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.
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.
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.
fractional exhaled nitric oxide (FeNO); asthma; allergic sensitization; atopic dermatitis; lung function; children; seasonality; atopy
Exhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.
Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.
The effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.
Even after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.
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.
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.
Exhaled nitric oxide; Children; Airway diseases; Asthma; Bronchiolitis; Community acquired pneumonia; Bronchiectasis; Diffuse lung disease
Fractional exhaled nitric oxide (FENO) levels are increased in children with asthma and in infants with recurrent wheezing, but the role of FENO in the acute phase of bronchiolitis is still not defined.
The aim of this study is to evaluate FENO values in the acute phase of bronchiolitis, compare them with healthy infants, and relate those values with the appearance of other wheezing episodes.
FENO values were determined in infants between 2 months and 2 years affected with RVS bronchiolitis by offline method. The FENO values collected in the acute phase were related with the respiratory clinical symptoms presented in the 2 years following the episode.
A total of 30 patients were recruited: 15 in the bronchiolitis group and 15 in the control group. The average of the FENO values in the acute phase was 18.74 ppb (range 2–88) in the bronchiolitis group, and 8.75 ppb (range 2–24) in the control group. However, these results showed no significant statistical differences (p=0.176). Nevertheless, we found a positive correlation between the FENO values and the clinical score (Downes) of the bronchiolitis episode (p=0.023). In infants that presented other wheezing episodes in the 2 years after, the average of FENO in the acute phase of the first episode was 23.1 ppb (average of 10.25 ppb) versus 8.4 ppb (average 5.4 ppb) in the group of patients with no other episodes. The comparison of averages has no statistical significance.
We found no differences in FENO between infants with bronchiolitis and healthy ones. The FENO values in the acute phase seems to be related to the severity of the disease but do not predict the appearance of wheezing episodes in the following 2 years.
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.
allergen; sensitization; tobacco smoke; inhaled corticosteroid
Measurement of fraction of exhaled nitric oxide (FeNO) is a relatively simple, noninvasive, and reproducible test for detection of endogenous inflammatory signals in childhood. The aim of this study was to evaluate the correlation between FeNo levels and forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) in a group of steroid-naive childhood asthma.
The study was conducted in a group of 60 steroid-naive asthmatic children (50 atopic and 20 nonatopic; mean age 7 years) who presented to Kyung Hee University Hospital and 20 healthy children. All patients underwent measurement of FeNO, skin prick tests with common inhaled allergens, and blood eosinophil, and flow-volume spirometry. FeNO levels were measured by chemiluminescence during exhalation into the NO analyzer. Measurements of FeNO in parts per billion (ppb) and spirometry, including FEV1 and FVC, were performed.
Compared to the healthy volunteers, FeNO was elevated in both groups of asthmatics. The mean FeNO level in the asthmatic children was 18.6 ppb. FeNO in the atopic asthma group was higher than in the group of nonatopic asthmatics. There was statistically significant correlation between FeNO levels and FEV1 (r = -0.36, P < 0.016) and FVC (r = -0.40, P < 0.01).
FeNO levels were related with pulmonary functions in childhood asthma. Thus measurement of FeNO is a promising clinical tool for assessing 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.
The fractional concentration of exhaled nitric oxide (FeNO) appears to be a good marker for airway inflammation in children with asthma.
To evaluate the effect of environmental exposures on exhaled nitric oxide in a community sample of children.
The relationship among exhaled nitric oxide, underlying disease and home environmental exposures was examined using questionnaire data and measurement of exhaled nitric oxide in a cross-sectional study of 1135 children that included healthy children, and children with allergies and/or asthma who were attending grades 4 through 6 in Windsor, Ontario.
Among healthy children, there was a positive association between FeNO and occupancy (P<0.02). Compared with forced air and hot water radiant heat, electric baseboard heating was associated with a significant increase of FeNO in healthy children (P=0.007) and children with allergies (P=0.043). FeNO was not associated with environmental tobacco smoke exposure or reported surface mold. The presence of pet dog(s), but not cats, was associated with a significantly lower FeNO in healthy children (P<0.001) and in children with reported allergies (P<0.001).
