呼出气一氧化氮在儿童呼吸道疾病中的应用进展

NO是人体内重要的信号因子,存在于正常人的呼出气中.各种呼吸道炎症性疾病均可导致呼出气NO增高,尤其是嗜酸性粒细胞性炎症.呼出气NO测定能直接反映气道炎症,具有无创、重复性好、易操作等优势,有助于临床对反复喘息、慢性咳嗽等呼吸道常见症状的病因鉴别,有助于对支气管哮喘等多种疾病的诊断、判断病情及预后,对于儿童呼吸道疾病的管理具有重要价值.     

呼出气一氧化氮在儿童哮喘中的临床价值

哮喘是一种气道慢性炎症性疾病,已成为儿童中最常见的慢性疾病之一.临床上对哮喘的诊断及治疗主要依据临床表现及肺功能,但两者并不能反映气道炎症.呼出气一氧化氮(exhaled nitric oxide,eNO)作为气道炎症的标志物,与气道炎症有显著相关性.eNO检测方法具有无创、简单、方便、特异性好等优点,在临床应用方面具有明显优势.该文介绍了NO在气道中的代谢及其作用,并从哮喘的诊断及鉴别诊断、哮喘管理方面阐述eNO检测在儿童哮喘临床应用中的研究进展.     

呼出气一氧化氮测定与哮喘的气道炎症

哮喘是一种常见病和多发病,其病理基础是气道炎症,而对哮喘气道炎症的监测是防治哮喘的关键.NO是近年来研究较多的一种生物活性物质,已证实其与许多炎症介质相关,在哮喘的发病机制中具有重要作用.目前认为呼出气中NO测定是反映哮喘气道炎症的新型无创伤性及敏感的生物指标,因而呼出气中NO测定对哮喘的诊断、治疗、病情监控和预后评估均有十分重要的意义.呼出气中NO测定技术的开展具有广阔的临床应用前景.     

婴幼儿期哮喘的诊断思路

婴幼儿期哮喘较年长儿哮喘的诊断难度明显增加,这已是全球业内人士的共识.诊断困难的原因主要与下列因素有关:(1)婴幼儿期气道的发育尚未成熟,在气道的生理、解剖及免疫等方面有其特殊性;(2)在婴幼儿期引起喘息的疾病种类繁多,增加了鉴别诊断的难度;(3)喘息性疾病的临床自然表型在婴幼儿期尚未充分显现,是暂时性喘息还是哮喘尚需日后观察;(4)对哮喘诊断有一定帮助的辅助检查,如肺功能、气道激发试验、呼出气NO测定、诱导痰液分析等,在婴幼儿期受到设备条件及配合的限制.因此,正如PRAC-TALL[1]共识报告所言,迄今尚无特异的诊断工具或诊断标识物用于婴幼儿哮喘的检测,对任何患有反复喘息和咳嗽发作的婴幼儿都应该被怀疑哮喘,通常,确诊只有通过长期随访、广泛鉴别和观察对支气管舒张剂和(或)抗炎治疗后的反应.     

支气管哮喘患儿血清一氧化氮、一氧化氮合酶水平变化临床研究

多年来已认识到哮喘是一种慢性气道变态反应性炎症性疾病。一氧化氮(NO)是几种最有希望成为气道炎症标志物的物质之一。检测呼出气NO需要精密昂贵的仪器设备，作者拟用血清NO、一氧化氮合酶(NOS)检测替代呼出气NO检测，以便于普遍推广，并为临床哮喘病情判断和疗效评价提供一定的参考依据。     

白三烯与一氧化氮在哮喘中关系的研究进展

一氧化氮(NO)是近年来研究较多的一种生物活性物质,在哮喘发病机制中具重要作用。而目前认为呼出气中NO(eNO)测定是反映哮喘气道炎症的新型无创伤性、极敏感的生物指标。eNO浓度在哮喘早期即增加,在哮喘恶化时进一步升高。白三烯是哮喘发病机制中又一重要的内源性炎性介质,与NO存在复杂的相互作用,而白三烯受体拮抗剂可降低哮喘患者的eNO浓度,其机制尚有待阐明。     

