Mannitol triggers mast cell-dependent contractions of human small bronchi and prostacyclin bronchoprotection.

BACKGROUND: Clinical research supports that exercise-induced bronchoconstriction (EIB) is caused by hyperosmolar triggering of mast cells. The reaction can be mimicked by inhalation of mannitol, but it has paradoxically previously not been possible to replicate this mode of action of mannitol in isolated airways. OBJECTIVE: We sought to establish an ex vivo model of EIB in human small bronchi. METHODS: Small bronchi (inner diameter, 0.5-2 mm) from macroscopically healthy human lung tissue were obtained from 48 patients and mounted in organ baths. Contractions and mediator release were analyzed after challenge with hyperosmolar mannitol (850 mOsm). RESULTS: Ten minutes of exposure to mannitol caused a small initial contraction (12% ± 1% of maximum) that was followed by a second and much larger contraction (maximum effect [Emax], 47% ± 5%) when mannitol was washed out. The mast cell stabilizer cromolyn reduced the second contraction (Emax, 27% ± 3%). Furthermore, this main contraction was abolished by the combination of antagonists of histamine and cysteinyl leukotrienes in the presence of indomethacin. Mannitol increased the release of the mast cell mediators histamine (9.0-fold), cysteinyl leukotrienes (4.5-fold), and prostaglandin (PG) D2 (5.4-fold), as well as PGE2 (6.3-fold) and the prostacyclin metabolite 6-keto PGF1α (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (Emax, 68% ± 6%). Likewise, receptor antagonists for PGE2 (EP2 and EP4) and prostacyclin (IP) also enhanced the mannitol-induced bronchoconstriction (Emax, 67% ± 5%, 66% ± 4%, and 68% ± 3%, respectively). In bronchi precontracted by carbachol, the IP receptor agonist cicaprost induced profound relaxation. CONCLUSION: This new protocol established an in vitro model for studies of EIB in isolated human bronchi. The IP receptor might be a new target for asthma treatment.

Exhaled nitric oxide and mannitol test to predict exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is diagnosed via exercise challenge on a treadmill, but such testing requires complex equipment and sufficient health-care resources. The fraction of exhaled nitric oxide (FeNO) test and mannitol bronchial provocation test (BPT) may serve as a surrogate for exercise testing. METHODS: We compared the diagnostic utilities of the FeNO test and mannitol BPT in predicting EIB in asthmatic children. We retrospectively analyzed data from 60 asthmatic children aged 6-16 years. We compared the exercise BPT results, FeNO levels, and mannitol BPT data. RESULTS: All subjects were divided into exercise-positive (n = 41) or -negative (n = 19) BPT groups. Of the 41 exercise-positive patients, 32 were mannitol BPT positive and nine were mannitol BPT negative. Of the 19 exercise-negative patients, nine and 10, respectively, were mannitol BPT positive and BPT negative. The maximum % forced expiratory volume in 1 s (FEV1 ) decrease after exercise was positively correlated with FeNO (r = 0.556, P < 0.001), and with mannitol response-dose ratio (RDR; r = 0.416, P = 0.001). The receiver operating characteristic (ROC) curve for FeNO to discriminate between asthmatic subjects with and without EIB had an area under the curve (AUC) of 0.771 (95%CI: 0.643-0.870). The discriminatory ROC curve for mannitol RDR had an AUC of 0.763 (95%CI: 0.633-0.864). The AUC of FeNO and mannitol RDR did not differ significantly. CONCLUSIONS: EIB significantly correlated with both FeNO and mannitol BPT data. Given that both methods similarly predicted EIB in asthmatic children, the simpler and safer FeNO test alone may be a clinically useful diagnostic tool.

Mechanisms and Biomarkers of Exercise-Induced Bronchoconstriction.

Exercise is a common trigger of bronchoconstriction. In recent years, there has been increased understanding of the pathophysiology of exercise-induced bronchoconstriction. Although evaporative water loss and thermal changes have been recognized stimuli for exercise-induced bronchoconstriction, accumulating evidence points toward a pivotal role for the airway epithelium in orchestrating the inflammatory response linked to exercise-induced bronchoconstriction. Overproduction of inflammatory mediators, underproduction of protective lipid mediators, and infiltration of the airways with eosinophils and mast cells are all established contributors to exercise-induced bronchoconstriction. Sensory nerve activation and release of neuropeptides maybe important in exercise-induced bronchoconstriction, but further research is warranted.

