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1.  Effects of atopy and rhinitis on exhaled nitric oxide values - a systematic review 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/2045-7022-1-8
PMCID: PMC3339369  PMID: 22409776
Exhaled Nitric Oxide; Atopy; Rhinitis; Systematic Review
2.  Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children 
Thorax  2003;58(12):1048-1052.
Background: Exhaled nitric oxide (FENO) is raised in asthmatic children, but there are inconsistencies in the relationship between FENO and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FENO and asthma, atopy, and increased AR in children.
Methods: One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FENO measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire.
Results: In multiple linear regression analyses FENO was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FENO and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms.
Conclusion: Raised FENO seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
doi:10.1136/thorax.58.12.1048
PMCID: PMC1746531  PMID: 14645971
3.  Role of exhaled nitric oxide as a predictor of atopy 
Respiratory Research  2013;14(1):48.
Background
The fractional exhaled nitric oxide (FeNO) is a quantitative, noninvasive and safe measure of airways inflammation that may complement the assessment of asthma. Elevations of FeNO have recently been found to correlate with allergic sensitization. Therefore, FeNO may be a useful predictor of atopy in the general population. We sought to determine the diagnostic accuracy of FeNO in predicting atopy in a population-based study.
Methods
We conducted a cross-sectional study in an age- and sex- stratified random sample of 13 to 15 year-olds in two communities in Peru. We asked participants about asthma symptoms, environmental exposures and sociodemographics, and underwent spirometry, assessment of FeNO and an allergy skin test. We used multivariable logistic regression to model the odds of atopy as a function of FeNO, and calculated area-under-the-curves (AUC) to determine the diagnostic accuracy of FeNO as a predictor of atopy.
Results
Of 1441 recruited participants, 1119 (83%) completed all evaluations. Mean FeNO was 17.6 ppb (SD=0.6) in atopics and 11.6 ppb (SD=0.8) in non-atopics (p<0.001). In multivariable analyses, a FeNO>20 ppb was associated with an increase in the odds of atopy in non-asthmatics (OR=5.3, 95% CI 3.3 to 8.5) and asthmatics (OR=16.2, 95% CI 3.4 to 77.5). A FeNO>20 ppb was the best predictor for atopy with an AUC of 68% (95% CI 64% to 69%). Stratified by asthma, the AUC was 65% (95% CI 61% to 69%) in non-asthmatics and 82% (95% CI 71% to 91%) in asthmatics.
Conclusions
FeNO had limited accuracy to identify atopy among the general population; however, it may be a useful indicator of atopic phenotype among asthmatics.
doi:10.1186/1465-9921-14-48
PMCID: PMC3654880  PMID: 23639047
Allergic sensitization; Asthma; Exhaled nitric; Allergic rhinitis
4.  Effect of Mannitol Dry Powder Challenge on Exhaled Nitric Oxide in Children 
PLoS ONE  2013;8(1):e54521.
Background
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.
Objective
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.
Methods
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.
Results
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).
Conclusion
MDP challenge test influences FENO values but differences are small and clinically barely relevant.
doi:10.1371/journal.pone.0054521
PMCID: PMC3548778  PMID: 23349918
5.  Seasonal Variation and Environmental Predictors of Exhaled Nitric Oxide in Children with Asthma 
Pediatric pulmonology  2008;43(6):576-583.
Summary
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.
doi:10.1002/ppul.20816
PMCID: PMC3483596  PMID: 18429012
allergen; sensitization; tobacco smoke; inhaled corticosteroid
6.  Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care 
Background
Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response.
Aim
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.
Methods
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.
Outcomes
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).
Conclusions
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.
doi:10.1186/2045-7022-3-37
PMCID: PMC3826517  PMID: 24195942
Fractional exhaled nitric oxide (FeNO); Practical guidance; Diagnosis; On-going asthma management; Steroid-responsive disease
7.  Measurements of fractional exhaled nitric oxide in pediatric asthma 
Korean Journal of Pediatrics  2013;56(10):424-430.
