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Airway Responsiveness (airway + responsiveness)

Distribution by Scientific Domains

Medical Sciences	100%

Distribution within Medical Sciences

Allergy & Clinical Immunology	59%
Respiratory Medicine	25%

Selected Abstracts

Reproducibility of Airway Responsiveness in Horses Using Flowmetric Plethysmography and Histamine Bronchoprovocation

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2009
R. D. Nolen-Walston
Background: Inflammatory airway disease has a high prevalence in horses, but is often a diagnostic challenge. Flowmetric plethysmography and histamine bronchoprovocation (FP/HBP) is a simple and effective tool for diagnosis, but reproducibility of these measurements made over time has not been established. Hypothesis: We hypothesize that the measurement of airway responsiveness in horses using FP/HBP is consistent over both short and long periods of time. Animals: Twenty-nine healthy adult horses from 2 university herds. Methods: In this prospective experimental study, airway responsiveness was determined in each horse at day 0 (baseline [BL]) with FP/ HBP, using PC35 (provocative concentration of histamine needed to increase ,flow by 35%) as a measure of airway responsiveness. Each horse was re-tested 1,4 weeks after BL (short-term [ST]) and again at 3,12 months after BL (long-term [LT]). Results: In the ST period, 23/27 (85%) of the horses had a PC35 that was within 1 doubling concentration of histamine of their BL value, with a mean change of 0.52 doubling concentrations (95% CI 0.26,0.79, range 0,2.06). For the LT data, 19/26 (73%) of horses were within 1 doubling concentration of their BL value, with a mean change of 0.81 doubling concentrations (95% CI 0.45,1.17, range 0.14,3.10). There was no significant difference in reproducibility between the 2 groups of subjects. Conclusions and Clinical Importance: Repeated measurements of airway responsiveness obtained with FP/HBP show acceptable reproducibility over time periods up to a year. However, caution must be used when testing horses when ambient air temperature is low. [source]

Prolonged Allergen Challenge in Murine Nasal Allergic Rhinitis: Nasal Airway Remodeling and Adaptation of Nasal Airway Responsiveness

THE LARYNGOSCOPE, Issue 5 2007
Muneo Nakaya MD
Abstract Background: Nasal airway remodeling exists in allergic rhinitis, but it appears to be far less extensive than in asthma. However, there has been little study about nasal airway remodeling and no study using mice models. It has been reported that airway hyperresponsiveness decreased after prolonged allergen challenge in a chronic murine asthma model together with the progression of remodeling. However, there has been no study of the relation of remodeling and airway responsiveness in nasal allergy. Therefore, we have undertaken this investigation to characterize nasal airway structural changes after prolonged allergen challenge and to examine the relationship between nasal airway hyperresponsivity and remodeling. Methods: We prepared murine allergic rhinitis for ovalbumin. Mice were subsequently challenged three times a week with ovalbumin from day 19 to days 53, 88, and 130. We examined allergen-induced nasal symptoms and objective nasal hyperresponsiveness using the enhanced pause system. Moreover, the pathologic changes were investigated after allergen challenge. Results: The extended allergen challenge protocol caused significant nasal airway remodeling. Specifically, remodeling was characterized by goblet cell hyperplasia and deposition of collagen in the submucosal area. Allergen-induced nasal hyperresponsiveness was first increased but gradually decreased in nasal symptoms and Penh after prolonged allergen challenge. Conclusions: We have demonstrated that a remodeling of nasal mucosa in a murine allergic rhinitis model prolonged allergen exposure. Moreover, prolonged allergen exposure induced a reduction of nasal hyperresponsiveness together with a progression of nasal remodeling. [source]

Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma

ALLERGY, Issue 1 2010
A. Tomkinson
Abstract Background:, Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4R, and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum -sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action. Methods:, Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment. Results:, Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC100 relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05,0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC100 relative to control (P < 0.05) at nominal b.i.d. doses of 3,100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control. Conclusion:, Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma. [source]

Reproducibility of Airway Responsiveness in Horses Using Flowmetric Plethysmography and Histamine Bronchoprovocation

