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1.  Storage conditions for stability of offline measurement of fractional exhaled nitric oxide after collection for epidemiologic research 
The measurement of fractional concentration of nitric oxide in exhaled air (FeNO) is valuable for the assessment of airway inflammation. Offline measurement of FeNO has been used in some epidemiologic studies. However, the time course of the changes in FeNO after collection has not been fully clarified. In this study, the effects of storage conditions on the stability of FeNO measurement in exhaled air after collection for epidemiologic research were examined.
Exhaled air samples were collected from 48 healthy adults (mean age 43.4 ± 12.1 years) in Mylar bags. FeNO levels in the bags were measured immediately after collection. The bags were then stored at 4°C or room temperature to measure FeNO levels repeatedly for up to 168 hours.
In the bags stored at room temperature after collection, FeNO levels were stable for 9 hours, but increased starting at 24 hours. FeNO levels remained stable for a long time at 4°C, and they were 99.7% ± 7.7% and 101.3% ± 15.0% relative to the baseline values at 24 and 96 hours, respectively. When the samples were stored at 4°C, FeNO levels gradually decreased with time among the subjects with FeNO ≥ 51 ppb immediately after collection, although there were almost no changes among the other subjects. FeNO levels among current smokers increased even at 4°C, although the values among ex-smokers decreased gradually, and those among nonsmokers remained stable. The rate of increase was significantly higher among current smokers than among nonsmokers and ex-smokers from 9 hours after collection onwards.
Storage at 4°C could prolong the stability of FeNO levels after collection. This result suggests that valid measurements can be performed within several days if the samples are stored at 4°C. However, the time course of the changes in FeNO levels differed in relation to initial FeNO values and cigarette smoking.
PMCID: PMC3515473  PMID: 23116255
Cigarette smoking; Epidemiologic research; Exhaled nitric oxide; Offline measurement; Refrigeration; Storage conditions; Wheezing
2.  294 Reference Values and Influencing Factors of Exhaled Nitric Oxide in Healthy Korean Adults 
The World Allergy Organization Journal  2012;5(Suppl 2):S112-S113.
Fractional exhaled nitric oxide (FeNO) is widely used as an inflammatory marker for asthma. However, reference values and influencing factors of FeNO using Niox Mino, which is the only device achieving US FDA approval, are not well described in healthy Asian adults. This study aimed to suggest the reference values and influencing factors of FeNO in healthy Korean adults.
Subjects who were over 19 years old and did not have any history of rhinitis, asthma or recent respiratory symptoms were enrolled. FeNO levels were measured using Niox Mino. Age, gender, body mass index (BMI), smoking status and lung function were also measured to analyze factors associated with FeNO levels.
The mean value of FeNO was 16.14 ± 10.04 ppb. The reference value of FeNO, which was defined as the value of 95% in distribution curve, was same or less than 34 ppb. In a univariate analysis, FeNO levels were not associated with age, BMI and smoking history. However, atopy status (18.2 ± 11.8 for atopy and 15.1 ± 8.5 for nonatopy groups, P = 0.008) and gender (17.8 ± 10.2 for male and 14.8 ± 9.8 for female groups, P < 0.001) were positively associated with FeNO levels. In stratified analysis, the significance of both variables remained unchanged (P < 0.001).
Our data suggested that the reference value of FeNO in healthy Korean adults seemed to be same or less than 34 ppb. Reference values of FeNO in Korean adults are influenced by gender and atopy status.
PMCID: PMC3512963
3.  Effect of Mannitol Dry Powder Challenge on Exhaled Nitric Oxide in Children 
PLoS ONE  2013;8(1):e54521.
Fractional exhaled nitric oxide (FENO), a non-invasive marker of eosinophilic airway inflammation, is increasingly used for diagnostic and therapeutic decisions in adult and paediatric asthma. Standardized guidelines for the measurement of FENO recommend performing FENO measurements before rather than after bronchial provocation tests.
To investigate whether FENO levels decrease after a Mannitol dry powder (MDP) challenge in a clinical setting, and whether the extent of the decrease is influenced by number of MDP manoeuvres, baseline FENO, atopy and doctor diagnosed asthma.
