CONCLUSIONS: Increased FE(NO) levels are more reflective of atopy rather than asthma, and increased nitric oxide production may be predominantly a feature of atopy in asthmatics.     

Airway hyperresponsiveness to mannitol and methacholine and exhaled nitric oxide in children with asthma

Objective: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and obstruction. AHR to stimuli that indirectly cause bronchial smooth muscle (BSM) contractions via release of endogenous mediators is thought to better reflect airway inflammation than AHR to stimuli that act directly on BSM. Fractional exhaled nitric oxide (FeNO) is a useful parameter for noninvasive clinical airway inflammation assessments. Accordingly, this study aimed to examine the relationships of mannitol and methacholine challenge test outcomes with FeNO and the influence of inhaled corticosteroid treatment in children with asthma. Methods: One hundred thirty-four asthmatic children (89 males; ages: 5–17 years, median: 9 years) underwent spirometry, FeNO measurement, serum total/specific IgE testing, and blood eosinophil count. All subjects were challenged with mannitol dry powder (MDP; AridolH, Pharmaxis, Australia) and methacholine at 7-day intervals. Data of steroid-treated and steroid-naïve children were compared. Results: Positive responses to MDP and methacholine challenge tests were observed in 74.6% and 67.2% of total subject group, respectively, and 72 children had positive response to both challenge tests. The median FeNO level, response-dose ratio (RDR) of PC₂₀ methacholine, and RDR of PD₁₅ MDP were significantly higher in the steroid-treated group than in the steroid-naïve group (p < 0.001, 0.226, and 0.004, respectively). FeNO levels associated significantly with PD₁₅ MDP and RDR PD₁₅ MDP in total subject populations (p = 0.016 and 0.003, respectively); however, a significant correlation between FeNO and RDR PD₁₅ MDP was observed only in the steroid-naïve group. Conclusions: Compared with AHR to methacholine, AHR to MDP more closely reflected the level of FeNO in steroid-naïve asthmatic children.     

呼出气一氧化氮与小气道功能预测咳嗽变异性哮喘患者支气管高反应性

目的 评估呼出气一氧化氮(FeNO)及小气道功能指标,预测慢性咳嗽患者支气管高反应性(BHR)的价值.方法 回顾性分析2019年1月-2020年1月期间我院呼吸内科就诊的慢性咳嗽患者资料,将慢性咳嗽患者分为支气管激发试验(BPT)阳性组与BPT阴性组,评估FeNO、肺通气功能及脉冲振荡肺功能(IOS)对BHR的诊断价值...     

老年支气管哮喘患者FeNO与肺功能的相关性

目的探讨老年支气管哮喘患者呼出气一氧化氮(Fe NO)水平与肺功能的相关性。方法对68例老年哮喘患者给予吸入舒利迭和异丙托溴铵喷雾剂,疗程为1个月。比较50例健康体检者及哮喘患者治疗前、治疗后Fe NO、肺功能变化,采用哮喘控制测试(ACT)评分评价其疗效。结果与对照组比较,哮喘组治疗前Fe NO、Eos、N水平明显升高,各肺功能指标明显下降(P0.05);治疗后,各指标均明显改善(P0.05),PEF、FEV1、Eos、N基本恢复至对照组水平(P0.05);治疗后完全控制组、部分控制组各项指标均优于未控制组,完全控制组Fe NO、Eos、N水平均明显低于部分控制组(P0.05);治疗前,哮喘组患者Fe NO水平与Eos、N呈正相关(P0.05),与肺功能指标呈负相关(P0.05),但治疗后,Fe NO水平与Eos、N呈正相关(P0.05)。结论 Fe NO水平在哮喘患者中明显升高,结合肺功能检查,有助于提高老年哮喘的诊断及治疗水平。     

