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.

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.

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.

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.

Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine.

Asthma-like symptoms, methacholine hyperresponsiveness, and use of asthma medication are prevalent in elite cross-country skiers. We quantitated mucosal inflammatory cell infiltration and tenascin expression in the subepithelial basement membrane in endobronchial biopsy specimens of the proximal airways from 40 elite, competitive skiers (mean: 17.5; range: 16 to 20 yr) without a diagnosis of asthma, in 12 subjects with mild asthma, and in 12 healthy controls, through immunohistochemistry and indirect immunofluorescence, respectively. All of the subjects were nonsmokers. T-lymphocyte, macrophage, and eosinophil counts were, respectively, greater by 43-fold (p < 0.001), 26-fold (p < 0.001), and twofold (p < 0.001) in skiers, and by 70-fold (p < 0.001), 63-fold (p < 0.001), and eightfold (p < 0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than twofold greater than in asthmatic subjects, and mast cell counts were not significantly different than in controls. Tenascin expression (as measured through the thickness of the tenascin-specific immunoreactivity band in the basement membrane) was increased in skiers (median: 6.7 microm; interquartile range [IQR]: 5.3 to 8.5 microm, p < 0.001) and asthmatic subjects (mean: 8.8 microm; IQR: 7.2 to 10.8 microm, p < 0. 001) compared with controls (mean: 0.8 microm; IQR: 0 to 3.1 microm) and did not correlate with inflammatory cell counts. Inflammatory changes were present irrespective of asthmalike symptoms, hyperresponsiveness, or atopy. Prolonged repeated exposure of the airways to inadequately conditioned air may induce inflammation and remodeling in competitive skiers.

Bronchoscopy and bronchoalveolar lavage findings in cross-country skiers with and without "ski asthma".

Bronchial hyperresponsiveness to methacholine with asthma-like symptoms ("ski asthma") is frequent in elite cross-country skiers. To further the understanding of "ski asthma", 10 nonasthmatic, nonatopic controls and 30 adolescent elite skiers were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Nine skiers were atopic without allergy symptoms. Compared with controls, the macroscopic inflammatory index in the proximal airways in skiers was three-fold greater (median (interquartile range) 3.0 (2.0-5.0) versus 1.0 (0.8-2.3), p=0.008). In the BAL fluid, skiers had significantly greater total cell (p<0.05) and percentage lymphocyte (p<0.01) and mast cell counts (p<0.05). Neutrophil and eosinophil counts were not significantly different and eosinophil cationic protein was not detected. Tumour necrosis factor-alpha and myeloperoxidase were detected in 12 (40%) and six (20%) skiers, respectively. In skiers with ski asthma, the inflammatory index was greater than in nonasthmatic skiers. Lymphocyte subtypes and activation markers, and concentration of albumin, fibronectin and hyaluronan were not different from those in controls. Cross-country skiers have a minor to moderate degree of macroscopic inflammation in the proximal airways at bronchoscopy and a bronchoalveolar lavage fluid profile which differs in several respects from healthy controls. Skiers with ski asthma tend to show even higher degrees of bronchial inflammation.

Efecto del ejercicio dinámico y estático sobre la función cardiorespiratoria en el paciente asmático / Effect of static and dynamic exercise on the cardiorespiratory function in the asthmatic