哮喘儿童呼出气一氧化氮水平的测定

目的：　探讨哮喘儿童呼出气一氧化氮(exhalednitricoxide,eNO)水平及其意义。方法：　设定13～15cmH2O呼出气阻力以关闭软腭,用化学发光法测定34例6～14岁哮喘儿童和36名6～13岁非呼吸道疾病儿童单次呼吸的eNO浓度 ,同时测定一秒钟用力呼气容积占预计值百分比 (FEV1%)。结果：哮喘儿童的eNO浓度为 (89.4± 56 .4) ppb ,较非呼吸道疾病儿童eNO浓度 [(15 .8±5.8) ppb]显著增高 (P<0.01) ;哮喘儿童eNO浓度与FEV1%之间无显著相关性(r=0.06 ,P>0.05)。结论：　哮喘儿童eNO浓度高于正常,其变化与FEV1%无关。     

肾上腺髓质素与支气管哮喘研究进展

支气管哮喘(哮喘)是由多种细胞(如嗜酸性粒细胞、肥大细胞、T淋巴细胞、中性粒细胞及呼吸道上皮细胞等)和细胞组分共同参与的呼吸道慢性炎性反应性疾病。肾上腺髓质素(AM)具有舒张支气管和一定程度的抗炎作用,在哮喘的发病中起一定作用。本文就AM的生物学特征,AM对呼吸道的作用等问题进行综述。     

哮喘的炎症标志物

哮喘是一种慢性气道炎症性疾病.检测、评估气道炎症对于哮喘的早期诊断、病情严重程度的判断、药物种类和剂量的选择以及对已控制症状患者停药时机的选择等,均有重要的临床指导意义,故迫切需要能客观地反映气道炎症的检测技术来指导哮喘的诊断和治疗.目前研究较多的炎症标志物主要有呼出气一氧化氮、白三烯、呼出气冷凝液测定、骨膜蛋白、人软骨糖蛋白等.该文就上述炎症标志物的生物学特性及在哮喘临床中的应用进行阐述.     

口鼻呼出气一氧化氮检测在儿童支气管哮喘控制评估及过敏性鼻炎诊断中的应用

目的 探讨口呼出气一氧化氮(fractional exhaled nitric oxide,FeNO)与鼻呼出气一氧化氮(nasal nitric oxide,nNO)检测值和儿童支气管哮喘(简称哮喘)控制水平的关系,以及对过敏性鼻炎的诊断价值.方法 以上海市儿童医院呼吸科门诊就诊的5～12岁哮喘和/或过敏性鼻炎患儿,...     

Exhaled carbon monoxide in childhood asthma.

OBJECTIVES: Oxidative stress and inflammation induce the expression of heme oxygenase-1, which produces carbon monoxide (CO), and nitric oxide synthase, which produces nitric oxide (NO). Exhaled CO and NO levels are elevated in asthmatic patients and are decreased after corticosteroid treatment, suggesting that they may be useful as noninvasive markers of airway inflammation. STUDY DESIGN: We measured forced expiratory volume in the first second, PC(20), and exhaled CO and NO levels in 29 children (18 boys, mean age 11.5 +/- 0.53 years) with asthma of different severity and 40 nonsmoking children without asthma (21 boys, mean age 8.1 +/- 0.35 years). We also studied whether upper respiratory tract infections were associated with elevated exhaled CO. RESULTS: Exhaled CO levels (ppm) were significantly higher (2.17 +/- 0.21) in children with persistent asthma compared with those in children with infrequent episodic asthma (1.39 +/- 0.18, P <.05) and healthy children (1.01 +/- 0.12, P <.001). The CO levels in children with infrequent episodic asthma and the normal control group, however, were not different. In contrast, exhaled NO levels (ppb) were higher in children with persistent asthma (24.2 +/- 5.9, P <.001) and infrequent episodic asthma (14.5 +/- 3.73, P <.05) than in normal subjects (5.1 +/- 0.24), but no significant difference was seen between the 2 asthmatic groups. In healthy children with upper respiratory tract infections (n = 12), exhaled CO concentrations were significantly elevated (2.16 +/- 0.33) during the acute symptomatic phase. No correlation was found between exhaled CO and forced expiratory volume in the first second or PC(20). CONCLUSIONS: Noninvasive measurement of exhaled CO may provide complementary data for assessment of asthma control in children. However, elevated CO levels are nonspecific and may be found in association with an acute viral illness.     