Exhaled nitric oxide (NO) has been extensively investigated as a noninvasive marker of airway inflammation in asthma. The increased NO expression induced by inflammatory mediators in airways can be monitored easily in exhaled air from asthmatic children. Based on the relationship between the increased NO expression and eosinophilic airway inflammation, fractional exhaled nitric oxide (FeNO) measurements become an important adjunct for the evaluation of asthma. In addition, the availability of portable devices makes it possible to measure FeNO more easily and frequently in the routine pediatric practice. Despite various confounding factors affecting its levels, FeNO can be applicable in diagnosing asthma, monitoring treatment response, evaluating asthma control, and predicting asthma exacerbations. Thus, although pulmonary function tests are the standard tools for objective measurements of asthmatic control, FeNO can broaden the way of asthma monitoring and supplement standard clinical asthma care guidelines.
doi:10.3345/kjp.2013.56.10.424
PMCID: PMC3827490  PMID: 24244210
Asthma; Breath test; Child; Nitric oxide
8.  Fractional Exhaled Nitric Oxide (FeNO) Measurements are Most Closely Associated with Allergic Sensitization in School Aged Children 
Background
Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood.
Objective
To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2009.07.024
PMCID: PMC2784153  PMID: 19748661
fractional exhaled nitric oxide (FeNO); asthma; allergic sensitization; atopic dermatitis; lung function; children; seasonality; atopy
9.  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.
doi:10.3390/ijms15010878
PMCID: PMC3907844  PMID: 24413755
nanoparticles; nanomaterials; workers’s respiratory health; airway inflammation; Fractional exhaled nitric oxide; occupational epidemiology
10.  Clinical application of exhaled nitric oxide measurement in pediatric lung diseases 
Summary
Fractional exhaled nitric oxide (FeNO) is a non invasive method for assessing the inflammatory status of children with airway disease. Different ways to measure FeNO levels are currently available. The possibility of measuring FeNO levels in an office setting even in young children, and the commercial availability of portable devices, support the routine use of FeNO determination in the daily pediatric practice. Although many confounding factors may affect its measurement, FeNO is now widely used in the management of children with asthma, and seems to provide significantly higher diagnostic accuracy than lung function or bronchial challenge tests. The role of FeNO in airway infection (e.g. viral bronchiolitis and common acquired pneumonia), in bronchiectasis, or in cases with diffuse lung disease is less clear. This review focuses on the most recent advances and the current clinical applications of FeNO measurement in pediatric lung disease.
doi:10.1186/1824-7288-38-74
PMCID: PMC3545741  PMID: 23273317
Exhaled nitric oxide; Children; Airway diseases; Asthma; Bronchiolitis; Community acquired pneumonia; Bronchiectasis; Diffuse lung disease
11.  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.
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1752-699X.2007.00045.x
PMCID: PMC3272347  PMID: 20298322
airway inflammation; atopy; exhaled nitric oxide; healthy adults; skin prick tests
12.  Exhaled nitric oxide measurements: clinical application and interpretation 
Thorax  2006;61(9):817-827.
The use of exhaled nitric oxide measurements (FEno) in clinical practice is now coming of age. There are a number of theoretical and practical factors which have brought this about. Firstly, FEno is a good surrogate marker for eosinophilic airway inflammation. High FEno levels may be used to distinguish eosinophilic from non‐eosinophilic pathologies. This information complements conventional pulmonary function testing in the assessment of patients with non‐specific respiratory symptoms. Secondly, eosinophilic airway inflammation is steroid responsive. There are now sufficient data to justify the claim that FEno measurements may be used successfully to identify and monitor steroid response as well as steroid requirements in the diagnosis and management of airways disease. FEno measurements are also helpful in identifying patients who do/do not require ongoing treatment with inhaled steroids. Thirdly, portable nitric oxide analysers are now available, making routine testing a practical possibility. However, a number of issues still need to be resolved, including the diagnostic role of FEno in preschool children and the use of reference values versus individual FEno profiles in managing patients with difficult or severe asthma.
