Development of a tool predicting severity of allergic reaction during peanut challenge.

BACKGROUND: Reliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFCs) have not been established. OBJECTIVE: To develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC. METHODS: Medical history and allergy test results were obtained for 120 peanut allergic participants who underwent double-blind, placebo-controlled food challenges. Reactions were assigned a CSS between 1 and 6 based on cumulative tolerated dose and a severity clinical indicator. Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multistep analysis to derive a flexible decision rule to understand risk during peanut of OFC. RESULTS: A total of 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following 3 variables (in order of importance) as predictors of reaction severity: ratio of percentage of CD63hi stimulation with peanut to percentage of CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (P < .001). CONCLUSION: The CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Laboratory values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFCs. Further testing of this decision rule is needed in a larger external data source before it can be considered outside research settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02103270.

Indices of nonspecific bronchial reactivity in severe asthma phenotype determination in schoolchildren.

OBJECTIVE: Introduction: Severe asthma phenotype is characterized by peculiarities of inflammatory process in the airways and consequently hypersensitivity and bronchial lability. The aim: The study aims at determining the diagnostic value of bronchial lability indices in identifying severe bronchial asthma phenotype compared to the moderate variant of disease in schoolchildren. PATIENTS AND METHODS: Materials and methods: We formed two clinical groups of observation, the first clinical group included 57 children with severe asthma phenotype, the second clinical group included 65 patients with moderate disease course. Bronchial lability was determined by evaluating their response to dosed physical activity (bronchospasm index) and shortacting ß2-agonist inhalation (200 mcg of salbutamol - bronchodilation index). RESULTS: Results: Despite the lack of probable differences in average bronchospasm index in children of comparison groups, patients with severe bronchial asthma tended to more pronounced bronchospasm after dosed physical activity. Pronounced bronchospasm after physical activity (bronchospasm index >20%) is characteristic for children with severe disease persistence. Significantly higher bronchodilation index and severe bronchodilation reaction (bronchodilation index >25%) was determined in children of the first clinical group. Statistical analysis showed that all bronchial lability indices at these distribution points in confirming severe bronchial asthma proved to be highly specific, but low-sensitive with insufficient likelihood ratio. CONCLUSION: Conclusions: So, the use of bronchial lability indices for screening of severe asthma phenotype is justified only in combination with other parameters reflecting the characteristic phenomena of disease because of the large proportion of false negative results and insufficient likelihood ratio.

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.

Increased density of intraepithelial mast cells in patients with exercise-induced bronchoconstriction regulated through epithelially derived thymic stromal lymphopoietin and IL-33.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect airway hyperresponsiveness. Mast cells are implicated in EIB, but the characteristics, regulation, and function of mast cells in patients with EIB are poorly understood. OBJECTIVES: We sought to examine mast cell infiltration of the airway epithelium in patients with EIB and the regulation of mast cell phenotype and function by epithelially derived cytokines. METHODS: Endobronchial biopsy specimens, epithelial brushings, and induced sputum were obtained from asthmatic patients with and without EIB and healthy control subjects. Mast cell proteases were quantified by using quantitative PCR, and mast cell density was quantified by using design-based stereology. Airway epithelial responses to wounding and osmotic stress were assessed in primary airway epithelial cells and ex vivo murine lung tissue. Mast cell granule development and function were examined in cord blood-derived mast cells. RESULTS: Tryptase and carboxypeptidase A3 expression in epithelial brushings and epithelial mast cell density were selectively increased in the asthma group with EIB. An in vitro scratch wound initiated the release of thymic stromal lymphopoietin, which was greater in epithelial cells derived from asthmatic patients. Osmotic stress induced the release of IL-33 from explanted murine lungs, which was increased in allergen-treated mice. Thymic stromal lymphopoietin combined with IL-33 increased tryptase and carboxypeptidase A3 immunostaining in mast cell precursors and selectively increased cysteinyl leukotriene formation by mast cells in a manner that was independent of in vitro sensitization. CONCLUSIONS: Mast cell infiltration of the epithelium is a critical determinant of indirect airway hyperresponsiveness, and the airway epithelium might serve as an important regulator of the development and function of this mast cell population.