Rhinitis: a complication to asthma

ALLERGY, Issue 7 2010
J. W. Hansen
To cite this article: Hansen JW, Thomsen SF, Nolte H, Backer V. Rhinitis: a complication to asthma. Allergy 2010; 65: 883,888. Abstract Background:, Asthma and rhinitis often co-occur, and this potentially increases the disease severity and impacts negatively on the quality of life. We studied disease severity, airway responsiveness, atopy, quality of life and treatment in subjects with both asthma and rhinitis compared to patients with asthma or rhinitis alone. Methods:, We examined 878 patients: 182 with asthma, 362 with rhinitis and 334 with both asthma and rhinitis. All had a clinical interview concerning severity of symptoms, treatment, and quality of life, a skin prick test, a lung function test and a bronchial provocation with methacholine. Results:, Patients with both asthma and rhinitis had less severe asthma based on the frequency of respiratory symptoms compared to patients with asthma alone (55%vs 66%P = 0.01). On the contrary, they were more airway responsive (P < 0.05) and had more perennial allergy (P < 0.001). Asthmatics had poor perception of the general health, independent of rhinitis (P < 0.001). No differences were found in asthma-specific quality of life, whereas rhinitis-specific quality of life was worse in those with both asthma and rhinitis compared to those with rhinitis alone (P < 0.01). Subjects with both diseases were undertreated in 85% of the cases. Conclusion:, We encourage that these observations be used in the evaluation and treatment of patients with asthma and rhinitis and that they contribute to the understanding of asthma and rhinitis as a uniform airways disease. [source]

A quantitative genetic analysis of intermediate asthma phenotypes

ALLERGY, Issue 3 2009
S. F. Thomsen
Aim:, To study the relative contribution of genetic and environmental factors to the correlation between exhaled nitric oxide (FeNO), airway responsiveness, airway obstruction, and serum total immunoglobulin E (IgE). Methods:, Within a sampling frame of 21 162 twin subjects, 20,49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins) who either themselves and/or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Traits were measured using standard techniques. Latent factor models were fitted to the observed data using maximum likelihood methods. Results:, Additive genetic factors explained 67% of the variation in FeNO, 43% in airway responsiveness, 22% in airway obstruction, and 81% in serum total IgE. In general, traits had genetically and environmentally distinct variance structures. The most substantial genetic similarity was observed between FeNO and serum total IgE, genetic correlation (,A) = 0.37, whereas the strongest environmental resemblance was observed between airway responsiveness and airway obstruction, specific environmental correlation (,E) = ,0.46, and between FeNO and airway responsiveness, ,E = 0.34. Conclusions:, Asthma is a complex disease characterized by a set of etiologically heterogeneous biomarkers, which likely constitute diverse targets of intervention. [source]

The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma

ALLERGY, Issue 9 2008
M. Duong
Background:, IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. Methods:, Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. Results:, When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV1%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively (P < 0.01). The degree of attenuation in the EAR [maxFEV1% (mean ± SE) 26.5 ± 2.8%vs placebo 31.0 ± 2.8%, P = 0.059] and LAR (15.6 ± 2.9%vs placebo 19.0 ± 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. Conclusions:, The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated. [source]

Distinct association of genetic variations of vascular endothelial growth factor, transforming growth factor-,, and fibroblast growth factor receptors with atopy and airway hyperresponsiveness

ALLERGY, Issue 4 2008
H.-K. Park
Background:, Recent studies showed that high levels of transforming growth factor (TGF)-,1 in the airways reduced airway responsiveness, which was reversed in conditions of basic fibroblast growth factor (FGF2) deficiency, whereas high levels of vascular endothelial growth factor (VEGF) enhanced airway sensitization to allergens and airway hyperresponsiveness (AHR). Objective:, We investigated the effect of single-nucleotide polymorphisms (SNPs) in the VEGF, TGF-,1, and FGF2 receptors on the expression of atopy and AHR in the general population. Methods:, Atopy and AHR were evaluated in a cohort of 2055 children and adolescents. Direct sequencing was used to identify informative SNPs (minor allele frequency >5%) in the receptors of candidate genes. Tagging SNPs were scored using the high-throughput single-base pair extension method, and the statistical significance of these scores was assessed via haplotype analysis. Results:, Informative SNPs were identified for VEGF receptors 1 (Flt-1); TGF-, receptor 3 (TGFBR3); and FGR receptors 1, 2, and 4 (FGFR1, FGFR2, and FGFR4), and 13 tagging SNPs were scored in the cohort. Atopy was significantly associated with haplotypes of TGFBR3, FGFR1, and FGFR2. Meanwhile, AHR was significantly associated with haplotypes of Flt-1, FGFR1, and FGFR4. However, atopy was not associated with genetic variations of Flt-1 and FGFR4, whereas AHR not associated with TGFBR3 and FGFR2. Conclusion:, The expression of atopy and AHR is distinctly associated with genetic variations in VEGF, TGF-,1, and FGFR in the Korean population. [source]

