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Background and Objective: The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed to the bronchodilator effect of deep inspirations that are required between concentrations to measure lung function. Using oscillometry, the response to methacholine can be measured without deep inspirations. Conveniently, oscillometry can also dissociate the contribution of large versus small airways. Herein, oscillometry was used to assess the cumulative effect of methacholine in the absence of deep inspirations on large and small airways. Methods: Healthy and asthmatic volunteers underwent a multiple‐concentration methacholine challenge on visit 1 and a single‐concentration challenge on visit 2 using the highest concentration of visit 1. The maximal response was compared between visits to assess the cumulative effect of methacholine. The lung volume was also measured after the final concentration to assess hyperinflation. Results: In both healthy and asthmatic subjects, increases in resistance at 19 Hz (Rrs19), reflecting large airway narrowing, did not differ between the multiple‐ and the single‐concentration challenge. However, increases in resistance at 5 Hz (Rrs5) minus Rrs19, reflecting small airway narrowing, were 117 and 270% greater in the multiple‐ than the single‐concentration challenge in healthy (p = 0.006) and asthmatic (p < 0.0001) subjects, respectively. Hyperinflation occurred with both challenges and was greater in the multiple‐ than the single‐concentration challenge in both groups. Conclusion: Without deep inspirations, the effect of methacholine is cumulative on small airways but not on large airways. Lung hyperinflation and derecruitment may partially explain these different responses. [ABSTRACT FROM AUTHOR]

Diabetes has been reported to modulate the airway smooth muscle reactivity and lead to attenuation of allergic inflammatory response in the lungs. In this study, we aimed to study the effect of insulin on cell activation and airway responsiveness in patients with diabetes mellitus (DM). The airway contraction in rat model groups including a non‐DM group, a non‐DM+INDUCTION group, a DM+INDUCTION group and a DM+INDUCTION+INSULIN group was measured to observe the effect of insulin on airway responsiveness. Radioenzymatic assay was conducted to measure the levels of histamine, and ELISA assay was conducted to measure bronchial levels of interleukin (IL)‐1b, tumour necrosis factor (TNF)‐a, cytokine‐induced neutrophil chemoattractant (CINC)‐1, P‐selectin and β‐hexosaminidase. The tension in the main and intrapulmonary bronchi of DM+INDUCTION rats was lower than that of the non‐DM+INDUCTION rats, whereas the treatment of insulin partly restored the normal airway responsiveness to OA in DM rats. The release of histamine was remarkably suppressed in DM+INDUCTION rats but was recovered by the insulin treatment. Also, OA significantly increased the levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in non‐DM rats, whereas insulin treatment in DM+INDUCTION rats partly restored the normal levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in DM rats. Moreover, the expression of IR and IGF1R was evidently suppressed in DM rats, with the methylation of both IR and IGF1R promoters was aggravated in DM rats. Therefore, we demonstrated that DM‐induced hypermethylation inhibited mast cell activation and airway responsiveness, which could be reversed by insulin treatment. [ABSTRACT FROM AUTHOR]

Introduction: Whether nonasthmatic eosinophilic bronchitis (NAEB) shows response to bronchodilator (RB) remains unclear. Objectives: To investigate the RB and its relationship with clinical and pathophysiological features in NAEB. Methods: Fifty‐one patients with NAEB were assigned in a 2:1 ratio to receive oral bambuterol hydrochloride (n = 34, 10 mg, once daily, for 3 days) or matched placebo (n = 17) randomly, of whom 48 patients (32 with bronchodilator and 16 with placebo) completed the study. Sputum induction, spirometry and cough reflex sensitivity were measured. RB was considered when cough Visual analogue scale (VAS) score decreased 30% or more after treatment. Cough reflex sensitivity was defined as the lowest concentration of capsaicin inducing five coughings or more (C5), and presented as Log C5. Results: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (34.4% vs 6.3%, P < 0.05). The VAS score decreased significantly in patients with bronchodilator (median: 6.0‐3.0, P < 0.01). There was a significantly higher median Log C5 (2.7 vs 1.3, P < 0.05), and a higher trend of decline in FEV1% predicted and MMEF% predicted after bronchial provocation in patients with RB as compared with patients without RB. No significant differences in baseline percentages of sputum eosinophil were found between patients with RB and that without RB. Conclusions: One third of patients with NAEB respond well to bronchodilator treatment, which are related with lower cough reflex sensitivity and increased airway responsiveness. The relationship between NAEB and asthma needs to be investigated further. [ABSTRACT FROM AUTHOR]

