An Overview of Fractional Exhaled Nitric Oxide and Children with Asthma

Asthma is the most common pediatric chronic disease and is characterized by lung inflammation. Fractional exhaled nitric oxide (FeNO) is thought to reflect the presence of eosinophilic airway inflammation, and is an easy, non-invasive test that has held promise in providing additional objective data. However, not all studies have shown a clinical benefit in the use of FeNO to guide management of asthma in children. This review will describe the results of the most recent studies examining the use of FeNO in the diagnosis and treatment of asthma in infants, preschool-aged children and in school-aged children. It will aid the clinician in providing a clinical context in which FeNO may be most useful in treating pediatric asthma.     

初诊哮喘患者的呼出气一氧化氮与大小气道功能的 相关性及临床价值分析

目的 探讨初诊支气管哮喘患者的呼出气一氧化氮水平与大小气道功能的相关性,以及在哮喘规范化治疗中的变化趋势及临床意义。方法 选择2016年3月~2016年5月就诊于新乡医学院第一附属医院呼吸科的初诊成人支气管哮喘患者80例,为哮喘组;选择同期健康体检志愿者40名,为对照组。哮喘组在治疗前及治疗后3、6、9、12月分别行FeNO和肺功能检查包括FEV1%、FEF75%、FEF50%、MMEF%以及哮喘控制测试（ACT）;健康志愿者仅行一次肺功能及FeNO检查。结果 初诊哮喘的FeNO与FEV1%无相关性（P＞0.05）,与FEF75%、FEF50%、MMEF%存在负相关（P＜0.05）。经治疗大气道功能的恢复时间6个月早于小气道功能的恢复时间12个月,FeNO的恢复时间约3月。小气道功能异常的哮喘患者比小气道功能正常者具有更高的FeNO,且在1年的治疗过程中具有更高的急性发作次数和吸入糖皮质激素（ICS）用量,差异有统计学意义（P＜0.05）。结论 相比于大气道,小气道功能异常与气道炎症FeNO的关系更密切。大气道功能不能完全反映哮喘的临床控制情况,需联合检测FeNO与小气道功能。     

哮喘儿童发病与血液一氧化氮、肿瘤坏死因子变化的研究

目的 研究哮喘儿童发病与血液一氧化氮、肿瘤坏死因子变化。方法 选择2018年1月~2019年1月在我院诊治的哮喘儿童70例作为研究对象,依据病情分为缓解组和发作组,各35例,另选取同期在我院在体检健康儿童35例作为对照组。分别检测各组血液一氧化氮（NO）、肿瘤坏死因子水平,并分析NO、肿瘤坏死因子与哮喘儿童发病的关系。结果 发作组NO水平为（46.67±18.92）μmol/L、肿瘤坏死因子水平为（198.77±42.29）ng/L,均高于缓解组的（32.41±14.22）μmol/L、（192.42±37.83）ng/L和对照组（29.54±14.34）μmol/L、（164.51±31.11）ng/L,差异有统计学意义（P＜0.05）;缓解组NO、肿瘤坏死因子水平高于对照组,差异有统计学意义（P＜0.05）;哮喘组肿瘤坏死因子水平与NO水平呈正相关（r=0.36、0.48,P＜0.05）。结论 NO、肿瘤坏死因子参与哮喘发作期气道炎症的形成,肿瘤坏死因子水平与NO水平密切相关,肿瘤坏死因子可作为哮喘缓解期患儿炎症持续的重要指标,具有重要的临床研究意义。     

Predicting Sputum Eosinophilia in Exacerbations of COPD Using Exhaled Nitric Oxide

Fractional exhaled nitric oxide (FENO) may be a pulmonary biomarker in chronic obstructive pulmonary disease (COPD). In this prospective study, the relationship between FENO and airway inflammation was assessed in COPD exacerbations. FENO and lung function were measured, and sputum was collected from 49 ex-smoking COPD patients, first at the time of hospital admission and again at discharge following treatment. There was a significant positive correlation between the percentage of sputum eosinophils and FENO concentrations, both at exacerbation (r?=?0.593, p?<?0.001) and discharge (r?=?0.337, p?=?0.044). The increase in forced expiratory volume in one second (FEV₁) after treatment was greater in patients with sputum eosinophilia (ΔFEV₁ 0.35?±?0.12 vs. 0.13?±?0.04 L, p?=?0.046), and FENO was a strong predictor of sputum eosinophilia (area under the receiver operating characteristic curve, 0.89). The optimum cut point was 19 parts per billion (sensitivity: 90 %; specificity: 74 %). Our data suggest that FENO is a good surrogate marker of eosinophilic inflammation in COPD patients with exacerbations.     