过敏性鼻炎与支气管哮喘患者的Fe NO比较研究

目的探讨呼出气一氧化氮(Fe NO)在支气管哮喘(BA)和过敏性鼻炎(AR)患者中的应用,比较Fe NO和外周血嗜酸粒细胞分类(EOS%)在健康对照组(A组)、AR(B组)、BA/AR(C组)及BA(D组)之间的不同,寻找两种疾病Fe NO、EOS%改变的意义,以及两种疾病之间的关系。方法采用按国际技术标准设计的尚沃纳库仑一氧化氮分析仪对A、B、C、D组患者检测Fe NO,同时测定各组患者血常规。结果三组病例ROC曲线下面积均大于0.5;AR、BA/AR、BA三组Fe NO、EOS%水平均高于对照组(P0.05),三组组间无明显差异(P0.05);Fe NO与EOS%间存在显著相关性(r=0.505,P0.0 5)。结论Fe NO诊断支气管哮喘和过敏性鼻炎有临床意义。Fe NO可以反映患者气道嗜酸性炎症水平。过敏性鼻炎与支气管哮喘这两种疾病存在密切的关系。     

Exhaled nitric oxide continues to reflect airway hyperresponsiveness and disease activity in inhaled corticosteroid-treated adult asthmatic patients

OBJECTIVE: Exhaled nitric oxide (eNO) has been used as a surrogate of airway inflammation in mild asthma. However, whether eNO levels reflect disease activity in symptomatic asthmatics receiving moderate doses of inhaled corticosteroid (ICS) is more uncertain. METHODOLOGY: To examine the relationship between eNO levels, sputum and blood eosinophils (SpE and PbE), PD(20) methacholine as a marker of airway hyperresponsiveness (AHR) and clinical status in 28 ICS-treated asthmatic subjects with persistent asthma compared to that in 25 symptomatic asthmatics managed with beta2-agonists alone. RESULTS: As expected, eNO levels were normalized in ICS-treated subjects and significantly elevated in the beta2-agonist only group (P < 0.001). SpE, PbE and PD20M did not differ between asthmatic groups but FEV1 was significantly worse in ICS-treated subjects (P < 0.01). Exhaled NO levels correlated with PbE within both asthmatic groups (P < 0.005), but with SpE only in ICS-untreated subjects (r(s) = 0.6, P < 0.05). In contrast, PD20M was negatively correlated with eNO and PbE in ICS-treated subjects only (r(s) = - 0.4, r(s) = - 0.4, respectively, P < 0.05). SpE and PbE were strongly correlated in both asthmatic groups (r(s) = 0.8, r(s) = 0.7, respectively, P < 0.005). Exhaled NO levels, SpE and PbE were all positively associated with increased nocturnal awakenings ( P < 0.05) in ICS-treated subjects, but not in ICS-untreated subjects. CONCLUSIONS: In ICS-treated asthma, eNO reflects clinical activity, PbE and AHR but not eosinophilic airway inflammation. Exhaled NO levels are quantitatively and relationally different in asthmatic subjects treated with ICS and continue to have potential for use as a surrogate of asthma pathophysiology in this group.     

Relationship between exhaled nitric oxide and treatment response in COPD patients with exacerbations

Background and objective: Fractional exhaled nitric oxide (FENO) has been implicated as a pulmonary biomarker in various respiratory diseases, including COPD. In this longitudinal study, the benefit of measuring FENO in a routine clinical setting was assessed in COPD patients hospitalized with an exacerbation of the disease. Methods: FENO, lung function and blood gases were measured in 58 COPD patients at hospital admission due to an exacerbation, and at discharge following treatment with corticosteroids and bronchodilators. Results: FENO levels were significantly decreased at discharge, compared with those at admission (geometric mean 25.3 ppb (95% CI: 21.2–30.1) vs 19.7 ppb (95% CI: 17.2–22.6); P = 0.002). There was a significant positive correlation between FENO concentrations at admission and the increase in FEV₁ after treatment (r = 0.441, P < 0.001), and a significant inverse correlation between FENO values at admission and the mean length of hospital stay (r = ?0.297, P = 0.016). Using receiver operating characteristic curve analysis, the optimum cut point for FENO as a predictor for significant increase in FEV₁ was 26.8 ppb (sensitivity: 74%, specificity: 75%). There were no correlations between FENO levels and absolute values for lung function variables at admission or discharge. Conclusions: These data suggest that FENO levels determined at hospital admission may predict the overall response to treatment in COPD patients with acute exacerbations.     

