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.     

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%.     

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.     

Allergic rhinitis with or without concomitant asthma: difference in perception of dyspnoea and levels of fractional exhaled nitric oxide

BACKGROUND/AIM: Allergic rhinitis (AR) is a risk factor for developing clinical asthma. Moreover, AR is often associated with bronchial hyper-responsiveness (BHR). The aim of the present study was to investigate whether patients with AR and asthma differed from AR with or without BHR in degree of perception of dyspnoea and airway inflammation, measured as fractionated exhaled nitric oxide (NO). MATERIALS: Twenty-nine patients with seasonal AR (timothy) were investigated with metacholine challenge test. Fourteen healthy non-reactive subjects served as controls. METHODS: (1) Metacholine challenge test, cut-off value forced expiratory volume in 1 s (FEV(1)) PD20 2,000 microg. Slope value for metacholine was calculated as %fall in FEV(1)/mol metacholine. Dyspnoea during challenge was measured with a 10-graded modified Borg score. (2) Measurement of fractional-exhaled nitric oxide (FENO) at flow rate 50 mL/s. RESULTS: Eighteen patients reported AR only, without asthma symptoms, and 12 (67%) were BHR. Eleven subjects had both rhinitis and asthma symptoms. Patients with rhinitis and asthma reported significantly more dyspnoea per percent fall in FEV(1) compared with those with rhinitis and BHR. Moreover, those with rhinitis and asthma had significantly higher NO values compared with those with rhinitis and BHR. CONCLUSION: The difference between rhinitis patients with or without asthma symptoms seems to be mainly a question of perception of dyspnoea. However, FENO measurement indicates that dyspnoea may also be associated with increased inflammatory activity in the peripheral airways.     

Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease

Nitric oxide (NO) is endogenously released in the airways, and the fractional concentration of NO in exhaled breath (FeNO) is now recognized as a surrogate marker of eosinophilic airway inflammation that can be measured using a noninvasive technique suitable for young children. Although FeNO levels are affected by several factors, the most important clinical determinants of increased FeNO levels are atopy, asthma, and allergic rhinitis. In addition, air pollution is an environmental determinant of FeNO that may contribute to the high prevalence of allergic disease. In this review, we discuss the mechanism for airway NO production, methods for measuring FeNO, and determinants of FeNO in children, including host and environmental factors such as air pollution. We also discuss the clinical utility of FeNO in children with asthma and allergic rhinitis and further useful directions using FeNO measurement.     

Lung Function Studies in Children with Allergic Rhinitis

Thirty carefully selected children with seasonal allergic rhinitis but without history or signs of lung involvement were examined clinically and by lung function tests during the pollen season as well as in the pollen-free season. During the pollen-free season the children had -if anything - slightly better lung function than a healthy control material. During the pollen season the only change was a slight increase in FRC and a decrease in lung clearance index, directly proportional to the change in FRC. Sixteen of the children performed an exercise test in the pollen-free season. A small increase in the volume of trapped gas (VTG) was noted, indicating a subclinical spasm in small airways. Salbutamol inhalation alter exercise reduced VTG below base-line values, indicating disappearance of subclinical bronchospasm. Hay Fever children thus have a tendency towards bronchospasm after exercise in the pollen-free season, which, owever, is of no clinical importance, as their VTG also after the exercise was less (better) than the predicted normal.     

The Prevalence of Serum Specific IgE to Superantigens in Asthma and Allergic Rhinitis Patients

Staphylococcus aureus is the most common bacterium present in upper respiratory tract, and the toxins it produced are involved in allergic inflammation pathogenesis. In this study, we investigated the clinical significance of IgE in association with staphylococcal superantigens in allergic asthma with rhinitis (BAwAR) and allergic rhinitis alone (AR). We recruited 100 patients with BAwAR (group I), 100 patients with AR (group II), and 88 healthy controls (group III). Patients were clinically diagnosed by physicians, and were sensitized to house dust mites. Specific IgE antibodies to staphylococcal superantigen A (SEA), B (SEB), and toxic shock syndrome toxin-1 (TSST-1) were measured using the ImmunoCAP system. Other clinical parameters were retrospectively analyzed. All specific IgE antibodies to SEA, SEB, and TSST-1 were detected most frequently in group I (22%, 21%, and 27%), followed by group II (11%, 14%, and 21%) and group III (4.5%, 3.4%, and 2.3%). Absolute values of serum specific IgE to SEA, SEB, and TSST-1 were also significantly higher in group I (0.300±1.533 kU/L, 0.663±2.933 kU/L, and 0.581±1.931 kU/L) and group II (0.502±2.011 kU/L, 0.695±3.337 kU/L, and 1.067±4.688 kU/L) compared to those in group III (0.03±0.133 kU/L, 0.03±0.14 kU/L, and 0.028±0.112 kU/L). The prevalence of serum specific IgE to SEA was significantly higher in group I compared to group II (P=0.025). Blood eosinophil counts were significantly higher in patients with specific IgE to SEA or SEB, and higher serum levels of specific IgE to house dust mites were noted in patients with specific IgE to TSST-1. In conclusion, the present study suggested that IgE responses to staphylococcal superantigens are prevalent in the sera of both BAwAR and AR patients. This may contribute to an augmented IgE response to indoor allergens and eosinophilic inflammation.     

