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1.  294 Reference Values and Influencing Factors of Exhaled Nitric Oxide in Healthy Korean Adults 
The World Allergy Organization Journal  2012;5(Suppl 2):S112-S113.
Fractional exhaled nitric oxide (FeNO) is widely used as an inflammatory marker for asthma. However, reference values and influencing factors of FeNO using Niox Mino, which is the only device achieving US FDA approval, are not well described in healthy Asian adults. This study aimed to suggest the reference values and influencing factors of FeNO in healthy Korean adults.
Subjects who were over 19 years old and did not have any history of rhinitis, asthma or recent respiratory symptoms were enrolled. FeNO levels were measured using Niox Mino. Age, gender, body mass index (BMI), smoking status and lung function were also measured to analyze factors associated with FeNO levels.
The mean value of FeNO was 16.14 ± 10.04 ppb. The reference value of FeNO, which was defined as the value of 95% in distribution curve, was same or less than 34 ppb. In a univariate analysis, FeNO levels were not associated with age, BMI and smoking history. However, atopy status (18.2 ± 11.8 for atopy and 15.1 ± 8.5 for nonatopy groups, P = 0.008) and gender (17.8 ± 10.2 for male and 14.8 ± 9.8 for female groups, P < 0.001) were positively associated with FeNO levels. In stratified analysis, the significance of both variables remained unchanged (P < 0.001).
Our data suggested that the reference value of FeNO in healthy Korean adults seemed to be same or less than 34 ppb. Reference values of FeNO in Korean adults are influenced by gender and atopy status.
PMCID: PMC3512963
2.  Effects of atopy and rhinitis on exhaled nitric oxide values - a systematic review 
Atopy and rhinitis are among the factors affecting exhaled nitric oxide (FeNO) values and may contribute to difficulties in the clinical interpretation of FeNO measurements. However, data assessing their effects on FeNO values had never been summarized. This review aims to evaluate the effect of atopy and rhinitis in FeNO values in otherwise healthy individuals.
A systematic review was performed in Pubmed, Scopus and ISI Web of Knowledge. A two-step selection process was completed, and from 2357 references 19 were included. The inclusion criteria were: participants without known diseases other than rhinitis; atopy assessement by SPT or Specific IgE; and FeNO measurements according to ATS/ERS recommendations.
The 8 articles measuring FeNO in children showed higher values in both allergic rhinitis and atopic children when compared with healthy children. The 11 articles performed in adults observed higher FeNO in AR patients comparatively with either healthy or atopic individuals. However, adult healthy and atopic individuals had similar FeNO values.
FeNO values are higher in individuals with rhinitis and/or atopy without other health problems. These effects are small, seem to be independent and should be further studied using multivariate models. The effect of atopy was observed only in children. The combined effect of atopy and rhinitis produced higher FeNO values in adults. These results support that both atopy and rhinitis should be considered when interpreting or when defining FeNO reference values.
PMCID: PMC3339369  PMID: 22409776
Exhaled Nitric Oxide; Atopy; Rhinitis; Systematic Review
3.  Exhaled nitric oxide in a population-based study of Southern California Schoolchildren 
Respiratory Research  2009;10(1):28.
Determinants of exhaled nitric oxide (FeNO) need to be understood better to maximize the value of FeNO measurement in clinical practice and research. Our aim was to identify significant predictors of FeNO in an initial cross-sectional survey of southern California schoolchildren, part of a larger longitudinal study of asthma incidence.
During one school year, we measured FeNO at 100 ml/sec flow, using a validated offline technique, in 2568 children of age 7–10 yr. We estimated online (50 ml/sec flow) FeNO using a prediction equation from a separate smaller study with adjustment for offline measurement artifacts, and analyzed its relationship to clinical and demographic characteristics.
FeNO was lognormally distributed with geometric means ranging from 11 ppb in children without atopy or asthma to 16 ppb in children with allergic asthma. Although effects of atopy and asthma were highly significant, ranges of FeNO for children with and without those conditions overlapped substantially. FeNO was significantly higher in subjects aged > 9, compared to younger subjects. Asian-American boys showed significantly higher FeNO than children of all other sex/ethnic groups; Hispanics and African-Americans of both sexes averaged slightly higher than non-Hispanic whites. Increasing height-for-age had no significant effect, but increasing weight-for-height was associated with decreasing FeNO.
FeNO measured offline is a useful biomarker for airway inflammation in large population-based studies. Further investigation of age, ethnicity, body-size, and genetic influences is needed, since they may contribute to substantial variation in FeNO.