Clinical Application of Exhaled Nitric Oxide Measurements in a Korean Population

Nitric oxide (NO) is a biologic mediator of various physiologic functions. Recent evidence suggests the clinical utility of fractional exhaled NO (FeNO) as a biomarker for assessing asthma and other respiratory diseases. FeNO methodologies have been recently standardized by international research groups and subsequently validated in several Korean population studies. Normal ranges for FeNO have been reported for various ethnic groups, and the clinical utility has been widely evaluated in asthma and various respiratory diseases. Based on current evidence including most of Korean population data, this position paper aims to introduce the methodological considerations, and provide the guidance for the proper clinical application of FeNO measurements in Korean populations.     

Exhaled Nitric Oxide Increases During High Frequency Oscillatory Ventilation in Rabbits

This study compared the effects of high frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) on the homeostasis of nitric oxide (NO) in the lower respiratory tract of healthy rabbits. The mechanisms underlying a putative stretch response of NO formation in the airways were further elucidated. Male New Zealand White rabbits were anaesthetized, tracheotomized and ventilated with IMV or HFOV in random order. Total NO excretion increased from 9.6 +/- 0.8 nl min-1 (mean +/- S.E.M.) during IMV to 22.6 +/- 2.7 nl min-1 during HFOV (P < 0.001). This increase was not explained by changes of functional residual capacity ([Delta]FRC). A similar increase in NO excretion during HFOV was seen in isolated buffer-perfused lungs under constant circulatory conditions (P < 0. 05, n = 4). Intratracheal mean CO2 and NO concentrations, measured at 2.5, 5, 7.5 and 10 cm below tracheostomy, increased significantly with increasing distance into the lung during both IMV and HFOV (P < 0.001 for each comparison). At every intratracheal location of the sampling catheter, particularly low in the airways, both CO2 and NO concentrations were significantly higher during HFOV than during IMV (P < 0.01 for each comparison). We conclude that HFOV increases pulmonary NO production in healthy rabbits. Increased stretch activation of the respiratory system during HFOV is suggested as a possible underlying mechanism. The increase in mean airway NO concentrations may have biological effects in the respiratory tract. Whether it can account for some of the benefits of HFOV treatment needs to be considered.     

The Association of Lung Function,Bronchial Hyperresponsiveness,and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children

Purpose

Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA.

Methods

One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5''-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured.

Results

The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only.

Conclusions

These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR.     

睡眠剥夺对大鼠一氧化氮和一氧化氮合酶的影响

目的：探讨睡眠剥夺对大鼠脑组织一氧化氮（NO）及一氧化氮合酶（NOS）影响。方法：采用小平台水环境法（Flower Pot)制作大鼠睡眠剥夺模型，采用化学法和酶法观察不同时间睡眠剥夺后大鼠额叶、海马、中脑和下丘脑NO含量及NOS活性变化。结果：与正常对照组及大平台组比较，大鼠在SD后额叶和海马的NO含量及NOS活性增高，有显著性差异（P＜0．01－0．05），其余脑区无显著性差异（P＞0．05）。随着剥夺时间的延长，额叶和海马NO含量及NOS活性增高更加明显。结论：睡眠剥夺可致NO及NOS升高，可能与其学习障碍有关，NO可能参与大鼠的睡眠调节。     

Fractional Exhaled Nitric Oxide and Impulse Oscillometry in Children With Allergic Rhinitis

Purpose

Airway inflammation, bronchial hyper-responsiveness (BHR), and bronchodilator response (BDR) are representative characteristics of asthma. Because allergic rhinitis (AR) is a risk factor for asthma development, we evaluated these 3 characteristics in AR using measurement of fractional exhaled nitric oxide (FeNO), a methacholine challenge test (MCT), and impulse oscillometry (IOS).

Methods

This study included 112 children with asthma (asthma group), 196 children with AR (AR group), and 32 control subjects (control group). We compared pulmonary function parameters and FeNO levels among the 3 groups. The AR group was subdivided into 2 categories: the AR group with BHR and the AR group without, and again pulmonary function and FeNO levels were compared between the 2 subgroups.

Results

FeNO levels were more increased in the AR and asthma groups than in the control group; within the AR group, FeNO was higher in the AR group with BHR than in the AR group without. The BDR was more increased in the AR group than in the control group when percent changes in reactance at 5 Hz (Δ X5) and reactance area (Δ AX) were compared. In the AR group, however, there was no difference in Δ X5 and Δ AX between the AR group with BHR and the AR group without.

