Exhaled Nitric Oxide In Children Research Articles

Seasonal variation and environmental predictors of exhaled nitric oxide in children with asthma

The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, shows promise as a noninvasive tool to guide asthma management, but there is a paucity of longitudinal data about seasonal variation and environmental predictors of FeNO in children. The objective of this project was to evaluate how environmental factors affect FeNO concentrations over a 12-month study period among children with doctor diagnosed asthma. We conducted a prospective cohort study of 225 tobacco-smoke exposed children age 6-12 years with doctor-diagnosed asthma including measures of FeNO, medication use, settled indoor allergens (dust mite, cat, dog, and cockroach), and tobacco smoke exposure. Baseline geometric mean FeNO was 12.4 ppb (range 1.9-60.9 ppb). In multivariable analyses, higher baseline FeNO levels, atopy, and fall season were associated with increased FeNO levels, measured 6 and 12 months after study initiation, whereas inhaled steroid use, summer season, and increasing nicotine exposure were associated with lower FeNO levels. In secondary analyses of allergen sensitization, only sensitization to dust mite and cat were associated with increased FeNO levels. Our data demonstrate that FeNO levels over a year long period reflected baseline FeNO levels, allergen sensitization, season, and inhaled steroid use in children with asthma. These results indicate that FeNO levels are responsive to common environmental triggers as well as therapy for asthma in children. Clinicians and researchers may need to consider an individual's baseline FeNO levels to manage children with asthma.

Analysis of Single-breath Profiles of Exhaled Nitric Oxide in Children with Allergy and Asthma: Guideline-derived Plateau Concentrations Compared to Results of Automatic Evaluation by Two Analyzers

Current guidelines recommend the single-breath measurement of fractional concentration of exhaled nitric oxide (FENO) at the expiratory flow rate of 50 mL/s as a gold standard. The time profile of exhaled FENO consists of a washout phase followed by a plateau phase with a stable concentration. This study performed measurements of FENO using a chemiluminescence analyzer Ecomedics CLD88sp and an electrochemical monitor NIOX MINO in 82 children and adolescents (44 males) from 4.9 to 18.7 years of age with corticosteroid-treated allergic rhinitis (N = 58) and/or asthma (N = 59). Duration of exhalation was 6 seconds for children less than 12 years of age and 10 seconds for older children. The first aim was to compare the evaluation of FENO-time profiles from Ecomedics by its software in fixed intervals of 7 to 10 seconds (older children) and 2 to 4 seconds (younger children) since the start of exhalation (method A) with the guideline-based analysis of plateau concentrations at variable time intervals (method B). The second aim was to assess the between-analyzer agreement. In children over 12 years of age, the median ratio of FENO concentrations of 1.00 (95% CI: 0.99–1.02) indicated an excellent agreement between the methods A and B. Compared with NIOX MINO, the Ecomedics results were higher by 11% (95% CI: 1–22) (method A) and 14% (95% CI: 4–26) (method B), respectively. In children less than 12 years of age, the FENO concentrations obtained by the method B were 34% (95% CI: 21–48) higher and more reproducible (p < 0.02) compared to the method A. The Ecomedics results of the method A were 11% lower (95% CI: 2–20) than NIOX MINO concentrations while the method B gave 21% higher concentrations (95% CI: 9–35). We conclude that in children less than 12 years of age, the guideline-based analysis of FENO–time profiles from Ecomedics at variable times obtains FENO concentrations that are higher and more reproducible than those from the fixed interval of 2 to 4 seconds and higher than NIOX MINO concentrations obtained during a short exhalation (6 seconds). The Ecomedics FENO concentrations of children more than 12 years of age calculated in the interval of 7 to 10 seconds represent plateau values and agree well with NIOX MINO results obtained during a standard 10-second exhalation.