PMCID: PMC2678086  PMID: 19379527
4.  Diagnostic value and influencing factors of fractional exhaled nitric oxide in suspected asthma patients 
Objective: To explore the critical value and possible influencing factors of fractional exhaled nitric oxide (FeNO) in suspected asthma patients. Methods: 923 suspected asthmatics consecutively referred to our hospital during December 2012 to July 2014 were selected. All cases were carried out FeNO measurement at first; next, spirometry, bronchoprovocation tests or bronchodilation tests were used to confirm or exclude asthma. Receiver operating characteristic curve (ROC) was used to determine the best cut-off value of FeNO for asthma diagnosis. Results: In bronchoprovocation test, 125 cases were diagnosed as asthma, other 283 were non-asthmatics. FeNO levels of asthmatics were significantly higher than non-asthmatics (median, 64.8 ppb vs. 27.9 ppb, P < 0.01). In this group of patients, 64 ppb was the best cut-off value of FeNO to identify asthma with sensitivity of 52.0% and specificity of 94.35%. In bronchodilation test, 185 patients were diagnosed as asthma, other 330 were non-asthmatics. FeNO levels of asthmatics were significantly higher than non-asthmatics (median, 60.6 ppb vs. 29.05 ppb, P < 0.01). In bronchodilation test patients, 41 ppb was the best cut-off value of FeNO to identify asthma with sensitivity of 72.43% and specificity of 74.85%. Influencing factors analysis showed that sex was an independent factor affecting patients’ FeNO level. Conclusion: FeNO was an effective auxiliary diagnosis method for bronchial asthma. 64 ppb and 41 ppb was the best cut-off value of FeNO to identify asthma in bronchoprovocation test or bronchodilation test, respectively. Sex was an independent factor affecting patients’ FeNO level.
PMCID: PMC4503137  PMID: 26191266
Fractional exhaled nitric oxide; asthma diagnosis; influencing factors
5.  Bronchial Responsiveness Is Related to Increased Exhaled NO (FENO) in Non-Smokers and Decreased FENO in Smokers 
PLoS ONE  2012;7(4):e35725.
Both atopy and smoking are known to be associated with increased bronchial responsiveness. Fraction of nitric oxide (NO) in the exhaled air (FENO), a marker of airways inflammation, is decreased by smoking and increased by atopy. NO has also a physiological bronchodilating and bronchoprotective role.
To investigate how the relation between FENO and bronchial responsiveness is modulated by atopy and smoking habits.
Exhaled NO measurements and methacholine challenge were performed in 468 subjects from the random sample of three European Community Respiratory Health Survey II centers: Turin (Italy), Gothenburg and Uppsala (both Sweden). Atopy status was defined by using specific IgE measurements while smoking status was questionnaire-assessed.
Main Results
Increased bronchial responsiveness was associated with increased FENO levels in non-smokers (p = 0.02) and decreased FENO levels in current smokers (p = 0.03). The negative association between bronchial responsiveness and FENO was seen only in the group smoking less <10 cigarettes/day (p = 0.008). Increased bronchial responsiveness was associated with increased FENO in atopic subjects (p = 0.04) while no significant association was found in non-atopic participants. The reported interaction between FENO and smoking and atopy, respectively were maintained after adjusting for possible confounders (p-values<0.05).
The present study highlights the interactions of the relationship between FENO and bronchial responsiveness with smoking and atopy, suggesting different mechanisms behind atopy- and smoking-related increases of bronchial responsiveness.
PMCID: PMC3338521  PMID: 22563393
6.  Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis 
Fractional exhaled nitric oxide (FeNO), a well-known marker of airway inflammation, is rarely evaluated in rhinitis of different etiology. We aimed to compare the eNO levels in allergic rhinitis (AR) and nonallergic rhinitis (NAR) with/without asthma, as well as the contributing factors that interfere with elevated FeNO.
Patients were enrolled based on chronic nasal symptoms. Orally exhaled NO was measured with the single exhalation method at 50 mL/s. All subjects underwent a panel of tests: skin-prick tests, asthma control test, blood sampling, spirometry, and health-related quality-of-life questionnaires.
The study group consisted of mainly women (130 women/41 men), with a mean age of 32.6 ± 13.2 years. AR was diagnosed in 122 (78.2%), NAR in 34 (21.8%), and 15 subjects were healthy controls. FeNO was insignificantly higher in patients with AR compared with patients with NAR and controls (32.2 parts per billion [ppb] versus 27 and 19.4 ppb), with no difference between genders. NAR + asthma had higher FeNO than those without asthma (40.5 ppb versus 14.9 ppb; p < 0.03), whereas accompanying asthma did not affect FeNO levels in the AR group. AR ± asthma had significantly higher FeNO levels than the NAR-only group (p < 0.01). Among AR + asthma, perennial sensitization caused higher FeNO levels than did seasonal allergens (48.5 ± 33.9 and 19.5 ± 13.6′ p = 0.003), whereas FeNO was significantly higher during the allergen season. Nasally inhaled corticosteroids insignificantly reduced FeNO levels in all groups. Severity and seasonality of rhinitis, asthma, and ocular symptoms, but not gender, age, body mass index, Total IgE, forced expiratory volume in 1 second, and smoking, were associated with FeNO.
