Epithelial alarmin levels in exhaled breath condensate in patients with idiopathic pulmonary fibrosis: A pilot study.

INTRODUCTION: Interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) are epithelial alarmins involved in innate immune responses and have been shown to play an important role in chronic lung diseases. No data are available regarding their levels in exhaled breath condensate (EBC) in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To examine IL-25, IL-33 and TSLP levels in the EBC obtained from patients with IPF and compare them to those in healthy controls, patients with asthma and chronic obstructive pulmonary disease (COPD). METHODS: Twenty-three patients with asthma, 25 patients with COPD, 15 patients with IPF and 16 healthy controls were studied. Concentrations of alarmins in the EBC were evaluated by means of ELISA. RESULTS: IL-25 EBC levels were numerically lowest in IPF (25.33 ± 8.84 pg/ml). However, they did not differ significantly from healthy subjects (43.18 ± 5.53 pg/ml), but were significantly lower compared to asthma (72.07 ± 6.03 pg/ml; P < .001). IL-33 EBC levels were significantly increased in IPF (3.41 ± 0.55 pg/ml) compared to healthy controls (1.20 ± 0.60 pg/ml; P < .01) but did not differ from asthma (3.68 pg/ml) and COPD levels (2.47 ± 0.34 pg/ml). There were significant correlations between IL-33 EBC levels and lung diffusion capacity of carbon monoxide (DLco ) absolute (r = .63; P < .05) and % of predicted values (r = .67; P < .01) as well as with time since diagnosis (r = -.59; P < .05) in IPF subjects. TSLP was undetectable in examined samples. CONCLUSION: IL-25 and IL-33 are detectable in the EBC obtained from IPF subjects. Increased levels of IL-33 compared to healthy controls indicate its possible role in the pathobiology of IPF.

HFA-BDP Metered-Dose Inhaler Exhaled Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial Asthma: A Blinded, Placebo-Controlled Study.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). Objective: To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma. Methods: Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN (n = 11) or placebo MDI ETN (n = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity. Results: HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10-30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance. Conclusions: Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).

Exhaled Nitric Oxide: An Update.

Fractional concentration of exhaled nitric oxide (FENO) is a biomarker used to identify allergic airway inflammation. Because it is noninvasive and easy to obtain, its utility has been studied in the diagnosis and management of several respiratory diseases. Much of the research has been done in asthma, and many studies support the use of FENO in aiding diagnosing asthma, predicting steroid responsiveness, and preventing exacerbations by guiding medication dosage and assessing adherence.

Exhaled Breath Condensate: An Update.

Exhaled breath condensate (EBC) is a promising source of biomarkers of lung disease. EBC research and utility has increased substantially over the past 2 decades. This review summarizes many of the factors regarding the composition of EBC, its collection, and analysis for the utility of both clinicians and researchers.

Markers of Airway Inflammation in the Exhaled Breath Condensate of Preschool Wheezers

Antecedentes: Los leucotrienos (LT), isoprostanos y nitritos/nitratos, que son biomarcadores de la inflamación de las vías aéreas, y el estrés oxidativo, pueden ser detectados en el condensado del aire exhalado (CAE). El objetivo de este estudio fue evaluar el LTB4, LTE4, 8-isoprostano, nitritos y nitratos en el CAE de niños preescolares sanos y con sibilancias. Material y métodos: Se realizó un estudio transversal en el que se incluyeron 21 niños sanos no atópicos y 25 pacientes con sibilancias recurrentes. El LTB4, LTE4 y 8-isoprostano, se midieron en el CAE mediante enzimoinmunoensayo, y los nitritos/nitratos mediante método colorimétrico. Resultados: Las concentraciones de LTB4 fueron mayores en los niños con episodios de sibilancias que en controles sanos (76 pg/ml vs 20 pg/ml, p<0,001); El LTE4 se incrementó también en niños con episodios de sibilancias en comparación con niños sanos (68 pg/ml vs 35 pg/ml, p<0,001). Las concentraciones de nitritos fueron mayores en los niños con episodios de sibilancias que en los controles (14 pg/ml vs 9,7 pg/ml, p<0,03). No hubo diferencias en las concentraciones de 8-isoprostano y nitratos entre el grupo de niños enfermos y el grupo control. Conclusiones: Nuestros hallazgos sugieren que el CAE es un método no invasivo para la evaluación de la inflamación de las vías respiratorias y del estrés oxidativo en lactantes y niños en edad preescolar. Las concentraciones de LTB4, LTE4 y de nitritos, se incrementaron en niños con episodios recurrentes de sibilancias en comparación con los controles sanos (AU)