New insights into treatment of children with exercise-induced asthma symptoms.

BACKGROUND: Exercise is one of the most common triggers of bronchoconstriction and affects up to 80% of children with asthma. OBJECTIVE: The purpose of this randomized, double-blind, placebo-controlled study was to assess the effectiveness of treatment with ciclesonide 160 microgram, either alone, with a higher dose, with a leukotriene receptor antagonist (LTRA), or with a long-acting beta-agonist (LABA) in children with asthma with postexercise-induced symptoms. METHODS: Eighty adolescents, ages 1218 years, with asthma and postexercise symptoms were enrolled. Children were treated in one of four treatment groups: ciclesonide 160 microgram daily dose (cic 160), ciclesonide 320 microgram daily dose (cic 320), ciclesonide 160 microgram daily dose combined with montelukast (cic + LTRA), or ciclesonide 160 microgram daily combined with formoterol (cic + LABA). The impact of treatment on clinical symptoms, maximum percentage decrease in forced expiratory volume in 1 second after intense exercise effort, fractional exhaled nitric oxide in exhaled breath, and the contribution of inflammatory mediators in exhaled breath condensate were assessed. RESULTS: In children with asthma and with postexercise symptoms, 8-week daily administration of ciclesonide 320 microgram, ciclesonide 160 microgram plus LABA, and ciclesonide 160 microgram alone decreased daytime symptoms; decrease in maximal fall in forced expiratory volume in 1 second reached the level of significance in the cic 320, cic + LABA, and cic + LTRA groups. A higher prevalence of positive responses to treatment after addition of an LTRA or LABA to ciclesonide 160 microgram for patients with exercise treadmill challengeinduced clinical symptoms only was revealed. CONCLUSION: Monotherapy with ciclesonide 320 microgram can be as effective as combined therapy in reducing exercise-induced bronchoconstriction. We revealed a higher prevalence of positive responses to treatment after the addition of LTRA or LABA to ciclesonide 160 microgram for patients with exercise treadmill challengeinduced clinical symptoms only. ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.ClinicalTrials.gov"www.ClinicalTrials.gov/ext-link NCT01798823.

Increased Postexercise Lipoxin A4 Levels in Exhaled Breath Condensate in Asthmatic Children With Exercise-Induced Bronchoconstriction.

BACKGROUND: Lipoxins could be potential modulators of inflammation in the lungs. To our knowledge, the role of exhaled breath condensate (EBC) lipoxin A4 (LXA4) in asthmatic children with exercise-induced bronchoconstriction (EIB) has not been investigated. OBJECTIVE: The aim of our study was to determine the involvement of EBC LXA4 in EIB. METHODS: Forty-five patients aged between 5 and 17 years were included in the study. Patients were divided into 2 groups: asthmatic children with a positive response to exercise (n = 17) and asthmatic children with a negative response to exercise (n = 28). Levels of LXA4 were determined in EBC before and immediately after the exercise challenge using ELISA. RESULTS: EBC LXA4 levels were significantly increased immediately after exercise in asthmatic children with a positive response to the exercise challenge (P = .05). No significant differences were observed in children with a negative response to exercise (P > .05). There was an inverse correlation between LXA4 levels and the percent degree of reduction in forced expiratory volume in the first second (FEV1%) postexercise in children with a positive exercise challenge (P = .05, r = -0.50). No significant differences were observed in LXA4 levels between atopic and nonatopic asthmatics (P > .05, Mann-Whitney U test). CONCLUSIONS: Levels of EBC LXA4 increased immediately after exercise in asthmatic children with a positive exercise challenge response. We hypothesize that airway LXA4 levels increase to compensate bronchoconstriction and suppress acute inflammation, and that spontaneous bronchodilatation after EIB may be due to LXA4.

Damage-associated molecular pattern and innate cytokine release in the airways of competitive swimmers.