Today's allergic rhinitis patients are different: new factors that may play a role

ALLERGY, Issue 9 2007
R. Mösges
Most of today's patients suffering from allergic rhinitis (AR) are sensitized to more than one trigger and suffer from persistent and moderate/severe symptoms, which severely impair their quality of life (QOL). The objective of this article was to review the data on the effect of increased air pollution, changes in indoor environment/lifestyle/affluence, exposure to new allergens and psychologically stressful lifestyles, as also to explore their potential in the development of this more ,aggressive' form of disease. Increased fossil fuel-generated air pollution may increase the risk of allergic sensitization, airway responsiveness to allergens, and allergenicity and the bioavailability of airborne allergens. Changes in indoor environment/lifestyle/affluence appear to have led to more time being spent indoors and resulted in perennial exposure to indoor allergens, changes in sensitization patterns, and polysensitization to a variety of novel cross-reacting exotic food and pet allergens. Although evidence suggests an association between psychological stress and increased risk for atopy and allergic disease, further studies are required to demonstrate this unequivocally. The more persistent and moderate/severe nature of the disease suggests a need for modification of current treatment strategies and advocacy of the use from the outset of agents, which are both efficacious and safe in managing severe and persistent AR symptoms and in improving the QOL of affected individuals. [source]

The potential use of spirometry during methacholine challenge test in young children with respiratory symptoms

PEDIATRIC PULMONOLOGY, Issue 7 2009
Daphna Vilozni PhD
Abstract Background The concentration of methacholine that causes a fall of 20% from baseline forced expiratory volume in the first second (PC20-FEV1) in the methacholine challenge test (MCT) is not usually considered a diagnostic tool in preschool children since PC20-FEV1 may not be achievable <6 years of age. Aim To assess the usefulness of various spirometry indices obtained during MCT in a large group of 3- to 6-year-old children with respect to their clinical diagnosis. Methods Standardized MCT (inhaled triple-concentration increments [0.057,13.925 mg] of methacholine solution) was performed by 84 children previously diagnosed with asthma (asthmatics) and 48 with prolonged cough (coughers). Spirometry was determined at baseline and between inhalations; PC20-FEV1 and PC25-FEV0.5 were calculated. Results PC20-FEV1 values were significantly less in the asthmatics than in the coughers (mean,±,SD was 3.21,±,4.32 vs. 22.35,±,3.66 ml/mg). Similarly, PC25-FEV0.5 was 1.48,±,3.08 in the asthmatics and 9.45,±,12.59 mg/ml/Mch in the coughers, P,<,0.0001. A cut-off at 4.0 mg/ml for PC20-FEV1 had 77.4% sensitivity and 75.0% specificity, a cut-off at 2.2 mg/ml for PC25-FEV0.5 had 73.8% sensitivity and 72.9% specificity, for clinical diagnosis of asthma. PC25-FEV0.5 also showed a correlation with age. Conclusions Our findings suggest that MCT can be performed in preschool children with various respiratory symptoms. PC25-FEV0.5 may be a better end-point parameter. Children with a clinical diagnosis of asthma respond to a lower MCT concentration than children with cough. Further studies are needed to determine airway responsiveness in healthy young children and to further assess the contribution of MCT to the clinical diagnosis in this age group. Pediatr Pulmonol. 2009; 44:720,727. © 2009 Wiley-Liss, Inc. [source]

Chronic inhaled corticosteroids do not affect the course of acute severe asthma exacerbations in children,