Background: Leukotrienes (LT), isoprostanes, and nitrites/nitrates are biomarkers of airway inflammation and oxidative stress that can be detected in exhaled breath condensate (EBC). The aim of this study was to evaluate LTB4, LTE4, 8-isoprostane, and nitrite/nitrate levels in the EBC of healthy and wheezing preschool children. Methods: We included 21 healthy nonatopic children and 25 patients with recurrent wheezing episodes in a cross-sectional study. LTB4, LTE4, and 8-isoprostane concentrations were measured directly in EBC using a specific enzyme immunoassay; nitrite/nitrate concentrations were measured using a colorimetric assay. Results: LTB4 concentrations were higher in children with wheezing episodes than in healthy controls (76 pg/mL vs 20 pg/mL, P<.001). LTE4 was increased in children with wheezing episodes than in healthy controls (68 pg/mL vs 35 pg/mL, P<.001). Nitrite concentrations were higher in children with wheezing episodes than in healthy controls (14 pg/mL vs 9.7 pg/mL, P<.03). We found no differences in 8-isoprostane and nitrate concentrations between the patients and the healthy controls. Conclusions: Our findings suggest that EBC is a suitable noninvasive method for the assessment of airway inflammation and oxidative stress in preschool children. Levels of LTB4, LTE4, and nitrites were higher in children with recurrent wheezing episodes than in healthy controls (AU)

Bronchial allergen challenges in children - safety and predictors.

BACKGROUND: In allergic asthma, the diagnosis of house dust mite (HDM) allergy is mainly based on the patient's history, allergy testing by the skin prick test (SPT) or the levels of allergen-specific IgE. We retrospectively analysed data from 350 bronchial provocations with HDM and related it to the following parameters: specific IgE, bronchial hyperresponsiveness (BHR) to methacholine testing (MCT) and exhaled NO (eNO). METHODS: Approximately 350 patients (5-18 yr of age) with allergic asthma and a positive SPT to HDMs were included. To define the sensitivity and specificity for the detection method of an early asthmatic response (EAR), a receiver-operating characteristic (ROC) curve was plotted. The accuracy was measured by the area under the ROC curve (AUC). A logistic regression model was used to predict the individual probability of a positive challenge. The results of the regression model were validated in a prospective group of n = 75 patients. RESULTS: The following cut-off values showed the best combination of sensitivity and specificity: specific IgE Dermatophagoides farinae 19.6 kU/l (AUC, 0.88), PD(20) FEV(1) 0.13 mg methacholine (AUC, 0.73) and eNO 20.1 ppb (AUC, 0.71). The following equation predicted the individual probability of a positive challenge in the retrospective and prospective group: p = 1(.) [1 + exp[-(-1.78 + 2.46.(10) log D. far - 1.25(.10) logPD(20) metha)]](-1) , (AUC = 0.88). CONCLUSIONS: The value of using the specific IgE and MCT as predictors was confirmed in a large number of patients. We also showed, for the first time, that the eNO predicted the EAR. The logistic regression model is repeatable with a good accuracy.

Children's urinary phthalate metabolites and fractional exhaled nitric oxide in an urban cohort.

RATIONALE: Phthalates are used widely in consumer products. Exposure to several phthalates has been associated with respiratory symptoms and decreased lung function. Associations between children's phthalate exposures and fractional exhaled nitric oxide (Fe(NO)), a biomarker of airway inflammation, have not been examined. OBJECTIVES: We hypothesized that urinary concentrations of four phthalate metabolites would be positively associated with Fe(NO) and that these associations would be stronger among children with seroatopy or wheeze. METHODS: In an urban ongoing birth cohort, 244 children had phthalate metabolites determined in urine collected on the same day as Fe(NO) measurement. Repeated sampling gathered 313 observations between ages 4.9 and 9.1 years. Seroatopy was assessed by specific IgE. Wheeze in the past year was assessed by validated questionnaire. Regression models used generalized estimating equations. MEASUREMENTS AND MAIN RESULTS: Log-unit increases in urinary concentrations of metabolites of diethyl phthalate (DEP) and butylbenzyl phthalate (BBzP) were associated with a 6.6% (95% confidence interval [CI] 0.5-13.1%) and 8.7% (95% CI, 1.9-16.0%) increase in Fe(NO), respectively, adjusting for other phthalate metabolites and potential covariates/confounders. There was no association between concentrations of metabolites of di(2-ethylhexyl) phthalate or di-n-butyl phthalate and Fe(NO). There was no significant interaction by seroatopy. The BBzP metabolite association was significantly stronger among children who wheeze (P = 0.016). CONCLUSIONS: Independent associations between exposures to DEP and BBzP and Fe(NO) in a cohort of inner-city children were observed. These results suggest that these two ubiquitous phthalates, previously shown to have substantial contributions from inhalation, are positively associated with airway inflammation in children.

