Exaled nitric oxide and air trapping correlation in asthmatic children

Exhaled nitric oxide (eNO) levels have been shown to correlate with atopy and with airway hyperresponsiveness but not with standard spirometry. The aim of our study was to evaluate the correlation between eNo levels and functional residual capacity (FRC), residual volume (RV), RV to total lung capacity (TLC) ratio, and pulmonary resistances in asthmatic children ages 6-13 years. Forty-nine patients (35 males) were enrolled in the study. Nineteen of them were not receiving inhaled corticosteroids. The eNO levels were measured by chemiluminescence's analyzer and lung function study were performed by body box plethysmography. As expected, there was no correlation between eNO levels and forced vital capacity (FVC); forced expiratory volume in the first second (FEV1); mid respiratory flow between 25 and 75% of the vital capacity (MEF(25 -75)), FEV1/FVC, and pulmonary resistances. Instead a correlation was found between eNO level and RV both considering all the study population together (r = 0.51, P = 0.001) and separately the asthmatic children not receiving ICS (r = 0.6, P = 0.003). In the patients receiving ICS the correlation was still present (r = 0.43, P = 0.01). The correlation between eNo levels and RV may reflect the effect of airway inflammation on NO production and diffusion as well as peripheral airway trapping and consequent RV.     

Bronchial hyperresponsiveness to mannitol,airway inflammation and Asthma Control Test in atopic asthmatic children

Introduction

The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children.

Material and methods

Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma.

Results

All the subjects showed positive AHR to mannitol. Pearson''s correlation test revealed a significant inverse correlation between AHR (mannitol PD₁₅) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD₁₅ (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD₁₅ was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma.

Conclusions

Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO.     

Acid-base equilibrium in exhaled breath condensate of allergic asthmatic children

BACKGROUND: The dysregulation of airway pH control may have a role in asthma pathophysiology. The measurement of exhaled breath condensate (EBC) pH and ammonia levels may be used as a noninvasive method to study acid-base status in the airway of asthmatics. METHODS: Exhaled breath condensate from 29 allergic stable asthmatic children and 13 healthy controls was collected by cooling exhaled air during tidal breathing. Ammonia was measured by high-performance liquid chromatography with fluorescence detection. pH was measured after deaeration of EBC samples by bubbling with argon. The children also underwent FENO measurement. RESULTS: Both pH and ammonia values in EBC were significantly lower in the asthmatics than in the control group [pH: ICS-treated (median and interquartile range) 7.70 (7.62-7.74), steroid-naive 7.53 (7.41-7.68), controls 7.85 (7.80-7.90), P <0.01 and P <0.001, respectively; ammonia: ICS-treated 476.17 microM (282.50-594.80), steroid-naive 253.24 microM (173.43-416.08), controls 788.30 microM (587.29-1310.39), P < 0.05 and P <0.001, respectively]. Both pH and ammonia values were higher in ICS-treated than in steroid-naive asthmatic children. There was a significant correlation between EBC pH and ammonia concentrations. CONCLUSIONS: These data show that EBC pH values of stable asthmatic children are lower compared with those of healthy controls and positively correlated with ammonia concentrations, supporting the hypothesis that airway acidification may have a role in the pathobiology of allergic asthma.     

3-Nitrotyrosine, a marker of nitrosative stress, is increased in breath condensate of allergic asthmatic children

BACKGROUND: Asthmatic patients have high exhaled nitric oxide (NO) levels. NO-mediated inflammatory actions are mainly due to NO conversion into reactive nitrogen species, which can lead to nitrotyrosine formation. The aim of this study was to assess 3-nitrotyrosine (3-NT) levels in exhaled breath condensate (EBC) of asthmatic and healthy children and to investigate whether there is any relationship with exhaled NO (FE(NO)) and lung function. METHODS: The study included 20 asthmatic children (10 steroid-naive with intermittent asthma, 10 steroid-treated with unstable persistent asthma) and 18 healthy controls. They underwent FE(NO) measurement, EBC collection and spirometry. 3-NT was measured by a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in isotopic dilution. RESULTS: The median EBC concentration of 3-NT (expressed as nitrotyrosine/tyrosine ratio x 100) in asthmatic children was fivefold higher than in healthy subjects [0.23% (0.12-0.32) vs 0.04% (0.02-0.06), P < 0.001] with no difference between steroid-naive and unstable steroid-treated asthmatic patients. FE(NO) levels were higher in asthmatic [44.6 ppb (36.0-66.0)] than in healthy children [7.5 ppb (6.0-8.8), P < 0.001]. No correlation was found among 3-NT, FE(NO) and lung function parameters. CONCLUSION: Nitrotyrosine is high in EBC of asthmatic children and could be considered as a noninvasive marker of nitrosative events in the airways.     