PEDIATRIC PULMONOLOGY, Issue 12 2006
Christopher L. Carroll MD
Abstract Chronic therapy with inhaled corticosteroids (ICS) suppresses airway inflammation and increases airway responsiveness to ,2 -adrenergic receptor agonists. We hypothesized that the chronic use of ICS would be associated with shorter duration of hospitalization in severely ill children with status asthmaticus. An 8-year retrospective chart review was conducted of all children admitted to the ICU with status asthmaticus. During the study period, 241 children were admitted, and 44% reported the use of chronic ICS. ICS use was associated with increased baseline asthma severity, previous hospitalization for asthma, and public insurance status. However, ICS use had no effect on hospital or ICU length of stay, type, and duration of treatments received, or the rate of recovery determined by a standard severity of illness scoring system. In the subsets of patients including children with persistent asthma and those who received intravenous terbutaline, there was also no improvement in outcomes with the use of chronic ICS showing that the chronic use of ICS did not improve response to ,2 -adrenergic receptor agonists in severely ill children with status asthmaticus. Although useful as a preventive therapy, the chronic use of ICS does not appear to affect the course of severe acute asthma exacerbations in pediatric patients once hospitalized. Pediatr Pulmonol. 2006; 41: 1213,1217. © 2006 Wiley-Liss, Inc. [source]

Modifier genes in cystic fibrosis

PEDIATRIC PULMONOLOGY, Issue 5 2005
J.C. Davies MD
Abstract Although over 1,000 disease-causing mutations in the CFTR gene have been described, the highly variable disease phenotype in cystic fibrosis (CF) cannot be explained on the basis of this gene alone. Both the environment and other non-CFTR genes are likely to be important. The increased understanding of pathophysiological processes in the CF lung has led to several studies on genes in these pathways, including those involved in host defense, mucin production, and airway responsiveness. Additionally, candidate modifiers of the gastrointestinal manifestations of CF have been explored. One of the major aims of such studies is to produce targets for novel drug developments. This review will summarize the field to date and discuss some of the methodological issues important in the design and interpretation of such studies. Pediatr Pulmonol. © 2005 Wiley-Liss, Inc. [source]

Extrathoracic airway responsiveness in children with asthma-like symptoms, including chronic persistent cough

PEDIATRIC PULMONOLOGY, Issue 3 2002
Ipek Turktas MD
Abstract Asthma-like symptoms, including chronic persistent cough, are not always specific for classical asthma. In order to investigate whether assessment of extrathoracic airway hyperresponsiveness (EAHR) during methacholine bronchial challenge helped in the evaluation of pediatric patients with asthma-like symptoms such as chronic cough, we examined 133 consecutive, unselected patients (mean age, 10.06,±,2.16 years) who had neither established asthma nor bronchial obstruction previously. We recorded the forced mid-inspiratory flow (FIF50) as an index of extrathoracic airway narrowing. In addition, a 25% decrease in FIF50 (PD25FIF50) below the cutoff concentration of ,,8 mg/mL methacholine was assumed to indicate EAHR. According to the methacholine response, 81 patients had EAHR, and 41 of them had combined EAHR and bronchial hyperresponsiveness (BHR); 39 patients had only BHR. Airway hyperresponsiveness was not demonstrated in 13 patients and not in any of the control children. When patients with cough as the sole presenting symptom (60.9%) were compared with those with cough and wheeze (20.3%), those with cough alone had a significantly greater probability of having EAHR (OR, 4.16; 95% CI, 1.32,13.13) and a lower probability of having BHR (OR, 0.70; CI, 0.25,1.95) than those with cough and wheeze. Patients with cough, wheeze, and dyspnea (18.8%) had a significantly greater chance of having BHR than those with cough alone (OR, 5.08; CI, 1.55,16.64). Patients with cough and wheeze as compared with those with cough, wheeze, and dyspnea had significantly greater probability of having both EAHR and BHR (OR, 4.71; CI, 1.94,11.47). In order to ascertain the clinical relevance of EAHR, we assessed in the second part of the study whether the effects of treatment of the underlying disease would result in relief of airway hyperresponsiveness. Rhinosinusitis and perennial allergic rhinitis accounted for EAHR in 71 patients, and 34 of them also demonstrated BHR. They received specific therapy for their upper airway diseases for 4 weeks. Compared with values before treatment, FIF50 and forced expiratory volume in 1 sec (FEV1) did not change significantly. The dose of methacholine causing a 20% fall in FEV1 (PD20FEV1) and PD25FIF50 values were significantly increased from 2.40,±,1.39 to 4.22,±,1.13 mg /mL (P,<,0.001) and from 1.03,±,1.75 to 8.71,±,1.21 mg /mL (P,<,0.0001), respectively. We conclude that measurements of EAHR and BHR are the most important ways to evaluate children with asthma-like symptoms, including chronic persistent cough when chest X-rays and pulmonary function tests remain within normal limits. Therefore, empirical treatment is not necessary when these investigations are available. Our results suggest that specific treatment of inflammation in the upper airways reversed persistant cough, and may play an important role in modulating lower airways responsiveness in patients with concomitant BHR. Pediatr Pulmonol. 2002; 34:172,180. © 2002 Wiley-Liss, Inc. [source]