Eotaxin in exhaled breath condensate of allergic asthma patients with exercise-induced bronchoconstriction.

BACKGROUND: Eosinophils are the key inflammatory cells in asthma, and more and more evidence suggests their crucial role in exercise-induced bronchoconstriction (EIB). Eotaxin, as the most important chemotactic factor for eosinophils, plays an important role in the pathogenesis of asthma. OBJECTIVES: The aim of the study was to evaluate the changes in eotaxin levels in exhaled breath condensate (EBC) following intensive exercise in allergic asthmatics. METHODS: The study was performed in a group of 27 asthmatics (17 with EIB, 13 without EIB) and 9 healthy volunteers. Changes induced by intensive exercise in the concentrations of eotaxin in EBC during the 24 h after an exercise test were assessed. The possible correlations of these measurements with the results of other tests commonly associated with eosinophilic airway inflammation were also determined. RESULTS: In asthmatic patients with EIB, a statistically significant increase in eotaxin concentrations in EBC collected during the first 24 h after an exercise test - with maximal increase after 6 h - was revealed. A statistically significant correlation between the maximum increase in eotaxin concentrations in EBC after exercise, and an increase in either serum eosinophil cationic protein or F(ENO) 24 h after exercise in the group of asthmatics with EIB, was observed. CONCLUSIONS: Our results confirm connections between EIB and airway eosinophilic inflammation. The increase of eotaxin in asthmatic airways, by promoting the migration and activation of eosinophils, may play an important role in upregulation and sustaining of the airway inflammation observed in EIB in asthmatic patients.

Wheat-dependent, exercise-induced anaphylaxis in Thai children: a report of 5 cases.

Wheat is not an uncommon cause of food-dependent, exercise-induced anaphylaxis. This study aims to describe common clinical characteristics and laboratory manifestations of the disease. Five children, aged 8-14 years were evaluated. An atopic history was found in 20% of the patients. All patients had symptoms which involved the skin and three had hypotension. Serum specific IgE for wheat was measured and showed a positive result in 2 patients. A three-day challenge protocol with an open challenge for wheat on day 1, an exercise challenge test on day 2 and another exercise challenge test on day 3 after a meal containing wheat was performed. Four patients completed the three-day challenge protocol. Anaphylaxis occurred in 2 out of 4 patients who consumed more than 100 grams of wheat prior to the exercise. The three-day challenge protocol is a definitive diagnostic tool to confirm the diagnosis of WDEIA. However, the amount of wheat used for challenging should be at least 100 grams.

Pediatric athletic asthmatics.

The main goals of this review are to help the reader to recognize the common symptoms and signs of exercise-induced asthma and the common objective tests used to confirm or rule out the diagnosis and to understand that different forms and intensities of exercise have different asthmagenicity. The review also aims to help the reader to recognize some of the theories of exercise-induced asthma's pathogenesis, to recognize management strategies (including medications), and to be able to identify medications placed on the 2008 prohibited list by the World Anti-Doping Agency and their therapeutic exemptions. It is also important to understand that respiratory symptoms associated with exercise are not necessarily asthma and that through safe participation in physical exercise, athletic asthmatics can excel in competitive sports.

Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes.