BACKGROUND: Daily intensive exercise by elite athletes can result in exercise-induced asthma especially in elite swimmers and this may be linked to epithelial damage. OBJECTIVE: To study airway epithelial damage and release of damage-associated molecular patterns (DAMPs) after intensive exercise in elite athletes and controls. METHODS: We recruited competitive swimmers (n = 26), competitive indoor athletes (n = 13) and controls (n = 15) without any history of asthma. Lung function was measured before, immediately after and 24 h after a 90-min intensive exercise protocol. Sputum induction was performed at baseline and 24 h after exercise. Exercise-induced bronchoconstriction (EIB) was assessed by the eucapnic voluntary hyperventilation test. RESULTS: Baseline sputum uric acid, high mobility group box-1, CXCL8 mRNA, sputum neutrophils and serum Clara cell protein-16 (CC-16) were significantly higher in competitive swimmers compared with controls. Intensive swimming for 90 min resulted in an increase of sputum IL-1ß, IL-6 and TNF mRNA in competitive swimmers, and of sputum IL-6 mRNA and sputum neutrophils in controls. Although all participants were asymptomatic, seven competitive swimmers, one indoor athlete and one control met the criteria for EIB. CONCLUSION: Our findings show that the intensive training combined with exposure to by-products of chlorination induces airway epithelial damage in competitive swimmers. This is associated with increased damage-associated molecular patterns, innate cytokine release and neutrophilic airway inflammation.

Prostaglandin E2 prevents hyperosmolar-induced human mast cell activation through prostanoid receptors EP2 and EP4.

BACKGROUND: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. OBJECTIVE: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. METHODS: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP(1-4) were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. RESULTS: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP(2) and EP(4) receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. CONCLUSIONS: Our data show a protective role for the PGE2 receptors EP(2) and EP(4) following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.

Exhaled breath condensate pH decreases during exercise-induced bronchoconstriction.

BACKGROUND AND OBJECTIVE: Exercise-induced bronchoconstriction (EIB) is the temporary narrowing of the airways caused by physical exercise. Its exact pathophysiology is unclear; however, acute changes in airways pH may play a role. Exhaled breath condensate (EBC) pH was suggested as a surrogate indicator for airway acid-base status, but its value is also affected by volatile molecules and respiratory droplet dilution. The aim of the study was to assess changes in EBC pH during EIB. METHODS: Twenty-two asthmatics who reported breathlessness following exercise and 16 healthy individuals participated in the study. Lung function test was performed and exhaled breath samples were collected for pH, dilution factor and volatile compound pattern measurements (Cyranose 320) pre-exercise and at 0, 10, 20 and 30 min after physical exercise challenge. Fractional exhaled nitric oxide was measured before exercise. RESULTS: EIB developed in 13 asthmatic subjects. In these participants, but not in the EIB-negative asthmatics (P = 0.51), EBC pH reduced significantly during exercise (P = 0.01). In addition, changes in EBC pH were related to the degree of bronchospasm in the EIB-positive group (P = 0.01, r = 0.68). Exhaled volatile pattern became altered (P < 0.05) during exercise in all subjects (asthmatics and controls). EBC pH changes were not related to EBC dilution or volatile compound pattern alterations (P > 0.05). CONCLUSIONS: The development of EIB was related to acute changes of EBC pH, which suggest the role of airway pH decrease in the pathophysiology of EIB. Exercise-induced changes in exhaled biomarkers suggest methodological precautions to avoid physical exercise before performing exhaled breath tests.

Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide.

RATIONALE: ß2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of ß2-agonists. OBJECTIVES: To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection. METHODS: A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 µg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB). MEASUREMENTS AND MAIN RESULTS: The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01). CONCLUSIONS: The LOB that occurs with chronic long-acting ß2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting ß2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).

Leptin and urinary leukotriene E4 and 9α,11ß-prostaglandin F2 release after exercise challenge.

BACKGROUND: Leptin-related effects on inflammation and bronchial hyperresponsiveness (BHR) in the human airway have not been demonstrated. OBJECTIVES: To investigate the relationship between the levels of serum leptin and BHR and urinary leukotriene E4 (LTE4) and 9α,11ß-prostaglandin F2 (9α,11ß-PGF(2)) release after exercise challenge in asthmatic children. METHODS: Eighty-six prepubertal children between 6 and 10 years old were enrolled and divided into 4 groups: 19 obese asthmatic children, 25 normal-weight asthmatic children, 21 obese nonasthmatic children, and 21 healthy controls. We measured serum leptin levels and urinary LTE4 and 9α,11ß-PGF2 levels in children before and 30 minutes after the exercise challenge. RESULTS: Serum leptin levels were significantly higher in obese asthmatic children compared with normal-weight asthmatic children. Significant increases in urinary levels of LTE4 and 9α,11ß-PGF2 were observed in obese asthmatic children after the exercise challenge. Although smaller than in obese asthmatic children, significant increases in the urinary levels of LTE4 and 9α,11ß-PGF2 were also observed in the normal-weight. Asthmatic children Logarithmic serum leptin values were significantly associated with the logarithmic maximum percentage change in forced expiratory volume in 1 second, the logarithmic urinary LTE4 change, and the logarithmic urinary 9α,11ß-PGF2 change from baseline to after exercise in both obese and normal-weight asthmatic children. CONCLUSION: The serum levels of leptin were significantly associated with BHR and urinary LTE4 and 9α,11ß-PGF2 release induced by exercise challenge in asthmatic children.