Respiratory morbidity and lung function in two Aboriginal communities in Western Australia

RESPIROLOGY, Issue 3 2002
Marieke W. VERHEIJDEN
Objective: To examine differences in the rates of respiratory symptoms, asthma and levels of lung function in two remote Aboriginal communities. Methodology: Respiratory symptoms, smoking history, skin prick test responses to common allergens, serum IgE, lung function, airway responsiveness to methacholine and white blood cell counts were compared in two Aboriginal communities, one from the central desert (n = 84) and another from the tropical north (n = 209) of Western Australia. Results: Compared with the tropical community, chest tightness and dyspnoea were more frequent and forced expiratory volume in 1 s and forced vital capacity were lower in the desert community, despite similar levels of wheeze, doctor-diagnosed asthma and skin prick test responses and lower levels of airway responsiveness and smoking. The total white cell and neutrophil counts were greater in the desert community. Serum IgE was very high and similar in both communities. Conclusions: Our findings show a low prevalence of asthma in children, a high prevalence of respiratory symptoms and low levels of lung function in remote Aboriginal communities. The greater prevalence of respiratory morbidity in the desert community was not explained by diagnosed asthma, airway hyperresponsiveness or cigarette smoking. The role of infection requires further investigation. The results suggest that the lower lung function observed in Aboriginal communities (compared with non-Aboriginal communities) results at least partly from environmental factors. [source]

Airway hyperresponsiveness: the usefulness of airway hyperresponsiveness testing in epidemiology, in diagnosing asthma and in the assessment of asthma severity

THE CLINICAL RESPIRATORY JOURNAL, Issue 1 2007
Celeste Porsbjerg MD
Abstract The present PhD thesis was conducted at the Respiratory Research Unit at the Pulmonary Department L in Bispebjerg Hospital, Copenhagen, Denmark and describes airway hyperresponsiveness in asthma patients in four studies. The first study concerned risk factors for the development of asthma in young adults in a 12-year prospective follow-up study of a random population sample of 291 children and adolescents from Copenhagen, who were followed up from the age of 7,17 years (1986) until the age of 19,29 years (1998). During follow-up, 16.1% developed asthma, and in these subjects, the most important predictor of asthma development was airway hyperresponsiveness to histamine at baseline. Airway hyperresponsiveness is associated with more severe asthma and a poorer prognosis in terms of more exacerbations and less chance of remission of the disease. The second study described the relation between airway hyper-responsiveness to methacholine and the quality of life in 691 asthma patients: In asthma patients with airway hyperresponsiveness to methacholine, the quality of life measured with a validated questionnaire (Junipers Asthma Quality of Life Questionnaire) was significantly reduced compared to asthma patients who did not respond to bronchial provocation with methacholine. Airway hyperresponsiveness is not uncommonly observed in non-asthmatics, and the response to bronchial provocation with methacholine is therefore relatively non-specific. The mannitol test is a relatively new bronchial provocation test that acts indirectly on the smooth airway muscle cells through the release of mediators from inflammatory cells in the airways; the mannitol could consequently be a more specific test compared with methacholine. The third study showed that out of 16 non-asthmatics with airway hyperresponsiveness to methacholine, 15 did not respond to bronchial provocation with mannitol Because of the mechanism of action of mannitol, it seems plausible that the response to mannitol is more closely correlated to airway inflammation in asthma compared with the response to methacholine. The fourth study showed that in 53 adult asthma patients, who did not receive treatment with inhaled steroids, there was a positive correlation between the degree of airway inflammation and the degree of airway responsiveness to mannitol as well as to methacholine. The mannitol does, however, have the advantage of being a faster and simpler test to perform, requiring no additional equipment apart from a spirometer. Conclusions:, Airway hyperresponsiveness in children and in adolescents without asthma predicts asthma development in adulthood. Asthma patients with airway hyperresponsiveness to methacholine have a poorer quality of life as well as more severe disease and a poorer prognosis compared with asthma patients without airway hyperresponsiveness. Bronchial provocation with mannitol as well as with methacholine were useful for evaluating the severity of asthma and the degree of airway inflammation, and accordingly for determining the need for steroid statement. The mannitol test does, however, have practical advantages over the methacholine test that make it preferable for clinical use. [source]