doi:10.1136/thx.2005.056093
PMCID: PMC2117092  PMID: 16936238
exhaled nitric oxide; asthma; diagnosis; monitoring; treatment
13.  Repeatability of exhaled nitric oxide measurements in patients with COPD 
The assessment of the presence of eosinophilic airway inflammation may help in predicting the steroid response in subjects with respiratory symptoms. Unlike patients with asthma, only a subset of patients with chronic obstructive pulmonary disease (COPD) benefits from steroid treatment. Fractional exhaled nitric oxide (FENO) is a useful surrogate marker for eosinophilic airway inflammation, but data on the repeatability of FENO measurements in COPD needed for the assessment of significant change are insufficient. The aim of this study was to assess the short-term repeatability of FENO measurement in subjects with moderate to very severe chronic airway obstruction compared to that in healthy subjects. We studied 20 patients with stable COPD and 20 healthy subjects, and determined FENO (flow rate 50 ml s−1) three times: at baseline, 10 min and 24 h after baseline. Spirometry was performed on the first study day after the FENO measurements. The median FENO concentration in patients with COPD was 15·6 ppb, and in healthy subjects, 15·2 ppb. The coefficient of variation (CoV) for 24-h measurements was 12·4% in COPD patients, and 15·9% in healthy subjects. Among COPD patients with global initiative for chronic obstructive lung disease stage 2 disease, the CoV was 13·7%, and among those with stage 3–4 disease, 10·5%. The findings indicate that the short-term repeatability of FENO measurement in patients with moderate to very severe COPD is equally good as in healthy subjects. A change in FENO exceeding 24% is likely to reflect a minimum measurable change in COPD.
doi:10.1111/j.1475-097X.2010.00975.x
PMCID: PMC3047709  PMID: 21143751
chronic obstructive pulmonary disease; eosinophilic inflammation; fixed bronchial obstruction; fractional exhaled nitric oxide; reproducibility
14.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/01.WOX.0000412051.20565.61
PMCID: PMC3512963
15.  Associations of Fraction of Exhaled Nitric Oxide with Beta Agonist Use in Children with Asthma 
The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, is a potential noninvasive tool to guide asthma management in children. It remains unclear, however, if FeNO adds any information beyond clinical assessment of asthma control. We evaluated the associations of FeNO level with short acting beta agonist use and compared it with other clinical asthma assessments. We examined a prospective cohort study of 225 tobacco-smoke-exposed children aged 6–12 years with doctor-diagnosed asthma, including measures of FeNO, reported days of short acting beta agonist use, and unscheduled asthma visits. FeNO was analyzed in relation to current and future (3 months later) short acting beta agonist use. Mean FeNO at baseline, 6, and 12 months was 15.5, 15.7, and 16.8 ppb. In multivariable analyses, higher FeNO level was associated with increased short acting beta agonist use but only among children who were not on inhaled corticosteroids. Among those not on an inhaled steroid, there was a 12% increase in current and 15% increase in future days of short acting beta agonist use for every 10 ppb increase in FeNO level. FeNO levels remained associated with current short acting beta agonist use even after adjusting for unscheduled asthma visits. FeNO levels remained associated with future short acting beta agonist use even after adjusting for current short acting beta agonist use or unscheduled asthma visits. We conclude that FeNO levels are associated with short acting beta agonist use but only among children who are not on an inhaled corticosteroid.
doi:10.1089/ped.2010.0047
PMCID: PMC3255503  PMID: 22276224
16.  Allergen exposure modifies the relation of sensitization to FENO levels in children at risk for allergy and asthma 
Background
Studies on airway inflammation, measured as fraction exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to elevation of FENO is unknown.
Objective
We evaluated (1) whether FENO was elevated in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not in unsensitized children; and (3) whether sedentary behavior increased FENO, independent of allergen exposures.
Methods
At age 12, in a birth cohort of children with parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, cockroach) by ELISA; specific allergic sensitization primarily by specific IgE ; and respiratory disease (current asthma, rhinitis, and wheeze) and hours of TV viewing/video game playing by questionnaire. Children performed spirometry maneuvers before and after bronchodilator responses, and had FENO measured using electrochemical detection methods (NIOX MINO).
Results
FENO was elevated in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2ppb) as compared to individuals without these respective symptoms/diagnoses (16.4 ppb to 16.6 ppb, p< 0.005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, dust mite) predicted higher levels of FENO, and explained one third of the variability of FENO. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday TV viewing was associated with a 0.64 log increase in FENO, after controlling indoor allergen exposure, BMI and allergic sensitization.
Conclusion
Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO.
doi:10.1016/j.jaci.2011.01.066
PMCID: PMC3137133  PMID: 21463890
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
17.  Bronchial Responsiveness Is Related to Increased Exhaled NO (FENO) in Non-Smokers and Decreased FENO in Smokers 
PLoS ONE  2012;7(4):e35725.
