NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children

Exhaled nitric oxide (FE_NO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FE_NO in adults with asthma and cystic fibrosis, was associated with the raised FE_NO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6–18 years) underwent measurements of FE_NO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FE_NO in either the whole sample of healthy children (n = 87) or in the subsample of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FE_NO.     

以225名健康儿童建立呼出气一氧化氮正常值

目的：探讨6~14岁儿童呼出气一氧化氮（FeNO）正常值范围及其影响因素。方法：选取苏州市6~14岁在校儿童进行问卷调查及FeNO、肺功能、外周血嗜酸粒细胞（EOS）计数的检测,筛选出健康儿童建立FeNO正常值。FeNO的测定采用电化学法,根据美国胸科学会/欧洲呼吸学会指南进行操作。分析性别、年龄、身高、体重、外周血EOS计数、肺功能和FeNO的相关性。结果：参与调查的450名儿童中符合纳入标准者225名（男生107名,女生118名）进入分析。FeNO值呈偏态分布,经自然对数转换后呈正态分布。FeNO平均值为11 ppb(95%CI:5~28 ppb）,最小值<5 ppb,最大值为83 ppb。男生FeNO平均值为11 ppb(95%CI:5~31 ppb）,女生FeNO平均值为11 ppb(95%CI:5~25 ppb）。FeNO与外周血EOS计数相关性最为显著（r=0.291,P<0.001）,与身高（r=0.148, P=0.027）和FEV1（r=0.138, P=0.038）显著相关;>9岁儿童FeNO显著高于≤9岁儿童（P=0.002）;FeNO与性别、体重、BMI、FEV1/FVC无显著相关性。结论：苏州地区6~14岁儿童FeNO正常参考值为5~28 ppb;FeNO水平与外周血EOS计数、身高、FEV1显著相关。     

Exhaled nitric oxide in asthmatic children and adolescents after nasal allergen challenge

Epidemiological data suggest a comorbidity link between nasal and bronchial allergic disease. Exhaled nitric oxide (FENO) is a sensitive marker of bronchial inflammation and increases after bronchial allergen provocation. We studied FENO in 19 children and adolescents with allergic asthma and 10 controls before and 2, 6 and 24 h after a single nasal allergen challenge. The correlation between FENO and other markers of allergic inflammation, such as eosinophils in blood and eosinophil cationic protein (ECP) in serum and nasal lavage was also assessed. FENO remained unchanged 24 h post-challenge in both steroid and steroid-naive patients. At 6 h post-challenge, FENO decreased in both asthmatics and controls. The asthmatic subjects showed a positive correlation between FENO and blood eosinophils before (r=0.71, p=0.001) and after the challenge, and between FENO and ECP in nasal lavage (r=0.62, p=0.02) 2 h after the challenge. Mean ECP in nasal lavage increased post-challenge but not significantly. We conclude that a single nasal allergen challenge does not augment bronchial inflammation although FENO, is related to blood eosinophil count and to the nasal inflammatory response. Our data do not support the theory of a direct transmission of the nasal inflammation to the lower airways.     

Consistently high levels of exhaled nitric oxide in children with asthma

Background: Exhaled nitric oxide (eNO) levels in children are unstable because they are regulated by many potent factors. The purpose of the current study was to evaluate the reliability of eNO levels between a long interval and other lung functions in normal and asthmatic children. Methods: Eighty‐three elementary school children (aged 11–12 years; male : female, 39 : 44) participated in this study. Lung function, airway resistance and eNO levels were measured twice: the first measurement was in autumn 2007, and the second was one year later. Results: There were 62 non‐asthmatic control children (male : female, 31 : 31) and 21 asthmatic children (male : female, 8 : 13). In both the first and the second examination, the levels of eNO in children with asthma were higher than those in children without asthma. The parameters of lung function and the respiratory resistance in children without asthma showed a good correlation between the results of the first and second examinations. The eNO level in non‐asthmatic children showed a good correlation between the two. On the other hand, the peripheral airway parameters of lung function and the respiratory resistance in children with asthma were not correlated between the first and the second examinations. The eNO level in these patients was well correlated between the two examinations. Conclusions: These data suggest that the eNO level showed good reproducibility in children with and without asthma. The eNO level is therefore considered to be a useful marker for reproducibly evaluating a subject's airway condition.     