Rhinitis and comorbid asthma are responsible for increased FeNO, irrespective of atopy. However, NAR without asthma may not be considered as a strong risk factor for airway inflammation.
PMCID: PMC3906508  PMID: 22487277
Airway inflammation; allergic rhinitis; asthma; atopy; exhaled nitric oxide; inhaled corticosteroids; nonallergic rhinitis
7.  Reference Ranges and Determinant Factors for Exhaled Nitric Oxide in a Healthy Korean Elderly Population 
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.
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.
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.
The current analysis presented reference ranges and the diagnostic utility of FeNO levels for asthma in Korean elderly adults.
PMCID: PMC4214970  PMID: 25374749
Adult; asthma; nitric oxide; reference values
8.  Storage conditions for stability of offline measurement of fractional exhaled nitric oxide after collection for epidemiologic research 
The measurement of fractional concentration of nitric oxide in exhaled air (FeNO) is valuable for the assessment of airway inflammation. Offline measurement of FeNO has been used in some epidemiologic studies. However, the time course of the changes in FeNO after collection has not been fully clarified. In this study, the effects of storage conditions on the stability of FeNO measurement in exhaled air after collection for epidemiologic research were examined.
Exhaled air samples were collected from 48 healthy adults (mean age 43.4 ± 12.1 years) in Mylar bags. FeNO levels in the bags were measured immediately after collection. The bags were then stored at 4°C or room temperature to measure FeNO levels repeatedly for up to 168 hours.
In the bags stored at room temperature after collection, FeNO levels were stable for 9 hours, but increased starting at 24 hours. FeNO levels remained stable for a long time at 4°C, and they were 99.7% ± 7.7% and 101.3% ± 15.0% relative to the baseline values at 24 and 96 hours, respectively. When the samples were stored at 4°C, FeNO levels gradually decreased with time among the subjects with FeNO ≥ 51 ppb immediately after collection, although there were almost no changes among the other subjects. FeNO levels among current smokers increased even at 4°C, although the values among ex-smokers decreased gradually, and those among nonsmokers remained stable. The rate of increase was significantly higher among current smokers than among nonsmokers and ex-smokers from 9 hours after collection onwards.
Storage at 4°C could prolong the stability of FeNO levels after collection. This result suggests that valid measurements can be performed within several days if the samples are stored at 4°C. However, the time course of the changes in FeNO levels differed in relation to initial FeNO values and cigarette smoking.
PMCID: PMC3515473  PMID: 23116255
Cigarette smoking; Epidemiologic research; Exhaled nitric oxide; Offline measurement; Refrigeration; Storage conditions; Wheezing
9.  Seasonal Variation and Environmental Predictors of Exhaled Nitric Oxide in Children with Asthma 
Pediatric pulmonology  2008;43(6):576-583.
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 to 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 to 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.
PMCID: PMC3483596  PMID: 18429012
allergen; sensitization; tobacco smoke; inhaled corticosteroid
10.  Effects of age, gender, and environmental exposures on exhaled nitric oxide level in healthy 12 to 18 years Qatari children 
Annals of Thoracic Medicine  2012;7(2):98-103.
Fractional exhaled nitric oxide (FENO) is a useful noninvasive diagnostic tool for asthma and some other pediatric respiratory diseases. Factors affecting FENO level are variable in different populations and studies.
To estimate the normal values of exhaled nitric oxide for Qataris 12 to 18 years of age. Other objectives were to measure the correlation of anthropometric and other potential factors with FENO levels.
Community-based, cross-sectional study.
A total of 438 Qatari national school children from both genders were randomly recruited in cross-sectional study. Of them, 203 were non-atopic and hence included in the statistical analysis. Questionnaires including personal data, demographic data, and other factors that may affect FENO level were distributed.
Comparison of means done using t-test. We performed Spearman's rho test to measure correlations. Data analysis was done using PASW 18.0 Release 18.0.0, 2009.
The geometric mean of FENO levels for all subjects was 14.1 ppb (upper level CI 95% - 36.3 ppb). FENO was significantly higher in males (R2 = −0.254, P<0.0001) and was negatively correlated with increasing age for the whole study population (P=0.036). This decline was interrupted by a significant upraise at the age of 15 years (P=0.0462) which seems to be driven by the males (P=0.0244). FENO levels were lower in subjects exposed to cats (P=0.019). We could not find significant correlation between FENO and other factors studied.