Variations in Exhaled Nitric Oxide in Children with Asthma During a 1-Week Stay in a Mountain Village Sanatorium

Knowing about spontaneous variations in the fractional concentration of exhaled nitric oxide (FENO) could improve monitoring of airway inflammation in asthmatic children. We aimed to assess FENO variations (expiratory flow 50 mL/sec) in subjects maintained in similar environmental conditions. We tested spirometry and FENO in symptom-free asthmatic children (9 corticosteroid-naive, 8 corticosteroid-treated) during a 1-week stay in a countryside sanatorium and in their healthy relatives (n = 12) staying in the immediate neighborhood on summer holiday (total 29 children, M/F:14/15, 5.8-16.8 yrs). Testing sessions were repeated every 12 hours (8:00 am, 8:00 pm) for 2 days and again on day 7. Measurements were defined as reproducible when they agreed with an intraclass correlation coefficient (ICC) above 0.60; deviation from mean differences was assessed by the coefficient of repeatability (CR = 2 SD). Lung function remained constant throughout the week in all groups. Baseline FENO levels in corticosteroid-naive asthmatic children tended to decrease at the end of the week (from 13.9 ppb, 95% CI 12.2-19.1 to 9.2 ppb, 95% CI 5.8–15.9, p = 0.057). No differences were found between nocturnal and diurnal FENO. Within-session reproducibility for two FENO measurements was high (ICC 0.99 in all groups and CR, 0.9 to 1.3 ppb). Between-session FENO reproducibility at 12 hours and 24 hours was still high for each group but decreased markedly after 6 days in corticosteroid-naive asthmatic children (ICC 0.79 and CR 9.6 ppb at 24 hours vs. ICC 0.13 and CR 20.8 ppb after 6 days), whereas it decreased slightly in corticosteroid-treated asthmatics (from ICC 0.89 and CR 3.1 ppb to ICC 0.88 and CR 3.0 ppb) and healthy children (from ICC 0.79 and CR 4.8 ppb to ICC 0.65 and CR 5.7 ppb). In conclusion, in healthy subjects and in asthmatic children receiving therapy with inhaled corticosteroids (but not in corticosteroid-naïve subjects), FENO measurements are reproducible across a week.

Parental Smoking Increases Exhaled Nitric Oxide in Children

Franklin PJ, Turner S, Mutch R, Stick SM. Eur Respir J. 2006;28:730–733 PURPOSE OF THE STUDY. Fraction of exhaled nitric oxide (FeNO) seems to reflect allergic airway inflammation. The authors sought to investigate the association between reported parental smoking and FeNO in young children. STUDY POPULATION. The study included 78 children (mean age: 51.3 weeks; range: 13–106 weeks) who had FeNO data and had been well for at least 2 weeks before testing. Fifty-six children lived in nonsmoking households, 14 lived with 1 smoking parent, and 8 lived with 2 smoking parents. METHODS. Children underwent pulmonary-function testing that included measures of lung volumes (forced expiratory volume [FEV] in 0.5 second) and FeNO. The effect of parental smoking on FeNO and FEV was analyzed by using unpaired t tests and analysis of variance. Dose-response relationships between the number of smoking parents and FeNO and FEV were determined by using the χ2 test. There were no significant anthropometric differences between children in smoking and nonsmoking households. RESULTS. Children who had at least 1 smoking parent had a higher FeNO compared with children who lived in nonsmoking households (41.9 vs 33.0 ppb, respectively). Within the smoking group, children who lived with 2 smoking parents had a higher FeNO compared with children who lived with 1 smoking parent (48.3 vs 38.0 ppb, respectively). The difference between these 3 groups was not significant. However, there was a significant dose-response relationship across the 3 groups. Moreover, after controlling for other factors, it was found that parental smoking significantly increased the FeNO. Age, gender, maternal atopy, and doctor-diagnosed eczema and FEV were not associated with FeNO. CONCLUSIONS. Exposure to environmental tobacco smoke was associated with increased FeNO in young children. There also was evidence of a dose-response relationship between childhood FeNO and the number of smoking parents. REVIEWER COMMENTS. The role of FeNO as a marker for airway inflammation after exposure to tobacco smoke seems ambiguous. The authors mentioned that although some studies have shown that tobacco smoke has been associated with lower FeNO in smokers, other studies have found a short-term increase in FeNO directly after smoking a cigarette. Moreover, most epidemiologic studies have not found an effect of parental smoking on FeNO in older children. The authors argued that reported parental smoking alone may not be a good indicator for exposure in older children, because they are able to remove themselves from the source, compared with younger children who are unable to move from the offending environment. Whether FeNO can prove to be a useful biomarker of allergic sensitization or airway inflammation still remains in question. In addition, even if the association between cigarette-smoke exposure and high FeNO remain after better-powered studies, further investigations are warranted to elucidate what the potential clinical ramifications are for children with high levels of exhaled nitric oxide.