Rationale
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.
Objectives
To investigate how the relation between FENO and bronchial responsiveness is modulated by atopy and smoking habits.
Methods
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).
Conclusions
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.
doi:10.1371/journal.pone.0035725
PMCID: PMC3338521  PMID: 22563393
18.  Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma 
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
doi:10.1164/rccm.200905-0695OC
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
19.  Fractional Exhaled Nitric Oxide and Impulse Oscillometry in Children With Allergic Rhinitis 
Purpose
Airway inflammation, bronchial hyper-responsiveness (BHR), and bronchodilator response (BDR) are representative characteristics of asthma. Because allergic rhinitis (AR) is a risk factor for asthma development, we evaluated these 3 characteristics in AR using measurement of fractional exhaled nitric oxide (FeNO), a methacholine challenge test (MCT), and impulse oscillometry (IOS).
Methods
This study included 112 children with asthma (asthma group), 196 children with AR (AR group), and 32 control subjects (control group). We compared pulmonary function parameters and FeNO levels among the 3 groups. The AR group was subdivided into 2 categories: the AR group with BHR and the AR group without, and again pulmonary function and FeNO levels were compared between the 2 subgroups.
Results
FeNO levels were more increased in the AR and asthma groups than in the control group; within the AR group, FeNO was higher in the AR group with BHR than in the AR group without. The BDR was more increased in the AR group than in the control group when percent changes in reactance at 5 Hz (Δ X5) and reactance area (Δ AX) were compared. In the AR group, however, there was no difference in Δ X5 and Δ AX between the AR group with BHR and the AR group without.
Conclusions
Reversible airway obstruction on IOS and elevated FeNO levels were observed in children with AR. Because elevated FeNO levels can indicate airway inflammation and because chronic inflammation may lead to BHR, FeNO levels may be associated with BHR in AR. IOS can be a useful tool for detecting lower airway involvement of AR independent of BHR assessed in the MCT.
doi:10.4168/aair.2014.6.1.27
PMCID: PMC3881396  PMID: 24404390
Asthma; allergic rhinitis; bronchial hyper-responsiveness; bronchodilator effect; child; nitric oxide
20.  Exhaled nitric oxide and urinary EPX levels in infants: a pilot study 
Background
Objective markers of early airway inflammation in infants are not established but are of great interest in a scientific setting. Exhaled nitric oxide (FeNO) and urinary eosinophilic protein X (uEPX) are a two such interesting markers.
Objective
To investigate the feasibility of measuring FeNO and uEPX in infants and their mothers and to determine if any relations between these two variables and environmental factors can be seen in a small sample size. This was conducted as a pilot study for the ongoing Swedish Environmental Longitudinal Mother and child Asthma and allergy study (SELMA).
Methods
Consecutive infants between two and six months old and their mothers at children's health care centres were invited, and 110 mother-infant pairs participated. FeNO and uEPX were analysed in both mothers and infants. FeNO was analyzed in the mothers online by the use of the handheld Niox Mino device and in the infants offline from exhaled air sampled during tidal breathing. A 33-question multiple-choice questionnaire that dealt with symptoms of allergic disease, heredity, and housing characteristics was used.
Results
FeNO levels were reduced in infants with a history of upper respiratory symptoms during the previous two weeks (p < 0.002). There was a trend towards higher FeNO levels in infants with windowpane condensation in the home (p < 0.05). There was no association between uEPX in the infants and the other studied variables.
Conclusion
The use of uEPX as a marker of early inflammation was not supported. FeNO levels in infants were associated to windowpane condensation. Measuring FeNO by the present method may be an interesting way of evaluating early airway inflammation. In a major population study, however, the method is difficult to use, for practical reasons.
doi:10.1186/1476-7961-9-8
PMCID: PMC3117812  PMID: 21575173
Nitric Oxide; Eosinophil Granule Proteins; Infant; Housing; Allergy and Immunology
21.  Measurement of Fractional Exhaled Nitric Oxide in Stable Bronchiectasis 
Background
Fractional exhaled nitric oxide (FeNO) can be measured easily, rapidly, and noninvasively for the assessment of airway inflammation, particularly mediated by eosinophil, such as asthma. In bronchiectasis (BE), the pathogenesis has been known as chronic airway inflammation and infection with abnormal airway dilatation; however, there are little studies to evaluate the role of FeNO in BE.