Estimated FENO level with 95% CI in Qatari children, which is probably close to those in other Gulf countries, will be helpful clinically. The lower level of FENO with female gender, increasing age, and exposure to cats needs to be further studied to establish the association and to understand the underlying mechanisms.
PMCID: PMC3339211  PMID: 22558015
Age; cat; children; exhaled nitric oxide; females; fractional exhaled nitric oxide; gender; males; puberty
11.  Fractional Exhaled Nitric Oxide (FeNO) Measurements are Most Closely Associated with Allergic Sensitization in School Aged Children 
Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood.
To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children.
Children at high-risk of asthma and other allergic diseases due to parental history were enrolled at birth and followed prospectively. FeNO was measured by online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated.
Reproducible FeNO measurements were obtained in 64% (135 of 210) of 6 year old and 93% (180 of 194) of 8 year old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at age 6 and 8 years had increased levels of FeNO compared to those not sensitized [geometric mean (6 years, 10.9 vs. 6.7 ppb, p<0.0001; 8 years, 14.6 vs. 7.1 ppb, p<0.0001)]. FeNO was higher in children with asthma than in those without asthma at 8 years, but not 6 years of age (6 years, 9.2 vs. 8.3 ppb, p = 0.48; 8 years, 11.5 vs. 9.2 ppb, p = 0.03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (p=0.33). There were no correlations between FeNO and spirometric indices at 6 or 8 years of age.
These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.
Clinical Implications
When FeNO is utilized as a biomarker for the diagnosis and/or monitoring of atopic diseases such as asthma, the presence or absence of allergic sensitization should be carefully considered.
Capsule Summary
This pediatric cohort study evaluates the relationships between FeNO and various atopic characteristics. The results suggest that allergic sensitization should be evaluated when FeNO is used as a biomarker in clinical or research settings.
PMCID: PMC2784153  PMID: 19748661
fractional exhaled nitric oxide (FeNO); asthma; allergic sensitization; atopic dermatitis; lung function; children; seasonality; atopy
12.  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® (FeNONIOX-MINO) and NObreath® (FeNONObreath) 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 FeNONIOX-MINO was 0.733 (P<0.001), and 0.751 between ISE and FeNONObreath (P<0.001). The ROC curve found that the FeNONIOXMINO of 37.5 ppb and the FeNONObreath 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%.
PMCID: PMC4446639  PMID: 25749783
Asthma; nitric oxide; electrochemical technique; eosinophils; sputum
13.  Reference Values and Determinants of Fractional Concentration of Exhaled Nitric Oxide in Healthy Children 
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.
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.
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.
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.
PMCID: PMC3936047  PMID: 24587955
FeNO; reference value; determinants; healthy; children
14.  Effect of Mannitol Dry Powder Challenge on Exhaled Nitric Oxide in Children 
PLoS ONE  2013;8(1):e54521.
Fractional exhaled nitric oxide (FENO), a non-invasive marker of eosinophilic airway inflammation, is increasingly used for diagnostic and therapeutic decisions in adult and paediatric asthma. Standardized guidelines for the measurement of FENO recommend performing FENO measurements before rather than after bronchial provocation tests.
To investigate whether FENO levels decrease after a Mannitol dry powder (MDP) challenge in a clinical setting, and whether the extent of the decrease is influenced by number of MDP manoeuvres, baseline FENO, atopy and doctor diagnosed asthma.
Children aged 6–16 years, referred for possible reactive airway disease to a respiratory outpatient clinic, performed an MDP challenge (Aridol®, Pharmaxis, Australia). FENO was measured in doublets immediately before and after the challenge test using the portable NIOX MINO® device (Aerocrine, Stockholm, Sweden). We analysed the data using Kruskal-Wallis rank tests, Wilcoxon signed rank tests and multivariable linear regressions.
One hundred and seven children completed both tests (mean±SD age 11.5±2.8 years). Overall, median (interquartile range) FENO decreased slightly by −2.5 ppb (−7.0, −0.5), from 18.5 ppb (10.5, 45.5) before the MDP challenge to 16.5 ppb thereafter (8.5, 40.5; p<0.001). In all participants, the change in FENO was smaller than one standard deviation of the baseline mean. The % fall in FENO was smaller in children with less MDP manoeuvres (e.g. higher bronchial responsiveness; p = 0.08) but was not influenced by levels of baseline FENO (p = 0.68), atopy (p = 0.84) or doctor diagnosed asthma (p = 0.93).
MDP challenge test influences FENO values but differences are small and clinically barely relevant.
