The effect of allergic rhinitis on adenosine concentration in exhaled breath condensate

BACKGROUND: Patients with allergic rhinitis (AR) frequently develop asthma. This initiating inflammation in the lower airways may result in increased levels of inflammatory mediators such as adenosine in the exhaled breath. OBJECTIVE: We compared adenosine levels in exhaled breath condensate (EBC) and both exhaled and nasal nitric oxide (NO) levels of AR patients and healthy control subjects. We also tested whether inhalation through inflamed nasal cavity during EBC sampling influences adenosine concentrations in exhaled air. METHODS: Exhaled and nasal NO levels were measured and EBC samples (at oral inhalation) were collected from 27 patients and 15 healthy controls. EBC collection was repeated after 15 min with subjects inhaling through their nose. Adenosine was measured by HPLC and NO was determined by chemiluminescence. RESULTS: The concentration of EBC adenosine was higher in patients with AR than in healthy controls (12.4+/-1.3 nM vs. 6.5+/-0.7 nM, P=0.0019) and this was accompanied by an increase in the concentration of exhaled NO (10.2+/-1.3 ppb vs. 5.3+/-0.5 ppb; P=0.0099, respectively). No difference in nasal NO was detected. EBC adenosine concentration showed a significant positive correlation with the level of exhaled NO. In contrast to healthy control subjects, patients with rhinitis had higher levels of exhaled adenosine when inhaling via the nose instead of the mouth (17.7+/-2.8 nM, P=0.007). CONCLUSION: When compared with healthy subjects, patients with AR exhibit an increased concentration of exhaled adenosine and a related increase in exhaled NO concentration. EBC adenosine is further increased when rhinitis patients inhale through their nose than via their mouth. Our data suggest that non-asthmatic patients with rhinitis may have subclinical inflammation in their lower airways.     

Exhaled air temperature in asthma: methods and relationship with markers of disease

BACKGROUND: Exhaled breath temperature has been proposed as a surrogate marker for the evaluation of airway inflammation in asthmatic patients. OBJECTIVE: The aim of the present study was to extend the investigation of exhaled air temperature as a means for the evaluation of airway inflammation using a professionally developed instrument. METHODS: Fifty-seven children, 41 allergic mild asthmatics and 16 healthy controls have been evaluated. They underwent exhaled air temperature and lung function measurement. The asthmatic children also underwent exhaled nitric oxide measurement, and hypertonic saline sputum induction for the evaluation of eosinophil (EOS) percentage. RESULTS: The level of exhaled temperature was significantly higher in asthmatics than in controls, being 30.18+/-0.14 degrees C vs. 27.47+/-0.24 degrees C (P<0.001). In asthmatic children, a positive relationship was observed between exhaled air temperature and both exhaled nitric oxide (r=0.39; P=0.01) and EOS percentage in samples from induced sputum (rho=0.53; P=0.04). CONCLUSION: The data from the present study support the hypotheses that exhaled breath temperature is related to the degree of airway inflammation in asthma.     

Exhaled nitric oxide and biomarkers in exhaled breath condensate indicate the presence, severity and control of childhood asthma

BACKGROUND: Exhaled nitric oxide and inflammatory biomarkers in exhaled breath condensate may be useful to diagnose and monitor childhood asthma. Their ability to indicate an asthma diagnosis, and to assess asthma severity and control, is largely unknown. OBJECTIVE: To study (1) the ability of exhaled nitric oxide and inflammatory markers in exhaled breath condensate (nitrite, nitrate, hydrogen peroxide, 8-isoprostane, IFN-gamma, TNF-alpha, IL-2, -4, -5, -10 and acidity) to discriminate between childhood asthma and controls. (2) The ability of these biomarkers to indicate asthma severity and control. METHODS: One-hundred and fourteen children were included: 64 asthmatics (10.7+/-3.0 years, 67.2% atopic) and 50 controls (10.0+/-0.4 years). Condensate was collected using a glass condenser. RESULTS: Exhaled nitric oxide, IFN-gamma and IL-4 in exhaled breath condensate differed significantly between asthma and controls. Multivariate backward logistic regression models demonstrated that IL-4 (odds ratio 7.9, 95% confidence interval 1.2-51.0) was the only significant indicator of an asthma diagnosis. Asthma control was best assessed by exhaled nitric oxide, 8-isoprostane, IFN-gamma and IL-4 (sensitivity 82%, specificity 80%, P<0.05), whereas exhaled nitric oxide, 8-isoprostane, nitrate and nitrite in condensate were the best indicators of asthma severity (sensitivity 89%, specificity 72%, P<0.05). CONCLUSION: Different markers in condensate are of an additional value to exhaled nitric oxide, and are needed in non-invasive inflammometry. They could be useful to diagnose asthma and to indicate asthma control and severity in childhood.     