Background Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. Methods Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhibition on allergic airway inflammation, hyperresponsiveness, and airway remodeling were analyzed in allergen-sensitized and airway-challenged mice. The effects of Syk inhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolated lungs of wild-type, PKCα-deficient, mast cell-deficient, or eNOS-deficient mice. Results Spleen tyrosine kinase expression was found in human and murine airway smooth muscle cells. Syk inhibition reduced allergic airway inflammation, airway hyperresponsiveness, and pulmonary collagen deposition. In naïve mice, Syk inhibition diminished airway responsiveness independently of mast cells, or PKCα or eNOS expression and rapidly reversed established bronchoconstriction independently of NO. Simultaneous inhibition of Syk and PKC revealed additive dilatory effects, whereas combined inhibition of Syk and rho kinase or Syk and p38 MAPK did not cause additive bronchodilation. Conclusions Spleen tyrosine kinase inhibition directly attenuates airway smooth muscle cell contraction independent of its protective immunomodulatory effects on allergic airway inflammation, hyperresponsiveness, and airway remodeling. Syk mediates bronchoconstriction in a NO-independent manner, presumably via rho kinase and p38 MAPK, and Syk inhibition might present a promising therapeutic approach in chronic asthma as well as acute asthma attacks. [ABSTRACT FROM AUTHOR]

Maternal obesity prior to and during pregnancy has been associated with an increased incidence of childhood asthma. As diets rich in saturated fat are linked to obesity and inflammation, we created a murine model to investigate the effect of maternal high-fat diet (HFD) on adult offspring airway hyperreactivity (AHR), a cardinal feature of asthma. Balb/cByJ dams were fed a HFD (60% fat Calories) or normal-fat diet (NFD) (10% fat Calories) from 8 weeks prior to first breeding through their pregnancies. Pups were weaned to either a HFD or NFD (at 4 weeks of age). AHR was measured in the 10-week-old offspring following inhaled methacholine challenge by end-inflation technique. Bronchial alveolar lavage fluid (BALF) was analyzed for cell count, total protein, and IL-6. Offspring of HFD dams weaned to NFD had increased AHR compared to offspring of NFD dams weaned to NFD. Offspring of HFD dams that remained on HFDs had increased AHR compared to offspring of NFD dams weaned to HFDs. Offspring of HFD dams had higher BALF cell counts, higher neutrophil percentage, greater total protein, and IL-6 in the BALF. These results demonstrate that a maternal diet high in saturated fat through pregnancy and lactation plays a key role in programming adult offspring AHR. [ABSTRACT FROM AUTHOR]

Background and objective Earlier studies on the levels of physical activity in asthma patients compared with controls have yielded varying results. We have previously reported that high versus moderate levels of physical activity were associated with higher prevalence of wheezing, especially in females. Here we studied the levels of physical activity in young patients with asthma and healthy subjects and their effect on asthma control. Methods Four hundred eight physician-diagnosed patients with asthma and 118 controls (10-34 years) answered questions concerning frequency and/or duration of physical activity and undertook the Asthma Control Test ( ACT), spirometry, methacholine challenges and exhaled nitric oxide measurements. Results Asthma patients were more frequently physically active ( P = 0.01) and for longer durations ( P = 0.002) than controls. Highly versus moderately physically active patients with asthma had a higher prevalence of not well-controlled asthma ( ACT < 20) when physical activity was assessed by frequency (40.6% vs 24.1%, P = 0.001) or duration (39.0% vs 21.7%, P < 0.001). This was only seen in females who had reduced ACT items ( P < 0.05). Frequently versus moderately active females had an odds ratio of 4.81 (2.43, 9.51) to have ACT < 20, while no such effect was found in males ( OR 1.18 (0.61, 2.30)) and this interaction was statistically significantly associated with gender ( P = 0.003). No differences in fraction of exhaled nitric oxide or methacholine reactivity were found between moderately and highly physically active females with asthma. Conclusion Young asthma patients were more active than controls. High levels of physical activity were associated with poor asthma control as judged by the ACT in females, but not in males, and this appears unrelated to airway inflammation or responsiveness. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2/ Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness. [ABSTRACT FROM AUTHOR]