The type of heating system, but not previously reported environmental tobacco smoke or mold exposure appears to affect exhaled nitric oxide in children. Exposure to different types of pets may have disparate effects on airway inflammation.
Air Pollution; Allergens; Child; Indoor heating; Nitric oxide analysis
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.
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.
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.
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.
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.
Exhaled Nitric Oxide; Atopy; Rhinitis; Systematic Review
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.
Diagnosis of eosinophilic esophagitis (EoE) and determination of response to therapy is based on histological assessment of the esophagus, which requires upper endoscopy. In children, in whom a dietary approach is commonly used, multiple endoscopies are needed, because foods are eliminated and then gradually reintroduced. Ideally, noninvasive methods could supplement or replace upper endoscopy to facilitate management. Fractionated exhaled nitric oxide (FeNO) has been proposed as a useful measure for monitoring disease activity in studies of patients with eosinophil-predominant asthma and in other atopic disorders. Thus, we evaluated whether FeNO levels could be a useful biomarker to assess the response to therapy in EoE patients. This study was designed to determine whether there is a change in FeNO levels during treatment with topical corticosteroids and whether changes correlated with clinical response. This was a prospective, multicenter study that enrolled nonasthmatic patients with established EoE. FeNO levels and symptom scores were measured at baseline, biweekly during 6-week swallowed fluticasone treatment, and 4 weeks posttreatment. Twelve patients completed the trial. We found a statistically significant difference between median pre- and posttreatment FeNO levels [20.3 ppb (16.0–29.0 ppb) vs 17.6 ppb (11.7–27.3 ppb), p=0.009]. However, neither the pretreatment FeNO level, a change of FeNO level after 2 weeks of treatment, nor the FeNO level at the end of treatment confidently predicted a clinical or histological response. Although our findings suggest nitric oxide possibly has a physiological role in EoE, our observations do not support a role of FeNo determination for management of EoE.
Biomarker; disease activity; eosinophilic esophagitis; fractionated exhaled nitric oxide; monitoring; noninvasive; treatment
Background: Exposure of patients with atopic asthma to allergens produces a long term increase in exhaled nitric oxide (FENO), probably reflecting inducible NO synthase (NOS) expression. In contrast, bradykinin (BK) rapidly reduces FENO. It is unknown whether BK suppresses increased FENO production after allergen exposure in asthma, and whether it modulates FENO via NOS inhibition.
Methods: Levels of FENO in response to aerosolised BK were studied before (day 3) and 48 hours after (day 10) randomised diluent (diluent/placebo/BK (Dil/P/BK)), allergen (allergen/placebo/BK (All/P/BK), and allergen/L-NMMA/BK (All/L/BK)) challenges (day 8) in 10 atopic, steroid naïve, mild asthmatic patients with dual responses to inhaled house dust mite extract. To determine whether BK modulates FENO via NOS inhibition, subjects performed pre- and post-allergen BK challenges after pretreatment with the NOS inhibitor L-NMMA in the All/L/BK period.
Results: Allergen induced a fall in FENO during the early asthmatic reaction (EAR) expressed as AUC0–1 (ANOVA, p=0.04), which was followed by a rise in FENO during the late asthmatic reaction (LAR) expressed as AUC1–48 (ANOVA, p=0.008). In the Dil/P/BK period, FENO levels after BK on pre- and post-diluent days were lower than FENO levels after placebo (difference 23.5 ppb (95% CI 6.2 to 40.9) and 22.5 ppb (95% CI 7.3 to 37.7), respectively; p<0.05). Despite the long lasting increase in FENO following allergen challenge in the LAR, BK suppressed FENO levels at 48 hours after allergen challenge in the All/P/BK period, lowering the increased FENO (difference from placebo 54.3 ppb (95% CI 23.8 to 84.8); p=0.003) to the baseline level on the pre-allergen day (p=0.51). FENO levels were lower after L-NMMA than after placebo on pre-allergen (difference 10.85 ppb (95% CI 1.3 to 20.4); p=0.03) and post-allergen (difference 36.2 ppb (95% CI 5.5 to 66.9); p=0.03) days in the All/L/BK and All/P/BK periods, respectively. L-NMMA did not significantly potentiate the pre- and post-allergen reduction in BK induced FENO.