Children aged 6–16 years, referred for possible reactive airway disease to a respiratory outpatient clinic, performed an MDP challenge (Aridol®, Pharmaxis, Australia). FENO was measured in doublets immediately before and after the challenge test using the portable NIOX MINO® device (Aerocrine, Stockholm, Sweden). We analysed the data using Kruskal-Wallis rank tests, Wilcoxon signed rank tests and multivariable linear regressions.
One hundred and seven children completed both tests (mean±SD age 11.5±2.8 years). Overall, median (interquartile range) FENO decreased slightly by −2.5 ppb (−7.0, −0.5), from 18.5 ppb (10.5, 45.5) before the MDP challenge to 16.5 ppb thereafter (8.5, 40.5; p<0.001). In all participants, the change in FENO was smaller than one standard deviation of the baseline mean. The % fall in FENO was smaller in children with less MDP manoeuvres (e.g. higher bronchial responsiveness; p = 0.08) but was not influenced by levels of baseline FENO (p = 0.68), atopy (p = 0.84) or doctor diagnosed asthma (p = 0.93).
MDP challenge test influences FENO values but differences are small and clinically barely relevant.
PMCID: PMC3548778  PMID: 23349918
4.  Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis 
Thorax  2005;60(1):22-26.
Background: It has been proposed that the pH of airway lining fluid may regulate the fractional exhaled concentration of nitric oxide (FENO) in respiratory disease.
Methods: FENO, exhaled breath condensate (EBC) pH, and EBC concentrations of nitrite plus nitrate (NO2/NO3) were compared in 12 subjects with stable asthma, 18 with stable cystic fibrosis (CF), and 15 healthy control subjects. Eight of the CF patients were studied on a separate occasion at the start of a pulmonary exacerbation.
Results: FENO was significantly greater in asthmatic subjects than in control subjects (mean 35 v 9 ppb, p<0.001). EBC pH, however, was similar in the asthmatic and control groups (median 5.82 v 6.08, p = 0.23). Levels of NO2/NO3 were on average higher in EBC samples from asthmatic subjects, but the difference was not significant. In patients with stable CF both the FENO (mean 4 ppb, p<0.001) and EBC pH (median 5.77, p = 0.003) were lower than in the control group. Levels of EBC NO2/NO3 (median 29.9 µM; p = 0.002) in patients with stable CF, in contrast, were significantly higher than in control subjects. During CF exacerbations, EBC pH was further reduced (median 5.30, p = 0.017) but FENO and NO2/NO3 were unchanged.
Conclusions: These findings demonstrate a dissociation between EBC pH and FENO in inflammatory airways disease.
PMCID: PMC1747154  PMID: 15618578
5.  Subjects in a Population Study with High Levels of FENO Have Associated Eosinophil Airway Inflammation 
ISRN Allergy  2011;2011:792613.
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.
PMCID: PMC4058119  PMID: 24977053
6.  AB 82. Specific nasal challenge induces late phase reactions in asthmatics sensitive to Alternaria 
Journal of Thoracic Disease  2012;4(Suppl 1):AB82.
Specific challenges provide a better understanding of the underlying inflammatory mechanisms in asthma. The aim of this study was to evaluate the immediate and late phase asthmatic response after specific nasal challenge (SNC) in asthmatic patients sensitive to Alternaria.
Patients and methods
The study population consisted of 15 adult patients with mild, allergic asthma sensitive to Alternaria and two control groups: (I) 8 patients with mild, allergic asthma non-attributed to Alternaria and (II) 7 healthy controls. Two nasal challenge tests were performed, one with normal saline (placebo) and another with Alternaria antigen (SNC) at two different days. FEV1, exhaled nitric oxide (FeNO) and nasal nitric oxide (nNO) were measured at 18 time points, during the 12-hour time period following nasal provocation tests.