呼出气一氧化氮和血嗜酸性粒细胞对哮喘患者气道高反应性程度的预测价值

目的分析呼出气一氧化氮(fraction of exhaled nitric oxide, FeNO)水平和血嗜酸性粒细胞(blood eosinophil, B-Eos)计数对哮喘患者气道高反应性(airway hyperresponsiveness, AHR)程度的预测价值,并探索AHR严重程度的预测模型。 方法选择2014年1月至2019年12月于我院首诊为哮喘的患者1 347例,将其中520例具有FeNO和B-Eos的纳入主要研究人群。依据乙酰甲胆碱激发试验(methacholine challenge test, MCT)结果,分为重度AHR组(MCT为中度或重度阳性183例和轻度AHR组(MCT为极轻度或轻度阳性337例。然后分析两组差异,用Logistic回归构建预测模型,最后绘制重度AHR风险的列线图和森林图。 结果重度AHR组的FeNO和B-Eos均高于轻度AHR组(73 vs. 36 ppb、394 vs. 243个/μl,P<0.001)。Logistic回归示年龄、性别、FEV₁/FVC、B-Eos、FeNO为重度AHR的独立危险因素,将它们纳入回归模型,其灵敏度为49.7%,特异度为87.8%。受试者工作特征曲线示模型的曲线下面积明显高于单独的FeNO或B-Eos(0.797 vs. 0.715或0.644,P<0.001)。重度AHR风险的亚组分析示：随着FeNO或B-Eos的增高风险逐步增高(趋势检验P<0.001);女性的风险为男性的1.57倍(P＝0.041),而低FEV₁/FVC组(<70%)为正常组的3.38倍(P<0.001)。 结论在哮喘患者中单独的FeNO或B-Eos对重度AHR具有中等程度的预测效能,通过多因素回归模型构建的列线图可以用于预测重度AHR的概率。     

Extrathoracic airway responsiveness in children with asthma-like symptoms,including chronic persistent cough

Asthma-like symptoms, including chronic persistent cough, are not always specific for classical asthma. In order to investigate whether assessment of extrathoracic airway hyperresponsiveness (EAHR) during methacholine bronchial challenge helped in the evaluation of pediatric patients with asthma-like symptoms such as chronic cough, we examined 133 consecutive, unselected patients (mean age, 10.06 +/- 2.16 years) who had neither established asthma nor bronchial obstruction previously. We recorded the forced mid-inspiratory flow (FIF(50)) as an index of extrathoracic airway narrowing. In addition, a 25% decrease in FIF(50) (PD(25)FIF(50)) below the cutoff concentration of < or = 8 mg/mL methacholine was assumed to indicate EAHR. According to the methacholine response, 81 patients had EAHR, and 41 of them had combined EAHR and bronchial hyperresponsiveness (BHR); 39 patients had only BHR. Airway hyperresponsiveness was not demonstrated in 13 patients and not in any of the control children. When patients with cough as the sole presenting symptom (60.9%) were compared with those with cough and wheeze (20.3%), those with cough alone had a significantly greater probability of having EAHR (OR, 4.16; 95% CI, 1.32-13.13) and a lower probability of having BHR (OR, 0.70; CI, 0.25-1.95) than those with cough and wheeze. Patients with cough, wheeze, and dyspnea (18.8%) had a significantly greater chance of having BHR than those with cough alone (OR, 5.08; CI, 1.55-16.64). Patients with cough and wheeze as compared with those with cough, wheeze, and dyspnea had significantly greater probability of having both EAHR and BHR (OR, 4.71; CI, 1.94-11.47).In order to ascertain the clinical relevance of EAHR, we assessed in the second part of the study whether the effects of treatment of the underlying disease would result in relief of airway hyperresponsiveness. Rhinosinusitis and perennial allergic rhinitis accounted for EAHR in 71 patients, and 34 of them also demonstrated BHR. They received specific therapy for their upper airway diseases for 4 weeks. Compared with values before treatment, FIF(50) and forced expiratory volume in 1 sec (FEV(1)) did not change significantly. The dose of methacholine causing a 20% fall in FEV(1) (PD(20)FEV(1)) and PD(25)FIF(50) values were significantly increased from 2.40 +/- 1.39 to 4.22 +/- 1.13 mg /mL (P < 0.001) and from 1.03 +/- 1.75 to 8.71 +/- 1.21 mg /mL (P < 0.0001), respectively.We conclude that measurements of EAHR and BHR are the most important ways to evaluate children with asthma-like symptoms, including chronic persistent cough when chest X-rays and pulmonary function tests remain within normal limits. Therefore, empirical treatment is not necessary when these investigations are available. Our results suggest that specific treatment of inflammation in the upper airways reversed persistant cough, and may play an important role in modulating lower airways responsiveness in patients with concomitant BHR.     