Background We recently reported an independent association between Ig E sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (Fe NO), in a population-based study ( J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine Fe NO, airway responsiveness and blood eosinophilia in relation to type and degree of Ig E sensitization. Method Fe NO, airway responsiveness, blood eosinophil count ( B- Eos) and Ig E sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. Results Asthmatics had higher prevalence of Ig E sensitization against all allergens than controls ( P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased Fe NO, airway responsiveness and B- Eos in asthmatics. Ig E sensitization to mould, furry animals and food allergens was independently related to Fe NO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. Ig E sensitization to mould ( P < 0.001) and furry animals ( P = 0.02) was related to airway responsiveness in a similar model. Finally, Ig E sensitization to mould ( P = 0.001), furry animals ( P < 0.001) and food allergens ( P < 0.001) was independently related to B- Eos. Conclusion Independent effects of Ig E sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food Ig E sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma. [ABSTRACT FROM AUTHOR]

Background Rhinitis is commonly reported by swimmers. Seasonal allergic rhinitis may impair athletes' performance and quality of life (QOL). No data are currently available on the changes of nasal symptoms during and after a swimming season. We aimed to determine in competitive swimmers: (1) the prevalence of rhinitis and its impact on their QOL during an intense training programme, (2) the changes in nasal symptoms and QOL after a resting period and (3) the relationship between rhinitis and airway hyperresponsiveness (AHR). Methods Thirty-nine swimmers and 30 healthy controls answered the Rhinitis Quality of Life Questionnaire (RQLQ) and scored nasal symptoms on a seven-point Likert scale during the week preceding their visit. Subjects had allergy skin prick tests and a methacholine challenge. Peak nasal inspiratory flows were also measured. The athletes performed these tests during an intense training period (V1), outside the pollen season and after at least 2 weeks without swimming (V2). Results At V1, rhinitis symptoms were reported by 74% of swimmers and 40% of controls ( P<0.01). Eighty-four percent of swimmers and 72% of controls were atopic (NS). RQLQ score was higher in swimmers compared with controls at V1 (27.3 ± 28.5 vs. 9.5 ± 12.7, respectively, P<0.005). The presence of AHR during training did not correlate with the presence of rhinitis symptoms. At V2, the nasal symptoms and RQLQ scores were similar in swimmers and controls. Conclusion Intense swimming training is associated with an increase in nasal symptoms and impairment in QOL in most competitive swimmers. Such an increase is not related to seasonal allergen exposure in atopic athletes and probably results from chlorine derivative exposure. Cite this as: V. Bougault, J. Turmel and L. P. Boulet, Clinical & Experimental Allergy, 2010 (40) 1238–1246. [ABSTRACT FROM AUTHOR]

Rationale Excessive airway narrowing in response to broncho-active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control. Objectives The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add-on effects of montelukast on the maximal response plateau and PD20 to inhaled methacholine in asthmatics on a stable dose of ICS. Methods Thirty-one patients with allergic asthma [14M/17F, 19–50 years, forced expiratory volume in 1 s (FEV1) >70% pred., PD20 <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double-blind (montelukast 10 mg or matching placebo once daily), 12-week parallel study. Bronchoprovocation tests with methacholine (0.03–256 μmol or ⩾40% decline in FEV1) were repeated every 4 weeks and after wash-out. The main study objectives were changes from baseline in maximal FEV1 decline at the response plateau (i.e. >2 post-dose FEV1 values within 5%) and PD20 to methacholine after 12 weeks' treatment. Results Neither treatment affected baseline FEV1 ( P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9–15.7; P<0.005), improved the FEV1 decline (mean change in FEV1 decline was 2.1% [montelukast] and −0.8% [placebo], respectively, P<0.05), and increased PD20 methacholine (mean change in PD20 of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001). Conclusion Add-on montelukast to ICS has disease-modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328). Cite this as: C. S. Ulrik and Z. Diamant, Clinical & Experimental Allergy, 2010 (40) 576–581. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma. Objectives To determine the effects of experimental hookworm infection in asthma. Methods Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD20AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects. Results Mean PD20AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: −1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated. Conclusions Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken. Cite this as: J. R. Feary, A. J. Venn, K. Mortimer, A. P Brown, D. Hooi, F. H. Falcone, D. I. Pritchard and J. R. Britton, Clinical & Experimental Allergy, 2010 (40) 299– 306. [ABSTRACT FROM AUTHOR]