Exhaled nitric oxide in healthy young children during tidal breathing through a facemask

The aim of this study was to establish reference values and to examine day-to-day and within-day variations of exhaled nitric oxide (eNO) during tidal breathing in healthy children using a newly described method. Exhaled NO was measured on-line and off-line during tidal breathing through a facemask. In a subgroup of children measurements were repeated during the course of a single day and on the same time on three consecutive days. A total of 133 healthy children were included in the study and measurements were obtained from 121 children aged 2-7 yr (61 boys and 60 girls). The geometric mean eNO concentration and 95% CI was 3.9 (3.5-4.2) parts per billion (p.p.b.) for on-line measurements and 3.0 (2.7-3.3) p.p.b. for off-line measurements. Exhaled NO was independent of gender, age, height and weight. The 95% reference intervals (RI) for on-line and off-line measurements were 1.2-8.2 and 1.3-7.1 p.p.b. respectively. Twenty-three children completed measurements of within-day and day-to-day variations, none of which showed significant variation. In conclusion, the established reference values and data on variability within and between days may facilitate the clinical application for measurement of eNO during tidal breathing in young children.     

北京地区学龄儿童呼出气一氧化氮调查分析

目的 了解北京地区学龄儿童呼出气一氧化氮(eNO)水平.方法 选择北京市11-18岁在校学生,采用过敏件疾病与哮喘的国际间对比研究调查问卷,通过填写问卷及现场体检对儿童进行分组(正常儿童组及曾患不同疾病儿童组),检测eNO水平、峰流速及过敏原.结果 共筛选出正常儿童395名,男177名,女218名.不同性别正常儿童eNO差异无统计学意义(P均>0.05),但与其年龄呈正相关(男性P=0.008,女性P=0.05),在男性与其身高呈正相关(P=0.02).11～14岁、14～18岁正常儿童eNO几何均数(G)分别为11.22、14.13 ppb(ppb=10~9),其95%正常值范围分别为4.17～30.20 ppb、5.50～36.31 ppb.曾患哮喘/喘息(68例)和曾患过敏性鼻炎(96例)儿童eNO几何均数分别是19.05 ppb、14.79 ppb,与正常儿童差异有统计学意义(P分别为0.001、0.008).过敏原皮肤点刺检查阳性与阴性儿童eNO几何均数分别为16.98 ppb、11.75 ppb,两组间差异有统计学意义(P=0.001).结论 北京地区11～18岁正常学龄儿童eNO随年龄波动于10.72～13.80ppb,与年龄、身高呈正相关,与性别无关.喘息性疾病、过敏性鼻炎患儿以及特应性个体eNO水平显著增加.     

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.     

Primary ciliary dyskinesia: Diagnosis in children with inconclusive ultrastructural evaluation

The purpose of this study was to distinguish between acquired and genetically determined ciliary abnormalities in children with severe chronic respiratory diseases. Samples of nasal ciliated epithelium from 50 subjects (25 male, 25 female; age-range 2–19 years) with severe chronic respiratory diseases were examined using transmission electron microscopy (TEM). Based on TEM findings, patients were divided into two groups: A and B. Group A comprised 39 children with ciliary alterations compatible with a condition probably occuring secondary to chronic inflammation (alterations of peripheral pairs, swollen cilia, and compound cilia). The other 11 patients, Group B, exhibited a greater number of alterations of the central pair and dynein arms (p< 0.001), which were qualitatively similar to, but less numerous than, those observed in primary ciliary dyskinesia (PCD). In both groups, analysis of ciliary beat frequency and waveform was performed by phase contrast microscopy (PCM). All the children with a ciliary beat frequency of < 7 Hz were treated with daily physiotherapy and with antibiotics, as recommended for PCD, for a 6-month period. After this treatment, the children were reexamined by PCM. Almost 50% of the children from Group B (i.e. those with a small proportion of specific ultrastructural defects) showed permanence of low ciliary beat frequency. This was also observed in two children of Group A. These children were considered to be affected by PCD. Our study describes a method for the diagnosis of PCD in the absence of specific ultrastructural defects or when these defects are present in only a small proportion of the cilia.     