Methods
From March 2010 to February 2012, 47 patients with BE, diagnosed by high resolution computed tomography (HRCT), performed FeNO, compared with asthma and chronic obstructive pulmonary disease (COPD). All patients carried out a complete blood count including eosinophil count, chemistry, sputum examination, and spirometry, if indicated. A retrospective analysis was performed to elucidate the clinical role of FeNO in BE patients.
Results
The mean FeNO levels in patients with BE was 18.8±1.5 part per billion (ppb), compared to 48.0±6.4 and 31.0±4.3 in those with asthma and COPD, respectively (p<0.001). The FeNO levels tended to increase along with the disease severity scores by HRCT; however, it was statistically not significant. FeNO in BE with a co-infection of nontuberculous mycobacteria was the lowest at 17.0±3.5 ppb among the study population.
Conclusion
FeNO in BE was lower than other chronic inflammatory airway diseases, particularly compared with asthma. For clinical application of FeNO in BE, more large-scaled, prospective studies should be considered.
doi:10.4046/trd.2013.74.1.7
PMCID: PMC3563703  PMID: 23390447
Nitric Oxide; Bronchiectasis; Nontuberculous Mycobacteria
22.  Reference values for exhaled nitric oxide (reveno) study 
Respiratory Research  2006;7(1):94.
Background
Despite the widespread use of fractional exhaled nitric oxide (FENO) as a biomarker of airways inflammation, there are no published papers describing normal FENO values in a large group of healthy adults.
Objective
The aim of this study was to establish adult FENO reference values according to the international guidelines.
Methods
FENO was measured in 204 healthy, non-smoking adults with normal spirometry values using the on-line single-breath technique, and the results were analysed chemiluminescently.
Results
The main result of the study was the significant difference in FENO values between men and women, thus indicating that gender-based reference FENO values are necessary. The FENO levels obtained at expiratory flows of 50 ml/s ranged from 2.6 to 28.8 ppb in men, and from 1.6 to 21.5 ppb in women.
Conclusion
We propose reference FENO values for healthy adult men and women that could be used for clinical and research purposes.
doi:10.1186/1465-9921-7-94
PMCID: PMC1534026  PMID: 16813647
23.  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.
OBJECTIVES:
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.
METHODS:
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.
RESULTS:
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).
CONCLUSIONS:
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.
doi:10.4103/1817-1737.98849
PMCID: PMC3425048  PMID: 22924074
Arabian Qahwa; adults; fractional exhaled nitric oxide; non smoker
24.  Storage conditions for stability of offline measurement of fractional exhaled nitric oxide after collection for epidemiologic research 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2466-12-68
PMCID: PMC3515473  PMID: 23116255
Cigarette smoking; Epidemiologic research; Exhaled nitric oxide; Offline measurement; Refrigeration; Storage conditions; Wheezing
25.  Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study 
Thorax  2010;65(3):258-262.
Background
Asthma is considered to be associated with elevated levels of exhaled nitric oxide (FeNO). The nature of this relationship and how it is influenced by atopy are still not resolved.
Methods
The Isle of Wight birth cohort (N=1456) was reassessed at 18 years of age. Participants able to attend the research centre were assessed by questionnaires, skin prick testing and FeNO in order to explore the interrelationship between asthma, atopy and FeNO.
Results
Atopy was significantly associated with higher levels of FeNO. However, the level of FeNO for non-atopic asthmatic participants was no different to the non-atopic no-asthma group. The highest levels of FeNO were seen in subjects with both atopy and asthma. In addition, FeNO was positively associated with increasing atopic burden as evidenced by increasing FeNO with increasing skin prick testing positivity, and with increasing severity of atopic asthma as evidenced by the number of attacks of wheezing. FeNO and current inhaled corticosteroid use were not significantly associated.
Conclusions
FeNO behaves as a biomarker of atopy and the “allergic asthma” phenotype rather than asthma itself. This may explain why FeNO-guided asthma treatment outcomes have proved to be of limited success where atopic status has not been considered and accounted for.
doi:10.1136/thx.2009.125443
PMCID: PMC2890070  PMID: 20335297

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