PMCID: PMC3548778  PMID: 23349918
15.  Environmental Exposures, Nitric Oxide Synthase Genes, and Exhaled Nitric Oxide in Asthmatic Children 
Pediatric pulmonology  2009;44(8):812-819.
Exhaled nitric oxide (FeNO), a measure of airway inflammation, is being explored as a tool to guide asthma management in children. Investigators have identified associations of genetic polymorphisms in nitric oxide synthase genes (NOS1 and NOS3) with FeNO levels; however, none have explored whether these polymorphisms modify the relationship of environmental exposures with FeNO. The objective of this project was to evaluate the association of NOS polymorphisms and environmental exposures with FeNO levels among children with asthma. We conducted a 12 month, prospective cohort study of 225 tobacco-smoke exposed children (6 to 12 years) with doctor-diagnosed asthma. We assessed environmental exposures (tobacco, indoor allergens, & airborne particulates), polymorphisms in NOS1 (an intronic AAT tandem repeat) and NOS3 (G894T), and FeNO levels. There was no association of NOS1 or NOS3 polymorphisms with FeNO levels. There were no significant interactions of environmental exposures and the NOS1 polymorphism with FeNO levels. In contrast, there was an interaction of the NOS3 polymorphism and airborne nicotine concentration with FeNO levels (p=0.01). Among GG genotype individuals, nicotine exposure did not affect FeNO levels; however, among individuals with at least one T allele, higher nicotine exposure was associated with lower FeNO levels (approximately 5ppb decrease from the lowest to the highest quartile). We conclude that genetic differences may explain some of the conflicting results in studies of the effects of tobacco smoke exposure on FeNO levels and may make FeNO interpretation difficult for a subset of children with asthma.
PMCID: PMC2857409  PMID: 19603529
allergen; asthma; sensitization; tobacco smoke; air nicotine; nitric oxide synthase; inhaled corticosteroid; exhaled nitric oxide
16.  Exhaled nitric oxide measurements in the first 2 years of life: methodological issues, clinical and epidemiological applications 
Fractional exhaled nitric oxide (FeNO) is a useful tool to diagnose and monitor eosinophilic bronchial inflammation in asthmatic children and adults. In children younger than 2 years of age FeNO has been successfully measured both with the tidal breathing and with the single breath techniques. However, there are a number of methodological issues that need to be addressed in order to increase the reproducibility of the FeNO measurements within and between infants. Indeed, a standardized method to measure FeNO in the first 2 years of life would be extremely useful in order to meaningfully interpret FeNO values in this age group. Several factors related to the measurement conditions have been found to influence FeNO, such as expiratory flow, ambient NO and nasal contamination. Furthermore, the exposure to pre- and postnatal risk factors for respiratory morbidity has been shown to influence FeNO values. Therefore, these factors should always be assessed and their association with FeNO values in the specific study population should be evaluated and, eventually, controlled for.
There is evidence consistently suggesting that FeNO is increased in infants with family history of atopy/atopic diseases and in infants with recurrent wheezing. These findings could support the hypothesis that eosinophilic bronchial inflammation is present at an early stage in those infants at increased risk of developing persistent respiratory symptoms and asthma. Furthermore, it has been shown that FeNO measurements could represent a useful tool to assess bronchial inflammation in other airways diseases, such as primary ciliary dyskinesia, bronchopulmonary dysplasia and cystic fibrosis. Further studies are needed in order to improve the reproducibility of the measurements, and large prospective studies are warranted in order to evaluate whether FeNO values measured in the first years of life can predict the future development of asthma or other respiratory diseases.
PMCID: PMC2717974  PMID: 19712438
17.  Reproducibility of exhaled nitric oxide in smokers and non-smokers: relevance for longitudinal studies 
Currently, there is much interest in measuring fractional exhaled nitric oxide (FENO) in populations. We evaluated the reproducibility of FENO in healthy subjects and determined the number of subjects necessary to carry out a longitudinal survey of FENO in a population containing smokers and non-smokers, based on the assessed reproducibility.
The reproducibility of FENO was examined in 18 healthy smokers and 21 non-smokers. FENO was assessed once at 9 AM on five consecutive days; in the last day this measurement was repeated at 2 PM. Respiratory symptoms and medical history were assessed by questionnaire. The within- and between-session repeatability of FENO and log-transformed FENO was described. The power of a longitudinal study based on a relative increase in FENO was estimated using a bilateral t-test of the log-transformed FENO using the between-session variance of the assay.