Prolonged Allergen Challenge in Murine Nasal Allergic Rhinitis: Nasal Airway Remodeling and Adaptation of Nasal Airway Responsiveness

Mannitol challenge for assessment of airway responsiveness, airway inflammation and inflammatory phenotype in asthma

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2010
L. G. Wood
Summary Background Assessment of airway inflammation in asthma is becoming increasingly important, as the inflammatory phenotype underpins the treatment response. Objective This study aimed to evaluate mannitol as a tool for assessing airway responsiveness and airway inflammation in asthma, compared with hypertonic saline. Methods Fifty-five subjects with stable asthma completed a hypertonic (4.5%) saline challenge and a mannitol challenge at two separate visits, performed 48,72 h apart, in random order. Results Induced sputum was obtained from 49 (89%) subjects during the saline challenge and 42 (76%) subjects during the mannitol challenge (P>0.05). There was a significant correlation between the greatest percentage fall in forced expiratory volume in 1 s (FEV1) (r=0.6, P<0.0001), the dose,response slope (r=0.73), cumulative dose (r=0.55) and PD15 (r=0.46) for mannitol and hypertonic saline. The greatest percentage fall in FEV1 to mannitol was less in non-eosinophilic asthma. There was a lower total cell count in mannitol vs. hypertonic-saline-induced sputum. However, sputum eosinophils and neutrophils were not significantly different. Using mannitol, a higher proportion of subjects were classified as having eosinophilic asthma. There were no differences in IL-8, neutrophil elastase or matrix-metalloproteinase 9 concentrations in sputum samples induced with mannitol or hypertonic saline. Conclusion We conclude that mannitol can be used to induce good-quality sputum, useful for analysis of inflammatory mediators and for predicting the inflammatory phenotype in asthma. Cite this as: L. G. Wood, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2010 (40) 232,241. [source]

The definition and diagnosis of Asthma

CLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2009
F. E. Hargreave
Summary The diagnosis of asthma depends on what we mean by the word. Its definition continues to be controversial because there is no single genetic or environmental cause. Addressed from a descriptive point of view, the disease components include airway inflammation, symptoms, variable airflow limitation and chronic airflow limitation. The essentialist definition conveys the message that asthma is a separate disease entity, fails to identify a primary defining characteristic which separates it from other diseases and is long winded. These disadvantages are overcome by the nominalist definition of asthma in which the word ,asthma'refers to an abnormality of airway function, specifically to wide variations in airflow limitation over short periods of time. In patients with asthma the other components of airway disease need to be considered. These have separate nominalist definitions and especially include different types of bronchitis for airway inflammation and chronic obstructive pulmonary disease for chronic airflow limitation. What is present will vary between and within patients. The accurate diagnosis of asthma and of other components of disease all require objective measurements. Currently spirometry and airway responsiveness should be available to the general practitioner, who sees milder disease, and additional quantitative sputum cell counts in specialist practice, where moderate to severe disease is more prevalent. Such measurements characterize the patient, identify heterogeneity and allow treatment to be personalized. [source]

Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study

CLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2009
J. A. Hirota
Summary Background Asthma is a disease characterized by variable and reversible airway obstruction and is associated with airway inflammation, airway remodelling (including goblet cell hyperplasia, increased collagen deposition and increased smooth muscle mass) and increased airway responsiveness. It is believed that airway inflammation plays a critical role in the development of airway remodelling, with IL-13 and TGF-,1 pathways being strongly associated with the disease progression. Mouse models of asthma are capable of recapitulating some components of asthma and have been used to look at both IL-13 and TGF-,1 pathways, which use STAT6 and SMAD2 signalling molecules, respectively. Objectives Using brief and chronic models of allergen exposure, we utilized BALB/c and C57Bl/6 to explore the hypothesis that observed differences in responses to allergen between these mouse strains will involve fundamental differences in IL-13 and TGF-,1 responses. Methods The following outcome measurements were performed: airway physiology, bronchoalveolar lavage cell counts/cytokine analysis, histology, immunoblots and gene expression assays. Results We demonstrate in BALB/c mice an IL-13-dependent phosphorylation of STAT6, nuclear localized in inflammatory cells, which is associated with indices of airway remodelling and development of airway dysfunction. In BALB/c mice, phosphorylation of SMAD2 is delayed relative to STAT6 activation and also involves an IL-13-dependent mechanism. In contrast, despite an allergen-induced increase in IL-4, IL-13 and eosinophils, C57Bl/6 demonstrates a reduced and distinct pattern of phosphorylated STAT6, no SMAD2 phosphorylation changes and fail to develop indices of remodelling or changes in airway function. Conclusion The activation of signalling pathways and nuclear translocation of signalling molecules downstream of IL-13 and TGF-,1 further support the central role of these molecules in the pathology and dysfunction in animal models of asthma. Activation of signalling pathways downstream from IL-13 and TGF-,1 may be more relevant in disease progression than elevations in airway inflammation alone. [source]