Measurement of exhaled nitric oxide in young children during tidal breathing through a facemask

Measurement of exhaled nitric oxide (eNO) offers a non-invasive means for assessment of airway inflammation. The currently available methods are difficult to apply in preschool children. We evaluated four methods potentially applicable for eNO measurement during tidal breathing in young children. eNO was assessed during tidal breathing in 24 children, 2-7 yr old, using a facemask which separated nasal and oral airflow. Facemasks with and without a one-way valve allowing exhalation through the nose were used. Expiratory flow control was not attempted. Measurements of eNO were performed both on-line and off-line. In 11 children, 8-12 yr old, measurements were compared with the standard single breath on-line method. eNO was significantly lower applying the one-way valve in on-line and off-line measurements in comparison with measurements without the valve [4.6 and 3.9 parts per billion (ppb) vs. 6.9 ppb and 6.5 ppb]. The mean within subject coefficient of variation (CV) was significantly lower in on-line measurements with the one-way valve (9.6%) compared with the other three methods (18.8, 27.7 and 29.3% respectively). Measurements with a facemask fitted with a one-way valve yielded similar eNO levels as the standard single breath method (7.0 ppb vs. 6.9 ppb) and reproducibility (9.8% vs. 7.1%). In conclusion, reproducible measurements of eNO can be obtained without control of expiration flow using a facemask fitted with a one-way valve on the nasal compartment. The likely explanation to this is that the one-way valve reduces the admixture of nasal NO, thereby improving the reliability of eNO measurements.     

Life-threatening effects of discontinuing inhaled nitric oxide in children

We treated 40 children, aged between 15 d and 17 y, diagnosed with acute respiratory distress syndrome and/ or pulmonary hypertension, with inhaled nitric oxide. The most frequent underlying diagnosis associated with ARDS were bronchopneumonia (eight), cardiac surgery (five), and sepsis (three). Pulmonary hypertension was secondary to cardiomyopathy in 2 patients and occurred in the postoperative period of cardiac surgery in 17 patients–the most frequent were ventricular septal defect (5), transposition of great arteries (4), and atrioventricular septal defect (3). In 11 patients, sudden discontinuation of nitric oxide induced a decrease in oxygenation associated in some of the patients with an increase in pulmonary artery pressure. In two patients discontinuation of nitric oxide induced severe pulmonary hypertension, extreme bradycardia and hypoxaemia, which required cardiopulmonary resuscitation. When exogenous nitric oxide is abruptly interrupted, hypoxaemia and pulmonary hypertension are found in some patients, due to a decrease in the nitric oxide concentration in the pulmonary circulation. This may be caused by the exogenous nitric oxide administration that may have inhibited endogenous production. We recommend making a progressive withdrawal of inhaled nitric oxide to avoid the side effects observed in the sudden discontinuation.     

健康儿童呼出气体一氧化氮水平及其与肺功能相关性研究

目的 测定健康儿童呼出气体一氧化氮(eNO)浓度及其与肺功能的相关性.方法 随机测定100名7～8岁健康儿童(男53名;7岁43名)eNO及肺功能,采用SAS(8.2版)软件进行秩相关分析.结果 受试儿童eNO水平[中位数(四分位数间距)为8×10-9[(6～11)×10-9],其中男8×10-9[(6～11)×10-9],女8×10-9[(6～11)×10-9].eNO与肺功能无相关性(复相关系数r=0.22,P=0.32).eNO与身高、体质量有明显的相关性(r=0.22,P=0.03;r=0.23,P=0.02).结论 健康儿童eNO与肺功能无相关性.eNO与肺功能联合检测可全面认识气道炎症和气道高反应性.     