No immediate reactions were recorded in terms of FEV1, FeNO and nNO both in patients and controls. Significant changes in FEV1 (decline >20% from baseline), in FeNO (increase >50% from baseline) and in nNO (increase >50% from baseline) were recorded in 10 patients (66.7%), in 12 (80%) and in 10 (66.7%) patients out of the 15 asthmatics sensitive to Alternaria respectively. In the above 15 patients the mean decline in FEV1 was 26.02±2.38%, the mean increase in FeNO was 113.69±24.07% and the mean increase in nNO was 91.53±19.90%. The lowest values of FEV1 were measured 9.30±1.77 hours after SNC, the highest values of FeNO were measured 10.00±1.53 hours and the highest values of nNO were measured 11.90±0.32 hours after SNC (P<0.001 compared to both control groups for all three parameters). Strong negative correlation between mean % changes in FEV1 and in FeNO for all 15 patients at the same time point was observed after SNC (R=-0.947, P<0.001).
SNC induces late phase asthmatic reactions in terms of airway obstruction and inflammation in asthmatics sensitive to Alternaria.
PMCID: PMC3537427
7.  Effect of bradykinin on allergen induced increase in exhaled nitric oxide in asthma 
Thorax  2003;58(10):840-845.
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.
PMCID: PMC1746484  PMID: 14514933
8.  Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide 
The Clinical Respiratory Journal  2008;2(3):141-148.
Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se– as verified with positive skin prick tests – affects FENO in healthy individuals.
The aim of this study was to examine the association between FENO and sensitization to common allergens in healthy nonsmoking adults with no signs or symptoms of airway disorders.
FENO measurements (flow rate: 50 mL/s), skin prick tests to common inhalant allergens, structured interviews, spirometry, bronchodilatation tests and bronchial histamine challenges were performed on a randomly selected population of 248 subjects. Seventy-three of them (29%) were nonsmoking asymptomatic adults with no history of asthma, persistent or recurrent upper or lower airway symptoms and no signs of airway disorders in the tests listed above.
FENO concentrations were similar in skin prick test positive (n = 32) and negative (n = 41) healthy subjects, with median values of 13.2 and 15.5 ppb, respectively (P = 0.304). No correlation appeared between FENO and the number of positive reactions (r = −0.138; P = 0.244), or the total sum of wheal diameters (r = −0.135; P = 0.254). The nonparametric one-tailed 95% upper limits of FENO among skin prick positive and negative healthy nonsmoking subjects were 29 and 31 ppb, respectively.
Atopic constitution defined as positive skin prick test results does not increase FENO in healthy nonsmoking adults with no signs or symptoms of airway disorders. This suggests that same reference ranges for FENO can be applied to both skin prick test positive and negative subjects.
Please cite this paper as: Rouhos A, Kainu A, Karjalainen J, Lindqvist A, Piirilä P, Sarna S, Haahtela T and Sovijärvi ARA. Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide. The Clinical Respiratory Journal 2008; 2: 141–148.
PMCID: PMC3272347  PMID: 20298322
airway inflammation; atopy; exhaled nitric oxide; healthy adults; skin prick tests
9.  Fractional exhaled nitric oxide (FeNo) in different asthma phenotypes 
Allergy & Rhinology  2014;5(3):e157-e161.
Fractioned exhaled nitric oxide (FeNO) is a noninvasive marker of inflammation in asthmatic patients. FeNO can be used to monitor airway inflammation, but individual responses make tailored interventions based on FeNO difficult. The correlation between the asthma control test (ACT), FEV1, and FeNO was evaluated in this study to ascertain the correct usage of FeNO with different asthma phenotypes regarding their control, allergy, comorbidity, obesity, age, smoking status, and severity. ACT, pulmonary function, and FeNO in 416 asthmatic patients on combined therapy were retrospective evaluated. Correlations between these parameters and the FeNO levels in different asthma phenotypes were calculated. In the study population, FeNO was 31.8 ± 28.5 parts per billion (ppb), FEV1 was 83.4 ± 19% and ACT was 19 ± 5.2. ACT scores were negatively correlated with FeNO (r = −0.31; p = 0.002). FeNO was different in patients with positive and negative skin-prick test (p < 0.05), with and without allergic rhinitis (p < 0.01), and with and without allergic conjunctivitis (p < 0.01). Significantly higher FeNO levels were found with logistic regression analysis only in patients with a history of emergency room visits (ERVs) (p = 0.024). The rate of the ERV of the patients with an ACT score more than or equal to 20 and with a FeNO value of more than 35 ppb was 22.9%, but with a FeNO value of less than 35 ppb was 6.5% (p = 0.004). Allergy and allergic comorbidities may lead to an increase in FeNO levels. Patients with a history of ERV have markedly higher FeNO levels, although they have an ACT score more than or equal to 20.