High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children

BACKGROUND: The fractional concentration of nitric oxide in exhaled air (FENO) is elevated in atopic asthma and typically responds to treatment with inhaled corticosteroids (ICS). However, some patients have persistently high FENO levels despite treatment. OBJECTIVE: We studied how optimizing the inhalation technique and increasing ICS doses would affect FENO in stable atopic asthmatic children who had elevated FENO while using ICS. METHODS: In 41 stable asthmatic children who were treated with ICS (median daily dose 800 microg budesonide equivalent, range 100-1600 microg) and maintained FENO> or =20 p.p.b., we optimized the inhalation technique by thorough instruction and measured FENO 2 weeks later. Then, if FENO remained > or =20 p.p.b., we increased the ICS dose and reassessed FENO 2 weeks later. RESULTS: Improving the inhalation technique did not reduce FENO. Increasing ICS from a daily median dose of 800 to 1200 microg budesonide had no significant effect on FENO. FENO correlated positively with symptom scores in the following 2 and 4 weeks (P=0.001, 0.002) and beta2-agonist use the 2 and 4 weeks following FENO measurement (P=0.02, 0.004). CONCLUSION: We conclude that common steps in asthma treatment, i.e. inhalation instruction and increasing ICS dose, were both ineffective in reducing FENO in atopic asthmatic children with elevated FENO values despite treatment with ICS. This implies that FENO cannot simply be incorporated in current treatment guidelines.     

The relationship between exhaled nitric oxide and allergic sensitization in a random sample of school children

BACKGROUND: Exhaled nitric oxide (NO) has been proposed as novel a non-invasive marker of airway inflammation. OBJECTIVE: The level of exhaled NO was determined in a random sample of school children (7-12 years old) with the aim of investigating the relationship between exhaled NO and sensitization to common allergens. RESULTS: In the 450 children tested by skin prick tests (SPT), the prevalence of sensitization was 29.5% (overall), 21.9% (sensitization to indoor allergens), and 15.0% (sensitization to outdoor allergens). Regression analysis showed that levels of exhaled nitric oxide were closely associated with various measures of sensitization to aeroallergens. Sensitization to indoor allergens was associated with higher levels of exhaled NO (eNO) than sensitization to outdoor allergens when assessed by IgE but not when assessed by SPT. Children with reported wheeze in the past 12 months had much stronger associations between sensitization and eNO than children without wheeze. CONCLUSION: We conclude that allergic sensitization is strongly associated with increased levels of exhaled NO, especially in children with wheeze.     

An economic evaluation of NIOX MINO airway inflammation monitor in the United Kingdom

Background: Fractional exhaled nitric oxide (FE_NO), a marker of eosinophilic airway inflammation, is easily measured by noninvasive means. The objective of this study was to determine the cost‐effectiveness of FE_NO measurement using a hand‐held monitor (NIOX MINO), at a reimbursement price of £23, for asthma diagnosis and management in the UK. Methods: We constructed two decision trees to compare FE_NO measurement with standard diagnostic testing and guideline recommendations for management. For asthma diagnosis, we compared FE_NO measurement with lung function and reversibility testing, bronchial provocation and sputum eosinophil count. For asthma management, we evaluated the impact on asthma control, including inhaled corticosteroid use, exacerbations and hospitalizations, of monitoring with FE_NO measurement vs symptoms and lung function as in standard care. Resource use and health outcomes were evaluated over a 1‐year time frame. Direct costs were calculated from a UK health‐care payer perspective (2005 £). Results: An asthma diagnosis using FE_NO measurement cost £43 less per patient as compared with standard diagnostic tests. Asthma management using FE_NO measurement instead of lung function testing resulted in annual cost‐savings of £341 and 0.06 quality‐adjusted life‐years gained for patients with mild to severe asthma and cost‐savings of £554 and 0.004 quality‐adjusted life‐years gained for those with moderate to severe asthma. Conclusions: Asthma diagnosis based on FE_NO measurement with NIOX MINO alone is less costly and more accurate than standard diagnostic methods. Asthma management based on FE_NO measurement is less costly than asthma management based on standard guidelines and provides similar health benefits.     