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目的将呼出气一氧化氮(FeNO)浓度检测与肺功能测定进行比较,评估其对儿童支气管哮喘诊断的临床价值。方法收集广州市儿童医院呼吸科门诊2009年6月至2010年5月反复咳嗽、间伴喘息等疑似支气管哮喘的患儿93例。使用FeNO测定仪(Medisoft HypairFeNo)进行测定,操作严格按照美国胸科协会制定指南进行;同时采用Medisoft hyp`Air型肺功能仪行基础肺功能检查,并进行支气管激发及舒张试验。根据结果并结合临床作为诊断儿童哮喘的标准,并以此作为FeNO诊断价值的参照,评价FeNO对支气管哮喘的鉴别诊断价值。结果 93例中激发试验阳性53例,支气管舒张试验阳性14例,结合临床最后均诊断为支气管哮喘。其余26例为激发试验阴性,诊断为非哮喘。哮喘组FeNO高于非哮喘组[(43.60±38.86)×10-9mol/L对(26.16±17.00)×10-9mol/L,P<0.05]。哮喘患儿FeNO与第1秒用力呼气容积(FEV1)占预计值百分比(FEV1%)之间无显著相关性(r=0.06,P>0.05)。激发试验阳性者FeNO值与PD20FEV1之间存在线性关系。结论 FeNO测定对支气管哮喘的诊断和鉴别诊断具有重要意义,但与肺功能、支气管激发试验检测相比仍存在一定局限性。     

Increased bronchial NO output in severe atopic eczema in children and adolescents.

Atopic children have an increased risk for asthma, which is preceded by bronchial inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess alveolar NO concentration and bronchial NO flux, which reflect inflammation in lung periphery and central airways, respectively. Exhaled breath condensate is another non-invasive method to measure lung inflammation. The purpose of the present study was to find out if the severity of atopic eczema is associated with lung inflammation that can be observed with these non-invasive tests. We studied 81 patients (7-22 yr old) with atopic eczema and increased wheat-specific IgE (>or=0.4 kUA/l) and no diagnosis of asthma. Exhaled NO was measured at multiple exhalation flow rates, and bronchial NO flux and alveolar NO concentration were calculated. Cysteinyl-leukotriene concentrations were measured in exhaled breath condensate. The patients were divided into two groups according to the severity of atopic eczema. Patients with severe atopic eczema had enhanced bronchial NO output as compared with patients with mild eczema (2.1 +/- 0.5 vs. 0.9 +/- 0.1, p = 0.003). No statistically significant differences in alveolar NO concentrations were found between the groups. In the whole group of patients, the bronchial NO output correlated positively with serum eosinophil protein X (r(s) = 0.450, p < 0.001), serum eosinophil cationic protein (r(s) = 0.393, p < 0.001), serum total IgE (r(s) = 0.268, p = 0.016) and with urine eosinophil protein X (r(s) = 0.279, p = 0.012), but not with lung function. Alveolar NO concentration correlated positively with serum eosinophil protein X (r(s) = 0.444, p < 0.001) and with serum eosinophil cationic protein (r(s) = 0.362, p = 0.001). Measurable cysteinyl-leukotriene concentrations in exhaled breath condensate were found only in one-third of the patients, and there were no differences between the two groups. The results show that increased bronchial NO output is associated with eosinophilic inflammation and severe atopic eczema in patients without established asthma.     

Exhaled nitric oxide in childhood asthma

Endogenous synthesis of nitric oxide (NO) and its presence in exhaled air was observed in various species including humans. Particularly high levels were found in adults with bronchial asthma, possibly because of the underlying pulmonary inflammatory activity. We studied oral and nasal exhaled NO by chemiluminescence in 47 children aged between 6 and 10 years. Thirty children had bronchial asthma, 17 were healthy controls. In asthmatic children oral exhaled NO was 13.4±1.4 parts per billion (ppb) (mean±SEM), nasal exhaled NO was 21.7±1.5 ppb. In healthy controls oral exhaled NO was 7.2±1.0 ppb, nasal exhaled NO was 18.2±2.2 ppb. Oral exhaled NO was significantly higher in asthmatic children compared to healthy controls (P=0.0017). Nasal exhaled NO did not differ significantly in the two groups. There was a significant negative correlation between oral exhaled NO and forced expiratory volume in 1 s (FeV₁). No significant correlation between oral or nasal exhaled NO and other markers of obstructive lung function impairment, oral minute ventilation, the body mass index and the presence of upper respiratory tract infection could be found.     