Background Epidemiological evidence suggests that hookworm infection protects against asthma. However, for ethical and safety reasons, before testing this hypothesis in a clinical trial in asthma it is necessary to establish whether experimental hookworm infection might exacerbate airway responsiveness during larval lung migration. Objective To determine whether hookworm larval migration through the lungs increases airway responsiveness in allergic individuals with measurable airway responsiveness but not clinical asthma, and investigate the general tolerability of infection and effect on allergic symptoms. Methods Thirty individuals with allergic rhinoconjunctivitis and measurable airway responsiveness to adenosine monophosphate (AMP) but not clinically diagnosed asthma were randomized, double-blind to cutaneous administration of either 10 hookworm larvae or histamine placebo, and followed for 12 weeks. The primary outcome was the maximum fall from baseline in provocative dose of inhaled AMP required to reduce 1-s forced expiratory volume by 10% (PD10AMP) measured at any time over the 4 weeks after active or placebo infection. Secondary outcomes included peak flow variability in the 4 weeks after infection, rhinoconjunctivitis symptom severity and adverse effect diary scores over the 12-week study period, and change in allergen skin test responses between baseline and 12 weeks. Results Mean maximum change in PD10AMP from baseline was slightly but not significantly greater in the hookworm than the placebo group (−1.67 and −1.16 doubling doses; mean difference −0.51, 95% confidence interval −1.80 to 0.78, P=0.42). Symptom scores of potential adverse effects were more commonly reported in the hookworm group, but infection was generally well tolerated. There were no significant differences in peak-flow variability, rhinoconjunctivitis symptoms or skin test responses between groups. Conclusion Hookworm infection did not cause clinically significant exacerbation of airway responsiveness and was well tolerated. Suitably powered trials are now indicated to determine the clinical effectiveness of hookworm infection in allergic rhinoconjunctivitis and asthma. [ABSTRACT FROM AUTHOR]

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 (ρA) = 0.37, whereas the strongest environmental resemblance was observed between airway responsiveness and airway obstruction, specific environmental correlation (ρE) = −0.46, and between FeNO and airway responsiveness, ρE = 0.34. Conclusions: Asthma is a complex disease characterized by a set of etiologically heterogeneous biomarkers, which likely constitute diverse targets of intervention. [ABSTRACT FROM AUTHOR]

Background Associations between Clara cell secretory protein gene variants ( SCGB1A1, also known as CC16, CC10, CCSP and uteroglobin) and the asthma phenotype have been found in five out of eight studies world-wide. No study has investigated the contribution of SCGB1A1 polymorphisms to the development and/or persistence of the asthma phenotype in a birth cohort followed over time. Objective The aim of this study was to determine the role of the SCGB1A1 gene in the development of the asthma phenotype. Methods The Perth Infant Asthma Follow-up (PIAF) cohort ( n=231 unrelated infants, unselected for asthma and recruited at birth) were seen at 1 month, 6 and 11 years of age, and had a questionnaire, lung function, airway responsiveness (AR) and skin prick tests (SPTs) completed. Blood was taken at 6 and 11 years for total and specific immunoglobulin E (sIgE) and DNA extraction. SPT positivity had at least one positive SPT. SIgE>4 kU/L had at least one sIgE above 4 kU/L. SCGB1A1 A38G (rs3741240), that alters gene transcription, was genotyped using Sau96I restriction digestion of exon 1 PCR products. Results At 6 and 11 years of age, 33.0% and 29.7% of those genotyped had doctor-diagnosed asthma, and 35.8% and 52.1% had SPT positivity. In cross-sectional analyses, children with 38G/38A or 38A/38A had increased AR at 1 month (1.72-fold, P=0.013); sIgE>4 kU/L [odds ratio (OR)=6.95, 95% confidence interval (CI)=1.35–35.91, P=0.021]; house dust mite (HDM) SPT positivity (OR=7.21, 95% CI=1.09–47.78, P=0.041) and sIgE (4.57-fold, P=0.045) at 6 years; and doctor-diagnosed asthma (OR=3.93, 95% CI=1.24–12.47, P=0.02) and cat SPT positivity (OR=4.34, 95% CI=1.01–18.77, P=0.049) at 11 years. Longitudinal analyses of 6 and 11 years paired data showed that children with 38A/38A had increased persistent sIgE>4 kU/L (OR=11.87, 95% CI=1.97–71.53, P=0.007) and persistent HDM SPT positivity (OR=7.84, 95% CI=1.04–58.92, P=0.045). Conclusion SCGB1A1 A38G may play a role in the development and persistence of the asthma phenotype in childhood. [ABSTRACT FROM AUTHOR]