Maternal allergy as a potential source of variability of exhaled nitric oxide in children non-sensitized to common domestic allergens.

The goal of the study is to evaluate the importance of maternal atopy as a potential biological source of variability of exhaled FeNO values in healthy children who were non-asthmatic and non-sensitized to common domestic allergens. The study sample consisted of 61 seven-year old children. Fractional exhaled nitric oxide (FeNO) has been measured by NObreath (Bedfont portable device). Children with reported maternal atopy had significantly higher mean FeNO values (geometric mean =10.7 ppb; 95%CI: 6.7-17.1 ppb) than those who denied it (geometric mean =5.2 ppb 95%CI: 3.9-6.9 ppb) (p=0.010). Neither the correlation between FeNO values and gender, respiratory and eczema symptoms, nor ETS exposure in the prenatal and postnatal period or body mass of children were significant. We also found no significant association of FeNO values with the amount of common domestic allergens measured in the households. The results of the ROC analysis suggested 11 ppb as the cut-off point for FeNO to distinguish groups of healthy children with and without maternal atopy. In conclusion, our study provided some evidence suggesting that maternal atopy may affect FeNO level in children independently of asthma and sensitization status to common domestic allergens. The data should be considered in the interpretation of FeNO levels in clinical practice and setting up FeNO screening criteria for identification of eosinophilic airway inflammation.

Utility of exhaled breath condensate pH for diagnosing occupational asthma.

INTRODUCTION: The current reference standard method for diagnosing occupational asthma (OA) is specific inhalation challenge (SIC) with the suspected agent. The alternative method is serial peak expiratory flow (PEF) monitoring. Nevertheless, PEF does not have optimal sensitivity and specificity for this purpose. The aim of this study was to evaluate the utility of exhaled breath condensate (EBC) pH for the diagnosis of OA. MATERIAL AND METHODS: A prospective study was performed in 37 subjects with suspected OA. Serial PEF monitoring was carried out for 2 weeks at work and for 2 weeks off work. At the end of each period, the EBC pH and the methacholine concentration resulting in a 20% FEV(1) decrease (PC20) were measured. SIC was subsequently performed. PEF graphs were interpreted visually by 3 experienced independent readers. RESULTS: Seventeen patients tested positive with SIC. Receiver-operating characteristic curves showed that a decrease in EBC pH greater than 0.4 units during the period at work compared to the off-work period achieved the most satisfactory sensitivity (40%, CI 19.4-66.5) and specificity (90%, CI 66.9-98.2) for diagnosing OA. When EBC pH findings were added to PEF results, the diagnostic yield of PEF generally increased. Other test combinations (e.g. EBC pH plus PC20 or EBC pH plus PC20 plus PEF) did not improve diagnostic performance. CONCLUSIONS: Acidification of EBC pH at work and adding the EBC pH measurement to PEF monitoring during periods at work and off work may be useful for improving the diagnosis of OA.

Asthma, atopy and exhaled nitric oxide in a cohort of 6-yr-old New Zealand children.

BACKGROUND: Exhaled nitric oxide has been promoted as a non-invasive measure of airway inflammation, with clinical utility for the diagnosis and management of asthma. AIM: We studied associations between exhaled nitric oxide, asthma and atopy in a variety of clinically relevant phenotypes in a cohort of 6-yr-old children. METHOD: Asthma was defined using standard questionnaire criteria, atopy was measured using skin prick tests (SPT) and specific IgE to common allergens, and exhaled nitric oxide was measured using a chemiluminescence analyser according to American and European Thoracic Society criteria. RESULTS: Exhaled nitric oxide was strongly related to atopy and in particular to sensitization to house dust mites. Children with non-allergic asthma had no increase in exhaled nitric oxide compared with non-asthmatic children. Compared with children who never wheezed both late onset and persistent, wheezing was associated with increased FE(NO), while early transient wheezing was not. Elevated levels of exhaled nitric oxide amongst children with allergic asthma were almost entirely explained by their levels of specific IgE to aeroallergens, predominantly D pteronyssinus. CONCLUSION: Airway inflammation as measured by exhaled nitric oxide in young New Zealand children is related to their level of specific IgE to aeroallergens. This has implications for the utility of nitric oxide as a diagnostic and management tool in childhood asthma and for the importance of specific IgE as a marker of asthma severity.