Increased bronchial NO output in severe atopic eczema in children and adolescents

Atopic children have an increased risk for asthma, which is preceded by bronchial inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess alveolar NO concentration and bronchial NO flux, which reflect inflammation in lung periphery and central airways, respectively. Exhaled breath condensate is another non‐invasive method to measure lung inflammation. The purpose of the present study was to find out if the severity of atopic eczema is associated with lung inflammation that can be observed with these non‐invasive tests. We studied 81 patients (7–22 yr old) with atopic eczema and increased wheat‐specific IgE (≥0.4 kUA/l) and no diagnosis of asthma. Exhaled NO was measured at multiple exhalation flow rates, and bronchial NO flux and alveolar NO concentration were calculated. Cysteinyl‐leukotriene concentrations were measured in exhaled breath condensate. The patients were divided into two groups according to the severity of atopic eczema. Patients with severe atopic eczema had enhanced bronchial NO output as compared with patients with mild eczema (2.1 ± 0.5 vs. 0.9 ± 0.1, p = 0.003). No statistically significant differences in alveolar NO concentrations were found between the groups. In the whole group of patients, the bronchial NO output correlated positively with serum eosinophil protein X (r_s = 0.450, p < 0.001), serum eosinophil cationic protein (r_s = 0.393, p < 0.001), serum total IgE (r_s = 0.268, p = 0.016) and with urine eosinophil protein X (r_s = 0.279, p = 0.012), but not with lung function. Alveolar NO concentration correlated positively with serum eosinophil protein X (r_s = 0.444, p < 0.001) and with serum eosinophil cationic protein (r_s = 0.362, p = 0.001). Measurable cysteinyl‐leukotriene concentrations in exhaled breath condensate were found only in one‐third of the patients, and there were no differences between the two groups. The results show that increased bronchial NO output is associated with eosinophilic inflammation and severe atopic eczema in patients without established asthma.     

Spirometry‐adjusted fraction of exhaled nitric oxide increases accuracy for assessment of asthma control in children

Spirometry and exhaled nitric oxide are two important complimentary tools to identify and assess asthma control in children. We aimed to determine the ability of a new suggested spirometry‐adjusted fraction of exhaled nitric oxide (NO) index in doing that. A random sample of 1602 schoolchildren were screened by a health questionnaire, skin prick tests, spirometry with bronchodilation and exhaled NO. A total of 662 children were included with median (IQR) exhaled NO 11(14) ppb. Receiver operating characteristic (ROC) curves using exhaled NO equations from Malmberg, Kovesi and Buchvald, and spirometry‐adjusted fraction of exhaled NO values were applied to identify asthmatic children and uncontrolled asthma. Receiver operating characteristic (ROC) curves failed to identify asthmatic children (all AUC < 0.700). Spirometry‐adjusted fraction of exhaled NO/FEV₁ (AUC = 0.712; P = .010) and NO/FEF_25%‐75% (AUC = 0.735 P = .004) had a fair and increased ability to identify uncontrolled disease compared with exhaled NO (AUC = 0.707; P = .011) or the Malmberg equation (AUC = 0.701; P = .014). Sensitivity and specificity identifying non‐controlled asthma were 59% and 81%, respectively, for the cut‐off value of 9.7 ppb/L for exhaled NO/FEV₁, and 40% and 100% for 15.7 ppb/L/s for exhaled NO/FEF_25%‐75%. Exhaled NO did not allow to identify childhood asthma. Spirometry‐adjusted fraction of exhaled NO performed better‐assessing asthma control in children. Thus, although more validation studies are needed, we suggest its use in epidemiological studies to assess asthma control.     