Exhaled nitric oxide indicates poorly athlete's asthma.

INTRODUCTION: In athletes, exercise-induced respiratory symptoms are common and their assessment is time and resource consuming. OBJECTIVE: The objective was to evaluate fractional concentration of exhaled nitric oxide (FENO) as a predictor of bronchial hyperresponsiveness (BHR) and of asthma. MATERIALS AND METHODS: Eighty-seven elite athletes and a control group of 87 sedentary patients with symptoms suggesting asthma underwent measurements of FENO and of BHR by using methacholine provocation test (MCH) and eucapnic voluntary hyperpnoea (EVH) (athletes) or histamine provocation test (HIST) (controls). RESULTS: In athletes, elevated FENO (>30 ppb) was not associated with lung function-confirmed asthma or with MCH positivity, but receiver operating characteristics (ROC) analysis showed some predictive value for EVH positivity [Area Under Curve (AUC) 0.652, 95% confidence interval (CI): 0.53 to 0.78, P = 0.020]. However, the sensitivity (55%) and the specificity (71%) were poor. In sedentary patients, FENO was significantly associated with both confirmed asthma and HIST positivity, ROC analysis showing FENO to be significantly predictive for HIST positivity (AUC 0.83, 95% CI: 0.70 to 0.96, P = 0.001) and for asthma (AUC 0.74, 95% CI: 0.63 to 0.85, P < 0.001). CONCLUSION: The results suggest that in contrast to sedentary patients, FENO seems to be a poor predictor of BHR and of clinical asthma in elite athletes. We find it unlikely that FENO could be a useful screening tool in athletes with exercise-induced respiratory symptoms.

Exhaled nitric oxide decreases during exercise in non-asthmatic children.

INTRODUCTION: Exhaled nitric oxide (FENO) measurements are recommended to be performed before spirometry and exercise challenge tests because forced breathing might influence FENO values. Information on the effect of exercise on FENO is lacking in non-asthmatic children. AIM: To investigate the effect on FENO of a standardized exercise challenge test on a treadmill in non-asthmatic children with and without allergic rhinoconjunctivitis (AR) symptoms. METHODS: From the case-control study 'Asthma and allergy among school children in Nordland', 330 non-asthmatic pupils age 8-16 years were enrolled. FENO was measured at baseline and at 1 min and 30 min after exercise challenge test by the single breath technique with EcoMedics Exhalazer® (Eco Physics, Duernten, Switzerland). RESULTS: Pair-wise comparison of FENO from baseline demonstrated a highly significant reduction in FENO post-exercise for all children at 1 min (27.4%) and at 30 min (16.1%) (P < 0.001). The AR group had a significantly higher decline in FENO value at 1 min post-exercise compared to the non-AR group, 4.2 parts per billion (ppb) vs 2.6 ppb (P < 0.001). Decline in FENO immediately post-exercise was more significant if baseline FENO was ≥ 20 ppb; mean reduction 9.9 (95% CI: 8.7-11.4) ppb. CONCLUSION: FENO is reduced by 27.4% immediately after a standardized treadmill exercise test in non-asthmatic children. Pupils reporting AR symptoms demonstrate a larger decline in FENO value at 1 min post-exercise compared to pupils without AR symptoms. These findings confirm that children should refrain from physical activity before FENO measurement.

Time spent in vigorous physical activity is associated with increased exhaled nitric oxide in non-asthmatic adolescents.