The increase in exhaled NO following allergen challenge is not associated with airway acidification.

BACKGROUND: Exhaled nitric oxide (NO), commonly accepted marker of airways inflammation, may be generated both by specific enzymes, NO synthases, as well as by nonenzymatic reduction in its metabolites. During asthma exacerbations, owing to lower airways pH, it has been reported that nitrite reduction may contribute to the increase in exhaled NO. Allergen exposure, an important cause of asthma exacerbations, is also known to increase exhaled NO. DESIGN: To investigate whether cat allergen exposure of cat-sensitized asthmatics leads to airway acidification, which could explain the expected increase in exhaled NO. Twelve nonsmoking, cat-sensitized patients (nine women) aged 33·5 (22-54) years with mild intermittent asthma performed a cat allergen challenge. Exhaled NO at 50-200 mL s(-1), nasal NO, exhaled breath condensate (EBC) pH, nitrite and nitrate were measured before, 8 and 24 h after allergen challenge. RESULTS: A significant increase in FE(NO 50) was observed 24 h after allergen challenge compared to baseline: 110 ppb (34, 143) vs. 60 ppb (19, 122), P = 0·006. This was mainly explained by an increase in bronchial NO flux (P = 0·02), while no changes in EBC pH were observed (P = 0·35). CONCLUSIONS: Allergen exposure is not associated with airways acidification, implying that the observed increase in exhaled NO is probably because of enzymatic NO production.

Effects of oral glucocorticoid therapy on CD4+CD25+CD127- and CD4+CD25high T cell levels in asthmatic patients.

Our purpose was to evaluate the effects of short-term oral glucocorticoid (GC) treatment on frequencies of T cells with putative regulatory phenotype (namely, CD4+CD25+CD127- and CD4+CD25high) in patients with asthma exacerbations. In addition, we sought to determine frequencies of above T cell subsets in adult asthmatic patients in relation to disease severity and different treatment regimens. The analysis was performed in 62 patients with different stages of asthma and ten healthy controls. Polychromatic flow cytometry was applied to delineate T cells with CD4+CD25+CD127- and CD4+CD25high phenotype. Exhaled nitric oxide analysis was used to assess allergic airway inflammation. Levels of neither CD4+CD25+CD127- nor CD4+CD25high T cells were significantly altered after 7-day oral GC treatment. Importantly, there were no detectable differences in frequencies of those cells among studied groups of asthmatics with different severity of disease and healthy controls. Moreover, levels of CD4+CD25+CD127- and CD4+CD25high T cells in asthmatic patients were not correlated to exhaled nitric oxide concentrations. Our data indicate that neither effects of average doses of oral GC treatment nor disease severity are related to changes in frequencies of CD4+CD25+CD127- and CD4+CD25high T cells in adult asthmatic patients.

Increased cytokines, chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children.