Exhaled nitric oxide predicts airway hyper-responsiveness to hypertonic saline in children that wheeze

BACKGROUND: Exhaled nitric oxide (eNO) has shown good validity for the assessment of airway inflammation in asthmatic children. In large-scale epidemiological studies, this method would be preferred above airway challenge tests, because it is a quick and easy applicable tool. OBJECTIVE: In this study, we aimed to assess the discriminatory capacity of eNO, and prechallenge FEV1 for airway hyper-responsiveness (AHR) in 8-13-year old schoolchildren. MATERIALS AND METHODS: Parents completed the ISAAC questionnaire, and children were tested for atopy, AHR to hypertonic (4.5%) saline (HS), and eNO. Diagnostic value was assessed by the area under the receiver operating curves (ROC), and calculation of positive and negative predicted values at different cut-off points for eNO and prechallenge FEV1. RESULTS: Areas under the ROC-curves of AHR were 0.65 for eNO and 0.62 for FEV1. Values increased to 0.71 and respectively 0.75 for a combined occurrence of AHR and current wheeze. Highest sensitivity and specificity were obtained at a cut-off value of 43 ppb for eNO and 103% predicted for FEV1. At these cut-off values, the positive predictive values for the presence of AHR in symptomatic children were respectively 83% (eNO) and 33% (FEV1), and negative predictive values in asymptomatic children were, respectively, 90 (eNO) and 80% (FEV1). CONCLUSION: Exhaled nitric oxide is a valid screening tool for AHR to HS in children that present with current wheeze, and it outperforms FEV1 as a predictor of AHR.     

Characterization of airway nitric oxide in allergic rhinitis: the effect of intranasal administration of L-NAME

BACKGROUND: Several studies have attempted to assess nasal nitric oxide (NO) levels in allergic rhinitis (AR). However, there seem to be differences in the results obtained. We therefore wanted to investigate this further by studying airway NO in AR and controls at several modalities, and also the effect of intranasal administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine-methyl ester.HCl (L-NAME). METHODS: Airway NO was determined through repeated measurements at three flow rates of air (0.5, 3, and 9 l/min), using a single-breath method and a method of nasal aspiration, in 18 patients with birch pollen AR during season and in 18 controls. RESULTS: Patients with AR were characterized by no difference in nasal but higher orally exhaled NO and a larger interindividual spread in nasal and orally exhaled NO compared to controls. We also found a greater reduction in nasal NO after L-NAME in patients compared to controls. DISCUSSION: These results indicate that several factors determine the levels of nasal NO in rhinitis. NO production in the nasal mucosa of patients with AR may be upregulated. On the other hand, this increase could be counteracted by swelling of the mucosa and secretions resulting in impaired NO diffusion from, for example, the paranasal sinuses, where particularly high levels of NO have been found. Also, the high background levels of NO from constitutive sources in the nose may blunt smaller increases in mucosal NO output. CONCLUSION: It seems that the methods for measurement of nasal NO need to be improved and standardized before we can consider to use this test in monitoring inflammation in AR.     

Resolution of allergic airways inflammation but persistence of airway smooth muscle proliferation after repeated allergen exposures

BACKGROUND: Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. OBJECTIVE: We investigated the long-term effects of repeated allergen exposure. METHODS: Brown-Norway (BN) rats sensitized to ovalbumin (OVA) were exposed to OVA or saline aerosol every third day on six occasions and studied 24 h, 7 days and 35 days after the final exposure. We measured airway inflammation, ASM cell proliferation (by incorporation of bromodeoxyuridine; BrdU) and bronchial responsiveness to acetylcholine. RESULTS: At 24 h, in OVA-exposed rats, we detected elevated OVA-specific serum IgE, increased numbers of macrophages, eosinophils, lymphocytes and neutrophils in the bronchoalveolar lavage (BAL) fluid and increased numbers of MBP+ (major basic protein) eosinophils and CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU and with bronchial hyper-responsiveness (BHR). At 7 days, BHR was detected in OVA-exposed rats, coincident with increased numbers of macrophages and lymphocytes in BAL fluid together with increased numbers of CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU. By day 35, the number of ASM cells expressing BrdU remained elevated in the absence of cellular infiltration and BHR. CONCLUSION: Repeated OVA-challenge results in persistent ASM cell proliferation in the absence of bronchial inflammation and BHR, which lasts for at least 1 week following cessation of exposure.     

Heterogeneity of FeNO response to inhaled steroid in asthmatic children

Background Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti‐inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern. Objective The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs. Methods Exhaled nitric oxide (FeNO), lung function, bronchial hyper‐responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double‐blind, placebo‐controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren. Results Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600. Conclusion Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high‐dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti‐inflammatory control in asthmatic children.