FENO measurements were highly reproducible throughout the study. FENO was significantly higher in males than females regardless of smoking status. FENO was positively associated with height (p < 0.001), gender (p < 0.034), smoking (p < 0.0001) and percent FEV1/FVC (p < 0.001) but not with age (p = 0.987). The between-session standard deviation was roughly constant on the log scale. Assuming the between-session standard deviation is equal to its longitudinal equivalent, either 111 or 29 subjects would be necessary to achieve an 80% power in detecting a 3% or a 10% increase in FENO respectively.
The good reproducibility of FENO is not influenced by gender or smoking habits. In a well controlled, longitudinal study it should allow detecting even small increases in FENO with a reasonable population size.
PMCID: PMC2292677  PMID: 18304367
18.  Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care 
Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response.
To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management.
Eligible patients (n = 678) were those in the Optimum Patient Care Research Database (OPCRD) aged 4–80 years who, at an index date, had their first FeNO assessment via NIOX MINO® or Flex®. Eligible practices were those using FeNO measurement in at least ten patients during the study period. Patients were characterized over a one-year baseline period immediately before the index date. Outcomes were evaluated in the year immediately following index date for two patient cohorts: (i) those in whom FeNO measurement was being used to identify steroid-responsive disease and (ii) those in whom FeNO monitoring was being used to guide on-going asthma management. Outcomes for cohort (i) were incidence of new ICS initiation at, or within the one-month following, their first FeNO measurement, and ICS dose during the outcome year. Outcomes for cohort (ii) were adherence, change in adherence (from baseline) and ICS dose.
In cohort (i) (n = 304) the higher the FeNO category, the higher the percentage of patients that initiated ICS at, or in the one month immediately following, their first FeNO measurement: 82%, 46% and 26% of patients with high, intermediate and low FeNO, respectively. In cohort (ii) (n = 374) high FeNO levels were associated with poorer baseline adherence (p = 0.005) but greater improvement in adherence in the outcome year (p = 0.017). Across both cohorts, patients with high FeNO levels were associated with significantly higher ICS dosing (p < 0.001).
In the UK, FeNO is being used in primary practice to guide ICS initiation and dosing decisions and to identify poor ICS adherence. Simple algorithms to guide clinicians in the practical use of FeNO could improved diagnostic accuracy and better tailored asthma regimens.
PMCID: PMC3826517  PMID: 24195942
Fractional exhaled nitric oxide (FeNO); Practical guidance; Diagnosis; On-going asthma management; Steroid-responsive disease
19.  The value of FeNO measurement in childhood asthma: uncertainties and perspectives 
Asthma is considered an heterogeneous disease, requiring multiple biomarkers for diagnosis and management. Fractional exhaled nitric oxide in exhaled breath (FeNO) was the first useful non-invasive marker of airway inflammation in asthma and still is the most widely used. The non-invasive nature and the relatively easy use of FeNO technique make it an interesting tool to monitor airway inflammation and rationalize corticosteroid therapy in asthmatic patients, together with the traditional clinical tools (history, physical examination and lung function tests), even if some controversies have been published regarding the use of FeNO to support the management of asthma in children. The problem of multiple confounding factors and overlap between healthy and asthmatic populations preclude the routine application of FeNO reference values in clinical practice and suggest that it would be better to consider an individual “best”, taking into account the context in which the measurement is obtained and the clinical history of the patient. Besides, there is still disagreement about the role of FeNO as a marker of asthma control, due to the complexity of balance among the different items involved in its determination and the lack of homogeneity in the population groups studied in the few studies conducted so far. Heterogeneity of problematic severe asthma greatly limits utility of FeNO alone as a biomarker of inflammation to optimize the disease management on an individual basis. None of the studies conducted so far demonstrated that the use of FeNO was better than current asthma guidelines in controlling asthma exacerbations. In summary, there is a large variation in FeNO levels between individuals, which may reflect the natural heterogeneity in baseline epithelial nitric oxide synthase activity and/or the contribution of other noneosinophilic factors to epithelial nitric oxide synthase activity. FeNO is a promising biomarker, but at present some limits are highlighted. We would recommend that further research can be carried out by organizing studies aimed to obtain reliable reference values of FeNO and in order to better interpret FeNO measurements in clinical settings, taking also into account the influence of genetic and environmental factors.
PMCID: PMC3750504  PMID: 23902719
20.  Asthma in the elderly: The role of exhaled nitric oxide measurements 
Respiratory medicine  2013;107(5):785-787.
Asthma in the elderly is poorly understood because only a small minority of asthma studies have investigated this patients group. Fractional Exhaled Nitric Oxide (FENO) has been extensively studied in children and adults with asthma, but little is known about FENO in elderly asthmatics. We studied the role of serial measurements of FENO in elderly subjects with asthma.