Exercise-induced bronchoconstriction (EIB) is a consequence of evaporative water loss in conditioning the inspired air. The water loss causes cooling and dehydration of the airway surface. One acute effect of dehydration is the release of mediators, such as prostaglandins, leukotrienes, and histamine, that can stimulate smooth muscle, causing contraction and a change in vascular permeability. Inspiring cold air increases dehydration of the surface area and causes changes in bronchial blood flow. This article proposes that the pathogenesis of EIB in elite athletes relates to the epithelial injury arising from breathing poorly conditioned air at high flows for long periods of time or high volumes of irritant particles or gases. The evidence to support this proposal comes from many markers of injury. The restorative process after injury involves plasma exudation and movement of cells into the airways, a process repeated many times during a season of training. This process has the potential to expose smooth muscle to a wide variety of plasma- and cell-derived substances. The exposure to these substances over time can lead to an alteration in the contractile properties of the smooth muscle, making it more sensitive to mediators of bronchoconstriction. It is proposed that cold-weather athletes have airway hyperresponsiveness (AHR) to pharmacologic agents as a result of epithelial injury. In those who are allergic, AHR can also be expressed as EIB. The role of beta(2)-receptor agonists in inhibiting and enhancing the development of AHR and EIB is discussed.

Eosinophils play a major role in the severity of exercise-induced bronchoconstriction in children with asthma.

Exercise-induced bronchoconstriction (EIB) was associated with eosinophilic airway inflammation, bronchial hyperresponsiveness (BHR), atopy and airway obstruction. To understand the pathogenesis of EIB, we determine whether eosinophil is more related to the mechanism of EIB than atopy, BHR and airway obstruction. This study comprised 268 asthmatic children who underwent lung function test, methacholine challenge test, exercise challenge test, and blood tests for total IgE levels and total eosinophil counts (TEC). Urine eosinophil protein X (EPX) levels after exercise were measured by using ELISA method. EIB was observed in 195 of 268 asthmatics (72.8%). Asthmatics with EIB showed significantly increased TEC (P < 0.01) and decreased log PC(20) as compared with asthmatics without EIB. Maximal percent fall in FEV(1) after exercise was significantly correlated with TEC, log IgE, FEF(25-75%), log PC(20) (P < 0.001, respectively) and FEV(1) (P = 0.013). When the same study was carried out in nonatopic asthmatics, those with EIB showed significantly increased TEC (P = 0.01) compared with those without EIB; however, log PC(20), FEV(1), and FEF(25-75%) showed no significant differences between the two groups of nonatopic asthmatics. In addition, there was a significant correlation between the severity of EIB and TEC in nonatopic asthmatics. Urine EPX/Cr levels after exercise were correlated with the severity of EIB (r = 0.238, P = 0.014). Blood eosinophils and urine EPX/Cr after exercise correlate significantly with the maximal percent fall in FEV(1) after exercise, therefore EIB may reflect a state of eosinophilic inflammation in the airway of asthmatic children.

Effect of body mass on exercise-induced bronchospasm and atopy in African children.

BACKGROUND: Sensitization to allergen is common in rural populations in less affluent countries, but atopic disease is less frequent than in richer countries. Variables explaining this dichotomy may provide insight into underlying mechanisms of atopic diseases like asthma. OBJECTIVE: To test whether risk of exercise-induced bronchospasm (EIB) in urbanized African populations is increased in association with greater skin sensitivity or increased body mass. METHODS: A total of 3322 children were enrolled in a prevalence survey of EIB in urban and rural South Africa. Children responding positively to an exercise challenge and a random sample of children responding negatively were recruited into a case-control study (393 controls, 380 cases). Subjects were investigated by using allergen skin prick testing, anthropometry, and assay of IgE. Stools were analyzed for parasite infestation. RESULTS: The prevalence of EIB was higher in urban (14.9%) than rural (8.9%) areas (P < .0001). The difference in risk of EIB between urban and rural subjects was associated with atopy (odds ratio [OR] for upper tertile of skin wheal diameter, 2.65; 95% CI, 1.43-4.89; P < .0001), increasing weight (OR for upper tertile of body mass index [BMI], 2.17; 95% CI, 1.45-3.26; P = .001), and affluence. Increasing BMI was also associated with a greater strength of association between specific IgE and the corresponding skin test (Dermatophagoides pteronyssinus, OR for a positive skin test result in presence of specific IgE: heavier subjects, OR, 34.6; 95% CI, 0.9-109.3; P < .0001; lighter subjects, OR, 8.05; 95% CI, 2.74-23.6; P < .001). CONCLUSION: Increases in BMI of rural children in subsistence economies may lead to an increased prevalence of atopic disease. This observation merits further investigation in prospective studies.

