Higher Fraction Of Exhaled Nitric Oxide Research Articles

Exhaled nitric oxide is only an asthma-relevant biomarker among children with allergic sensitization.

Fraction of exhaled nitric oxide (FeNO) is used for diagnosing and monitoring asthma in children, but the influence of allergic sensitization is still poorly understood. Here, we investigate how asthma and allergic sensitization influence FeNO levels during childhood. We investigated the associations between asthma, aeroallergen sensitization, and FeNO measured from age 5-18 years in the COPSAC2000 birth cohort of 411 children using repeated measurement mixed models adjusted for gestational age, sex, concurrent airway infection, inhaled corticosteroids, and tobacco exposure. Replication was sought in the similarly designed COPSAC2010 cohort of 700 children. In the COPSAC2000 cohort, 133 had asthma between age 5 and 18 years, and in the COPSAC2010 cohort, 112 had asthma between age 5 and 10 years. In the COPSAC2000 cohort, asthma and aeroallergen sensitization were both associated with higher FeNO from age 5 to 18 years: adjusted geometric mean ratio (aGMR), 1.22 (1.08-1.35), p < .01, and 1.41 (1.21-1.65), p < 0.001, respectively. However, asthma was associated with increased FeNO among children with aeroallergen sensitization: 1.44 (1.23-1.69), p < .0001, whereas asthma was associated with decreased FeNO among nonsensitized children: 0.80 (0.65-0.99), p = .05 (p-interaction<.0001 for asthma x sensitization). Replication in the COPSAC2010 cohort showed similar results (p-interaction <.01). Further, blood eosinophil count, total-IgE, bronchodilator response, and bronchial hyperreactivity were all associated with increased FeNO among children sensitized to aeroallergens, but not among nonsensitized children. Fraction of exhaled nitric oxide is elevated through childhood in children with asthma and is correlated with asthma-associated traits depending on the presence of aeroallergen sensitization. These findings indicate that FeNO is only a valid asthma biomarker in children with concurrent aeroallergen sensitization, which is important for guideline recommendations on the clinical use of FeNO.

Simultaneous evaluation of the fractional exhaled nitric oxide and blood eosinophil count of T2-high endotype in patients with non-cystic fibrosis bronchiectasis.

Recently, a type 2 inflammation (T2) high endotype in bronchiectasis was identified. The fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (BEC) are recognized as representative biomarkers of T2 inflammation. Herein, we investigate the clinical characteristics of T2-high endotype in non-cystic fibrosis bronchiectasis patients classified by FeNO and BEC. This retrospective study included 164 bronchiectasis patients treated in the First Affiliated Hospital of Sun Yat-sen University from December 2017 to July 2022. Clinical characteristics were analyzed after classifying patients into four groups according to T2 inflammation biomarkers (FeNO ≥25ppb; BEC ≥200/µL). Among the 164 bronchiectasis patients, 35.3% (58/164) presented with high FeNO, 30.5% (50/164) presented with high BEC, and 10.4% (17/164) had high FeNO and BEC. Patients with high FeNO and low BEC presented with better lung function, fewer affected lobes, and lower dyspnea prevalence compared with the three other groups. Moreover, decreased FeNO, instead of decreased BEC, is revealed to be an independent predictor for disease severity and airflow obstruction in bronchiectasis. Simultaneous evaluation of FeNO and BEC proposed different endotypes of bronchiectasis established that patients with low BEC and high FeNO had better lung function, fewer affected lobes, lower dyspnea prevalence, and less disease severity. This result will contribute to a more comprehensive assessment of the disease severity and lead to more precise treatment of T2 inflammation in bronchiectasis patients.

Possible presence of undiagnosed asthma in children in Japan.