Asthma and Allergic Rhinitis in the Same Patients

This study from Danish general practice gives Figures about the simultaneous prevalence of asthma and allergic rhinitis and the order of onset among 7662 patients, who during 1 year consulted for one or both of these diseases. Twenty-eight percent of patients with asthma consulted because they also had allergic rhinitis, and 17% of patients with allergic rhinitis consulted because they also had asthma. Age- and sex-distributions are presented. In 25% of patients with both diseases the onset of both diseases occurred within the same year, while in 35% the onset of asthma occurred first and in 40% allergic rhinitis.
Among patients with both diseases, who did not have onset of both within the same year, more than 75% of them had onset of one disease within 2 years of the other.     

A Comparison of Intranasal and Oral Flunisolide in the Therapy of Allergic Rhinitis

Intranasal flunisolide is an effective treatment for allergic rhinitis. Flunisolide has high bioavailability when administered to normal subjects (50% of an intranasal dose reaches the systemic circulation) with minimal systemic effects. Bioavailability in patients with active rhinitis averages 62.4 +/- 15.7%. The oral dose bioequivalent to 100 micrograms intranasally is 500 micrograms. To define the comparative trial and systemic effects of intranasal flunisolide in patients with active allergic rhinitis, a multicenter, randomized, double-blind, placebo-controlled study was conducted during the 1983 ragweed hayfever season. Ninety-nine patients with ragweed hayfever for greater than or equal to 2 years and positive prick skin tests to ragweed were randomly allocated to one of three treatment groups: 0 = oral flunisolide 500 micrograms b.i.d. and intranasal placebo b.i.d.; N = intranasal flunisolide 50 micrograms per nostril b.i.d. and oral placebo b.i.d.; P = intranasal and oral placebo b.i.d. Treatment continued for 4 weeks. Patients kept daily symptom scores. Patients were evaluated by a blinded observer every 2 weeks and were globally evaluated at the study's end. Data were analyzed for each center and pooled. There were no significant differences in symptom severity of sneezing, nasal congestion, and throat itch in the 0 (oral flunisolide) and P (placebo) groups. N (nasal flunisolide) was significantly more effective than O or P (P less than or equal to 0.005) for each symptom for at least one 2-week period. Global evaluation demonstrated control of overall hayfever severity for N (nasal flunisolide) but not for O (oral flunisolide). We conclude that the therapeutic efficacy of flunisolide is achieved by topical and not by systemic action.     

过敏性鼻炎患儿过敏原特异性IgE检测与临床意义

目的 了解过敏性鼻炎儿童主要过敏原分布情况及特点,以指导临床防治.方法 采用免疫印迹法体外定量检测患儿血清中特异性IgE抗体及20种常见过敏原.结果 938例过敏性鼻炎患儿中,100%至少对一种以上的过敏原呈阳性反应,其中487例患儿总IgE〉400IU/Ml,230例患儿总IgE在200IU/ml~400IU/ml之间.在检测20种过敏原中以户尘螨和屋尘的阳性率最高（90.0%,80.8%）.结论 过敏性鼻炎患儿至少有一种特异性IgE抗体显著增加,户尘螨、屋尘、动物皮屑、羊肉和牛奶是引起儿童过敏性鼻炎的主要过敏原.儿童在春秋温暖季节易发过敏性鼻炎.     

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.     

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.     

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.     

Ratio of Leukotriene E4 to Exhaled Nitric Oxide and the Therapeutic Response in Children With Exercise-Induced Bronchoconstriction

Purpose

This study assessed the association between the ratio of leukotriene E₄ (LTE₄) to fractional exhaled nitric oxide (FE_NO) in the response of children with exercise-induced bronchoconstriction (EIB) enrolled in a therapeutic trial with montelukast or inhaled corticosteroid (fluticasone propionate [FP]).