Conclusions: Bradykinin suppresses the allergen induced increase in exhaled NO in asthma; this is not potentiated by L-NMMA. Bradykinin and L-NMMA may follow a common pathway in reducing increased NO production before and after experimental allergen exposure. Reinforcement of this endogenous protective mechanism should be considered as a therapeutic target in asthma.
Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation. In the nitric oxide (NO) synthesis pathway, nitric oxide synthases (encoded by NOS1, NOS2A and NOS3) and arginases (encoded by ARG1 and ARG2) compete for L-arginine. Although FeNO levels are higher in children with asthma/allergy, influence of these conditions on the relationships between variations in these genes and FeNO remains unknown. The aims of the study were to evaluate the role of genetic variations in nitric oxide synthases and arginases on FeNO in children and to assess the influence of asthma and respiratory allergy on these genetic associations.
Among children (6–11 years) who participated in the southern California Children’s Health Study, variations in these five genetic loci were characterized by tagSNPs. FeNO was measured in two consecutive years (N = 2298 and 2515 in Years 1 and 2, respectively). Repeated measures analysis of variance was used to evaluate the associations between these genetic variants and FeNO.
Sequence variations in the NOS2A and ARG2 loci were globally associated with FeNO (P = 0.0002 and 0.01, respectively). The ARG2 association was tagged by intronic variant rs3742879 with stronger association with FeNO in asthmatic children (P-interaction = 0.01). The association of a NOS2A promoter haplotype with FeNO varied significantly by rs3742879 genotypes and by asthma.
Variants in the NO synthesis pathway genes jointly contribute to differences in FeNO concentrations. Some of these genetic influences were stronger in children with asthma. Further studies are required to confirm our findings.
airway inflammation; asthma; biomarker; exhaled nitric oxide; nitrosative stress
Fractional exhaled nitric oxide (FeNO) and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) are not included in routine monitoring of asthma control. We observed changes in FeNO level and FEF25-75 after FeNO-based treatment with inhaled corticosteroid (ICS) in children with controlled asthma (CA).
We recruited 148 children with asthma (age, 8 to 16 years) who had maintained asthma control and normal forced expiratory volume in the first second (FEV1) without control medication for ≥3 months. Patients with FeNO levels >25 ppb were allocated to the ICS-treated (FeNO-based management) or untreated group (guideline-based management). Changes in spirometric values and FeNO levels from baseline were evaluated after 6 weeks.
Ninety-three patients had FeNO levels >25 ppb. These patients had lower FEF25-75% predicted values than those with FeNO levels ≤25 ppb (P<0.01). After 6 weeks, the geometric mean (GM) FeNO level in the ICS-treated group was 45% lower than the baseline value, and the mean percent increase in FEF25-75 was 18.% which was greater than that in other spirometric values. There was a negative correlation between percent changes in FEF25-75 and FeNO (r=-0.368, P=0.001). In contrast, the GM FeNO and spirometric values were not significantly different from the baseline values in the untreated group.
The anti-inflammatory treatment simultaneously improved the FeNO levels and FEF25-75 in CA patients when their FeNO levels were >25 ppb.
Nitric oxide; Spirometry; Inhaled corticosteroids; Asthma; Child
Asthma is a chronic inflammatory disorder in the airways. Measurement of FeNO (fractional exhaled nitric oxide) is a non-invasive tool for measuring airway inflammation. The aim of this study was to investigate the relationship of FeNO and acute asthmatic exacerbation in children and to decide whether measurement of FeNO could predict acute exacerbation of asthma.