Exhaled nitric oxide and exercise-induced bronchoconstriction in young wheezy children – interactions with atopy

The association between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (FE_NO) has not been investigated in young children with atopic or non-atopic wheeze, two different phenotypes of asthma in the early childhood. Steroid naïve 3- to 7-yr-old children with recent wheeze (n = 84) and age-matched control subjects without respiratory symptoms (n = 71) underwent exercise challenge test, measurement of FE_NO and skin prick testing (SPT). EIB was assessed by using impulse oscillometry, and FE_NO by standard online technique. Although FE_NO levels were highest in atopic patients with EIB, both atopic and non-atopic wheezy children with EIB showed higher FE_NO than atopic and non-atopic control subjects, respectively. In atopic wheezy children, a significant relationship between FE_NO and the severity of EIB was found ( r  = 0.44, p = 0.0004), and FE_NO was significantly predictive of EIB. No clear association between FE_NO and EIB or predictive value was found in non-atopic wheezy children. Both atopic and non-atopic young wheezy children with EIB show increased FE_NO levels. However, the association between the severity of EIB and FE_NO is present and FE_NO significantly predictive of EIB only in atopic subjects, suggesting different interaction between bronchial responsiveness and airway inflammation in non-atopic wheeze.     

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??Abstract: Objective To learn the level of exhaled nitric oxide??ENO?? in Jinan schoolchildren??setting up normal reference value range and analyzing associate influencing factors. Method A total of 473 school children in Jinan aged 7 to 13 years were included in this study. By means of filling out the questionnaire and site examination??we selected eligible children and then measured the exhaled nitric oxide and Peak Expiratory Flow ??PEF??. Result The 473 cases of healthy schoolchildren were selected??male 257??female 216??in this study and we concluded the geometric mean and the 95% CI was 7.780??4.656??13.002??× 109 mol/L. We found that ENO’s level of 10??13-years-old children significantly higher than 7??9 year-old children??P??0.05??. The geometric mean and the 95% CI were 8.680??5.936??12.692??× 109 mol/L and 6.710??3.588??12.546??× 109 mol/L.In our study we found that age had positive relation with ENO ??P??0.05??while gender??height??weight ??PEFR and passive smoking had no significant correlation with ENO??P??0.05??. Conclusion The geometric mean and the 95% CI of ENO in children aged 7??13 years in Jinan is 7.780??4.656??13.002??× 109 mol/L?? in which 10??13-year- old children was significantly higher than 7??9-years old children ??P??0.05?? and the geometric mean and the 95% CI are 8.680??5.936??12.692??× 109 mol/L and 6.710??3.588??12.546??× 109 mol/L. Gender is an independent influencing factor of ENO level.     

Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV ₁, MEF₂₅ and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.     

Nasal peak inspiratory flow through Turbuhaler® in children with symptomatic rhinitis and in healthy children

Topical treatment of allergic or vasomotor rhinitis is possible by means of pressurized metered dose inhalers, aqueous spray, or dry powder inhalers. In children, little is known about nasal drug delivery by dry powder inhalation. The airflow through the device is critical for the drug release and a sufficient nasal inspiratory flow is needed for intranasal drug delivery from a dry powder inhaler. In order to investigate from what age children with allergic or vasomotor rhinitis can reliably use such a device, device-dependent nasal peak inspiratory flow (DnPIF) was measured. The maximal DnPIF was measured in children aged 4–13 years making use of a dry powder inhaler (Turbuhaler^®) connected to a spirometer (Vitalograph^®). In the clinically relevant context, instructions from the doctor and one week's use of a Turbuhaler at home were found to be sufficient to obtain a good inhalation technique and were shown to improve DnPIF at least as effectively as visual feedback training at the clinic. Children with rhinitis, as well as healthy children from the age of 6 years, were able to generate a DnPIF sufficient to obtain a reliable nasal delivery of a dry powder drug dose. DnPIF values correlated with age. Consequently, a recommendation to use a nasal Turbuhaler from the age of 6 for topical drug delivery in the treatment of allergic or vasomotor rhinitis seems reasonable.     