External validation of exhaled breath profiling using an electronic nose in the discrimination of asthma with fixed airways obstruction and chronic obstructive pulmonary disease

Background Fixed airflow limitation can be found both in asthma and chronic obstructive pulmonary disease (COPD), posing a day‐to‐day diagnostic challenge. Objective We aimed to determine the external validity of metabolomic analysis of exhaled air by electronic nose for distinguishing asthma and COPD in patients with fixed airways obstruction. Methods One hundred patients were included in a cross‐sectional design: 60 asthma patients: 21 with fixed airways obstruction (fixed asthma), 39 with reversible airways obstruction (classic asthma) and 40 COPD patients (GOLD stages II–III). Standardized sampling of exhaled breath was performed and volatile organic compounds were captured using an electronic nose resulting in breathprints. External validity in newly recruited patients (validation sets) was tested using a previous and independent training set. Breathprints were analysed by principal component and canonical discriminant analysis and area under the curve (AUC) of receiver operating characteristic curves. Results External validity of breathprints showed 88% accuracy for distinguishing fixed asthma from COPD (AUC 0.95, 95% CI 0.84–1.00, sensitivity 85%, specificity 90%) and 83% for classic asthma (AUC 0.93, 95% CI 0.87–1.00, sensitivity 91%, specificity 90%) (both P<0.001). Discriminative accuracy was not confounded by current smoking. Conclusions and Clinical Relevance External validation of exhaled breath molecular profiling shows high accuracy in distinguishing asthma and COPD in newly recruited patients with fixed airways obstruction. Exhaled air analysis may therefore reduce misdiagnosis in obstructive airways diseases, potentially leading to more appropriate management. Cite this as: N. Fens, A. C. Roldaan, M. P. van der Schee, R. J. Boksem, A. H. Zwinderman, E. H. Bel and P. J. Sterk, Clinical & Experimental Allergy, 2011 (41) 1371–1378.     

Exhaled breath analysis by electronic nose in airways disease. Established issues and key questions

Exhaled air contains many volatile organic compounds (VOCs) that are the result of normal and disease‐associated metabolic processes anywhere in the body. Different omics techniques can assess the pattern of these VOCs. One such omics technique suitable for breath analysis is represented by electronic noses (eNoses), providing fingerprints of the exhaled VOCs, called breathprints. Breathprints have been shown to be altered in different disease states, including in asthma and COPD. This review describes the current status on clinical validation and application of breath analysis by electronic noses in the diagnosis and monitoring of chronic airways diseases. Furthermore, important methodological issues including breath sampling, modulating factors and incompatibility between eNoses are raised and discussed. Next steps towards clinical application of electronic noses are provided, including further validation in suspected disease, assessment of the influence of different comorbidities, the value in longitudinal monitoring of patients with asthma and COPD and the possibility to predict treatment responses. Eventually, a Breath Cloud may be constructed, a large database containing disease‐specific breathprints. When collaborative efforts are put into optimization of this technique, it can provide a rapid and non‐invasive first line diagnostic test.     

