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Acute Effects of Salmeterol and Fluticasone propionate Alone and in Combination on Airway Blood Flow in Subjects with Asthma.

The airway contains airway smooth muscle and airway vascular smooth muscle. While the acute effects of inhaled long-acting β2-adrenergic agonists (LABAs) alone or in combination with an inhaled glucocorticoid (ICS) on airway smooth muscle tone in asthma are known, their effect on airway vascular smooth muscle tone have not previously been investigated.

OBJECTIVE:To investigate the immediate effect of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma.

METHODS:Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 μg), fluticasone (250 μg), salmeterol/fluticasone (50/250 μg) or placebo; Qaw was measured before and serially for 240 min post drug administration.

Main RESULTS:Mean Qaw increased after salmeterol and salmeterol/fluticasone with a peak at 60 min of 34% and 40 %, respectively; mean Qaw returned toward baseline by 240 min post inhalation. Fluticasone alone caused a transient decrease in mean Qaw. The maximum changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone, and -19 % for fluticasone (p< 0.05 vs. placebo for all).

CONCLUSIONS:The LABA salmeterol has an acute vasodilator action in the airway of subjects with stable asthma. The addition of fluticasone, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway.

Obesity-associated asthma in children- a distinct entity.

Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children.

We hypothesize that pediatric obesity-associated asthma will be characterized by T helper 1(Th1), rather than the Th2 polarization associated with atopic asthma. Moreover, we speculate that Th1 biomarkers and anthropometric measures will correlate with pulmonary function tests (PFTs) in obese asthmatics.

METHODS:We recruited 120 children with 30 in each of the 4 study groups: obese asthmatics, non-obese asthmatics, obese non-asthmatics and non-obese non-asthmatics. All underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae, were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-gamma (IFNγ) (Th1) or IL-4 (Th2) within the CD4 population.

RESULTS:Obese asthmatics had significantly higher Th1 responses to PMA (p<0.01) and tetanus toxoid (p<0.05) and lower Th2 responses to PMA (p<0.05) and D. farinae (p<0.01) compared to non-obese asthmatics. Th cell patterns did not differ between obese asthmatics and obese non-asthmatics. Obese asthmatics had lower FEV(1)/FVC (p<0.01) and RV/TLC ratios (p<0.005) compared to the other study groups, which negatively correlated with serum interferon inducible protein-10 (IP-10) and IFNγ levels, respectively. PFTs, however, did not correlate with BMI z-score or waist hip ratio.

CONCLUSIONS:We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatics.

Relationships Between Airway Hyperresponsiveness, Inflammation, and Calibre in Asthma.

Previous studies have focused upon the relationship between airway inflammation and hyperresponsiveness with different conclusions. We re-examined the relationship between airway inflammation (FE(NO)), hyperresponsiveness to methacholine (AHR), and calibre (FEV(1) % predicted) in mild-to-moderate asthmatics.

METHODS: We searched our database for asthmatics who had attended our research department. FEV(1) % predicted, FE(NO), and methacholine PC(20) were collected. Patients were divided into groups based upon AHR as follows: severe (<0.5 mg/ml, group A), moderate (>0.5-2 mg/ml, group B), and mild (>2-8 mg/ml, group C), and upon FE(NO): low (<25 ppb, group D), medium (25-50 ppb, group E), and high (>50 ppb, group F).

RESULTS: In 208 asthmatics, when stratified by AHR, there was an 8.5% difference in FEV(1) % predicted (95% CI 2.6-14.4%; P = 0.002) and a 29% difference in FE(NO) between groups A and C (95% CI 2-48%; P = 0.034). When stratified by FE(NO,) there was a 1.29 doubling dilution difference in methacholine PC(20) (95% CI 0.26-2.33; P = 0.009) between groups D and F. There was no difference between FEV(1) % predicted when grouped by FE(NO). Multivariate regression analysis with covariates, including inhaled corticosteroids, supported our findings from categorical analysis.

CONCLUSIONS: We found no relationship between airway inflammation and calibre, whilst showing significant relationships between AHR and airway calibre and AHR and airway inflammation. Whilst relationships exist, the lack of complete concordance highlights the important role each contributes to the assessment of the asthmatic individual.

Vitamin D Deficiency as a Strong Predictor of Asthma in Children.

Epidemiological studies suggest a link between vitamin D deficiency in early life and development of asthma in later life. Aim: The aim of this study was to measure serum vitamin D levels in asthmatic children and to compare these to healthy non-asthmatic controls.

Methods: Asthmatic (n = 483) and healthy control (n = 483) children were recruited from the Pediatric Allergy-Immunology Clinics of Hamad General Hospital and the Primary Health Care Clinics in Qatar from October 2009 to July 2010. All children were below 16 years of age and asthma was diagnosed by a physician. Parents of all children completed extensive questionnaires documenting demographics, child's feeding practice and vitamin D intake. Serum vitamin D (25-hydroxyvitamin D), calcium, phosphorus, alkaline phosphatase, magnesium, creatinine and parathyroid hormone assays were performed. Subjects with serum containing less than 20 ng/ml vitamin D were deemed deficient.

Results: Asthmatic children had significantly reduced serum vitamin D levels compared to non-asthmatic children (p < 0.001); 68.1% of all asthmatics were vitamin D deficient. Asthmatic children had significantly higher degrees of moderate (41.8 vs. 25.1%) and severe (26.3 vs. 11.0%) vitamin D deficiency compared to healthy controls (p < 0.001). Positive familial history of vitamin D deficiency (35.6%, p = 0.005) and asthma (36.4%, p = 0.009) were significantly higher in asthmatic children. Along with vitamin D deficiency, asthmatics also had reduced phosphorus (p < 0.001) and magnesium (p = 0.001) levels but elevated serum alkaline phosphatase (p < 0.001) and IgE (p < 0.001). The majority of asthmatic children had less exposure to sunlight (66.7%, p = 0.006) and less physical activity (71.3%, p < 0.001). Vitamin D deficiency was the strongest predictor of asthma in this population (OR 4.82; 95% CI 2.41-8.63, p < 0.001).

Conclusion: The present study revealed that the majority of asthmatic children had vitamin D deficiency compared to control children. Vitamin D deficiency was the major predictor of asthma in Qatari children.

Long-term clinical and immunological effects of allergen immunotherapy.

The present review updates current findings on long-term clinical and immunological outcomes after cessation of allergen immunotherapy for allergic respiratory disease.

RECENT FINDINGS: Recent studies have shown that allergen immunotherapy has sustained disease-modifying effects that persist for years after discontinuation. This is in contrast to the effects of antiallergic drugs that do not induce tolerance to offending allergens. Long-term effects of immunotherapy include a reduction in nasal symptoms, a decrease in the use of rescue medication and improvement in quality of life. These benefits are accompanied by immunological changes such as the induction of allergen-specific IgG antibodies with inhibitory activity for IgE-facilitated binding of allergen-IgE complexes to B cells. One study reported a reduction in the development of asthma in children with seasonal pollen-induced rhinitis.

SUMMARY: Allergen immunotherapy induces clinical and immunological tolerance as defined by persistence of clinical benefit and associated long-term immunological parameters after discontinuation of treatment. These findings are largely confined to studies of subcutaneous and sublingual immunotherapy for seasonal pollinosis. Further studies are needed to address potential long-term clinical effects for other seasonal and perennial inhaled allergens in both children and adults, and to identify potential biomarkers of tolerance.

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