Asthma diagnosis in children is occasionally challenging, and the issue of undiagnosed asthma before adolescence has been poorly studied in Japan. The present study was conducted to investigate the possible presence of undiagnosed asthma in the general population of children living in a rural area of Japan. The participants comprised 120 fourth graders aged 9-10 years (boys/girls: 63/57) attending five elementary schools in Yawatahama, Ehime, Japan. All the children underwent respiratory function tests and fraction of exhaled nitric oxide (FeNO) measurements. Based on the results of a questionnaire, the children were also categorized into groups depending on their allergic diseases.The authors assessed the results of both the respiratory function tests and the FeNO measurements for children who were classified into the nonallergic group. A total of 76 (63%) children, who completed the tests appropriately, were included in the analysis. According to the report, among the 24 children in the nonallergic group, six (25%) showed abnormalities in respiratory tests. One had an abnormal % forced vital capacity (%FVC; <80%), three had abnormalities in both forced expiratory volume in 1 sec (FEV1)/FVC (<80%) and % maximal mid-expiratory flow (<65%), three had concave flow-volume curves, and one had a high FeNO measurement (41 ppb). A certain proportion of Japanese elementary school children, categorized as having no allergy, showed respiratory function test abnormalities. A follow-up study is needed to determine the prognosis and outcomes of the children with these abnormalities.

Fraction of Exhaled Nitric Oxide Levels Are Elevated in People Living With Human Immunodeficiency Virus Compared to Uninfected Controls, Suggesting Increased Eosinophilic Airway Inflammation.

Increased risk of asthma and chronic obstructive pulmonary disease has been reported in people living with human immunodeficiency virus (PLWH). Fraction of exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation. We assessed FeNO levels in PLWH and matched uninfected controls and investigated whether human immunodeficiency virus (HIV) status is independently associated with elevated FeNO. FeNO was quantified by NIOX Vero and pulmonary function was assessed by spirometry in 432 PLWH from the Copenhagen Comorbidity in HIV Infection Study and in 1618 age- and sex-matched uninfected controls from the Copenhagen General Population Study. Elevated FeNO was defined as ≥25 parts per billion. Associations between FeNO and HIV status were adjusted for known potential confounders. Mean age of PLWH was 50.7 (standard deviation [SD], 11.1) years and 97.4% received combination antiretroviral therapy. PLWH had higher FeNO than uninfected controls (median, 17.0 [interquartile range {IQR}, 11.0-26.0] vs 13.0 [IQR, 9.0-19.0]; P < .001). Also, PLWH had a higher prevalence of elevated FeNO than uninfected controls (27.5% vs 12.3%; P < .001). This association remained after adjusting for age, sex, height, smoking status, use of airway medication, blood eosinophils, and immunoglobulin E (adjusted OR [aOR], 3.56 [95% CI, 2.51-5.04]; P < .001). Elevated FeNO was associated with self-reported asthma (aOR, 2.65 [95% CI, 1.66-4.24]; P < .001) but not with airflow limitation (aOR, 1.07 [95% CI, .71-1.62]; P = .745). HIV status was independently associated with elevated FeNO, suggesting increased eosinophilic airway inflammation. The potential impact on chronic lung disease pathogenesis needs further investigation.

The Role of FeNO in Predicting Asthma.

Asthma-like symptoms like wheezing and dyspnea affect 1 in every 3 preschool children. An easily available biomarker that predicts later asthma or unfavorable lung growth in these children may be helpful in targeting the right child with the right drugs and avoiding exposure to potentially harmful drugs in others. The fraction of exhaled nitric oxide (FeNO) has been suggested as a marker of eosinophilic inflammation. FeNO can be measured in a standardized way from the age of 4 but several methods have been developed to measure FeNO also in younger children. Several studies have assessed the predictive value of FeNO in preschool wheezing children for asthma later in life. These studies have shown that FeNO may be helpful in defining different preschool wheezing phenotypes, and in assessing the risk of later asthma or impaired lung growth. However, data are conflicting on the added value over clinical parameters. In two studies in school children, high FeNO was predictive for asthma development during follow up and also predicted lower lung function growth. In school children with respiratory symptoms suggestive of asthma, particularly in atopic children, FeNO has diagnostic value for an asthma diagnosis, mostly for ruling in asthma. There are not enough data to assess if FeNO has a predictive value for lung development in school children.