,2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children

CLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2004
S. W. Turner
Summary Background We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function. Objective The current study aimed to determine whether the Arg16Gly polymorphism of the ,2 adrenoceptor (,2AR) gene was important to this relationship. Methods A cohort that initially numbered 253 individuals underwent assessments of AR and lung function aged 1 month, 6 and 11 years; genotyping for polymorphisms of the ,2AR was performed. Results At 1 month of age, the genotype homozygous Arg16 (n=24) was associated with a mean increase in log dose,response slope (AR) of 0.27 [95% confidence interval (CI) 0.07, 0.49] compared with the genotype homozygous Gly16 (n=58), P=0.01. At 11 years of age, the genotype homozygous Arg16 (n=35) was associated with a mean reduction in the percentage of forced expiratory volume in 1 s of 5.3% [95% CI 0.3, 10.2] compared with the genotype homozygous Gly16 (n=65), P=0.03. There was no association between the Arg16Gly polymorphism and atopy or diagnosed asthma. However, nine of 69 individuals with the genotype homozygous Gly16 were admitted to hospital with asthma compared with five out of 111 individuals with the remaining genotypes (P<0.05). Conclusion The Arg16Gly polymorphism may be important to the association between increased AR in infancy and reduced lung function in childhood and may also be a determinant of asthma severity in children but not asthma per se. [source]

Mycobacterium vaccae administration during allergen sensitization or challenge suppresses asthmatic features

CLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2003
J. J. Smit
Summary Background and objective The hygiene hypothesis suggests that a lack of bacterial infections would favour the development of allergic disease. For this reason, bacteria or their components can be used as potential treatment for allergic asthma. We investigated whether heat-killed Mycobacterium vaccae is either able to suppress the induction of allergic asthma or able to suppress already established allergic asthma. Methods Mice were sensitized with ovalbumin (OVA)/alum on days 0 and 14. Thereafter, mice were challenged on days 35, 39 and 42 by inhalation of either OVA or saline aerosols. M. vaccae -treated mice received an injection with 106, 107 or 108 CFU heat-killed M. vaccae on days 0 and 14 or 107 CFU on days 35 and 39. On day 43, the airway responsiveness of the mice to increasing concentrations of methacholine was assessed, blood was withdrawn to measure serum parameters, and lung lavage was performed to detect cytokines and inflammatory cell number. Results Treatment of OVA-sensitized mice with 107 CFU M. vaccae either during sensitization or challenge suppresses airway hyper-responsiveness, airway eosinophilia and IL-5 production after OVA challenge. The increases in OVA-specific serum IgE and in IL-4 by respiratory challenges with OVA were only diminished after M. vaccae treatment (107 CFU) during sensitization. Conclusions Heat-killed M. vaccae prevents allergic and asthmatic manifestations in a mouse model and, more importantly, M. vaccae treatment during challenge suppresses features of asthma, which opens up possibilities for new therapeutic interventions. [source]

The NK-2 receptor antagonist SR 48968C does not improve adenosine hyperresponsiveness and airway obstruction in allergic asthma