El ejercicio constituye un factor desencadenante del asma bronquial, pues representa un estímulo no farmacológico y no inmunológico, que puede producir episodios agudos de obstrucción de las vías aéreas en los pacientes asmáticos. El objetivo del presente estudio fue el de evaluar el efecto del ejercicio dinámico y estático, sobre la función respiratoria y cardiovascular en pacientes asmáticos adolescentes y adultos jóvenes, por ser este grupo etario, el que más frecuentemente se ve sometido a un alto nivel de actividad física. Se estudiaron 30 pacientes asmáticos leves a moderados (F=16; M=14) entre 10 y 30 años (E.P.=18,7), en condiciones estables al menos durante 14 días; sin recibir tratamiento con drogas broncodilatadoras durante 24 horas ni drogas preventivas por lo menos un mes antes. A los pacientes seleccionados se les evaluaban los parámetros espirométricos (VEF-lseg; CVF; PEFR), presión arterial y frecuencia cardíaca en condiciones basales y a los 3,5,10,15,30,60 y 120 minutos posterior a la realización de un ejercicio dinámico (15 minutos pedaleando en un engómetro) o ejercicio estático (elevar una columna de mercurió a 140 mmHg y mantener por 10 minutos). El ejercicio dinámico produjo un descenso de los tres parámetros respiratorios, siendo la respuesta mayor a los 3 minutos para el PEFR y CVF (11,49 por ciento y 6,93 por ciento respectivamente) y a los 10 minutos para el VEF-1seg de 6,29 por ciento (p mayor e igual 0.005) con relación al valor basal. El ejercicio estático produjo una disminución de los parámetros estudiados, pero en menor porcentaje que el ejercicio dinámico, pero estadísticamente significativos (p mayor e igual 0.05) en relación a los valores previos. La presión arterial sistólica se elevó con los dos tipos de ejercicio (p mayor e igual 0.001), la presión arterial diastólica ascendió más con el ejercicio estático que con el ejercicio dinámico y la frecuencia cardíaca se elevó con ambos tipos de ejercicio. En conclusión, ambos ejercicios tanto dinámico como estático lograron descender los parámetros de funcionalismo pulmonar, siendo la disminución más acentuada con el ejercicio dinámico y la presión arterial diastólica se eleva considerablemente con el ejercicio estático

Efecto del Salmeterol en el asma inducido por ejercicio / Effect of Salmeterol in the exercise induced asthma

El propósito de esta investigación fue analizar el nivel de protección y la duración de la acción de xinofoato de salmeterol en 16 pacientes (8-14 años) con asma inducida por ejercicio. Se efectuó una espirometría basal y después del ejercicio (realizado en cinta ergométrica durante 7') se efectuó otra espirometría a los 30' y una tercera a las 5 horas. Durante la misma semana, el mismo test fue realizado después de la administración de salmeterol, 50 µg (2 dosis). Los valores del FEV1 basales fueron comparados con los hallazgos con salmeterol y se los clasificó por el nivel de protección alcanzado. *Protección TOTAL (< 5 por ciento de disminución del FEV1). *Protección PARCIAL (< 10 por ciento de disminución del FEV1). *Protección NULA. Observándose a los 30': 12 casos (75 por ciento) con protección total, 3 casos (18,75 por ciento) con protección parcial y en 1 caso (6,25 por ciento), protección nula. Cinco horas después del ejercicio se observó: 10 casos (62,50 por ciento) con protección total, 5 casos (32,25 por ciento) con protección parcial, y 1 caso, sin protección. Se concluye que el salmeterol es una importante droga profiláctica dado que su efecto es prolongado no presenta efectos colaterales, siendo muy útil para los atletas asmáticos

Airway effects of local challenge with hypertonic saline in exercise-induced asthma.

Hypertonicity of airway lining fluid has been suggested as the stimulus for bronchoconstriction in exercise-induced asthma. We explored the airway effects of delivering a direct hypertonic stimulus to asthmatic airways via a fiberoptic bronchoscope, comparing hypertonic saline challenge by direct instillation with local aerosol delivery. A group of 18 asthmatic subjects responsive to inhaled hypertonic saline with a history of EIA were studied; the first 9 subjects received local challenge with hypertonic saline by direct instillation, and the next 9 subjects were challenged by local aerosol delivery. A control challenge with isotonic saline by either instillation or aerosol was performed at a same bronchoscopy. Local challenge with hypertonic saline by aerosol delivery was found to be more effective in inducing local bronchoconstriction (8 of 9 subjects) than instillation (2 of 6 subjects). Paired BAL fluid samples and bronchial biopsies were obtained in total of 11 and 9 subjects, respectively. Local challenge with hypertonic saline either by instillation or aerosol produced no significant change in histamine, tryptase, or PGD2 levels in BAL fluid or mast cell numbers and degranulation in bronchial biopsies. A significant correlation was observed between histamine levels in BAL fluid and airway responsiveness to inhaled hypertonic saline (rs = -0.59, p < 0.05). Bronchial biopsies showed evidence of extensive epithelial damage; however, this was not related to airway responsiveness to inhaled hypertonic saline.