Exhaled nitric oxide in children with asthma and sinusitis

Exhaled nitric oxide (FE_NO) is a surrogate marker of eosinophilic airway inflammation. The measurement of this gas can be easily performed in children and the result is immediately available. Because of these characteristics, measurement of FE_NO is slowly becoming part of the routine clinical evaluation of an asthmatic patient. FE_NO measurement may have a role both in the diagnosis of asthma and as a guide in therapy algorithms. For example when FE_NO levels are persistently normal and the asthmatic child is asymptomatic, the steroid therapy may be decreased or even stopped. In patients with acute or chronic rhinosinusitis the levels of nasal nitric oxide (nNO) are significantly decreased, while they rise up after a course of antibiotics. The measurement of nasal NO has been proposed as a functional test to evaluate sinus ventilation. Nasal NO is significantly reduced also in primary ciliary dyskinesia and can be used as a screening tool to identify patients affected by this condition.     

Additive effect of eosinophilia and atopy on exhaled nitric oxide levels in children with or without a history of respiratory symptoms

Although atopy and blood eosinophilia both influence exhaled nitric oxide (eNO) measurements, no study has quantified their single or combined effect. We assessed the combined effect of atopy and blood eosinophilia on eNO in unselected schoolchildren. In 356 schoolchildren (boys/girls: 168/188) aged 9.0-11.5 yr, we determined eNO, total serum IgE, blood eosinophil counts and did skin prick tests (SPT) and spirometry. Parents completed a questionnaire on their children's current or past respiratory symptoms. Atopy was defined by a SPT >3 mm and eosinophilia by a blood cell count above the 80th percentile (>310 cells/ml). eNO levels were about twofold higher in atopic-eosinophilic subjects than in atopic subjects with low blood eosinophils [24.3 p.p.b. (parts per billion) vs. 14.1 p.p.b.] and than non-atopic subjects with high or low blood eosinophils (24.3 p.p.b. vs. 12.2 p.p.b. and 10.9 p.p.b.) (p <0.001 for both comparisons). The additive effect of atopy and high eosinophil count on eNO levels remained unchanged when subjects were analyzed separately by sex or by a positive history of wheeze (n=60), respiratory symptoms other than wheeze (n=107) or without respiratory symptoms (n=189). The frequency of sensitization to Dermatophagoides (Dpt or Dpf) was similar in atopic children with and without eosinophilia (66.2% and 67.4%, respectively); eosinophilia significantly increased eNO levels in Dp-sensitized children as well in children sensitized to other allergens. In a multiple linear regression analysis, eNO levels were mainly explained by the sum of positive SPT wheals and a high blood eosinophil count (t=4.8 and 4.3, p=0.000), but also by the presence of respiratory symptoms (especially wheeze) and male sex (t=2.6 and 2.0, p=0.009 and 0.045, respectively). Measuring eNO could be a simple, non-invasive method for identifying subjects at risk of asthma in unselected school populations.     

急性肾炎患儿循环内皮细胞与一氧化氮的改变

探讨小儿急性肾炎对循环内皮细胞与一氧化氮的改变。方法随机选择急性肾炎组20例，健康儿童40例为对照组。住院翌日晨采静脉血3ml、1ml于肝素抗凝管中待测NO水平，2ml由3．8％枸橼酸钠抗凝，测定CEC用。并对测定结果进行统计学分析。结果对照组循环内皮细胞（CEC）为20．5±7．6n／0．9μl，肾炎极期为47．8±31.7n／0．9μl，肾炎恢复期27．7±9．9n/0．9μl。与正常对照组比较，小儿肾炎极期明显高于对照组和恢复期（P＜0．01）。一氧化氮（NO）仅测10例，正常组19．19±9．9μmol／L，肾炎组24．42±10．32μmol／L，两组对比，有增加趋势。结论小儿急性肾炎时CEC明显高于正常对照组，同时高于恢复期，结果表明循环内皮细胞在小儿急性肾炎的发生发展中起着重要的作用，因此动态观察CEC可作为判断肾炎恢复的标准之一。急性肾炎患儿NO水平与CEC是正相关，提示NO参与了小儿急性肾炎的致病过程。