Montelukast decreased exhaled nitric oxide in children with perennial allergic rhinitis

Measurement of exhaled nitric oxide (eNO) is a simple and noninvasive method for assessment of inflammatory airway diseases. eNO is elevated in adolescent patients with perennial allergic rhinitis and related to bronchial hyperresponsiveness. The aim of this study was to investigate whether oral loratadine, montelukast, nasal budesonide or nasal sodium cromoglycate could reduce airway inflammation as indicated by decrease of eNO in children with perennial allergic rhinitis as demonstrated by eNO levels. A randomized and investigator-blinded study was conducted in a hospital-based outpatient clinic. Children with perennial allergic rhinitis were divided into four groups and treated by loratadine, loratadine with nasal sodium cromoglycate, loratadine with oral montelukast, and loratadine with nasal budesonide, respectively. Allergic rhinitis scores, eNO and peak expiratory flow were measured before and 2, 4, 6 and 8 weeks after treatment. Results showed that eNO in children with perennial allergic rhinitis was reduced by nasal budesonide and oral montelukast within 2 weeks (24.56 +/- 14.42 vs 18.42 +/- 12.48, P < 0.001, in budesonide group; 27.81 +/- 13.4 vs 19.09 +/- 10.45, P < 0.001, in montelukast group), but not in the loratadine and cromoglycate groups. In contrast, loratadine or sodium cromoglycate also did not decrease eNO levels although they could decrease the symptom scores. It was concluded that four common treatment modalities could effectively release symptom scores, but decrease of airway inflammation as determined by decrease of eNO might be only achieved by nasal budesonide and montelukast, but not nasal sodium cromoglycate and loratadine. Children with perennial allergic rhinitis with high eNO levels may require oral montelukast or nasal budesonide treatment to prevent airway hyperresponsiveness.

Increase of Exhaled Nitric Oxide in Children Exposed to Low Levels of Ambient Ozone

Ozone (O3) is known to induce lung function impairment and airways inflammation during episodes of photochemical smog. The aim of the present study was to assess the inflammatory effect of ambient O3 in healthy children using nitric oxide in exhaled air (eNO) as a noninvasive test. The study was performed on 6 groups of children (n = 11–15), aged 6.5 to 15 yr, who attended summer camps in rural areas of the south of Belgium in 2002. Ambient O3 concentrations continuously monitored in the camps ranged from 48 to 221 μg/m3 (1-h maximal concentration). Children remained outdoors during the experimental days, doing various recreational activities but no sports. Lung function tests (forced expiratory volume in 1s [FEV1] and forced vital capacity [FVC]) and eNO were measured twice in each child in the morning and in the evening. While lung function tests did not show any consistent pattern of decrease at these O3 levels, a highly significant increase in eNO was found in all subjects from an ambient 1-h O3 level of 167 μg/m3. A multivariate analysis did not reveal any influence of age, gender, height, weight, and body mass index (BMI) of the children. The threshold for this O3-induced increase in eNO estimated benchmark dose analysis was 135 μg/m3 for 1-h exposure and 110 μg/m3 for 8-h exposure. These observations suggest that ambient ozone produces early inflammatory changes in the airways of children at levels slightly below current air quality standards.

Environmental exposures and exhaled nitric oxide in children with asthma

To evaluate the relation of environmental factors with exhaled nitric oxide (FENO) concentrations among asthmatic children. Cross-sectional analysis of 170 tobacco smoke-exposed children, ages 6 to 12 years, who have doctor-diagnosed asthma using measures of FENO, medication use, and exposures to settled indoor allergens and tobacco smoke. In multivariable analysis, child's age, uncarpeted flooring, not owning a cat, higher income, dust mite exposure, and being sensitized to any allergens were associated with higher FENO concentrations. Children who were sensitized to indoor allergens had an adjusted geometric mean FENO of 15.4 ppb (95% CI, 13.1, 18.2) compared with 10 ppb (95% CI, 8.2, 12.2) for unsensitized children. There was no statistically significant association of serum cotinine, hair cotinine, or reported corticosteroid therapy with FENO. FENO is higher among children who are sensitized to indoor allergens and exposed to dust mites. The results hold promise for the use of FENO as a tool to manage childhood asthma by using both pharmacologic and environmental treatments.