Association of upper and lower airway eosinophilic inflammation with response to omalizumab in patients with severe asthma

Background: The anti-immunoglobulin E monoclonal antibody, omalizumab, is used to treat severe asthma and has the potential to ameliorate airway inflammation. However, the effect of omalizumab in ameliorating upper airway inflammation has not been fully elucidated. Objective: We investigated the association of upper and lower airway inflammation with the response to omalizumab treatment. Methods: We used the Global Evaluation of Treatment Effectiveness to assess the efficacy of omalizumab in treating 16 patients with severe asthma. We also investigated the symptom score, short-acting β-agonist inhaler use, pulmonary function, biomarkers, computed tomography scans, and nasal mucosa pathology at omalizumab initiation and after four months of treatment. Results: When the fraction of exhaled nitric oxide (FeNO) and the percentage of sputum eosinophil were used as indicators of lower airway inflammation, positive correlations were found between CD20 B-cell, mast cell, and eosinophil counts in the nasal mucosa. Improved asthma symptoms were observed in 12 of the 16 severe asthma cases. The FeNO and eosinophil levels in the nasal tissue, prior to the administration of omalizumab were predictors of the response to asthma treatment. Conclusions: These findings suggest heterogeneity among people with severe asthma. In addition, the phenotype associated with response to omalizumab, leading to improvement in asthma symptoms, comprises upper airway eosinophilia and high FeNO levels.

IgE sensitization to food allergens and airborne allergens in relation to biomarkers of type 2 inflammation in asthma.

We have recently reported that sensitization to food allergens and sensitization to airborne allergens had independent associations with increased fraction of exhaled nitric oxide (FeNO) and blood eosinophils in middle-aged adults and in young subjects with asthma. To investigate the relation between IgE sensitization and several type 2 inflammation biomarkers in adult asthmatics. FeNO, urinary eosinophil-derived neurotoxin (U-EDN), serum eosinophil cationic protein (S-ECP) and periostin were measured in 396 asthmatics, aged 17-76years, from the Swedish GA2LEN study. Sensitization to airborne allergens was examined with skin prick tests (≥3mm wheal) and sensitization to food allergens with measurement of specific IgE (≥0.35kU/L). Asthmatics sensitized to food allergens had higher FeNO, 22.3ppb (18.6, 26.7) vs 16.1ppb (14.2, 18.2) (P=.005), S-ECP, 17.7mg/L (14.8, 21.1) vs 12.8mg/L (10.9, 14.9) (P=.01), and periostin, 73.7 (67.5, 80.3) ng/mL vs 59.9 (55.8, 64.2) ng/mL (P=.003), than non-sensitized subjects. Periostin levels in this group were also significantly higher than in the group sensitized only to airborne allergens (P=.01). Sensitization to food allergens related independently to FeNO (P=.02), S-ECP (P=.006) and periostin (P=.004), whereas sensitization only to airborne allergens related only to FeNO (P=.02) after adjustments for age, sex, height, weight and smoking history. FeNO correlated weakly with S-ECP (r=.17, P<.001), periostin (r=.19, P<.001) and U-EDN (0.16, P<.001). S-ECP also correlated weakly with U-EDN (r=.12, P=.02). None of the correlations between the remaining pairs of markers of type 2 inflammation were significant. Sensitization to food allergens related to several local and systemic type 2 inflammation markers, such as FeNO, S-ECP and periostin. Assessing the profile of allergic sensitization, including to food allergens, might improve the understanding and interpretation of inflammatory markers and potentially improve asthma management.

Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy

BackgroundWhether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. ObjectiveTo explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. MethodsIn this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (≥30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (≤20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. ResultsThe 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). ConclusionThese results suggest that prior investigation may not predict response to anti-inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. Trial RegistrationClinicalTrials.gov Identifier: NCT02479074.

Arginine metabolic endotypes related to asthma severity.

AimsArginine metabolism via inducible nitric oxide synthase (iNOS) and arginase 2 (ARG2) is higher in asthmatics than in healthy individuals. We hypothesized that a sub-phenotype of asthma might be defined by the magnitude of arginine metabolism categorized on the basis of high and low fraction of exhaled nitric oxide (FENO).MethodsTo test this hypothesis, asthmatics (n = 52) were compared to healthy controls (n = 51) for levels of FENO, serum arginase activity, and airway epithelial expression of iNOS and ARG2 proteins, in relation to clinical parameters of asthma inflammation and airway reactivity. In parallel, bronchial epithelial cells were evaluated for metabolic effects of iNOS and ARG2 expression in vitro.ResultsAsthmatics with high FENO (≥ 35 ppb; 44% of asthmatics) had higher expression of iNOS (P = 0.04) and ARG2 (P = 0.05) in the airway, indicating FENO is a marker of the high arginine metabolic endotype. High FENO asthmatics had the lowest FEV1% (P < 0.001), FEV1/FVC (P = 0.0002) and PC20 (P < 0.001) as compared to low FENO asthmatics or healthy controls. Low FENO asthmatics had near normal iNOS and ARG2 expression (both P > 0.05), and significantly higher PC20 (P < 0.001) as compared to high FENO asthmatics. In vitro studies to evaluate metabolic effects showed that iNOS overexpression and iNOS+ARG2 co-expression in a human bronchial epithelial cell line led to greater reliance on glycolysis with higher rate of pyruvate going to lactate.ConclusionsThe high FENO phenotype represents a large portion of the asthma population, and is typified by greater arginine metabolism and more severe and reactive asthma.