INTRODUCTION: Physical activity (PA) is important in preventing disease, but endurance elite athletes have increased prevalence of asthma and airway inflammation. OBJECTIVES: We aimed to determine if PA was associated with increased fractional exhaled nitric oxide (FENO ) in asthmatic and non-asthmatic adolescents. METHODS: FENO was recorded (Niox Mino®, Aerocrine AB, Stockholm, Sweden) in 169 adolescents (13-14 years) in a nested case-control analysis from the Environment and Childhood Asthma study, Oslo, 92 adolescents with and 77 without asthma. They underwent clinical examination, lung function measurements and treadmill run measuring peak oxygen uptake, and objectively recorded PA for four consecutive days. PA was classified as moderate, vigorous and very vigorous, and total number of hours of each category was recorded for each subject. Associations between FENO and PA were tested using linear robust multiple regression analyses. RESULTS: In non-asthmatic adolescents, FENO was associated with daily hours of vigorous to very vigorous (r=0.27, P=0.02) and very vigorous PAs (r=0.25, P=0.036) in bivariate analyses. In multivariate analyses, FENO was associated with vigorous to very vigorous PA [regression coefficients (95% confidence interval) 1.9 (0.6, 3.1); P=0.004] and more strongly with very vigorous PA [3.9 (1.5, 6.4); P=0.002] in non-asthmatic but not in asthmatic adolescents. Total daily PA was not associated with FENO in either group. Thus, 1 h of very vigorous PA per day increased FENO by 3.9ppb. CONCLUSION: Vigorous to very vigorous PA, contrasting total daily PA, was significantly associated with increased FENO in non-asthmatic adolescents, suggesting that intensive PA may induce airway inflammation independent of asthma.

Exhaled RANTES and interleukin 4 levels after exercise challenge in children with asthma.

BACKGROUND: Despite the universality and clinical significance of exercise-induced bronchospasm (EIB), the mechanisms responsible for it are incompletely understood. OBJECTIVE: To investigate the role of exhaled RANTES (regulated on activation, normal T-cell expressed and secreted) and interleukin (IL) 4 in EIB in children with asthma. METHODS: Fifty-six children with asthma were evaluated with exercise challenge and exhaled RANTES and IL-4 levels. Exhaled breath condensate was collected before and 30 minutes after exercise challenge. RANTES and IL-4 concentrations were determined using a specific immunoassay kit. RESULTS: A significant increase was found in RANTES levels after exercise challenge in the asthmatic children (P<.001). A statistically significant increase in RANTES levels was noted after exercise challenge in both the asthmatic children with EIB (n=25, P=.007) and in the non-EIB asthmatic group (n=31, P=.005). Our study revealed that exhaled RANTES level correlates significantly well with percentage of forced expiratory volume in 1 second (FEV1), exacerbation frequency, serum IgE, and body mass index. No statistically significant increase was found in IL-4 levels after exercise challenge. The maximal postexercise decrease in FEV1 strongly correlated with total eosinophil count (P<.001, r = -0.61) and baseline ratio of FEV1 to forced vital capacity (FVC) (P=.002, r=0.40). Results from multivariate regression analysis adjusted for age, sex, and atopy as covariates showed that eosinophil count and FEV1/FVC ratio were significantly associated with EIB. CONCLUSION: We found that exercise challenge, leading to hyperosmolar stimulus, may increase exhaled RANTES levels in children with asthma. In addition, exhaled RANTES levels correlate well with serum IgE, severity of asthma, FEV1/FVC ratio, and body mass index. RANTES and IL-4 may not be independent predictors for EIB. Furthermore, eosinophil count and FEV1/FVC ratio may predict the presence and severity of EIB in asthmatic children.

Bronchial and alveolar nitric oxide in exercise-induced bronchoconstriction in asthmatic children.

BACKGROUND: Epidemiological studies have shown an association between the severity of exercise-induced bronchoconstriction (EIB) and fractional exhaled nitric oxide at the flow of 50 mL/s (FeNO(50)). However, no study has assessed the correlation between alveolar production (C(alv)) and bronchial flux (J(NO)) of nitric oxide (NO) and EIB in asthmatic children. OBJECTIVE: To identify the relationship between severity of EIB and bronchial or alveolar nitric oxide. METHODS: Our group included 36 allergic children with intermittent asthma. The EIB was determined by a standard exercise challenge and the severity was expressed as the maximum change in percentage from the baseline value of lung function (ΔFEV(1)%, ΔFEF(25-75)%) after exercising. A chemiluminescence analyser at multiple flows was used to calculate FeNO(50), J(NO) and C(alv,) which reflect large airways, J(NO) and alveolar concentration of NO respectively. RESULTS: Sixteen (44.4%) children presented a ∆FEV(1) ≥ 10%, eight (22.2%) had ∆FEV(1) ≥ 15% and nine (25%) children had a ∆FEF(25-75) ≥ 26%. A significant correlation was observed between severity of EIB and FeNO(50) , J(NO) and C(alv.) EIB was significantly more severe in children sensitive to indoor allergens compared with outdoor allergens only (P = 0.014); those children showed also higher levels of C(alv) (P = 0.003) and of J(NO) (P = 0.044). CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that inflammation is present in the central and peripheral airways and that it is associated with the severity of EIB. Clinicaltrials.gov NCT00952835.