Background and objectives: Increased airway responsiveness to β-agonists is noted in asthmatics and smokers. The lung may be exposed to chemical warfare agents such as mustard gas and pulmonary complications of exposure range from no effect to severe bronchial stenosis. There is little understanding of airway hyperresponsiveness to β-agonist drugs in chemical war victims and this study examined airway responsiveness to salbutamol in victims of chemical warfare. Methods: The threshold concentrations of inhaled salbutamol required for a 20% change in FEV1 as PC20, or a 35% change in specific airway conductance (sGaw) as PC35 were measured in 22 persons exposed to chemical warfare and 15 normal control subjects. Results: In 11 of the 22 subjects PC20 salbutamol could be measured and in 15 of the 22 subjects PC35 salbutamol could be measured. This group of patients was the responder group (PC20 = 10.79 and PC35 = 8.55 mg/L) and in them the concentration of salbutamol needed for a response was significantly lower than that required in normal controls (PC20 = 237.68 and PC35 = 88.72 mg/L, P < 0.001). There was a significant correlation between FEV1 and PC20 salbutamol ( r = 0.815, P < 0.001). Conclusions: These results showed increased airway responsiveness to salbutamol in most subjects exposed to chemical warfare; this was correlated with airway calibre. [ABSTRACT FROM AUTHOR]

Background Early age at onset of atopy is associated with more severe asthma and increased airway responsiveness (AR); the underlying mechanism is unclear but may involve T cell responses. Objective To test the hypothesis that enhanced T cell responses may be associated with early-onset atopy. Methods In a longitudinal study, atopy was determined in infancy and at 6 and 11 years of age. Individuals were categorized as persistent infant-onset atopy (PIOA), early childhood-onset atopy (ECOA) and later childhood-onset atopy (LCOA). At 11 years of age, peripheral blood T cell cytokine responses, AR, exhaled nitric oxide (FENO) and forced expiratory volume in 1 s were determined. Results The age at onset of atopy was determined for 60 children, of whom 15 had PIOA, 24 had ECOA and 21 had LCOA. An additional 76 children who were never atopic were also included. T cell responses to house dust mite, including interleukin-5, -9, -10 and tumour necrosis factor α, were higher among children with PIA and ECOA, and lower in children with LCOA, P<0.05. In contrast, those children with LCOA or who were not atopic had the highest IL-10 response to PHA ( P=0.014). Children with PIOA and ECOA, but not LCOA, had higher AR and FENO compared with non-atopic children ( P<0.05). The group with PIOA were more likely among the atopic children to be admitted to hospital for asthma ( P<0.05) and also had lower %FEV1 compared with non-atopic children ( P=0.023). Conclusions Early age at sensitization is associated with enhanced T cell cytokine responses and indices of adverse asthma outcome. T cell cytokine responses might be programmed at the time of initial atopic sensitization. [ABSTRACT FROM AUTHOR]

Background House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV1)(PC20 allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. Objective We derived prediction equations for HDM challenges using PC20 histamine or PC20 methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. Methods PC20 histamine or PC20 methacholine, skin sensitivity, and PC20 allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups ( n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC20 allergen, and a validation group to test the new equations. Results Multiple linear regression analysis revealed that PC20 allergen could be predicted either from PC20 methacholine only (10log PC20 allergen=−0.902+0.741·10log PC20 methacholine) or from PC20 histamine and skin sensitivity (SS) (10log PC20 allergen=−0.494+0.231·10log SS+0.546·10log PC20 histamine). In the validation study, these new equations accurately predicted PC20 allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC20 allergen in all cases. Conclusion The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC20 allergen and hence are suitable for implementation in HDM inhalation studies. [ABSTRACT FROM AUTHOR]

Aim: Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Methods: Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). Results: First, dose–response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. Conclusion: We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats. [ABSTRACT FROM AUTHOR]