PMCID: PMC4275462  PMID: 25565052
Airway markers; allergic rhinitis; asthma; asthma control; asthma control test; emergency room visit; fractional exhaled nitric oxide; noninvasive monitoring; pulmonary function; reflux.
10.  Reference Ranges and Determinant Factors for Exhaled Nitric Oxide in a Healthy Korean Elderly Population 
Exhaled nitric oxide (NO) is a useful non-invasive biomarker for asthma diagnosis; however, the literature suggests that exhaled NO levels may be affected by demographic factors. The present analysis investigated determinant factors that present exhaled NO reference levels for Korean elderly adults.
For reference levels, we analyzed the baseline data of healthy adult participants in the Ansung cohort. The fraction of exhaled NO (FeNO) was measured by NIOX MINO®. The characterization of the subjects was performed through structured questionnaires, spirometry, and methacholine challenge tests. To validate the diagnostic utility of the determined reference levels, asthma patients were recruited from medical institutions for FeNO measurement.
A total of 570 healthy subjects were analyzed (mean age, 59.9±12.3; male, 37.0%) for reference levels. FeNO levels significantly correlated with weight, height, body mass index, atopy, or forced expiratory volume in 1 second % predicted by simple linear regression analysis. Multiple linear regression analysis identified gender as an independent determinant for FeNO levels; subsequently, the reference values for FeNO were 18.2±10.6 ppb (5th to 95th percentile, 6.0 to 37.4 ppb) for males and 12.1±6.9 ppb (5th to 95th percentile, 2.5 to 27.0 ppb) for females. The diagnostic utility of FeNO reference levels was validated by receiver operating curve analysis (area under curve, 0.900 for males and 0.885 for females) for diagnosing asthma. The optimal cutoff values for the prediction of asthma were 30.5 ppb for males and 20.5 ppb for females.
The current analysis presented reference ranges and the diagnostic utility of FeNO levels for asthma in Korean elderly adults.
PMCID: PMC4214970  PMID: 25374749
Adult; asthma; nitric oxide; reference values
11.  Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children 
Thorax  2003;58(12):1048-1052.
Background: Exhaled nitric oxide (FENO) is raised in asthmatic children, but there are inconsistencies in the relationship between FENO and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FENO and asthma, atopy, and increased AR in children.
Methods: One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FENO measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire.
Results: In multiple linear regression analyses FENO was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FENO and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms.
Conclusion: Raised FENO seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
PMCID: PMC1746531  PMID: 14645971
12.  Diesel exhaust but not ozone increases fraction of exhaled nitric oxide in a randomized controlled experimental exposure study of healthy human subjects 
Environmental Health  2013;12:36.
Fraction of exhaled nitric oxide (FENO) is a promising non-invasive index of airway inflammation that may be used to assess respiratory effects of air pollution. We evaluated FENO as a measure of airway inflammation after controlled exposure to diesel exhaust or ozone.
Healthy volunteers were exposed to either diesel exhaust (particle concentration 300 μg/m3) and filtered air for one hour, or ozone (300 ppb) and filtered air for 75 minutes. FENO was measured in duplicate at expiratory flow rates of 10, 50, 100 and 270 mL/s before, 6 and 24 hours after each exposure.
Exposure to diesel exhaust increased FENO at 6 hours compared with air at expiratory flow rates of 10 mL/s (p = 0.01) and at 50 mL/s (p = 0.011), but FENO did not differ significantly at higher flow rates. Increases in FENO following diesel exhaust were attenuated at 24 hours. Ozone did not affect FENO at any flow rate or time point.
Exposure to diesel exhaust, but not ozone, increased FENO concentrations in healthy subjects. Differences in the induction of airway inflammation may explain divergent responses to diesel exhaust and ozone, with implications for the use of FENO as an index of exposure to air pollution.
PMCID: PMC3639134  PMID: 23602059
Air pollution; Particulate matter pollution; Airway inflammation
13.  Seasonal Variation and Environmental Predictors of Exhaled Nitric Oxide in Children with Asthma 
Pediatric pulmonology  2008;43(6):576-583.