Airway inflammation and occurrence of delayed bronchoconstriction in exercise-induced asthma.

We studied nine asthmatic patients with a history of exercise-induced asthma (EIA) in order to investigate whether inflammatory changes in the airways occur after exercise and are eventually associated with the development of a late-phase asthmatic response. On two separate study days, bronchoalveolar lavage (BAL), bronchial lavage (BL), and bronchial biopsy (BB) were performed 3 h after an exercise or a methacholine (MCh) challenge. On two other separate occasions, FEV1 was monitored for 12 h after identical exercise and MCh challenges not followed by BAL, BL, and BB. We found a greater percentage of eosinophils in BAL after exercise versus MCh challenge (p < 0.05). In five patients, BAL eosinophils after exercise were > or = 2% of total inflammatory and immunoeffector cells. In three of these patients an FEV1 fall > 20% of control was recorded 5 to 12 h after exercise. However, two of these patients had 2% or more eosinophils in BAL and similar late falls of FEV1 after MCh challenge. The percentage of degranulating mast cells in BB was higher (p < 0.05) after EIA than after MCh, but no significant differences were found in BL histamine and leukotrienes. We conclude that (1) exercise may enhance mast cell degranulation and eosinophilic inflammation of the airways, and (2) a delayed bronchoconstriction after exercise is not specific to EIA but is more likely the result of fluctuations in lung function associated with airway inflammation.

Enhancement of leukocyte cytotoxicity after exercise-induced asthma.

We have previously shown that there were elevations of neutrophil chemotactic activity (NCA) and increases in the percentages of neutrophil and monocyte complement rosettes after exercise-induced asthma (EIA). These observations suggested that leukocyte activation may occur after EIA, possibly as a result of the release of mast-cell-associated mediators. In the present study, we have attempted to establish whether neutrophils and monocytes are functionally altered after EIA as assessed by changes in their cytotoxic capacity. Cytotoxicity was assessed by a direct visual killing assay using opsonized (complement-coated) schistosomula of Schistosoma mansoni as target organisms. Neutrophils and mononuclear cells obtained from 8 patients after exercise-induced asthma (EIA+ve) had increased cytotoxicity for opsonized schistosomula for as long as 60 min after exercise. These changes were preceded by elevations in the concentrations of serum high molecular weight NCA (which were maximal at 10 min after exercise). In asthmatic patients who did not develop exercise-induced asthma (EIA-ve), no significant increases in neutrophil or mononuclear cell killing of schistosomula, or serum NCA concentrations, were observed. There was a highly significant correlation (p less than 0.001) between the reduction in FEV1 and the increases in neutrophil cytotoxicity. In 5 EIA+ve patients, administration of disodium cromoglycate (cromolyn) prior to the exercise task inhibited both the enhancement in neutrophil and mononuclear cell cytotoxicity, as well as the elevations in circulating NCA and the reductions in FEV1.(ABSTRACT TRUNCATED AT 250 WORDS)

Upper airway obstruction presenting as exercise-induced asthma.

A patient presented with a ten-year history of exercise-induced wheezing. After trials of metaproterenol and cromolyn failed to improve her symptoms, she was observed during exercise. She proved to have inspiratory stridor caused by collapse of the posterior aryepiglottic folds over the vocal cords during inspiration only following exercise. Symptoms primarily improved with physical conditioning. Further improvement came after treatment of her chronic rhinitis and post-nasal drip with a steroid nasal spray.