Effect of inhalation aspirin challenge on exhaled nitric oxide in patients with aspirin-inducible asthma

BACKGROUND: A complex relationship between arachidonic acid metabolites and nitric oxide (NO) synthesis has been reported in asthma. The effects of inhaled aspirin on fractional exhaled NO (FENO) in patients with aspirin-tolerant (ATA) and aspirin-inducible (AIA) asthma compared with normal controls have been investigated. METHODS: The FENO was measured baseline, after saline and lysine-aspirin (L-ASA) bronchial challenge in 10 patients with ATA and in 10 patients with AIA [mean (PD(20)FEV(1) L-ASA): 14.7 +/- 12.7 mg], who had comparable age and baseline FEV(1). Ten healthy subjects served as controls. Sputum eosinophils were counted after saline and after L-ASA challenge in the two groups of asthmatics. RESULTS: Asthmatic patients had baseline FENO significantly higher than controls (29.7 +/- 6.8 vs 9.8 +/- 2.05 p.p.b. respectively, P < 0.0001). No difference was observed in methacholine PD(20)FEV(1) and baseline FENO between ATA and AIA patients. After L-ASA inhalation, FENO increased significantly only in patients with AIA, reaching the peak value 4 h after bronchoconstriction (from 31.1 +/- 6 to 43 +/- 4.8 p.p.b., P < 0.001), while no change was observed in patients with ATA and in controls. Sputum eosinophils increased significantly after L-ASA inhalation only in patients with AIA (from 8.1 +/- 2.7 to 11.1 +/- 2.8%, P < 0.005) and there was a significant relationship between the increase in sputum eosinophils and the increase in FENO after ASA challenge. CONCLUSION: Exhaled NO may indicate eosinophilic airway inflammation during ASA exposure in patients with ASA inducible asthma.     

Increased exhaled H2O2 and impaired lung function in patients undergoing bioincompatible hemodialysis

BACKGROUND: Chronic renal failure (CRF) and hemodialysis (HD) accumulate an inflammatory milieu, contributing to increased systemic and airway oxidative stress that may lead to lung damage. OBJECTIVES: This study was designed to assess exhaled hydrogen peroxide (H2O2), lung function and whole blood chemiluminescence in HD and CRF patients and healthy controls. METHODS: The study included 59 patients (Polyamide STM or Hemophan membranes--19, cuprophane--16, hemodiafiltration--14, continuous ambulatory peritoneal dialysis--10), 16 CRF and 16 healthy controls. The assessment of lung function included FVC (forced vital capacity), FEV1 (forced expiratory volume in the first second) and DLCOc (single breath CO diffusing capacity). Exhaled H2O2 was determined fluorometrically and resting and n-formyl-methionyl-leucyl-phenylalanine (fMLP) luminol-dependent whole blood chemiluminescence (LBCL) were measured simultaneously. RESULTS: Only cuprophane HD patients presented decreased lung function (FVC 63.8+/-17.4%, FEV1 55.9+/-20.3 and DLCOc 72.1+/- 9.3 % of predicted; p<0.05 vs. controls). These patients exhaled the highest H2O2 levels in comparison to CRF (p<0.01): median 0.36 microM (range R: 0.09-0.56 microM) and controls (p<0.05): 0.17 microM (0.2-17.8 microM). These levels were not decreased during the HD session: preHD 1.25 microM (0.2-16.5 microM) and postHD 1.3 microM (0.2-17.8 microM). As a marker of systemic oxidative stress, fMLP-induced LBCL (total light emission) was increased in these patients (1570.6 aUxs/10(4) phagocytes; R: 274.2-8598.9) and in the CRF group (2389.4 aUxs /10(4) phagocytes; R: 491.5- 6184; p<0.05 vs. controls). Other patient groups did not express elevated LBCL and revealed decreased exhaled H2O2 after a session. CONCLUSIONS: An increased oxidative burden in the lungs may contribute to functional lung impairment in patients dialyzed with a cellulose membrane. Biocompatible dialysis with other modalities might reduce airway-borne oxidative stress and is not related with lung damage.     

Nasal and bronchial response to exercise in patients with asthma and rhinitis: the role of nitric oxide