Methods

Children aged 6 to 18 years with EIB were randomized in a 4-week, placebo-controlled, double-blinded trial with montelukast or FP. Before and after treatment, treadmill exercise challenges were performed. The LTE₄ levels in the induced sputum and urine and the FE_NO levels were measured in subjects before and 30 minutes after the exercise challenges. The same tests were conducted after treatment.

Results

A total of 24 patients completed the study: 12 in the montelukast group and 12 in FP group. Both study groups displayed a similar postexercise maximum decrease in forced expiratory volume in one second (FEV1) before treatment as well as after treatment. However, there were significant differences in the magnitude of change between the two (Δ; -18.38±14.53% vs. -4.67±8.12% for the montelukast and FP groups, respectively; P=0.021). The Δ logarithmic sputum baseline and postexercise LTE₄/FE_NO ratio were significantly lower in the montelukast group than in the FP group (baseline; -0.09±0.21 vs. -0.024±0.03, P=0.045; postexercise, -0.61±0.33 vs. -0.11±0.28, P=0.023).

Conclusions

These data indicate that the efficacy of montelukast for preventing a maximum decrease in FEV1 after exercise is significantly higher than that of FP, and the high LTE₄/FE_NO ratio is associated with a greater response to montelukast than to FP for EIB therapy. These results suggest that LTE₄ may play an important role in EIB.     

惊恐障碍一氧化氮、一氧化氮合酶及脑血流研究

目的:研究惊恐障碍(PD)一氧化氮、一氧化氮合酶及脑血流的改变以及影响这些改变的相关因素.方法:研究组为30例PD组,对照组为30例广泛焦虑障碍(GAD) PD组,30例GAD组及22例正常对照(NC)组.所有样本均测一氧化氮(NO)、一氧化氮合酶(NOS)及脑血流量.比较PD组分别与GAD PD组、GAD组及正常对照(NC)组之间的差别,并在PD组内部对有关指标作多元逐步回归分析.结果:PD组NO浓度较GAD组低(67.22±39.62,102.8±60.69).NOS测重浓度PD组与其他各组无显著性差异(P>0.05).脑血流测定,PD组左侧大脑中动脉收缩峰、右侧大脑中动脉收缩峰及右侧大脑中动脉平均峰较NC组低且差异有显著性.右侧椎动脉收缩峰较GAD组及NC组低.PD组NO浓度与HAMA负相关.左侧大脑中动脉收缩峰与左侧大脑中动脉平均峰、右侧大脑中动脉收缩峰及精神性焦虑呈正相关,与右侧大脑中动脉平均峰及右侧大脑前动脉收缩峰、年龄及女性呈负相关.右侧大脑中动脉收缩峰与右侧大脑中动脉平均峰、右侧大脑前动脉收缩峰呈正相关,与右侧大脑前动脉平均峰呈负相关.右侧大脑中动脉平均峰与右侧大脑中动脉收缩峰、左侧大脑中动脉平均峰、右侧大脑前动脉平均峰及NO呈正相关,与年龄、左侧大脑中动脉收缩峰及右侧大脑前动脉收缩峰呈负相关.右侧椎动脉收缩峰与右侧椎动脉平均峰、左侧大脑中动脉平均峰呈正相关,与左侧大脑前动脉收缩峰、右侧大脑前动脉平均峰呈负相关.结论:NO、脑血流量改变可能是PD的神经生物学机制之一.测定NO水平及脑血流量可作为PD的诊断或鉴别诊断指标.     

Symptoms of Chronic and Allergic Rhinitis and Occurrence of Nasal Secretion Granulocytes in University Students, School Children and Infants

The prevalence of chronic and allergic rhinitis was studied in an unselected population sample consisting of 315 university students and 319 school children. History was taken by questionnaire, nasal appearance was examined by rhinoscopy, and a nasal smear was studied in all subjects. For comparison, nasal smears were also collected from 60 normal infants. Allergic rhinitis complaints were reported by 28% of the students and by 13% of the school children, with no significant difference in sex distribution. The cytological examination revealed secretion eosinophilia in 20% of the students, 28% of the school children, and 22% of the infants. Secretion eosinophilia correlated significantly with allergic rhinitis history, and with nasal mucosal swelling and nasal secretion seen on rhinoscopy. Nasal secretion neutrophilia, which occurred in 47% of the students, 79% of the school children and 97% of the infants, seemed to have an adverse effect on the reliability of secretion eosinophilia as an indicator of active nasal allergy. Possible reasons for the rising prevalence rates of allergic rhinitis are discussed.