Airway immunopathology of asthma with exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a common cause of symptoms in a subgroup of asthmatic subjects. The pathobiology that makes this group of asthmatic subjects susceptible to bronchoconstriction after a brief period of exercise remains poorly understood. OBJECTIVE: We sought to determine whether there are differences in lower airway inflammation and production of cytokines and eicosanoids between asthmatic subjects with and without EIB. METHODS: Two distinct groups of asthmatic subjects based on a priori definitions were identified, one with moderate-to-severe EIB and the other without significant bronchoconstriction after exercise challenge. Both groups met the definition of asthma on the basis of bronchodilator response, bronchial hyperresponsiveness, or both. A comparative immunopathology study was conducted by using induced sputum to identify differences in lower airway inflammation and production of cytokines and eicosanoids. RESULTS: The groups had similar baseline lung function and bronchodilator response and did not have any asthma exacerbations within the prior year. The concentration of columnar epithelial cells was markedly higher in the group with EIB (1.4 x 10(5) vs 2.9 x 10(4) cells/mL, P=.01). The concentration of eosinophils was higher in the group with EIB (3.6 x 10(4) vs 4.9 x 10(3) cells/mL P=.04). Cysteinyl leukotrienes (CysLTs; 727.7 vs 151.9 pg/mL, P=.01) and the ratio of CysLTs to prostaglandin E(2) (1.85 vs 1.04, P=.002) in the airways were higher in the group with EIB. CONCLUSION: Injury to the airway epithelium, overexpression of CysLTs, relative under production of prostaglandin E(2), and greater airway eosinophilia are distinctive immunopathologic features of asthma with EIB.

Lower airway inflammatory responses to high-intensity training in athletes.

PURPOSE: There is an increased prevalence of asthma and airway hyperresponsiveness in elite athletes, particularly in swimmers. High intensity exercise may induce airway inflammation and subsequent remodelling in these subjects. Our aim was to evaluate the effects of high-intensity training on induced-sputum cell populations in elite athletes. METHODS: Swimmers and runners with hyperresponsive airways (SH and RH), defined by a provocative concentration of methacholine inducing a 20% decrease in FEV1 (PC20) <16 mg/ml or with normoresponsive airways (PC20 > 16 mg/ml; SN, RN) to methacholine were enrolled. The mean PC20 was 2.27 mg/ml in SH (n=12), 32.2 in SN (n=10), 3.25 in RH (n=10) and 41.5 in RN (n=13). All athletes had two induced sputum analyses at one- to two-week intervals in random order: after a period of 72 hours without training, 24 hours after a training session. RESULTS: PC20 was unchanged after training. The median % neutrophils and eosinophils in groups SH, SN, RH, and RN, respectively, were 26.5-1.6, 8.6-0.3, 28.0-0.03 and 25.5-0.1 before and 45.0-0.5, 31.1-0.4, 54.0-0.6 and 48.3-0.3 after training. While the magnitude of the increase in neutrophils was similar for all groups, it reached statistical significance (pre-post-training) only in the SH group (P = 0.039). CONCLUSION: A one-hour session of high-intensity training was associated with an increase in airway neutrophils among hyperresponsive swimmer athletes, while airway responsiveness remained unchanged in all groups.

Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients.