Summary Background Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. Objectives The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. Methods Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5′-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20 ). ENO was measured with the single-exhalation method. Results The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4 p.p.b. (54.9–93.3 p.p.b) vs. 44.7 p.p.b. (30.9–64.6 p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (ρ = -0.57, P = 0.02), whereas no correlation was detected between ENO and PC20 methacholine (ρ =- 0.35, P = 0.14). Conclusions Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine. [ABSTRACT FROM AUTHOR]

Summary Background Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. Objectives The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. Methods Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5′-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20 ). ENO was measured with the single-exhalation method. Results The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4 p.p.b. (54.9–93.3 p.p.b) vs. 44.7 p.p.b. (30.9–64.6 p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (ρ = -0.57, P = 0.02), whereas no correlation was detected between ENO and PC20 methacholine (ρ =- 0.35, P = 0.14). Conclusions Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. Objective We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. Subjects and methods We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 µg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. Results There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). Conclusion These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling. [ABSTRACT FROM AUTHOR]

Investigates the effects of methacholine and Provocholine, a methacholine formulation, on airway responses. Uses of the compounds; Comparison of the bronchoconstriction produced by the two compounds; Absence of product impurities in both compunds; Similarity of structures and effects.

BackgroundThe airway inflammation observed in asthma is orchestrated by activated Th-2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro-inflammatory cytokines interleukin (IL)-4 and IL-5 but also the immunomodulating cytokines IL-12 and possibly IL-10 are crucial for regulating the allergic airway inflammation. ObjectiveSince IL-10 is capable of downregulating a broad spectrum of pro-inflammatory cytokines, we wanted to address the role of endogenously produced IL-10 in vivo in allergic asthma. MethodsKnockout (IL-10-/-) mice (C57BL/6-IL10tm1Cgn) and wild-type (WT) counterparts were immunized (day 0) and exposed (day 14–21) to ovalbumin (OVA). Airway inflammation and reactivity (AR), serum allergen-specific IgE responses and cytokine profiles in the bronchoalveolar lavage fluid (BALF) were studied. ResultsThe IL-10-/- mice had more eosinophilic airway inflammation but comparable levels of allergen-specific serum IgE compared to the WT mice after allergen challenge. The AR was comparably increased in the OVA challenged WT and IL-10-/- mice vs sham-exposed WT, but not vs sham-exposed IL-10-/- mice since these showed a higher baseline AR. IFN γ, IL-4 and IL-13 were comparable and IL-5 was even lower in the BALF of the in IL-10-/- mice compared to the similarly exposed WT mice. ConclusionThese results indicate that IL-10 plays an important and possibly direct role in the control of airway inflammation and responsiveness in an in vivo mouse model of allergy. [ABSTRACT FROM AUTHOR]

Background: Different mechanisms may underlie bronchial hyperresponsiveness (BHR) in different diseases. The aim of this study was to investigate the bronchial responsiveness profile produced by three different challenge tests, methacholine, a direct simulus, and two indirect stimuli, adenosine 5′‐monophosphate (AMP) and cold air, in subjects with asthma and patients with Sjögren's syndrome. Methods: The study population comprised 40 adult patients with asthma, 18 subjects with Sjögren's syndrome, and 20 controls. Blood samples were collected before each challenge for measurements of serum eosinophil peroxidase (S‐EPO) and eosinophil cationic protein (S‐ECP). The investigated subjects recorded peak expiratory flow and kept a symptom diary. Results: Atopic subjects with asthma were significantly more hyperresponsive to AMP than nonatopic subjects with asthma (P=0.01) and subjects with Sjögren's syndrome (P=0.02). No difference was seen between atopic and nonatopic subjects with asthma in the case of challenges with methacholine or cold air. In atopic subjects with asthma, a significant correlation was found between challenges with methacholine and AMP (r=0.91, P=0.0001) and methacholine and cold air (r=0.83, P=0.004), but, in nonatopic subjects with asthma, no significant correlation was seen between methacholine and AMP or cold air challenges. In atopic subjects with asthma, the dose‐response slope for AMP was correlated to S‐EPO (r=-0.56; P=0.01) and S‐ECP (r=-0.51, P=0.02), while no correlation between BHR and inflammation markers was found in the two other patient groups. Conclusions: The results of this study suggest that patients with asthma and subjects with Sjögren's syndrome display different bronchial responsiveness profiles for different challenge agents. Atopic subjects with asthma are more hyperresponsive to AMP than nonatopic subjects and patients with Sjögren's syndrome.... [ABSTRACT FROM AUTHOR]