The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, shows promise as a noninvasive tool to guide asthma management, but there is a paucity of longitudinal data about seasonal variation and environmental predictors of FeNO in children. The objective of this project was to evaluate how environmental factors affect FeNO concentrations over a 12-month study period among children with doctor diagnosed asthma. We conducted a prospective cohort study of 225 tobacco-smoke exposed children age 6 to 12 years with doctor-diagnosed asthma including measures of FeNO, medication use, settled indoor allergens (dust mite, cat, dog, and cockroach), and tobacco smoke exposure. Baseline geometric mean FeNO was 12.4 ppb (range 1.9 to 60.9 ppb). In multivariable analyses, higher baseline FeNO levels, atopy, and fall season were associated with increased FeNO levels, measured 6 and 12 months after study initiation, whereas inhaled steroid use, summer season, and increasing nicotine exposure were associated with lower FeNO levels. In secondary analyses of allergen sensitization, only sensitization to dust mite and cat were associated with increased FeNO levels. Our data demonstrate that FeNO levels over a year long period reflected baseline FeNO levels, allergen sensitization, season, and inhaled steroid use in children with asthma. These results indicate that FeNO levels are responsive to common environmental triggers as well as therapy for asthma in children. Clinicians and researchers may need to consider an individual’s baseline FeNO levels to manage children with asthma.
PMCID: PMC3483596  PMID: 18429012
allergen; sensitization; tobacco smoke; inhaled corticosteroid
14.  Fractional exhaled nitric oxide and forced expiratory flow between 25% and 75% of vital capacity in children with controlled asthma 
Korean Journal of Pediatrics  2012;55(9):330-336.
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.
PMCID: PMC3454575  PMID: 23049590
Nitric oxide; Spirometry; Inhaled corticosteroids; Asthma; Child
15.  Impaired Pulmonary Nitric Oxide Bioavailability in Pulmonary Tuberculosis: Association With Disease Severity and Delayed Mycobacterial Clearance With Treatment 
The Journal of Infectious Diseases  2013;208(4):616-626.
Background. Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months.
Methods. In Papua, we measured FENO in patients with pulmonary tuberculosis at baseline and serially over 6 months and once in healthy controls. Treatment outcomes were conversion of sputum culture results at 2 months and time to conversion of sputum microscopy results.
Results. Among 200 patients with pulmonary tuberculosis and 88 controls, FENO was lower for patients with pulmonary tuberculosis at diagnosis (geometric mean FENO, 12.7 parts per billion [ppb]; 95% confidence interval [CI], 11.6–13.8) than for controls (geometric mean FENO, 16.6 ppb; 95% CI, 14.2–19.5; P = .002), fell further after treatment initiation (nadir at 1 week), and then recovered by 6 months (P = .03). Lower FENO was associated with more-severe tuberculosis disease, with FENO directly proportional to weight (P < .001) and forced vital-capacity (P = .001) and inversely proportional to radiological score (P = .03). People whose FENO increased or remained unchanged by 2 months were 2.7-fold more likely to achieve conversion of sputum culture than those whose FENO decreased (odds ratio, 2.72; 95% CI, 1.05–7.12; P = .04).
Conclusions. Among patients with pulmonary tuberculosis, impaired pulmonary NO bioavailability is associated with more-severe disease and delayed mycobacterial clearance. Measures to increase pulmonary NO warrant investigation as adjunctive tuberculosis treatments.
PMCID: PMC3719909  PMID: 23737604
tuberculosis; exhaled nitric oxide; L-arginine; M2 macrophages; biomarker
16.  Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitric oxide formation 
Thorax  2005;60(3):219-225.
Background: Raised concentrations of nitrate and nitrite have been found in exhaled breath condensate (EBC) in airway disease, and it has been postulated that this reflects increased nitric oxide (NO) metabolism. However, the chemical and anatomical origin of nitrate and nitrite in the airways has not yet been sufficiently studied.