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients

Background: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. Methods: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO₅₀), nasal NO levels, Lund–Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. Results: Asthma was associated with higher FeNO₅₀ levels irrespective of the UAD category. FeNO₅₀ levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO₅₀ levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund–Macay (ρ = ?0.46, p = 0.03) and ACQ scores (ρ = ?0.52, p = 0.009) in asthmatics with CRS. Conclusions: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO₅₀ levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.     

Pulmonary dysanapsis, methacholine airway responsiveness and sensitization to airborne antigen

Abstract Whether the disproportional growth of airways relative to lung parenchyma (dysanapsis) has any relationship to the development of non-specific bronchial hyperresponsiveness and atopy was investigated in 45 family members of the patients with atopic asthma. As indices of pulmonary dysanapsis, forced expiratory flow_25-75/forced vital capacity (FEF_25-75/FVC) and the tracheal cross sectional area divided by the forced expiratory volume (X-SA/FVC) were examined. As an index of non-specific airway responsiveness, the cumulative dose of inhaled methacholine needed to induce 35% reduction of respiratory conductance (PD₃₅) was determined by continuous respiratory resistance measurement. For examination of atopy, skin prick tests were conducted, and total serum IgE and IgE specific to common inhaled antigens were measured. FEF_25-75/FVC showed no significant correlation to FVC but showed a significant correlation to log (PD₃₅). When the analysis was done in the subjects whose FEVI/FVC was more than 0.8, FEF_25-75/FVC showed a significant negative correlation to FVC but lost its correlation to log(PD35). X-SA/FVC showed a significant negative correlation to FVC but had no significant correlation to log(PD₃₅). These relations were conserved when the analysis was done in subjects without airway obstruction. In addition, FEV₁/FVC had a significant correlation to log(PD₃₅) and FEF_25-75/FVC. However, subjects who had a positive IgE(MAST) had a significantly smaller X-SA/FVC than those with a negative IgE(MAST) (0.60 ± 0.14[SD] and 0.72 ± 0.18, respectively, P<0.02). These results suggest that although pulmonary dysanapsis does not have a significant relation to airway responsiveness to inhaled methacholine, it may be associated with sensitization to airborne antigens.     

呼出气一氧化氮检测在儿童呼吸系统疾病的临床应用

一氧化氮作为非肾上腺能、非胆碱能神经的神经递质,可作用于血管并参与调节支气管平滑肌的功能。自从1993年 Alving 等首次发现呼出气一氧化氮(FeNO)在哮喘患者中明显升高,就开始了对 FeNO 的广泛研究。FeNO 测定作为一种评估伴有呼吸系统疾病的儿童气道炎症水平的非侵入性方法,目前已广泛应用于儿童哮喘的管理中。很多方法可以检测 FeNO 水平,尽管很多因素可以影响检测结果,但似乎它比肺功能及支气管激发试验有更高的准确性。目前 FeNO 在慢性咳嗽、ARDS、鼻炎、病毒性细支气管炎、社区获得性肺炎、支气管扩张、闭塞性细支气管炎及弥漫性肺疾病等儿童呼吸系统疾病的诊断、治疗及评估预后中也有很大的意义。     

Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide

Background: Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se– as verified with positive skin prick tests – affects FENO in healthy individuals. Objective: The aim of this study was to examine the association between FENO and sensitization to common allergens in healthy nonsmoking adults with no signs or symptoms of airway disorders. Methods: FENO measurements (flow rate: 50 mL/s), skin prick tests to common inhalant allergens, structured interviews, spirometry, bronchodilatation tests and bronchial histamine challenges were performed on a randomly selected population of 248 subjects. Seventy‐three of them (29%) were nonsmoking asymptomatic adults with no history of asthma, persistent or recurrent upper or lower airway symptoms and no signs of airway disorders in the tests listed above. Results: FENO concentrations were similar in skin prick test positive (n = 32) and negative (n = 41) healthy subjects, with median values of 13.2 and 15.5 ppb, respectively (P = 0.304). No correlation appeared between FENO and the number of positive reactions (r = ?0.138; P = 0.244), or the total sum of wheal diameters (r = ?0.135; P = 0.254). The nonparametric one‐tailed 95% upper limits of FENO among skin prick positive and negative healthy nonsmoking subjects were 29 and 31 ppb, respectively. Conclusions: Atopic constitution defined as positive skin prick test results does not increase FENO in healthy nonsmoking adults with no signs or symptoms of airway disorders. This suggests that same reference ranges for FENO can be applied to both skin prick test positive and negative subjects. Please cite this paper as: Rouhos A, Kainu A, Karjalainen J, Lindqvist A, Piirilä P, Sarna S, Haahtela T and Sovijärvi ARA. Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide. The Clinical Respiratory Journal 2008; 2: 141–148.     

Spirometry effects on conventional and multiple flow exhaled nitric oxide in children

Objective: Clinical and research settings often require sequencing multiple respiratory tests in a brief visit. Guidelines recommend measuring the concentration of exhaled nitric oxide (FeNO) before spirometry, but evidence for a spirometry carryover effect on FeNO is mixed. Only one study has investigated spirometry carryover effects on multiple flow FeNO analysis. The objective of this study was to evaluate evidence for carryover effects of recent spirometry on three exhaled NO summary measures: FeNO at 50?ml/s, airway wall NO flux [J′_awNO] and alveolar NO concentration [C_ANO] in a population-based sample of schoolchildren. Methods: Participants were 1146 children (191 with asthma), ages 12–15, from the Southern California Children’s Health Study who performed spirometry and multiple flow FeNO on the same day. Approximately, half the children performed spirometry first. Multiple linear regression was used to estimate differences in exhaled NO summary measures associated with recent spirometry testing, adjusting for potential confounders. Results: In the population-based sample, we found no evidence of spirometry carryover effects. However, for children with asthma, there was a suggestion that exhaled NO summary measures assessed ≤6?min after spirometry were lower (FeNO: 25.8% lower, 95% CI: ?6.2%, 48.2%; J′_awNO: 15.1% lower 95% CI: ?26.5%, 43.0%; and C_ANO 0.43 parts per billion lower, 95% CI: ?0.12, 0.98). Conclusions: In clinical settings, it is prudent to assess multiple flow FeNO before spirometry. In studies of healthy subjects, it may not be necessary to assess FeNO first.     

支气管激发试验、FeNO及诱导痰ECP在哮喘中的相关性及FeNO、诱导痰ECP诊断价值

目的探讨哮喘患者中支气管激发试验、Fe NO、诱导痰中的ECP相关性及Fe NO、ECP诊断哮喘的临床价值。方法收集2014年2月至2016年2月我院疑似支气管哮喘患者160例(最终诊断哮喘92例,非哮喘68例),测定诱导痰嗜酸性粒细胞阳离子蛋白、呼出气一氧化氮水平,行肺通气功能、支气管激发试验检查。结果 Fe NO水平与诱导痰ECP呈正相关(r=0.669,P=0.000);Fe NO水平与支气管激发定量试验呈负相关(r=-0.759,P=0.000);诱导痰ECP与支气管激发定量试验呈负相关(r=-0.909,P=0.000)。通过ROC曲线分别评价Fe NO、诱导痰ECP诊断支气管哮喘的价值,其约登指数的最大值分别为:59.1%、76.0%,最佳截断值分别为:42.2 ppb、98.05μg/l,灵敏度分别为82.6%、84.8%,特异度分别为76.5%、91.2%,阳性预测值分别为82.6%(95%CI 73.3%~89.7%)、92.9%(95%CI 85.1%~97.3%),阴性预测值分别为:76.5%(95%CI 64.6%~85.9%)、81.6%(95%CI 71.0%~89.5%),曲线下面积分别为0.850、0.956(P0.05)。结论哮喘患者中,支气管激发试验、Fe NO、诱导痰ECP水平有显著相关性。支气管激发试验是公认的哮喘诊断的客观依据,Fe NO、诱导痰ECP两者对哮喘的诊断均有较高价值,且诱导痰ECP诊断哮喘的价值优于Fe NO,可作为哮喘诊断的重要辅助工具,但需要注意两者尚有临床局限性。