Strategies for molecular classification of asthma using bipartite network analysis of cytokine expression.

Asthma is a chronic inflammatory disease of the airways that leads to various degrees of recurrent respiratory symptoms affecting patients globally. Specific subgroups of asthma patients have severe disease leading to increased healthcare costs and socioeconomic burden. Despite the overwhelming prevalence of the asthma, there are limitations in predicting response to therapy and identifying patients who are at increased risk of morbidity. This syndrome presents with common clinical signs and symptoms; however, awareness of subgroups of asthma patients with distinct characteristics has surfaced in recent years. Investigators attempt to describe the phenotypes of asthma to ultimately assist with diagnostic and therapeutic applications. Approaches to asthma phenotyping are multifold; however, it can be partitioned into 2 essential groups, clinical phenotyping and molecular phenotyping. Innovative techniques such as bipartite network analysis and visual analytics introduce a new dimension of data analysis to identify underlying mechanistic pathways.

Fractional exhaled nitric oxide (FeNO) may predict exercise-induced bronchoconstriction (EIB) in schoolchildren with atopic asthma.

BACKGROUND: There is a need for the performance of exercise-induced bronchoconstriction (EIB) tests in the monitoring of childhood asthma control. We aimed to evaluate whether in children with atopic asthma, EIB can be predicted by one or more of the following parameters or by their combination: fractional exhaled nitric-oxide (FeNO), allergy profile, asthma treatment, total IgE serum concentration and eosinophil blood count (EBC). METHODS: It was a retrospective, cross-sectional study. We evaluated data from medical documentation of children with atopic asthma who had performed standardized spirometric exercise challenge test. RESULTS: One hundred and twenty six patients with atopic asthma, aged 5-18, were included in the analysis. There were two groups of patients: the EIB group (n=54) and the no-EIB group (n=72). The median FeNO level prior to exercise in the EIB group was 27.6 vs. 16.3 ppb in the no-EIB group (p=0.002). FeNO level higher than 16 ppb had the highest diagnostic value to confirm EIB. When using the FeNO level of >16 ppb, the sensitivity, specificity, negative predictive and positive predictive values for EIB were 83%, 46.9%, 74.2%, and 60%, respectively. In the EIB group, the degree of FeNO elevation did correlate positively with the absolute fall in FEV(1) (p=0.002; r=0.45). The FeNO value of >16 ppb, EBC value of >350 cell/mm(3) and allergy to house dust mites presented the highest odds ratios of EIB. However, the FeNO value of >16 ppb was the only independent odds ratio of EIB. CONCLUSIONS: Elevated FeNO level increased the odds of EIB in asthmatic schoolchildren, independently of other asthma severity markers and the intensity of anti-asthma therapy. It seems likely that FeNO measurement may act as a screening tool and help to prevent under-diagnosis and under-treatment of exercise-induced bronchoconstriction in schoolchildren with atopic asthma.

Exhaled breath temperature and exercise-induced bronchoconstriction in asthmatic children.

It has been hypothesized that exhaled breath temperature (EBT) is related to the degree of airway inflammation/remodeling in asthma. The purpose of this study was to evaluate the relationship between the level of airway response to exercise and EBT in a group of controlled or partly controlled asthmatic children. Fifty asthmatic children underwent measurements of EBT before and after a standardized exercise test. EBT was 32.92 ± 1.13 and 33.35 ± 0.95°C before and after exercise, respectively (P < 0.001). The % decrease in FEV(1) was significantly correlated with the increase in EBT (r = 0.44, P = 0.0013), being r = 0.49 (P < 0.005) in the children who were not receiving regular inhaled corticosteroids (ICS) and 0.37 (n.s.) in those who were. This study further supports the hypothesis that EBT can be considered a potential composite tool for monitoring asthma.