BACKGROUND: Physical exercise is associated with a decrease in nasal resistance in rhinitis and an increase in bronchial resistance in asthma. The objective was to evaluate the relationship between the levels of nasal nitric oxide (nNO) and exhaled bronchial nitric oxide (eNO) with bronchial responses to exercise in patients with rhinitis and asthma. METHODS: We submitted 24 subjects with asthma and rhinitis to an exercise test. A decrease in FEV(1)> or =15% was considered positive. The volume of the nasal cavity and the minimal cross-sectional area (MCA) was evaluated by means of acoustic rhinometry (AR), and nNO and eNO were evaluated by chemoluminiscence. The measurements were recorded at baseline, 15 and 50 min after the end of the exercise test. RESULTS: The exercise test was positive in 17 cases. Fifteen minutes after exercise test, the nasal volume increased by 57% (P < 0.0001) and was still increased by 30% after 50 min (P < 0.0001). There was no correlation between decrease in FEV(1) and increase in nasal volume. The baseline value of nNO was 1185 +/- 439 ppb, and the value at 15 and 50 min was 1165 +/- 413 and 1020 +/- 368 ppb, the latter value being significantly lower (P < 0.01) than the baseline. The baseline value of eNO was 21 +/- 19 ppb, with no significant differences at 15 and 50 min. There was no significant correlation between either the decrease in FEV(1) and the nasal response, or the baseline eNO and nNO values. CONCLUSIONS: The nasal and bronchial response to exercise is completely different in rhinitis and asthma; in the former, an increase in nasal volume occurs, while in the latter there is a drop in FEV(1). There is no relationship between the values of nasal or exhaled NO and the nasal and bronchial response after exercise.     

High serum levels of tumour necrosis factor‐α and interleukin‐8 in severe asthma: markers of systemic inflammation?

BACKGROUND: Severe asthma is characterized by elevated levels of pro-inflammatory cytokines and neutrophilic inflammation in the airways. Blood cytokines, markers of 'systemic' inflammation, may be a feature of amplified inflammation in severe asthma. OBJECTIVE: To detect differences in IL-8, TNF-alpha, IL-16 and IL-13 levels in the serum(s) of stable severe and mild-moderate asthmatics related to blood leucocytes proportion, airway calibre and exhaled nitric oxide (NO) levels. METHODS: We assessed cytokine serum levels by ELISA and blood leucocyte counts by an alkaline peroxidase method in 20 healthy controls, 22 mild-moderate [forced expiratory volume in 1 s (FEV1)(%pred): 89+/-3] and 14 severe asthmatics [FEV1(%pred): 49+/-2]. RESULTS: IL-8 and TNF-alpha levels were higher in severe asthmatics than in mild-moderate asthmatics or in controls (P<0.05). No differences in IL-16 and IL-13 levels were detected. Severe asthmatics showed higher circulating neutrophil and eosinophil number than controls (P<0.05). In severe asthmatics, exhaled NO levels were superior than in controls (P<0.05), but inferior than in mild-moderate asthmatics (P<0.05). We found positive correlation between TNF-alpha levels and exhaled NO (r=0.67; P=0.01) or circulating neutrophil counts (r=0.57; P=0.03) in severe asthmatics. CONCLUSION: sTNF-alpha and sIL-8 are markers of 'systemic' inflammation in severe asthmatics, in conjunction with augmented circulating neutrophils, suggesting the involvement of neutrophil-derived cytokine pattern in severe asthma.     

Analysis of growth factors and inflammatory cytokines in exhaled breath condensate from asthmatic children

BACKGROUND: Vascular endothelial growth factor (VEGF), AA isoform of platelet-derived growth factor (PDGF-AA), and epidermal growth factor (EGF) are involved in the pathogenesis of airway inflammation in asthma. These molecules are closely associated with cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-4. This study investigates the relation between childhood asthma and levels of these mediators in exhaled breath condensate (EBC). METHODS: EBC was collected from asthmatic children and controls using a disposable collection kit, and the concentrations of VEGF, PDGF-AA, EGF, TNF-alpha and IL-4 in EBC were measured using sandwich enzyme immunoassays. Exhaled nitric oxide concentration was measured by a chemiluminescence analyzer. RESULTS: Thirty-five asthmatic patients aged between 7 and 18 years and 11 controls were recruited. Sixteen patients had intermittent asthma (IA) whereas 19 of them suffered from persistent asthma (PA). A significant correlation was found between IL-4 and TNF-alpha in EBC (rho = 0.374, p = 0.010). PDGF-AA levels in EBC were higher in subjects with diminished FEV1 (p = 0.023) whereas IL-4 concentrations were increased in asthmatics (p = 0.007) as well as subjects with increased plasma total IgE (p = 0.033). Patients with PA receiving high-dose inhaled corticosteroid (ICS) had higher EBC IL-4 concentration than those on low-dose ICS (p = 0.007). Linear regression revealed that PDGF-AA levels in EBC were negatively associated with FEV1 percentage (beta = -0.459, p = 0.006) among the asthmatic patients. CONCLUSIONS: IL-4 in EBC is increased in childhood asthma, and growth factors are detectable in a significant proportion of these children. Increased PDGF-AA is found in asthmatics with more severe airflow limitation.     

The effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in subjects with asthma

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.     

支气管哮喘患者外周血Th17 与Th9 细胞的变化及临床意义

目的:探讨Th17、Th9 细胞水平在支气管哮喘患者中的表达及其临床意义。方法:选取67 例哮喘患者为研究对象,30 例健康体检者为对照组,根据全球哮喘防治倡议(GINA)将哮喘患者分为间歇与轻度持续组20 例,中度持续组25 例和重度持续组22 例。收集患者临床资料,完成哮喘控制测试(ACT)评分、肺功能和呼出气一氧化氮(FeNO)值测定,流式细胞仪检测外周血PBMC 中CD3+ CD8- IL-17+ 、CD3+ CD8- IL-9+细胞水平。结果:与健康对照组相比,哮喘患者Th17、Th9 细胞水平均明显升高(P<0.05);中重度哮喘患者Th17 及Th9 细胞水平显著高于间歇与轻度哮喘组(P<0.05),而间歇与轻度哮喘组患者与健康对照组比较,差异无统计学意义(P>0.05)。哮喘患者外周血Th17 及Th9 细胞的表达均与FeNO 值正相关(r 值依次为0.501、0.438;P<0.05),与ACT 评分、肺功能FEV1、FEV1/ FVC 及PEF 负相关(r 值依次为-0.441、-0.362;-0.307、-0.377;-0.419、-0.411;-0.428、-0.24;P<0.05),同时Th17 与Th9 细胞在哮喘患者外周血中的表达率正相关(r 值为0.443,P<0.05)。结论:Th17、Th9 细胞在哮喘患者中高表达,具有协同致炎作用,且与症状严重程度相关,提示Th17 及Th9 细胞对哮喘患者病情评估有潜在的参考价值。     

Relationship between cysteinyl leukotriene in exhaled breath condensate and the severity of asthma in adult asthmatics in Japan]

BACKGROUND: The measurement of several mediators in exhaled breath condensate (EBC) can be useful as the biomarker for asthma. But there are a few reports about EBC of asthmatics in Japan. Aim: We examined the safety of the collection of EBC and the utility of cysteinyl leukotriene (cysLTs) in EBC as the biomarker of asthma. METHODS: Fifty-three asthmatics and eleven subjects without asthma were recruited. After the measuring of exhaled nitric oxide (eNO) and spirometory, EBC were collected. The levels of cysLTs in EBC were measurement by ELISA within 2 months. RESULTS: The collection of EBC did not induce any other symptoms in all subjects. In 48 subjects, the collection significantly increased their FEV1 and MMF level (DeltaFEV1: 2.27+/-0.77%, DeltaMMF 14.6+/-3.92% (mean+/-SEM). The level of cysLTs in EBC on asthmatics treated with high-dose ICS was significantly high compared with control group (p=0.0034), steroid-na?ve asthmatics or asthmatics treated with low-dose ICS (steroid naive vs. high dose ICS, p=0.041, low dose ICS vs. high dose ICS, p=0.021). The relationship between cysLTs in EBC and the levels of LTE4 in urine was significantly correlated (n=34, r=0.32, p=0.0435). The relationship between cysLTs in EBC and the levels of eNO was significantly correlated only in steroid-na?ve asthmatics (r=-0.57, p=0.0369). There was no relationship between cysLTs in EBC and FEV1, or log PC20Ach. CONCLUSION: The collection of EBC was perfectly non-invasive. The level of cysLTs can be useful as a biomarker of asthma.     

Comparison of exhaled nitric oxide to spirometry during emergency treatment of asthma exacerbations with glucocorticoids in children.