Conclusions

Reversible airway obstruction on IOS and elevated FeNO levels were observed in children with AR. Because elevated FeNO levels can indicate airway inflammation and because chronic inflammation may lead to BHR, FeNO levels may be associated with BHR in AR. IOS can be a useful tool for detecting lower airway involvement of AR independent of BHR assessed in the MCT.     

Reference Values and Determinants of Fractional Concentration of Exhaled Nitric Oxide in Healthy Children

Purpose

Measurement of the fractional concentration of exhaled nitric oxide (FeNO) is a quantitative, noninvasive, simple, safe method of assessing airway inflammation. While FeNO measurement has been standardized, reference values for elementary school children are scarce. The aim of this study was to establish reference values for FeNO in children.

Methods

FeNO was measured in elementary school children at 6-12 years of age in Seoul, Korea, following American Thoracic Society guidelines and using a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden). A total of 1,252 children completed a modified International Study of Asthma and Allergy in Children (ISAAC) questionnaire; FeNO was measured in 1,063 children according to the protocol and in 808 children defined as healthy controls.

Results

Mean FeNO were 10.32 ppb, 16.58 ppb, and 12.36 ppb in non-atopic, atopic, and all 808 healthy controls, respectively. FeNO was not associated with age and gender. The FeNO reference equations were determined by multiple linear regression analysis, taking into account the variables of age, height, weight, total IgE, eosinophil percent, and bronchial hyper-responsiveness (methacholine PC20). FeNO=0.776+0.003×total IgE+0.340×eosinophil percent; coefficient of determination (R2)=0.084 in the 501 healthy non-atopic controls. FeNO=-18.365+1.536×eosinophil percent, R2=0.183 in the 307 healthy atopic controls; and FeNO=-7.888+0.130×Height+0.004×total IgE+1.233×eosinophil percent, R2=0.209 in the 808 all healthy controls. Eosinophil percent was correlated with FeNO in all healthy controls. FeNO was not associated with BMI.

Conclusion

This study provides reference values for FeNO that can be used to evaluate airway inflammation in elementary school children. Determinants that could most accurately predict FeNO in healthy school-age children were assessed.     

低剂量γ射线辐照对血清一氧化氮及一氧化氮合酶水平的影响

目的：观察低剂量γ射线照射人离体外周血对血清中一氧化氮（NO）和一氧化氮合酶（NOS）水平的影响。方法：采集10份健康献血员全血，肝素抗凝，然后采用γ射线照射，照射剂量率为17Gy／min，总吸收剂量为1Gy，分别于照射前及照射后1h，2h采用分光光度法检测血清中NO含量和NOS活性。结果：经γ射线照射1h后，血清中NO及NOS水平与照射前比较明显升高（P〈0.01）；照射后2h，血清中NOS水平与照射后1h比较无统计学差异（P〉0、05），但是还明显高于照射前的水平（P〈0．01）；在照射后2h，血清中NO含量与照射后1h比较明显降低（P〈0.01），但仍明显高于照射前水平（P〈0．01）。结论：采用剂量为1Gy的γ射线照射外周血，可引起血清中NO水平及NOS活性的显著升高．从而为低剂量辐照自体血回输对肿瘤的辅助治疗提供了理论支持。     

Inflammatory Markers: Exhaled Nitric Oxide and Carbon Monoxide During the Ovarian Cycle

Nitric oxide (NO) production and carbon monoxide (CO) production are increased in inflammatory lung diseases. Although there are some pieces of evidence for hormonal modulation by estrogen, little is known about exhaled NO and CO during the ovarian cycle. In 23 subjects, we measured exhaled NO and CO by an online analyzer. Significantly higher levels of exhaled NO were found at the midcycle compared with those in the premenstrual period or during menstruation. Higher levels of CO were after ovulation and reached a peak in the premenstrual phase. The lowest levels of CO were observed in the first days of the estrogen phase. In males, there was no significant variation in exhaled NO and CO. Exhaled NO and CO levels vary during the ovarian cycle in women, and this fact should be taken into account during serial measurements of these markers in the female population.     

Reference Ranges and Determinant Factors for Exhaled Nitric Oxide in a Healthy Korean Elderly Population

Purpose

Exhaled nitric oxide (NO) is a useful non-invasive biomarker for asthma diagnosis; however, the literature suggests that exhaled NO levels may be affected by demographic factors. The present analysis investigated determinant factors that present exhaled NO reference levels for Korean elderly adults.