Can exhaled nitric oxide differentiate causes of pulmonary fibrosis?

Interstitial lung diseases (ILD) comprise a heterogeneous group of disorders, and when diagnosed at the stage of pulmonary fibrosis, the underlying lung disease can sometimes be difficult to identify. The aim of the present study was to determine whether there are differences in FENO (fraction of exhaled nitric oxide) between different subtypes of fibrotic ILD. Sixty-one patients, with honeycombing on computed tomography (CT) scan, and whose FENO levels had been measured during chronic dyspnoea evaluation, were divided into four groups based on pulmonary fibrosis aetiology: idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), connective tissue disease-associated ILD disorders (CTD-ILD), drug-induced pneumonia. The FENO values of each group were compared and CT scan features were analysed to identify the mechanisms involved in FENO change. The median FENO value of patients with chronic HP was 51ppb (IQR 36-74), higher than that of the other groups (22ppb (IQR 17-30) in IPF, 19ppb (IQR 17-21) in drug-induced pneumonia, and 25ppb (IQR 17-37) for CTD-ILD; p=0.008). At the cut-off value of 41ppb, the optimal sensitivity and specificity to diagnose HP with FENO were respectively 76.9% and 85.4%. On CT scans, only extensive lobular areas with decreased attenuation, a recognized marker of bronchiolar disease, were associated with high FENO values (p=0.0002). FENO could be a tool for differentiating chronic HP from other types of pulmonary fibrosis. The mechanism involved seems to be bronchiolar disease.

Longitudinal Relationship between Sputum Eosinophils and Exhaled Nitric Oxide in Children with Asthma

Longitudinal Relationship between Sputum Eosinophils and Exhaled Nitric Oxide in Children with Asthma

Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma

Prediction of asthma in young children with respiratory symptoms is hampered by the lack of objective measures applicable in clinical routine. In this prospective study in a preschool children cohort, we assessed whether the fraction of exhaled nitric oxide (FeNO), a biomarker of airway inflammation, is associated with asthma at school age. At baseline, IgE and eosinophils were measured in the blood, and FeNO was measured offline in 391 children aged 3-47 months with lower airway symptoms. We developed an asthma predictive index (API) including high FeNO as major criterion. At follow-up, primary outcome was physician-diagnosed asthma based on standardized interviews in those children reaching school age (n = 166). FeNO was significantly elevated in those children with later asthma (68/166) as compared to children not developing asthma. Median (IQR) FeNO was 10.5 (6.6-17.2) vs. 7.4 (5.3-10.3) ppb. Per 5 ppb FeNO increase, the odds ratio (95% CI) for asthma increased by 2.44 (1.61-3.70) without changing when adjusting for confounders. Using the new API, children scored at risk had 58.0% probability for later asthma, whereas the negative predictive value was 78.2%, which was comparable to the classical API. In this cohort of high-risk preschool children, elevated FeNO is associated with increased risk for school-age asthma. The new API including FeNO identifies children at risk of later asthma comparably to the classical API, but does not require blood sampling.

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics

The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Subjects in a Population Study with High Levels of FENO Have Associated Eosinophil Airway Inflammation.