BACKGROUND: Asthma is characterized as a chronic inflammatory process; however, there is no easily measured marker for airway inflammation. Such a marker, particularly in children, would be very helpful in the management of asthma even in the acute setting. OBJECTIVE: The purposes of this study were to determine whether asthmatic children have (1) elevation of exhaled breath nitric oxide (ENO) during acute exacerbations when presenting to the emergency room, (2) reduction of ENO following glucocorticoid treatment, or (3) improvement in spirometry and clinical examination accompanying reduction of ENO levels. METHODS: Peak ENO levels were measured by chemiluminescence during exhalation into the NO analyzer. Ten asthmatic children (mean age 10 years) who presented to the Pediatric Special Care Unit at National Jewish Medical and Research Center in acute respiratory distress with an asthma exacerbation were studied. The subjects were recruited, after informed consent was obtained from the parent, on the basis of specific inclusion/exclusion criteria. Measurements of ENO in parts per billion (ppb) and spirometry, including percentiles of forced expiratory volume in one second (FEV1%) and peak expiratory flow (PEF%), were performed before and after at least 5 days of glucocorticoid therapy. RESULTS: The mean ENO level in the asthmatic children prior to glucocorticoid treatment was 48 +/- 8ppb, and after glucocorticoid treatment the ENO level was 17 +/- 1ppb; (P < .002). Prior to glucocorticoid treatment, the mean FEV1% value was 68 +/- 3% compared with the postglucocorticoid treatment FEV1% value of 100 +/- 5%; (P < .0001). Prior to glucocorticoid treatment, the mean PEF% value was 81 +/- 7%, compared with the postglucocorticoid treatment PEF% value of 105 +/- 6%; (P < .02). CONCLUSIONS: The mean peak ENO level after glucocorticoid therapy was significantly less than that measured before treatment in children with acute asthma exacerbations. Concomitant with the decrease in ENO levels, there was improvement in the spirometry values and physical examination in the asthmatic children; thus, ENO is a sensitive marker for response to anti-inflammatory treatment in children.     

Exhaled nitric oxide levels correlate with measures of disease control in asthma

BACKGROUND: Asthma guidelines emphasize maintaining disease control. However, objective measures of asthma disease control are lacking. OBJECTIVE: We sought to examine the relationship between exhaled nitric oxide (NO) levels and measures of asthma disease control versus asthma disease severity. METHODS: We performed a cross-sectional study of 100 patients (age range, 7-80 years) with asthma. We administered a questionnaire to identify characteristics of asthma, performed spirometric testing before and after administration of a bronchodilator, and measured exhaled NO levels in all participants. RESULTS: Exhaled NO was significantly correlated with the following markers of asthma disease control: asthma symptoms within the past 2 weeks (P =.02), dyspnea score (P =. 02), daily use of rescue medications (P =.01), and reversibility of airflow obstruction (P =.02). Exhaled NO levels were not correlated with the following markers of asthma disease severity: history of respiratory failure (P =.20), health care use (P =.08), fixed airflow obstruction (P =.91), or a validated asthma severity score (P =.19). Markers with relevance to both disease control and severity showed either a weak correlation (FEV(1) and FEV(1) percent predicted) or no correlation (controller drug use) with exhaled NO. CONCLUSION: We conclude that exhaled NO levels are correlated predominantly with markers of asthma control rather than asthma severity. Monitoring of exhaled NO may be useful in outpatient asthma management.     

The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge

BACKGROUND: The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma. OBJECTIVES: To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure. METHODS: In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 mug), formoterol (12 mug), budesonide (400 mug), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured. RESULTS: All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV(1) fall: placebo, [mean +/- SEM] 21.2% +/- 3.1%; budesonide/formoterol, 4.2% +/- 1.4%; formoterol, 7.5% +/- 1.7%; budesonide, 10.4% +/- 1.6%). Allergen-induced change in methacholine PC(20) was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response. CONCLUSION: A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen. CLINICAL IMPLICATIONS: The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles.     

Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children.