Personal and Ambient Air Pollution is Associated with Increased Exhaled Nitric Oxide in Children with Asthma

BackgroundResearch has shown associations between pediatric asthma outcomes and airborne particulate matter (PM). The importance of particle components remains to be determined.MethodsWe followed a panel of 45 schoolchildren with persistent asthma living in Southern California. Subjects were monitored over 10 days with offline fractional exhaled nitric oxide (FeNO), a biomarker of airway inflammation. Personal active sampler exposures included continuous particulate matter < 2.5 μm in aerodynamic diameter (PM2.5), 24-hr PM2.5 elemental and organic carbon (EC, OC), and 24-hr nitrogen dioxide. Ambient exposures included PM2.5, PM2.5 EC and OC, and NO2. Data were analyzed with mixed models controlling for personal temperature, humidity and 10-day period.ResultsThe strongest positive associations were between FeNO and 2-day average pollutant concentrations. Per interquartile range pollutant increase, these were: for 24 μg/m3 personal PM2.5, 1.1 ppb FeNO [95% confidence interval (CI), 0.1–1.9]; for 0.6 μg/m3 personal EC, 0.7 ppb FeNO (95% CI, 0.3–1.1); for 17 ppb personal NO2, 1.6 ppb FeNO (95% CI, 0.4–2.8). Larger associations were found for ambient EC and smaller associations for ambient NO2. Ambient PM2.5 and personal and ambient OC were significant only in subjects taking inhaled corticosteroids (ICS) alone. Subjects taking both ICS and antileukotrienes showed no significant associations. Distributed lag models showed personal PM2.5 in the preceding 5 hr was associated with FeNO. In two-pollutant models, the most robust associations were for personal and ambient EC and NO2, and for personal but not ambient PM2.5.ConclusionPM associations with airway inflammation in asthmatics may be missed using ambient particle mass, which may not sufficiently represent causal pollutant components from fossil fuel combustion.

Reduced Exhaled Nitric Oxide in Children After Testing of Maximal Expiratory Pressures

Spirometry in adult subjects can induce a fall in concentration of exhaled nitric oxide (FE(NO)). Scarce information is available on the FE(NO) decrease after spirometry or after other forced lung-function maneuvers in children. We compared changes in FE(NO) induced by repeated spirometry and testing of maximal expiratory pressures (P(Emax)). Twenty-four sex- and age-matched children aged 9-18 years (mean age +/- SD, 13.3 +/- 2.8 years; 12 healthy, 12 asthmatic) were allocated to 1-week-apart sessions of repeated maneuvers of either forced vital capacity (FVC) or P(Emax). Baseline FE(NO) measurements were followed by FVC or P(Emax) maneuvers every 15 min for 45 min, whereas FE(NO) was measured at each step for 60 min. After repeated P(Emax) but not after FVC maneuvers, FE(NO) values decreased significantly from baseline in both groups. In healthy children, geometric mean FE(NO) (95% confidence intervals) decreased from 9.1 (7.0-11.8) ppb at baseline to 8.2 (6.3-10.6) ppb at 15 min and 7.7 (5.6-10.6) ppb at 30 min (P < 0.05 and P < 0.01, respectively), and remained unchanged at 45 and 60 min. In asthmatic children, FE(NO) levels fell from 21.6 (13.3-34.9) ppb at baseline to 15.1 (9.1-25.1) ppb at 15 min and remained low at 30, 45, and 60 min: 17.8 (10.7-29.5) ppb, 17.5 (10.2-30.1) ppb, and 17.6 (10.6-29.2) ppb, P < 0.01, for all differences from baseline. Repeated P(Emax) and FVC maneuvers increased FE(NO) variability, as compared with repeated FE(NO) measurements alone. Previous forced lung-function maneuvers may affect FE(NO) measurements in children. Although P(Emax) testing has a greater influence than spirometry on FE(NO) levels in children, both procedures should be avoided before measuring FE(NO).