Background. Measurement of fraction of exhaled nitric oxide (FENO) is a promising tool to increase validity in epidemiological studies of asthma. The association between airway inflammation and FENO has, however, only been examined in clinical settings and may be biased by selection of patients with asthma. Methods. In a population study with FENO registrations on 370 individuals, we identified nine subjects out of thirty subjects with high levels of FENO (>85th percentile, 30.3 ppb), irrespective of presence of respiratory symptoms, and 21 control subjects with FENO at median levels (11.1–16.4 ppb) willing to undergo bronchoscopy and bronchoalveolar lavage (BAL), all nonsmokers. FENO was measured in accordance with ATS criteria, and the examination also included spirometry, methacholine challenge test, and sampling of exhaled breath condensate (EBC). Results. Subjects with high FENO levels had significantly higher median the percentage of eosinophils in BAL than controls (2.1 versus 0.6, P < .006), and there was a significant association between FENO and the percentage of eosinophils in BAL (ρ=0.6, P < .002) and ECP in BAL (ρ=0.65, P < .05) examining the whole group, but no association with gender, FEV1, or degree of metacholine sensitivity or any of the biomarkers in EBC. All subjects with high FENO had respiratory symptoms, but only three had diagnosed asthma. There were a significant association between hydrogen peroxide in EBC and the percentage of neutrophils in bronchial wash. Conclusion. High FENO levels signal asthmatic or allergic respiratory disease in a population-based study. FENO levels are associated with degree of eosinophil airway inflammation as measured by the percentage of eosinophils and ECP in BAL.

Is it necessary to treat all asthmatic children with raised levels of exhaled nitric oxide? Treating the patient or the data

Background The aim of the present study is to assess whether a single determination of the fraction of exhaled nitric oxide (FENO), added to the measurements usually taken during a routine checkup, helps in the prediction of the recurrence of asthma attacks in controlled patients who are not receiving any baseline treatment; and whether or not treatment of the said latent inflammation is appropriate. Methods Observational study of prospective cohorts. Over a period of three months, data was collected from 28 patients (6 to 14 years) who met the conditions of the inclusion criteria, with a follow up appointment after six months. Results Patients were divided into two groups: 13 with FENO values of 49 and over, and 15 with values of under 49. Five patients in the subgroup with low FENO values suffered recurrence, in contrast to only one in the group with high values. The positive predictive value of the high values of the FENO was 7.69, with no significant differences between the two groups. Conclusions Certain doubts were raised about the usefulness of the FENO, as opposed to the traditional methods of asthma control with regard to the therapeutic management of clinically controlled patients who are not receiving treatment and who have high FENO values. It would appear unwise to recommend the systematic treatment of patients with high FENO values, when measured during a routine check-up, in cases of asthma with an allergic component and are asymptomatic or in a phase of asthma under good control.

Symptom-pattern phenotype and pulmonary function in preschool wheezers

Pulmonary function in preschool wheezing phenotypes based on wheeze onset and duration and atopic status has been extensively described but has not been studied in symptom-pattern phenotypes of episodic (viral) and multiple-trigger wheeze. We investigated whether multiple-trigger wheezers were more likely to have abnormal pulmonary function and increased fraction of exhaled nitric oxide (FeNO) than episodic (viral) wheezers and whether multiple-breath wash-out was more sensitive at detecting abnormal pulmonary function than specific airways resistance (sR(aw)) in preschool wheezers. FeNO, multiple-breath wash-out indices (lung clearance index [LCI] and conductive airways ventilation inhomogeneity [S(cond)]) and sR(aw) were measured in healthy children and those with recurrent wheeze aged 4 to 6 years. Subgroup analysis was performed according to current symptom-pattern (multiple-trigger vs episodic [viral]), atopic status (atopic vs nonatopic), and wheeze status (currently symptomatic vs asymptomatic). Seventy-two control subjects and 62 wheezers were tested. Multiple-trigger wheezers were associated with an average increase of 11% (95% CI, 7% to 18%; P < .001) in LCI, 211% (95% CI, 70% to 470%; P < .001) in S(cond), and 15% (95% CI, 3% to 28%; P = .01) in sR(aw) compared with episodic (viral) wheezers. Pulmonary function in episodic (viral) wheezers did not differ significantly from control subjects. The presence of current atopy or wheeze was associated with higher FeNO (P = .05) but did not influence pulmonary function significantly. On average, LCI was abnormal in 39% (95% CI, 32% to 45%), S(cond) was abnormal in 68% (95% CI, 61% to 74%), and sR(aw) was abnormal in 26% (95% CI, 16% to 35%) of multiple-trigger wheezers. Multiple-trigger wheeze is associated with pulmonary function abnormalities independent of atopic and current wheeze status. S(cond) is the most sensitive indicator of abnormal pulmonary function in preschool wheezers.

Parental Smoking Increases Exhaled Nitric Oxide in Children

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