Effect of nasal steroid treatment on airway inflammation determined by exhaled nitric oxide in allergic schoolchildren with perennial rhinitis and asthma

Rhinitis is common in asthmatic schoolchildren who are allergic to animal dander and constantly and indirectly exposed to these allergens in their everyday environment. As a patho‐physiological linkage between nasal and bronchial inflammation has been proposed to exist, the primary objective of this study was to determine whether nasal administration of mometasone furoate (MSNF) can reduce bronchial inflammation, as reflected in the level of exhaled nitric oxide (F_ENO) in asthmatic schoolchildren with dander allergy and mild‐to‐moderate rhinitis. Forty such children were assigned randomly to be treated for 4 wk with MSNF or placebo, employing a double‐blind procedure. F_ENO was the primary end‐point measured and secondary end‐points were nasal levels of NO, the concentration of eosinophilic cationic protein (ECP) in nasal lavage, the relative numbers of eosinophils in blood, forced expiratory volume in 1 s (FEV₁), peak expiratory flow (PEF) and scoring of symptoms. There was no significant difference in the F_ENO values of the treated and control groups at any time‐point, whereas the nasal level of ECP was lower in the treated group compared with placebo (p = 0.05) on both days 7 and 28, and compared with baseline for the treated group (p = 0.06 on day 7, p = 0.02 on day 28). Furthermore, the mean blood eosinophil count decreased in the treated group, which also demonstrated lower scores for nasal symptoms compared with placebo, but neither of these differences were statistically significant. FEV₁, PEF and nasal levels of NO remained unchanged in both groups. Four weeks of nasal treatment with MSNF had no effect on bronchial inflammation, as reflected by exhaled NO, whereas signs of nasal and systemic eosinophil activation were reduced. Thus, nasal administration of a steroid as a strategy to reduce asthmatic inflammation remains questionable in mild‐to‐moderately severe cases of perennial rhinitis and asthma.     

Exhaled NO and breath condensate

A growing interest has recently directed toward non invasive methods, such as exhaled nitric oxide (FE(NO)) measurement and exhaled breath condensate (EBC) collection, for the assessment of asthmatic inflammation. FE(NO) is a reliable marker of eosinophilic airway inflammation and it can be measured by means of a standardized technique in children starting from the age of 4. FE(NO) may have useful applications both in asthma diagnosis and monitoring. EBC is obtained cooling exhaled air and its composition is believed to mirror the characteristics of airway lining fluid. The compounds detected in EBC are markers of inflammation and oxidative stress occurring in asthmatic lung. While EBC is still only a research tool, FENO measurement is closer to clinical practice and lately it has been included in some treatment algorithms for asthma.     

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??Objective??To study the clinical value of the test of tidal breathing lung function and exhaled nitric oxide in asthmatic children aged 2 to 5. Methods??216 children with asthma treated from January 2012 to June 2015 in the Pediatric Department of Xijing Hospital of Fourth Military Medical University were listed in asthma group??and 128 normal children in the same period were selected as control group. Tidal breathing lung function and exhaled nitric oxide at the acute and remission stages of asthma were tested respectively??and compared with control group. Tidal breathing lung function were compared before and after bronchial dilation test. Correlation between exhaled nitric oxide level and tidal breath lung function parameters was analyzed. Results??The ratio of time to peak tidal expiratory flow to total expiratory time??TPEF/TE?? and ratio of volume to peak expiratory flow to total expiratory volume??VPEF/VE?? in acute stage of asthma group were significantly lower than those of the asthma group in the remission stage and the control group??P??0.05??. TPEF/TE and VPEF/VE had significantly improved in asthma group in remission stage??but were still significantly lower than those of the control group??P??0.05??. TPEF/TE and VPEF/VE had significantly improved after bronchial dilation test in the acute stage of asthma group??P??0.05??. Taking an improvement rate of ≥15% either for TPEF/TE or for VPEF/VE as an indicator of positive bronchial dilation test??thus the positive rate was 69.90%. The levels of FeNO in acute and remission stages of asthma group???35.50±14.13??×10-9????28.16±5.52??×10-9?? were significantly higher than those of the control group???12.77±7.00??×10-9??P??0.05?????and the levels of FeNO in acute stage of asthma group were significantly higher than those of asthma group in remission stage??P??0.05??. FeNO levels were not correlated with TPTEF/TE and VPEF/VE in acute or in remission stages of asthma group. Conclusion??Tidal breathing lung function??exhaled nitric oxide test and bronchial dilation test are complementary??combined applications can effectively improve the diagnosis and treatment in early childhood asthma.