Background Although airway hyperresponsiveness to inhaled acetaldehyde has been documented in Japanese patients with asthma, the response to this bronchoconstrictor agent has never been studied in Caucasians. Objectives The objectives of the study were to determine differences in airway responsiveness to acetaldehyde between asthmatic and healthy subjects, and to examine the relationship between acetaldehyde responsiveness and the variability of peak expiratory flow (PEF). Methods The response to methacholine and acetaldehyde challenges was measured in 81 non-smoking adults (61 asthmatics and 20 normal controls). Subjects recorded PEF morning and evening for 14 days. The response to both bronchoconstrictor agents was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). PEF variation was expressed as amplitude percentage mean, and as low percentage best (lowest PEF expressed as a percentage of the best PEF recorded). Results The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) and specificity (90 and 100%, respectively) to distinguish between asthma and controls. Asthmatic subjects were on average 265-fold less sensitive to acetaldehyde than to methacholine. PC20 acetaldehyde correlated weakly but significantly with both indices of PEF variation (amplitude percentage mean: ρ = - 0.36, P = 0.004; low percentage best: ρ = 0.42, P = 0.001). Conclusions These results indicate that airway hyperresponsiveness to acetaldehyde is a sensitive and specific indicator for separating asthmatic and normal subjects. Airway responsiveness to methacholine or acetaldehyde and PEF variation are not reflecting the same pathophysiological process in the airways. [ABSTRACT FROM AUTHOR]

Background Airway hyperresponsiveness to pharmacological agonists is a common feature in subjects with allergic rhinitis. Objective The aim of this study was to investigate differences in threshold value and shape of the concentration-response curves to methacholine between subjects with perennial allergic rhinitis and subjects with seasonal rhinitis. Methods We studied a sample of 72 non-asthmatic patients with allergic rhinitis. They were subdivided into two groups: subjects with only seasonal symptoms and skin sensitization to grass and/or Parietaria pollen allergens (seasonal group, n = 38), and subjects with perennial symptoms and skin sensitization to house dust mite, alone or with other allergens (perennial group, n = 34). They were challenged with methacholine (up to 200mg/mL), and concentration-response curves were characterized by the threshold value (PC20 = provocative concentration of methacholine required to produce a 20% fall in FEV1) and maximal response plateau, if possible. The measurements in the seasonal group were done within the pollen season. Results The geometric mean methacholine PC20 for subjects of the perennial group was 6.9 mg/mL, compared with 23.4mg/mL in subjects of the seasonal group (P < 0.01). A plateau response was detected in 16 subjects of the perennial group and in 28 subjects of the seasonal group (P < 0.05). Moreover, the level of plateau was higher in subjects of the perennial group when compared with subjects of the seasonal group (23.8 ± 2.0% vs 19.2 ± 1.6%, P < 0.05). Conclusion In subjects with allergic rhinitis, sensitization to perennial allergens is associated not only with lower methacholine threshold values, but also with lower prevalence and higher level of plateau than sensitization to pollen allergens. [ABSTRACT FROM AUTHOR]

Adenosine, a naturally occurring purine nucleoside, elicits dose-related bronchoconstriction in asthmatic subjects when administered by inhalation and it is recovered in increased amounts from the bronchial lavage fluid of subjects with active asthma when compared to normal controls. Although the mechanism by which adenosine mediates bronchoconstriction in asthmatic subjects is not clear, recent data indicate an important role for mast cell mediator release. We have recently shown that local airway challenge with adenosine in subjects with asthma and rhinitis provokes an increase in the levels of PGD2, histamine and tryptase. However, airway responsiveness and atopic status are the most important determinants of adenosine-induced responses, regardless of any increases in mast cell mediators in airway fluids. New discoveries suggest that the airway response to adenosine may be an index of mast cell priming and therefore may provide a useful tool to further explore the inflammatory processes in allergic asthma and rhinitis. Therefore adenosine provocation may gain increasing acceptance as an additional measure of disease activity in asthma and rhinitis. [ABSTRACT FROM AUTHOR]