BACKGROUND: Airway inflammation in asthma is characterized by the production of cytokines, chemokines and soluble adhesion molecules. The assessment of these inflammatory biomarkers in exhaled breath condensate (EBC) is hampered by low detection rates. However, the use of a glass condenser system combined with a sensitive analytical technique may increase the possibility to assess these biomarkers in EBC in a reliable way. OBJECTIVE: (1) To assess the detection rates of cytokines (IL-1alpha, -1beta, -2, -4, -5, -6, -10, -12p70, -13, -18, IFN-gamma, TNF-alpha), chemokines [MIP1alpha (CCL3), MIF, eotaxin (CCL11), RANTES (CCL5), IP10 (CXCL10), IL8 (CXCL8), MCP1] and soluble adhesion molecules [soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM)] in EBC of children with asthma and healthy control children; (2) To study the differences in the biomarker concentration between children with asthma and controls. METHODS: Sixty children were included: 31 asthmatics (71% atopic) and 29 controls. Exhaled breath condensate was collected using a glass condenser system. The inflammatory markers (IM) were analysed using multiplex immunoassay technology. RESULTS: Detection percentages of cytokines, chemokines and adhesion molecules ranged from 94% to 100%, except for eotaxin (CCL11) and RANTES (CCL5) (detection rates of 10% and 45% in healthy controls, respectively). The intra-subject variability of biomarkers in EBC in the group as a whole ranged from 5.2% to 35.0%. In asthmatics, the levels of cytokines (IL-2, -4, -5, -6, -13, IFN-gamma), chemokines (MIP1alpha [CCL3], MIF, RANTES [CCL5], IP10 [CXCL10], IL8 [CXCL8], MCP1) and adhesion molecules (sICAM, sVCAM) were significantly increased in comparison with controls (P<0.05). CONCLUSION: If collected with a glass condenser and analysed by multiplex immunoassay technology, cytokines, chemokines and soluble adhesion molecules can be reliably demonstrated in EBC of children. Most of these IM were elevated in EBC of asthmatics compared with controls.

Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age 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 because of parental history were enrolled at birth and followed prospectively. FeNO was measured by an 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% (135/210) of 6-year-old and 93% (180/194) of 8-year-old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at ages 6 and 8 years had increased levels of FeNO compared with those not sensitized (geometric mean; 6 years, 10.9 vs 6.7 parts per billion [ppb], P < .0001; 8 years, 14.6 vs 7.1 ppb, P < .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 = .48; 8 years, 11.5 vs 9.2 ppb, P = .03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (P = .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.

Extended exhaled nitric oxide analysis in field surveys of schoolchildren: a pilot test.

Extended exhaled nitric oxide (eNO) analysis can distinguish proximal and distal airway contributions to FeNO. Thus, it has the potential to detect effects of different environmental influences, allergic phenotypes, and genetic variants on proximal and distal airways. However, its feasibility in field surveys has not been demonstrated, and models for estimating compartmental NO contributions have not been standardized. In this study we verified that extended NO tests can be performed by children in schools, and assessed different analytical models to estimate bronchial flux and alveolar NO concentration. We tested students at a middle school, using EcoMedics NO analyzers with ambient NO scrubbers, at flows of 50 (conventional), 30, 100, and 300 ml/sec, with 2-3 trials at each flow. Data from 65 children were analyzed by two linear and four nonlinear published models, plus a new empirical nonlinear model. Bronchial NO flux estimates from different models differed in magnitude but were strongly correlated (r >or= 0.95), and increased in subjects with allergic asthma. Alveolar concentration estimates differed among models and did not consistently show the same effects of allergy or asthma. A novel index of nonlinear behavior of NO output versus flow was significantly related to asthma status, and not strongly correlated with bronchial flux or alveolar concentration. Field-based extended NO testing of children can yield useful information about NO in different regions of the respiratory tract that is not obtainable from conventional FeNO. Extended NO analysis holds promise for investigating environmental and genetic determinants of regional airway inflammatory states.

Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma.

BACKGROUND: Assessment of the adverse effects of oxidative stress related to air pollution is limited by the lack of biological markers of dose to the lungs. OBJECTIVE: We evaluated the use of exhaled breath condensate (EBC) malondialdehyde as a biomarker of exposure to traffic-related pollution in children with asthma as part of a panel study in Mexico City. METHODS: Standard spirometry and collection of EBC and nasal lavage were performed. Environmental monitoring sites were located within 5 km of the children's homes and schools. Data were analyzed by using generalized estimating equations. RESULTS: A total of 480 samples of malondialdehyde were obtained from 107 patients with asthma, with a median level of 18.7 (interquartile range [IQR], 12.4-28.7) nmol. Ambient particulates less than 2.5 microg/m(3) and ozone levels on the day of sampling were significantly associated with higher malondialdehyde levels. A 14.2-microg/m(3) (IQR) increase in 8-hour moving average particulates less than 2.5 microg/m(3) in size was associated with a 1.12-nmol increase in malondialdehyde and a 15.9-ppb (IQR) increase in 8-hour moving average ozone with a 1.16-nmol increase in malondialdehyde. Malondialdehyde levels were inversely associated with forced vital capacity and FEV(1) and positively associated with IL-8 levels in nasal lavage. CONCLUSION: Exhaled breath condensate malondialdehyde was related to both air pollution exposure and changes in lung function and inflammatory markers.

Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide.

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.