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2001
J. Kraan
When stimulated, excitatory nonadrenergic noncholinergic (e-NANC) nerves locally release tachykinins like Neurokinin (NK) A and Substance P, causing neurogenic inflammation and airway obstruction via activation of specific NK-1 and NK-2 receptors. The recently developed nonpeptide NK-2 receptor antagonist SR 48968C has a high affinity for the NK-2 receptor, and is a strong and selective antagonist of NK-2 receptor mediated airway obstruction. In a placebo-controlled cross-over study, we investigated the effect of SR 48968C, administrated orally once-daily in a dosage of 100 mg during 9 days, on airway responsiveness to adenosine 5,-monophosphate (AMP) in 12 allergic asthmatic patients. Furthermore, we assessed its effect on airway obstruction, by measuring FEV1 on the first and last day of each treatment period and by peak flow registration at home throughout the study period. SR 48968C had no significant effect on PC20AMP or on FEV1 measured on day 1 and 9, and morning and evening peakflow measured at home on day 2,8. Thus, although SR 48968C was administrated in a dosage that might cause a demonstrable blocking effect on airway NK-2 receptors in asthma, it did not have a significant bronchodilatory or bronchoprotective effect against adenosine hyperresponsiveness in this study. Further studies are needed to assess the value of SR 48968C and other NK receptor antagonists in the treatment of asthma [source]

Serum immunoglobulin E levels predict human airway reactivity in vitro

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2000
Schmidt
Background Airway hyperresponsiveness to non-specific stimuli is one characteristic feature of airway diseases such as bronchial asthma and chronic bronchitis. Until now, studies aiming to demonstrate a relationship between in vivo conditions associated with airway hyperreactivity and in vitro airway responsiveness have been inconclusive. Objective Since serum immunoglobulin (Ig) E is believed to be one determinant of airway reactivity in vivo, we studied whether in vitro airway reactivity in lung resection material from patients with elevated levels of serum IgE was increased as compared with patients with undetectable IgE. By this approach, we aimed to elucidate the role of circulating IgE for bronchial smooth muscle reactivity in vitro. Methods Bronchial rings from nine patients with total serum IgE levels above 200 U/mL and 10 patients with total serum IgE levels below 10 U/mL were passively sensitized, i.e. incubated overnight with buffer or sensitizing serum containing high levels of total IgE (> 250 U/mL). Afterwards, contractile responses to histamine were assessed in the organ bath. Results Histamine responsiveness was significantly increased in airways obtained from patients with IgE levels above 200 U/mL as compared with airways from patients with IgE levels below 10 U/mL (P < 0.05). Passive sensitization of bronchi from patients with low IgE significantly increased histamine responsiveness, as compared with non-sensitized controls from the same patients (P < 0.05). In contrast, passive sensitization of airways from patients with elevated IgE did not further increase responsiveness. There was no difference in histamine reactivity between non-passively sensitized and passively sensitized tissue preparations from patients with IgE above 200 U/mL and passively sensitized tissues from patients with IgE below 10 U/mL. Conclusion Our findings reveal that elevated levels of serum IgE predict airway hyperresponsiveness to histamine in vitro. At the same time, they indicate that the in vitro model of passive sensitization, in addition to its ability to induce allergen responses, also mimics conditions of non-specific airway hyperreactivity, which are relevant under in vivo conditions. [source]

Extrathoracic airway responsiveness in children with asthma-like symptoms, including chronic persistent cough

The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome

CLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2004
P. Taramarcaz
Summary Background Allergic rhinitis (AR) and asthma often coexist and may represent two manifestations of the same disease recently named combined AR and asthma syndrome (CARAS). Aim To review the common pathophysiology of combined AR and asthma and to investigate the efficacy of intranasal corticosteroids (INCS). Methods Medline was used to identify articles relevant to mechanisms. A Cochrane systematic review was performed to assess the efficacy of INCS in CARAS. Results There is cross-talk, evidence of a common inflammatory response in both sites, linked by a systemic component. The efficacy of anti-inflammatory INCS on asthma outcomes was assessed in a systematic review of 12 randomized controlled trials involving 425 subjects. After INCS there were non-significant trends for improvement in asthma symptom score (standardized mean difference (SMD) of 0.61; P=0.07), forced expiratory volume in 1 s (SMD of 0.31; P=0.08), and morning peak expiratory flow (weighted mean difference of 36.51; P=0.06). There was no impact on methacholine airways responsiveness (SMD of ,0.20; P=0.4). The review identified two promising new treatment options in united airway disease such as INCS as monotherapy in rhinitis and mild asthma, and a combined intranasal and intrabronchial corticosteroid (IBCS) deposition technique. Conclusion Common mucosal inflammatory responses occur in CARAS. This systematic review shows trends for a benefit of INCS in CARAS, but recognizes that more research is needed. At this stage, the current best practice is to treat asthma conventionally with IBCS with or without ,2 -agonist and to add INCS to improve specific rhinitis symptoms. [source]