Methods: The fraction of exhaled NO at an exhalation flow rate of 50 ml/s (FENO) and nitrite and nitrate in EBC, nasal condensate, and saliva were measured in 17 tracheostomised and 15 non-tracheostomised subjects, all of whom were non-smokers without respiratory disease. Tracheal and oral samples were taken from the tracheostomised subjects and nasal (during velum closure) and oral samples from the non-tracheostomised subjects. Measurements were performed before and after sodium nitrate ingestion (10 mg/kg) and use of antibacterial mouthwash (chlorhexidine 0.2%).
Results: In tracheostomised subjects oral FENO increased by 90% (p<0.01) while tracheal FENO was not affected 60 minutes after nitrate ingestion. Oral EBC nitrite levels were increased 23-fold at 60 minutes (p<0.001) whereas the nitrite levels in tracheal EBC showed only a minor increase (fourfold, p<0.05). Nitrate was increased the same amount in oral and tracheal EBC at 60 minutes (2.5-fold, p<0.05). In non-tracheostomised subjects oral FENO and EBC nitrite increased after nitrate ingestion and after chlorhexidine mouthwash they approached baseline levels again (p<0.001). Nasal NO, nitrate, and nitrite were not affected by nitrate intake or mouthwash. At baseline, mouthwash with deionised water did not affect nitrite in oral EBC or saliva, whereas significant reductions were seen after antibacterial mouthwash (p<0.05 and p<0.001, respectively).
Conclusions: Besides the salivary glands, plasma nitrate is taken up by the lower airways but not the nasal airways. Nitrate levels in EBC are thus influenced by dietary intake. Nitrate is reduced to nitrite by bacterial activity which takes place primarily in the oropharyngeal tract of healthy subjects. Only oropharyngeal nitrite seems to contribute to exhaled NO in non-inflamed airways, and there is also a substantial contribution of nitrite from the oropharyngeal tract during standard collection of EBC.
PMCID: PMC1747344  PMID: 15741439
17.  Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma 
Thorax  2003;58(6):494-499.
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.
PMCID: PMC1746693  PMID: 12775859
18.  Allergen exposure modifies the relation of sensitization to FENO levels in children at risk for allergy and asthma 
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.
PMCID: PMC3137133  PMID: 21463890
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
19.  Exhaled nitric oxide and urinary EPX levels in infants: a pilot study 
Objective markers of early airway inflammation in infants are not established but are of great interest in a scientific setting. Exhaled nitric oxide (FeNO) and urinary eosinophilic protein X (uEPX) are a two such interesting markers.
To investigate the feasibility of measuring FeNO and uEPX in infants and their mothers and to determine if any relations between these two variables and environmental factors can be seen in a small sample size. This was conducted as a pilot study for the ongoing Swedish Environmental Longitudinal Mother and child Asthma and allergy study (SELMA).
Consecutive infants between two and six months old and their mothers at children's health care centres were invited, and 110 mother-infant pairs participated. FeNO and uEPX were analysed in both mothers and infants. FeNO was analyzed in the mothers online by the use of the handheld Niox Mino device and in the infants offline from exhaled air sampled during tidal breathing. A 33-question multiple-choice questionnaire that dealt with symptoms of allergic disease, heredity, and housing characteristics was used.
FeNO levels were reduced in infants with a history of upper respiratory symptoms during the previous two weeks (p < 0.002). There was a trend towards higher FeNO levels in infants with windowpane condensation in the home (p < 0.05). There was no association between uEPX in the infants and the other studied variables.
The use of uEPX as a marker of early inflammation was not supported. FeNO levels in infants were associated to windowpane condensation. Measuring FeNO by the present method may be an interesting way of evaluating early airway inflammation. In a major population study, however, the method is difficult to use, for practical reasons.
PMCID: PMC3117812  PMID: 21575173
Nitric Oxide; Eosinophil Granule Proteins; Infant; Housing; Allergy and Immunology
20.  Evaluation of exhaled nitric oxide in acute paraquat poisoning: A pilot study 
Fractional exhaled nitric oxide (FENO) is nitric oxide (NO) in the lower airway measured by oral exhalation. FENO can be a useful non-invasive marker for asthma. Paraquat-mediated lung injury can be reflective of an ROS-induced lung injury. We aimed to verify if FENO is a clinical parameter of ROS formation and responsiveness to medical therapies in acute paraquat intoxication.