The effects of inhaled allergen on airway responsiveness and on β- and α-1-adrenergic receptors on lung membrane were investigated in guinea pigs. After measuring the respiratory threshold to histamine (RT-HIS), one group of guinea pigs passively sensitized for ovalbumin was challenged by allergen inhalation (challenged group). Measurement of the RT-HIS 24 h following challenge revealed a significant decrease from 687 µg/ml (mean, n = 16) to 407 µg/ml (P < 0.05). In addition the RT-HIS 24 h after challenge was also significantly lower in the challenged group than in controls (n = 9, P < 0.05). The density of β-adrenergic receptors on the lung membrane of the challenged group was 594 ± 32 (mean ± SE) fmol/mg protein (n = 11) compared with 712 ± 24 fmol/mg protein (n = 9) in the controls, a statistically significant difference (P < 0.05). A significant correlation was found between the RT-HIS and density of β-adrenergic receptors. From these results, we concluded that the exaggerated airway responsiveness 24 h after allergen challenge is in part due to a decrease in the density of β-adrenergic receptors. There was no difference in the density of α-1-adrenergic receptors nor a significant correlation between the RT-HIS and the number of α-1-adrenergic receptors in the challenged vs the control groups. [ABSTRACT FROM AUTHOR]

Early life changes in the microbiome contribute to the development of allergic asthma, but little is known about the importance of the microbiome for other forms of asthma. Ozone is a nonatopic asthma trigger that causes airway hyperresponsiveness and neutrophil recruitment to the lungs. The purpose of this study was to test the hypothesis that early life perturbations in the gut microbiome influence subsequent responses to ozone. To that end, we placed weanling mouse pups from The Jackson Laboratories or from Taconic Farms in sex‐specific cages either with other mice from the same vendor (same‐housed) or with mice from the opposite vendor (cohoused). Mice were maintained with these cagemates until use. The gut microbial community differs in mice from Jackson Labs and Taconic Farms, and cohousing mice transfers fecal microbiota from one mouse to another. Indeed, 16S rRNA sequencing of fecal DNA indicated that differences in the gut microbiomes of Jackson and Taconic same‐housed mice were largely abolished when the mice were cohoused. At 10–12 weeks of age, mice were exposed to room air or ozone (2 ppm for 3 hr). Compared to same‐housed mice, cohoused male but not female mice had reduced ozone‐induced airway hyperresponsiveness and reduced ozone‐induced increases in bronchoalveolar lavage neutrophils. Ozone‐induced airway hyperresponsiveness was greater in male than in female mice and the sex difference was largely abolished in cohoused mice. The data indicate a role for early life microbial perturbations in pulmonary responses to a nonallergic asthma trigger. [ABSTRACT FROM AUTHOR]

Histamine is an important mediator of allergic inflammation and bronchial hyperresponsiveness (BHR), a hallmark of asthma. Studies on the relationship between plasma histamine and BHR in allergic asthmatic patients have yielded controversial results. We therefore measured plasma histamine and bronchial rcactivity in 30 nonsmoker volunteers taking no medication. Eleven were normal subjects; 19 were stable, mildly allergic asthmatic patients. Venous blood was taken to measure blood cells and basal plasma histamine by radioimmunoassay. After blood sampling, all subjects underwent a measurement of PC20M (concentration of methacholine causing a 20% fall in FEV1). Mean plasma histamine levels were 0.21 ± 0.1 ng/ml and 0.44 ± 0.3 ng/ml in normal and asthmatic subjects, respectively (P < 0.05). We found a significant increase of blood eosinophils and basophils in asthmatic patients, and a positive correlation between plasma histamine and circulating basophils. PC20M was greater than 16 mg in normal volunteers, and mean PC20M was 2.1 ± 2 mg/ml in asthmatic patients. PC20M did not correlate with plasma histamine levels, but it did so negatively with blood eosinophils. The increased plasma histamine concentration in mildly atopic asthmatic patients might be a consequence of the high basophil releasability of atopics and the higher basophil counts in allergic asthma. Plasma histamine is thus unlikely to be a determinant of BHR in asthma. [ABSTRACT FROM AUTHOR]

Summary Background Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. Objective To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. Methods Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. Results All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P < 0.05, respectively). Furthermore, the degree of EIB significantly correlated with atopy score in all subjects (r = 0.35, P < 0.01). This relationship was maintained even after the exclusion of EIB-negative asthmatic subjects. Conclusion Atopy defined as skin test reactivity may contribute to the development of EIB in asthma, independently of AHR to methacholine. [ABSTRACT FROM AUTHOR]