BACKGROUND: Inhaled glucocorticosteroids (GCS) are the most effective long-term controller medications for the treatment of persistent asthma. Currently, however, available delivery devices limit their use in young children. A nebulized formulation of budesonide has been developed to address the needs of infants and young children. OBJECTIVE: To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS. METHODS: Three hundred fifty-nine children were randomized to receive once-daily budesonide inhalation suspension (0.25 mg, 0.50 mg, or 1.0 mg) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks. Efficacy assessments included nighttime/daytime asthma symptoms, pulmonary function (subset of patients), rescue medication use, and treatment discontinuations. Safety was based on adverse events and assessment of HPA-axis function. RESULTS: Demographics, baseline characteristics, asthma symptoms, and pulmonary function were similar across treatment groups. Mean nighttime/daytime asthma symptom scores were 1.19 +/- 0.63 and 1.34 +/- 0.53, respectively. Mean duration of asthma was 36.3 months and mean FEV1 was 81.3% of predicted with 27.7% reversibility. Following 12 weeks of treatment, all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms (P < or = .049) and significant decreases in rescue medication use (P < or = .038) compared with placebo. Significant improvements (P < or = .044) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups. There were no differences between doses of budesonide inhalation suspension. Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups. CONCLUSION: Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments.     

A comparative study in atopic subjects with asthma of the effects of salmeterol and salbutamol on allergen-induced bronchoconstriction, increase in airway reactivity, and increase in urinary leukotriene E4 excretion.

Salmeterol (SM) is a novel beta 2-adrenoceptor agonist with a duration of action in excess of 12 hours. Evidence from in vitro studies has also demonstrated that, unlike the short-acting beta 2-agonists, such as salbutamol (SB), it may have some anti-inflammatory properties. With a randomized, double-blind, crossover design, we have compared the inhibitory effects of SM (50 micrograms) and SB (200 micrograms) delivered by metered-dose inhaler on allergen-induced bronchoconstriction, changes in airway reactivity, and urinary leukotriene (LT) E4 excretion in 12 atopic subjects with mild asthma. The immediate bronchoconstriction to allergen was significantly reduced by both beta 2-agonists (p less than 0.005), when reduction was expressed either in terms of maximum fall in FEV1 at 15 minutes after allergen (percent fall in FEV1, mean +/- SEM: 6.2 +/- 4.9, SM; 5.7 +/- 2.5, SB; 40.4 +/- 6.3, placebo) or the area under the FEV1 time curve (AUC) for the first 120 minutes after allergen. Four hours after challenge, results in the SB-treated and placebo-treated groups were not significantly different and demonstrated a small persistent bronchoconstriction compared to bronchodilatation in the SM-treated group (percent fall in FEV1, respectively, 9.3 +/- 3.7, 14.3 +/- 7.1, and -6.3 +/- 2.7; p less than 0.005, SM versus SB; p less than 0.02, SM versus placebo). Expressed in terms of AUC, only SM significantly reduced bronchoconstriction in the period 120 to 240 minutes after allergen (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Relation between exhaled carbon monoxide levels and clinical severity of asthma

Carbon monoxide (CO) can be detected in exhaled air and is increased in asthmatic patients not treated with corticosteroids. However, it is uncertain whether exhaled CO is related to severity of asthma. To study whether exhaled CO is related to severity of asthma in clinical courses, exhaled CO concentrations were measured on a CO monitor by vital capacity manoeuvre in 20 mild asthmatics treated with inhaled beta2-agonists alone, 20 moderate asthmatics treated with inhaled corticosteroids, and 15 stable asthmatics treated with high dose inhaled corticosteroids and oral corticosteroids once a month over 1 years. Exhaled CO concentrations were also measured in 16 unstable severe asthmatics who visited the hospital every 7 or 14 days for treatment with high dose inhaled corticosteroids and oral corticosteroids. The mean values of exhaled CO in severe asthma over 1 year were 6.7 +/- 9.5 p.p.m. (n = 31, mean +/- SD) and significantly higher than those of non-smoking control subjects (1.2 +/- 0.9 p.p.m., n = 20, P < 0.01). Exhaled CO concentrations in unstable severe asthmatics were significantly higher than those in stable severe asthmatics. However, exhaled CO concentrations in mild and moderate asthmatics did not differ significantly from those in non-smoking control subjects (P > 0.20). There was a significant relationship between the exhaled CO concentrations and forced expiratory volume in one second in all asthmatic patients. These findings suggest that exhaled CO concentrations may relate to the severity of asthma and measurements of exhaled CO concentrations may be a useful means of monitoring airway inflammation in asthma.