We recruited 12 patients admitted with acute paraquat poisoning. A portable and noninvasive device called NIOX MINO™ (Aerocrine AB, Solna, Sweden) was used to measure FENO. Measurements were made at the time of hospital admission and at 24, 48, 72, 96, and 120 h after paraquat ingestion.
Six out of the total 12 recruited patients had general conditions (e.g. oral pain) that made it difficult for them to exhale with adequate force. Mean plasma paraquat level was 1.4±2.5 μg/mL. We found no direct correlation between the paraquat levels (both ingestion amount and plasma concentration) and FENO (initial, maximal, and minimal values). All the measured FENO values were no greater than 20 ppb for the 2 patients who died. FENO did not vary more than 20% from the baseline. Compared to the above findings, FENO measurements were found to be greater than 20 ppb for the patients who survived. FENO tends to reach its peak value at between 50 h and 80 h.
FENO did not predict mortality, and there was no increase of FENO in patients with severe paraquat intoxication.
PMCID: PMC3914929  PMID: 24487780
Oxidative Stress; Nitric Oxide; Paraquat - adverse effects; Paraquat - toxicity; Asthma - diagnosis
21.  Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis 
Fractional exhaled nitric oxide (FeNO), a well-known marker of airway inflammation, is rarely evaluated in rhinitis of different etiology. We aimed to compare the eNO levels in allergic rhinitis (AR) and nonallergic rhinitis (NAR) with/without asthma, as well as the contributing factors that interfere with elevated FeNO.
Patients were enrolled based on chronic nasal symptoms. Orally exhaled NO was measured with the single exhalation method at 50 mL/s. All subjects underwent a panel of tests: skin-prick tests, asthma control test, blood sampling, spirometry, and health-related quality-of-life questionnaires.
The study group consisted of mainly women (130 women/41 men), with a mean age of 32.6 ± 13.2 years. AR was diagnosed in 122 (78.2%), NAR in 34 (21.8%), and 15 subjects were healthy controls. FeNO was insignificantly higher in patients with AR compared with patients with NAR and controls (32.2 parts per billion [ppb] versus 27 and 19.4 ppb), with no difference between genders. NAR + asthma had higher FeNO than those without asthma (40.5 ppb versus 14.9 ppb; p < 0.03), whereas accompanying asthma did not affect FeNO levels in the AR group. AR ± asthma had significantly higher FeNO levels than the NAR-only group (p < 0.01). Among AR + asthma, perennial sensitization caused higher FeNO levels than did seasonal allergens (48.5 ± 33.9 and 19.5 ± 13.6′ p = 0.003), whereas FeNO was significantly higher during the allergen season. Nasally inhaled corticosteroids insignificantly reduced FeNO levels in all groups. Severity and seasonality of rhinitis, asthma, and ocular symptoms, but not gender, age, body mass index, Total IgE, forced expiratory volume in 1 second, and smoking, were associated with FeNO.
Rhinitis and comorbid asthma are responsible for increased FeNO, irrespective of atopy. However, NAR without asthma may not be considered as a strong risk factor for airway inflammation.
PMCID: PMC3906508  PMID: 22487277
Airway inflammation; allergic rhinitis; asthma; atopy; exhaled nitric oxide; inhaled corticosteroids; nonallergic rhinitis
22.  The value of FeNO measurement in childhood asthma: uncertainties and perspectives 
Asthma is considered an heterogeneous disease, requiring multiple biomarkers for diagnosis and management. Fractional exhaled nitric oxide in exhaled breath (FeNO) was the first useful non-invasive marker of airway inflammation in asthma and still is the most widely used. The non-invasive nature and the relatively easy use of FeNO technique make it an interesting tool to monitor airway inflammation and rationalize corticosteroid therapy in asthmatic patients, together with the traditional clinical tools (history, physical examination and lung function tests), even if some controversies have been published regarding the use of FeNO to support the management of asthma in children. The problem of multiple confounding factors and overlap between healthy and asthmatic populations preclude the routine application of FeNO reference values in clinical practice and suggest that it would be better to consider an individual “best”, taking into account the context in which the measurement is obtained and the clinical history of the patient. Besides, there is still disagreement about the role of FeNO as a marker of asthma control, due to the complexity of balance among the different items involved in its determination and the lack of homogeneity in the population groups studied in the few studies conducted so far. Heterogeneity of problematic severe asthma greatly limits utility of FeNO alone as a biomarker of inflammation to optimize the disease management on an individual basis. None of the studies conducted so far demonstrated that the use of FeNO was better than current asthma guidelines in controlling asthma exacerbations. In summary, there is a large variation in FeNO levels between individuals, which may reflect the natural heterogeneity in baseline epithelial nitric oxide synthase activity and/or the contribution of other noneosinophilic factors to epithelial nitric oxide synthase activity. FeNO is a promising biomarker, but at present some limits are highlighted. We would recommend that further research can be carried out by organizing studies aimed to obtain reliable reference values of FeNO and in order to better interpret FeNO measurements in clinical settings, taking also into account the influence of genetic and environmental factors.