Nitric Oxide Metabolites Are Not Reduced in Exhaled Breath Condensate of Patients With Primary Ciliary Dyskinesia

To investigate whether nitric oxide (NO) metabolites would be reduced in children affected by primary ciliary dyskinesia (PCD). Single-center observational study. Fifteen children with PCD (seven boys; mean [+/- SEM] age, 10.3 +/- 0.7 years; mean FEV(1), 73 +/- 2.1% predicted) were recruited along with 14 healthy age-matched subjects (seven boys; mean age, 11.5 +/- 0.4 years; mean FEV(1), 103 +/- 5% predicted). We assessed the levels of nitrite (NO(2)(-)), NO(2)(-)/NO(3)(-) (NO(2)(-)/NO(3)(-)), and S-nitrosothiol in exhaled breath condensate, exhaled NO, and nasal NO from children with PCD compared to those in healthy children. The mean exhaled and nasal NO levels were markedly decreased in children with PCD compared to those without PCD (3.2 +/- 0.2 vs 8.5 +/- 0.9 parts per billion [ppb], respectively [p < 0.0001]; 59.6 +/- 12.2 vs 505.5 +/- 66.8 ppb, respectively [p < 0.001]). Despite the lower levels of exhaled NO in children with PCD, no differences were found in the mean levels of NO(2)(-) (2.9 +/- 0.4 vs 3.5 +/- 0.3 microM, respectively), NO(2)(-)/NO(3)(-) (35.2 +/- 5.0 vs 34.3 +/- 4.5 microM, respectively), or S-nitrosothiol (1.0 +/- 0.2 vs 0.6 +/- 0.1 microM, respectively) between children with PCD and healthy subjects. These findings suggest that NO synthase activity may not be decreased as much as might be expected on the basis of low exhaled and nasal NO levels.

Reduction in exhaled nitric oxide immediately after methacholine challenge in asthmatic children

Background: The measurement of exhaled nitric oxide (NO) has recently been proposed as a useful technique for the evaluation of airway inflammation in asthma. The purpose of this study was...

Inhaled budesonide in acute asthma?

Inhaled budesonide in acute asthma?

A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma

This study was conducted to investigate whether a single dose of nebulized budesonide effectively decreased airway inflammation as demonstrated by exhaled nitric oxide (eNO) levels. A single dose of nebulized budesonide, but not nebulized terbutaline, rapidly decreased eNO levels in 6 hours. The decrease in eNO levels induced by nebulized budesonide was correlated to an increase in peak expiratory flow rate. (J Pediatr 2001;139:433-7)

Controlled low flow off line sampling of exhaled nitric oxide in children

BACKGROUNDThe aim of this study was to validate exhaled nitric oxide (eNO) values obtained with an alternative off line, single breath, low flow balloon sampling method against on line sampling...

Sampling of exhaled nitric oxide in children: end-expiratory plateau, balloon and tidal breathing methods compared

Nitrogen dioxide is known as a deep lung irritant. The aim of this study was to find out whether the relatively low ambient air NO2 concentrations in the northern city of Helsinki had an impact on the respiratory health of children. The association between personal exposure to ambient air NO2 and respiratory health was investigated in a 13-week follow-up study among 163 preschool children aged 3-6 yrs. Personal weekly average exposure to NO2 was measured by passive diffusion samplers attached to the outer garments. Symptoms were recorded daily in a diary by the parents. Among 53 children, peak expiratory flow (PEF) was measured at home in the mornings and evenings. The association between NO2 exposure and respiratory symptoms was examined with Poisson regression. The median personal NO2 exposure was 21.1 microg x m(-3) (range 4-99 microg x m(-3)). An increased risk of cough was associated with increasing NO2 exposure (risk ratio = 1.52; 95% confidence interval 1.00-2.31). There was no such association between personal weekly NO2 exposure and nasal symptoms, but a nonsignificant negative association was found between the exposure and the weekly average deviation in PEF. In conclusion, even low ambient air NO2 concentrations can increase the risk of respiratory symptoms among preschool children.

Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children.

While it is known that exhaled nitric oxide (ENO) is increased in adults and school children with asthma exacerbation probably as an expression of disease activity, no studies have investigated whether this phenomenon also occurs in infants and young children with recurrent wheeze exacerbation. We measured ENO in 13 young children (mean age 20.2 mo) with recurrent wheeze (Group 1) during an acute episode and after 5 d of oral prednisone therapy. ENO was measured also in nine healthy control subjects (Group 2) (mean age 16.9 mo) and in six children with a first-time viral wheezy episode (Group 3) (mean age 11 mo). To measure ENO, infants inhaled NO-free air via a face mask from a reservoir and, through a nonrebreathing valve, exhaled in a collecting bag that was analyzed by chemiluminescence. To address the question of whether the levels of ENO collected in the bag are a reflection of the pulmonary airway, ENO determinations were performed in two healthy infants before and after tracheal intubation for elective surgery. During the acute episode of wheezing the mean (+/- SEM) value of ENO in children with recurrent wheeze (Group 1) was 14.1 +/- 1.8 ppb, almost threefold higher than in healthy control subjects (5.6 +/- 0.5 ppb, p < 0.001). After steroid therapy we found a mean fall of 52% in ENO (5.9 +/- 0.7 ppb, p < 0.01) compared with baseline values. ENO values measured before and after intubation in two infants were 6 ppb and 5 ppb in one child and 7 ppb and 6 ppb in the other one. The mean value of ENO of children with first-time wheeze (Group 3) was 8.3 +/- 1.3 ppb, significantly lower (p < 0.05) than the value of children with recurrent wheeze (Group 1). In conclusion, we describe a method to measure ENO in young children and show that infants with recurrent wheeze have elevated levels of ENO during exacerbation that rapidly decrease after steroid therapy. This suggests that, in these children, airway inflammation could be present at a very early stage.

Corticosteroids decrease exhaled nitric oxide in children with acute asthma

Nitric oxide (NO) produced in human airways seems to have both homeostatic and proinflammatory actions in the respiratory system. NO production has been shown to be higher in the exhaled air of asthmatic adults than in normal subjects. The aim of this study was to evaluate exhaled NO production during asthma exacerbation in children and the effect of a rescue course of oral steroid therapy. We measured NO in the exhaled air of 16 children (8 girls and 8 boys, aged 6 to 13 years) with an acute asthmatic episode before and after 5 days of therapy with prednisone, and in 16 healthy children. To measure NO, children inhaled NO-free air and, breathing at tidal volume, exhaled in a circuit from which a chemiluminescence analyzer sampled continuously. To assess the effect of acute changes in bronchial caliber on exhaled NO levels, we measured NO before and after a positive bronchodilation test result with albuterol in seven children with asthma whose disease was stable. In the group with acute asthma (forced expiratory volume in 1 second 62% +/- 4.4% predicted, mean +/- SEM), NO levels were significantly higher (31.3 +/- 4.2 parts per billion [ppb]) than in healthy children (5.4 +/- 0.4 ppb, p < 0.001). Administration of prednisone (1 mg/kg per day orally) for 5 days resulted in a mean decrease of 46% +/- 4% in exhaled NO concentrations (16.5 +/- 2.3 ppb, p < 0.001) compared with baseline, accompanied by a significant improvement in lung function (forced expiratory volume in 1 second 90.7% +/- 4.3% predicted). However, in patients with asthma exhaled NO levels remained significantly higher than in control children (p < 0.001) after steroid treatment. When exhaled NO was measured before and after a positive result after bronchodilator reversibility testing, we found no difference in exhaled NO levels (24 +/- 3.8 ppb vs 23.8 +/- 3 ppb; difference not significant). This demonstrates that inhaled albuterol and acute changes in bronchial caliber do not affect exhaled NO measurement. These data show that children with asthma exacerbation have high levels of exhaled NO that rapidly decrease with oral steroid therapy. We suggest that measurement of exhaled NO may represent a noninvasive method of monitoring airway inflammation in children with asthma.