BACKGROUND: There is evidence that the bronchial microcirculation has the potential to contribute to the pathophysiological mechanisms of exercise induced bronchoconstriction (EIB) in asthmatic subjects. Vascular endothelial growth factor (VEGF), which is highly expressed in asthmatic airways, increases vascular permeability. The relationship between VEGF levels in induced sputum and the severity of EIB in asthmatic subjects was studied. METHODS: The concentration of VEGF in induced sputum was examined in 23 asthmatic subjects and 11 normal controls. The asthmatic subjects performed an exercise test and the % maximal fall in forced expiratory volume in 1 second (FEV(1)) was measured. Beclomethasone dipropionate (BDP) 400 micro g twice daily was administered to the asthmatic subjects for 8 weeks and the exercise test and sputum induction were repeated. RESULTS: The concentration of VEGF in induced sputum was significantly higher in asthmatic subjects than in normal controls. There was a significant correlation between the concentration of VEGF and the % maximal fall in FEV(1) (r=0.826, p=0.0001) and between the concentration of VEGF and airway vascular permeability index (r=0.621, p=0.0037). After treatment with inhaled BDP there was a significant decrease in the concentration of VEGF in the asthmatic subjects (before treatment: 7051 (2361) pg/ml, after treatment: 4498 (2135) pg/ml, p<0.0001). The change in the concentration of VEGF was significantly correlated with the change in the % maximal fall in FEV(1) (r=0.463, p=0.031). CONCLUSIONS: Excessive production of VEGF in asthmatic airways may contribute to the pathogenesis of EIB via increased airway vascular permeability.

Effects of single-dose fluticasone on exercise-induced asthma in asthmatic children: a pilot study.

A single high dose of inhaled corticosteroid (ICS) can increase airway caliber in children with asthma attacks and laryngitis subglottica. Presumably the effect is due to the vasoconstrictive and antiedematous properties of topical steroids. Enlarged vessels have been suggested to play a role in the pathophysiology of exercise-induced bronchial obstruction (EIB). To investigate this, we evaluated the effect of a single high dose of fluticasone propionate (FP) on EIB in asthmatic children. Nine children aged 8-16 years with mild to moderate asthma were included. All children had a history of EIB, which was confirmed by an exercise test. None was taking ICS maintenance therapy. The children inhaled either a single dose of 1 mg FP or placebo on 2 separate days within 7-14 days. After inhalation, airway caliber (FEV(1)) was assessed for 4 hr before exercise. Then an exercise challenge was performed on a treadmill to assess EIB (% fall FEV(1)). A significant increase in FEV(1) was observed 1 hr after inhalation of FP compared to placebo. Response to exercise was expressed as maximal % fall in FEV(1) from baseline (% fall) and as area under the curve (AUC) of the 30-min time/response curve. The % fall FEV(1) after exercise and the AUC were significantly reduced when FP was inhaled compared to placebo inhalation (% fall 9.7% vs. 19.2%, respectively, P = 0.038 and AUC 92.0%.min vs. 205.7%.min, respectively, P = 0.03). There was considerable individual variability in reduction of EIB, with 5 out of 9 children having a clinically significant response. We conclude that a single high dose of inhaled FP has an acute protective effect on the bronchial response to exercise in a substantial proportion of asthmatic children.

Exercise-induced bronchoconstriction among Malay schoolchildren.

OBJECTIVE: Exercise-induced bronchoconstriction (EIB) may be demonstrated in 60-70% of asthmatic children in temperate climates. In areas of high humidity it is postulated to be low. The aim of the study was to determine the prevalence of EIB in a population of schoolchildren with wheezing, living in the humid tropical climate of Kuala Lumpur, Malaysia. METHOD: We performed a cross-sectional study using the International Study of Asthma and Allergies in Childhood questionnaire to identify 7-12-year-old Malay children with asthma symptoms from a primary school in central Kuala Lumpur. Sixty-five of 76 children with 'ever wheeze' performed an exercise challenge test successfully in an uncontrolled environment. A random sample of 80 schoolchildren with no history of wheeze were similarly tested as controls. The relative humidity and temperature were recorded. A fall of > 15% was considered as clinically important. RESULTS: The prevalence of EIB in schoolchildren with 'ever wheeze' was 47.7%. The prevalence of EIB in children with 'current wheeze' was 51.6%. The prevalence of EIB in controls was 7.5%. The relative humidity during the study ranged from 41 to 90%. There was no significant relationship between different humidity levels and EIB (P = 0.58, regression analysis). CONCLUSION: This study demonstrates that EIB is present in asthmatic children despite the highly humid tropical environment.