PMCID: PMC3750504  PMID: 23902719
23.  526 Relationship between Fractional Exhaled Nitric Oxide (Feno) and Forced Expiratory Volume in One Second (Fev1) and Forced Vital Capacity (Fvc)i Children with Asthma 
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.
PMCID: PMC3512691
24.  Associations of Fraction of Exhaled Nitric Oxide with Beta Agonist Use in Children with Asthma 
The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, is a potential noninvasive tool to guide asthma management in children. It remains unclear, however, if FeNO adds any information beyond clinical assessment of asthma control. We evaluated the associations of FeNO level with short acting beta agonist use and compared it with other clinical asthma assessments. We examined a prospective cohort study of 225 tobacco-smoke-exposed children aged 6–12 years with doctor-diagnosed asthma, including measures of FeNO, reported days of short acting beta agonist use, and unscheduled asthma visits. FeNO was analyzed in relation to current and future (3 months later) short acting beta agonist use. Mean FeNO at baseline, 6, and 12 months was 15.5, 15.7, and 16.8 ppb. In multivariable analyses, higher FeNO level was associated with increased short acting beta agonist use but only among children who were not on inhaled corticosteroids. Among those not on an inhaled steroid, there was a 12% increase in current and 15% increase in future days of short acting beta agonist use for every 10 ppb increase in FeNO level. FeNO levels remained associated with current short acting beta agonist use even after adjusting for unscheduled asthma visits. FeNO levels remained associated with future short acting beta agonist use even after adjusting for current short acting beta agonist use or unscheduled asthma visits. We conclude that FeNO levels are associated with short acting beta agonist use but only among children who are not on an inhaled corticosteroid.
PMCID: PMC3255503  PMID: 22276224
25.  Asthma in the elderly: The role of exhaled nitric oxide measurements 
Respiratory medicine  2013;107(5):785-787.
Asthma in the elderly is poorly understood because only a small minority of asthma studies have investigated this patients group. Fractional Exhaled Nitric Oxide (FENO) has been extensively studied in children and adults with asthma, but little is known about FENO in elderly asthmatics. We studied the role of serial measurements of FENO in elderly subjects with asthma.
Thirty stable asthmatics 65 years old and older were followed for one year with evaluations at baseline and every three months. We looked for associations between FENO and subjects’ demographics, comorbidities, asthma treatment, spirometric values and Asthma Control Test (ACT) scores. FENO was not elevated in our study subjects throughout the study period (mean < 30 ppb). FENO significantly increased and FEV1% decreased between first and last study visit, while ACT scores and steroid dose remained unchanged. No significant correlation was found between FENO and FEV1/FVC, other spirometric values, inhaled steroid dose or ACTscores at any time point. No associations of FENO were found with age, sex, Body Mass Index (BMI), atopic status, disease duration, presence of rhinitis or gastroesophageal reflux disease (GERD), or other medications used. Moderate asthma exacerbations did not consistently cause an increase of FENO.
In stable elderly asthmatic patients, FENO was not elevated and did not correlate with subjects’ demographics, comorbidities, treatment, symptoms or spirometric values. Routine measurements of FENO may not be clinically valuable in elderly asthmatics.
PMCID: PMC4034737  PMID: 23481173
Asthma; FENO; Elderly

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