Methods

For reference levels, we analyzed the baseline data of healthy adult participants in the Ansung cohort. The fraction of exhaled NO (FeNO) was measured by NIOX MINO®. The characterization of the subjects was performed through structured questionnaires, spirometry, and methacholine challenge tests. To validate the diagnostic utility of the determined reference levels, asthma patients were recruited from medical institutions for FeNO measurement.

Results

A total of 570 healthy subjects were analyzed (mean age, 59.9±12.3; male, 37.0%) for reference levels. FeNO levels significantly correlated with weight, height, body mass index, atopy, or forced expiratory volume in 1 second % predicted by simple linear regression analysis. Multiple linear regression analysis identified gender as an independent determinant for FeNO levels; subsequently, the reference values for FeNO were 18.2±10.6 ppb (5th to 95th percentile, 6.0 to 37.4 ppb) for males and 12.1±6.9 ppb (5th to 95th percentile, 2.5 to 27.0 ppb) for females. The diagnostic utility of FeNO reference levels was validated by receiver operating curve analysis (area under curve, 0.900 for males and 0.885 for females) for diagnosing asthma. The optimal cutoff values for the prediction of asthma were 30.5 ppb for males and 20.5 ppb for females.

Conclusions

The current analysis presented reference ranges and the diagnostic utility of FeNO levels for asthma in Korean elderly adults.     

Fractional Exhaled Nitric Oxide: Comparison Between Portable Devices and Correlation With Sputum Eosinophils

This study was performed to compare the 2 different portable devices measuring fractional exhaled nitric oxide (FeNO) and to see the correlation between FeNO and induced sputum eosinophil count (ISE). Forty consecutive subjects clinically suspected to have asthma underwent FeNO measurement by NIOX-MINO® and NObreath® concurrently. All also had induced sputum analysis, methacholine provocation test or bronchodilator response test, and spin prick test. Agreement between the 2 devices was evaluated. The correlation between FeNO and ISE was assessed, as well as the cut-off level of FeNO to identify ISE ≥3%. The intraclass correlation coefficient (ICC) between FeNO levels measured by NIOX-MINO® (FeNO_NIOX-MINO) and NObreath® (FeNON_Obreath) was 0.972 with 95% confidence interval of 0.948-0.985. The 95% limits of agreement were -28.9 to 19.9 ppb. The correlation coefficient between ISE and FeNO_NIOX-MINO was 0.733 (P<0.001), and 0.751 between ISE and FeNO_NObreath (P<0.001). The ROC curve found that the FeNO_NIOXMINO of 37.5 ppb and the FeNO_NObreath of 36.5 ppb identified ISE ≥3% with 90% sensitivity and 81% specificity. Age, sex, body mass index, smoking history, atopy, and the presence of asthma did not affect the FeNO level and its correlation with ISE. The NIOX-MINO ® and NObreath® agree with each other to a high degree. Both devices showed close correlation with ISE with similar cut-off value in identifying ISE ≥3%.     

慢性阻塞性肺疾病患者不规则趋化因子、白三烯B4及呼出气一氧化氮水平变化及其临床意义

目的 探究慢性阻塞性肺疾病(COPD)患者不规则趋化因子(FKN)、白三烯B4(LTB4)及呼出气一氧化氮(FeNO)水平变化及其临床意义.方法 选择2019年4月至2020年4月在我院就诊的120例COPD患者,另选取同期健康体检者60例作为对照组,按病情严重程度将120例患者分为COPD急性加重期患者(n= 64)...     

呼出气一氧化氮浓度检测在儿童咳嗽变异性哮喘中的应用

目的 探讨FeNO检测在儿童咳嗽变异性哮喘中的临床价值。方法 选择2016年3月~2017年3月在我院确诊为CVA的患儿80例及健康儿童40例作为研究对象,比较两组儿童FeNO水平,比较FeNO正常的CVA患儿与FeNO升高患儿的皮肤点刺结果、肺功能,分析CVA患儿FeNO水平与肺功能的相关性。结果 CVA患儿FeNO水平高于健康儿童,差异有统计学意义（P＜0.05）。同FeNO正常的CVA患儿相比,FeNO升高的CVA患儿拥有更高的体重指数,皮肤点刺阳性率更高,强度更强,差异有统计学意义（P＜0.05）,但两组患儿肺功能无统计学差异,CVA患儿FeNO水平与肺功能无相关性（P＞0.05）。结论 FeNO可以辅助诊断CVA,但不能作为评估病情严重程度的指标。