Thirty stable asthmatics 65 years old and older were followed for one year with evaluations at baseline and every three months. We looked for associations between FENO and subjects’ demographics, comorbidities, asthma treatment, spirometric values and Asthma Control Test (ACT) scores. FENO was not elevated in our study subjects throughout the study period (mean < 30 ppb). FENO significantly increased and FEV1% decreased between first and last study visit, while ACT scores and steroid dose remained unchanged. No significant correlation was found between FENO and FEV1/FVC, other spirometric values, inhaled steroid dose or ACTscores at any time point. No associations of FENO were found with age, sex, Body Mass Index (BMI), atopic status, disease duration, presence of rhinitis or gastroesophageal reflux disease (GERD), or other medications used. Moderate asthma exacerbations did not consistently cause an increase of FENO.
In stable elderly asthmatic patients, FENO was not elevated and did not correlate with subjects’ demographics, comorbidities, treatment, symptoms or spirometric values. Routine measurements of FENO may not be clinically valuable in elderly asthmatics.
PMCID: PMC4034737  PMID: 23481173
Asthma; FENO; Elderly
21.  Exhaled nitric oxide and airway hyperresponsiveness in workers: a preliminary study in lifeguards 
Airway inflammation and airway hyperresponsiveness (AHR) are two characteristic features of asthma. Fractional exhaled nitric oxide (FENO) has shown good correlation with AHR in asthmatics. Less information is available about FENO as a marker of inflammation from work exposures. We thus examined the relation between FENO and AHR in lifeguards undergoing exposure to chloramines in indoor pools.
39 lifeguards at six indoor pools were given a respiratory health questionnaire, FENO measurements, spirometry, and a methacholine bronchial challenge (MBC) test. Subjects were labeled MBC+ if the forced expiratory volume (FEV1) fell by 20% or more. The normalized linear dose-response slope (NDRS) was calculated as the percentage fall in FEV1 at the last dose divided by the total dose given. The relation between MBC and FENO was assessed using logistic regression adjusting on confounding factors. The association between NDRS and log-transformed values of FENO was tested in a multiple linear regression model.
The prevalence of lifeguards MBC+ was 37.5%. In reactors, the median FENO was 18.9 ppb (90% of the predicted value) vs. 12.5 ppb (73% predicted) in non-reactors. FENO values ≥ 60% of predicted values were 80% sensitive and 42% specific to identify subjects MBC+. In the logistic regression model no other factor had an effect on MBC after adjusting for FENO. In the linear regression model, NDRS was significantly predicted by log FENO.
In lifeguards working in indoor swimming pools, elevated FENO levels are associated with increased airway responsiveness.
PMCID: PMC2805603  PMID: 20043846
22.  Factors attributable to the level of exhaled nitric oxide in asthmatic children 
European Journal of Medical Research  2009;14(Suppl 4):9-13.
Asthma is a heterogeneous disease with variable symptoms especially in children. Exhaled nitric oxide (FeNO) has proved to be a marker of inflammation in the airways and has become a substantial part of clinical management of asthmatic children due to its potential to predict possible exacerbation and adjust the dose of inhalant corticosteroids.
We analyzed potential factors that contribute to the variability of nitric oxide in various clinical and laboratory conditions.
Materials and methods
Study population consisted of 222 asthmatic children and 27 healthy control subjects. All children underwent a panel of tests: fractioned exhaled nitric oxide, exhaled carbon monoxide, asthma control test scoring, blood sampling, skin prick tests, and basic spirometry.
FeNO and other investigated parameters widely changed according to clinical or laboratory characteristics of the tested children. Asthmatics showed increased levels of FeNO, exhaled carbon monoxide, total serum IgE, and higher eosinophilia. Boys had higher FeNO levels than girls. We found a significant positive correlation between FeNO levels and the percentage of blood eosinophils, %predicted of forced vital capacity, total serum IgE levels, and increasing age.
Various phenotypes of children's asthma are characterized by specific pattern of the results of clinical and laboratory tests. FeNO correlates with total serum IgE, blood eosinophilia, age, and some spirometric parameters with different strength. Therefore, the coexistence of atopy, concomitant allergic rhinitis/rhinoconjunctivitis, and some other parameters should be considered in critical evaluation of FeNO in the management of asthmatic children.