Thirty eight children with mild to moderate persistent asthma aged from 3 to 15 years were included. Patient's data were based on out-patient records. FeNO was measured thorough chemiluminescence analyzer. Prospectively, the patients were followed for 6 month. The FeNO levels of asthma exacerbation group and non-exacerbation groups were evaluated.
Mean age of the patients is 5.4 years. There were no difference of peripheral blood total eosinophil count, serum IgE, age, sex between asthma exacerbation group and non-exacerbation group. In the range of abnormal FeNO level (more than 10 ppb), there was significant difference of FeNO level between exacerbation group and non-exacerbation group (P = 0.004). There was also significant correlation between FeNO level and acute asthma exacerbation (P = 0.003).
Measurement of FeNO can be a useful tool to predict asthma exacerbation in mild to moderate persistent asthmatic children.
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.
airway inflammation; atopy; exhaled nitric oxide; healthy adults; skin prick tests
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.
This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (FeNO) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA.
We report on 102 children, mean±SD age 11.6±2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and FeNO before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial.
Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02–0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13–26.07) and high baseline forced expiratory volume in 1 s (FEV1) (OR 1.08, 95% CI 1.02–1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR. FeNO data was available in 70 patients, of whom 53 (75%) had normal FeNO. Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV1 (OR 0.93, 95% CI 0.90–0.97).
Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
Corticosteroid responsiveness; difficult asthma; eosinophil; nitric oxide; paediatric asthma
Background: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (FeNO) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of FeNO and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test.
Methods: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. FeNO was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (δN2) and the closing volume (CV) were assessed from the single breath washout curve.
Results: The median FeNO level was 30.4 ppb (range 10.1–82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6–2.7), and the mean (SD) δN2 value was 1.1 (0.4)% N2/l. FeNO was positively associated with δN2 (rs = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs = –0.58; p = 0.017) and CV as a percentage of vital capacity (rs = 0.58; p = 0.019).
Conclusions: FeNO and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.
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.
Arabian Qahwa; adults; fractional exhaled nitric oxide; non smoker
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.
The aim of this study was to establish adult FENO reference values according to the international guidelines.
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.
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.
We propose reference FENO values for healthy adult men and women that could be used for clinical and research purposes.
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.
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.
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).
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.
Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO.
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
Background: Respiratory function and airway inflammation can be evaluated in preschool children with special techniques, but their relative power in identifying young children with asthma has not been studied. This study was undertaken to compare the value of exhaled nitric oxide (FENO), baseline lung function, and bronchodilator responsiveness in identifying children with newly detected probable asthma.
Methods: Ninety six preschool children (age 3.8–7.5 years) with asthmatic symptoms or history and 62 age matched healthy non-atopic controls were studied. FENO was measured with the standard online single exhalation technique, and baseline lung function and bronchodilator responsiveness were measured using impulse oscillometry (IOS).
Results: Children with probable asthma (n=21), characterised by recent recurrent wheeze, had a significantly higher mean (SE) concentration of FENO than controls (22.1 (3.4) ppb v 5.3 (0.4) ppb; mean difference 16.8 ppb, 95% CI 12.0 to 21.5) and also had higher baseline respiratory resistance, lower reactance, and larger bronchodilator responses expressed as the change in resistance after inhalation of salbutamol. Children with chronic cough only (n=46) also had significantly raised mean FENO (9.2 (1.5) ppb; mean difference 3.9 ppb, 95% CI 0.8 to 7.0) but their lung function was not significantly reduced. Children on inhaled steroids due to previously diagnosed asthma (n=29) differed from the controls only in their baseline lung function. The analysis of receiver operating characteristics (ROC) showed that FENO provided the best power for discriminating between children with probable asthma and healthy controls, with a sensitivity of 86% and specificity of 92% at the cut off level of 1.5 SD above predicted.
Conclusions: FENO is superior to baseline respiratory function and bronchodilator responsiveness in identifying preschool children with probable asthma. The results emphasise the presence of airway inflammation in the early stages of asthma, even in young children.