PMCID: PMC3521341  PMID: 20156716
bronchial asthma; exhaled carbon monoxide; exhaled nitric oxide; children
23.  Effect of Nanoparticles Exposure on Fractional Exhaled Nitric Oxide (FENO) in Workers Exposed to Nanomaterials 
Fractional exhaled nitric oxide (FENO) measurement is a useful diagnostic test of airway inflammation. However, there have been few studies of FENO in workers exposed to nanomaterials. The purpose of this study was to examine the effect of nanoparticle (NP) exposure on FENO and to assess whether the FENO is increased in workers exposed to nanomaterials (NM). In this study, both exposed workers and non-exposed controls were recruited from NM handling plants in Taiwan. A total of 437 subjects (exposed group = 241, non-exposed group = 196) completed the FENO and spirometric measurements from 2009–2011. The authors used a control-banding (CB) matrix to categorize the risk level of each participant. In a multivariate linear regression analysis, this study found a significant association between risk level 2 of NP exposure and FENO. Furthermore, asthma, allergic rhinitis, peak expiratory flow rate (PEFR), and NF-κB were also significantly associated with FENO. When the multivariate logistic regression model was adjusted for confounders, nano-TiO2 in all of the NM exposed categories had a significantly increased risk in FENO > 35 ppb. This study found associations between the risk level of NP exposure and FENO (particularly noteworthy for Nano-TiO2). Monitoring FENO in the lung could open up a window into the role nitric oxide (NO) may play in pathogenesis.
PMCID: PMC3907844  PMID: 24413755
nanoparticles; nanomaterials; workers’s respiratory health; airway inflammation; Fractional exhaled nitric oxide; occupational epidemiology
24.  Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide 
The Clinical Respiratory Journal  2008;2(3):141-148.
Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se– as verified with positive skin prick tests – affects FENO in healthy individuals.
The aim of this study was to examine the association between FENO and sensitization to common allergens in healthy nonsmoking adults with no signs or symptoms of airway disorders.
FENO measurements (flow rate: 50 mL/s), skin prick tests to common inhalant allergens, structured interviews, spirometry, bronchodilatation tests and bronchial histamine challenges were performed on a randomly selected population of 248 subjects. Seventy-three of them (29%) were nonsmoking asymptomatic adults with no history of asthma, persistent or recurrent upper or lower airway symptoms and no signs of airway disorders in the tests listed above.
FENO concentrations were similar in skin prick test positive (n = 32) and negative (n = 41) healthy subjects, with median values of 13.2 and 15.5 ppb, respectively (P = 0.304). No correlation appeared between FENO and the number of positive reactions (r = −0.138; P = 0.244), or the total sum of wheal diameters (r = −0.135; P = 0.254). The nonparametric one-tailed 95% upper limits of FENO among skin prick positive and negative healthy nonsmoking subjects were 29 and 31 ppb, respectively.
Atopic constitution defined as positive skin prick test results does not increase FENO in healthy nonsmoking adults with no signs or symptoms of airway disorders. This suggests that same reference ranges for FENO can be applied to both skin prick test positive and negative subjects.
Please cite this paper as: Rouhos A, Kainu A, Karjalainen J, Lindqvist A, Piirilä P, Sarna S, Haahtela T and Sovijärvi ARA. Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide. The Clinical Respiratory Journal 2008; 2: 141–148.
PMCID: PMC3272347  PMID: 20298322
airway inflammation; atopy; exhaled nitric oxide; healthy adults; skin prick tests
25.  Effect of drinking Arabian Qahwa on fractional exhaled nitric oxide levels in healthy nonsmoking Saudi adults 
Annals of Thoracic Medicine  2012;7(3):153-156.
Fractional exhaled nitric oxide (FENO) is an emerging marker of inflammation in respiratory diseases. However, it is affected by a number of confounding factors. We aimed to study the effect of drinking Arabian Qahwa on FENO in non-smoking Saudi healthy adults.
We recruited 12 nonsmoker healthy male adults aged 36.6 ± 2.7 (21-50) years. All subjects were free from acute respiratory infections or allergies and had normal ventilatory functions and serum IgE levels. At 8 am in the morning, their baseline values of FENO were recorded. They had not taken tea or coffee in the morning and had taken similar light breakfast. They were given three cups of Arabian Qahwa to drink and then after every 30 minutes, serial levels of FENO were recorded.
Average FENO levels at baseline were 28.73 ± 9.33 (mean ± SD) parts per billion (ppb). The mean FENO levels started to decrease significantly after 30 minutes of drinking Arabian Qahwa (P=0.002). This decrease in FENO level was further observed till two hours after Qahwa drinking and then it started to increase in next 90 minutes but still was significantly lower than the baseline (P=0.002). The mean FENO level recorded after 4 hours was 27.22 ± 10.22 (P=0.039).
FENO levels were significantly lowered by intake of Arabian Qahwa and this effect remains for about 4 hours. Therefore, history of recent Qahwa intake and abstinence is essential before performance of FENO and its interpretation.
PMCID: PMC3425048  PMID: 22924074
Arabian Qahwa; adults; fractional exhaled nitric oxide; non smoker

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