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Complement mediators: key regulators of airway tissue remodeling in asthma.

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The complement mediators are the major effectors of the immune balance, which operates at the interface between the innate and adaptive immunity, and is vital for many immunoregulatory functions.

Activation of the complement cascade through the classical, alternative or lectin pathways thus generating opsonins like C3b and C5b, anaphylatoxins C3a and C5a, chemotaxin, and inflammatory mediators, which leads to cellular death. Complement mediators that accelerate the airway remodeling are not well defined; however, an uncontrolled Th2-driven adaptive immune response has been linked to the major pathophysiologic features of asthma, including bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The mechanisms leading to complement mediated airway tissue remodeling, and the effect of therapy on preventing and/or reversing it are not clearly understood.

This review highlights complement-mediated inflammation, and the mechanism through it triggers the airway tissue injury and remodeling in the airway epithelium that could serve as potential targets for developing a new drug to rescue the asthma patients.

PMID: 26289385 [PubMed - in process]

Age at asthma onset and asthma self-management education among adults in the United States.

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Asthma self-management education improves asthma-related outcomes. We conducted this analysis to evaluate variation in the percentages of adults with active asthma reporting components of asthma self-management education by age at asthma onset.

METHODS: Data from 2011 to 2012 Asthma Call-back Surveys were used to estimate percentages of adults with active asthma reporting six components of asthma self-management education. Components of asthma self-management education include having been taught to what to do during an asthma attack and receiving an asthma action plan. Differences in the percentages of adults reporting each component and the average number of components reported across categories of age at asthma onset were estimated using linear regression, adjusted for age, education, race/ethnicity, sex, smoking status, and years since asthma onset.

RESULTS: Overall, an estimated 76.4% of adults with active asthma were taught what to do during an asthma attack and 28.7% reported receiving an asthma action plan. Percentages reporting each asthma self-management education component declined with increasing age at asthma onset. Compared with the referent group of adults whose asthma onset occurred at 5-14 years of age, the percentage of adults reporting being taught what to do during an asthma attack was 10% lower among those whose asthma onset occurred at 65-93 years of age (95% CI: -18.0, -2.5) and the average number of components reported decreased monotonically across categories of age at asthma onset of 35 years and older.

CONCLUSIONS: Among adults with active asthma, reports of asthma self-management education decline with increasing age at asthma onset.

Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma.

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OBJECTIVES: Fluticasone furoate (FF; inhaled corticosteroid) combined with vilanterol (VI; long-acting beta2 agonist) is a once-daily therapy for asthma and chronic obstructive pulmonary disease. This 12-week phase III study compared the efficacy and safety of once-daily (evening dosing) FF/VI 100/25 mcg versus FF 100 mcg (primary objective) and FF/VI 100/25 mcg versus FF/VI 200/25 mcg (descriptive comparison only) in patients (n = 1039) ≥12 years with moderate-to-severe persistent asthma.

METHODS: The primary end point was weighted mean (wm) 0-24-h serial forced expiratory volume in 1 s (FEV1) at week 12. Secondary end points (change from baseline) were trough FEV1 and the proportion (%) of rescue-free 24-h periods (both powered), the proportion (%) of symptom-free 24-h periods, and morning and evening peak expiratory flow (PEF). Safety data (adverse events, AEs) were collected throughout.

RESULTS: Compared with FF 100 mcg, FF/VI 100/25 mcg significantly improved wmFEV1 (p < 0.001), trough FEV1 (p = 0.014), % rescue-free (p < 0.001), % symptom-free (p = 0.002) 24-h periods, and morning and evening PEF (p < 0.001). FF/VI 200/25 mcg produced small numerical improvements versus FF/VI 100/25 mcg for all end points. Incidence of AEs was similar across groups.

CONCLUSIONS: FF/VI 100/25 mcg resulted in significant improvements in all primary and secondary end points versus FF 100 mcg. Numerical improvements occurred with FF/VI 200/25 mcg versus FF/VI 100/25 mcg. All treatments were well tolerated.

Defining the Asthma-COPD overlap syndrome in a COPD cohort.

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Asthma-COPD overlap syndrome (ACOS) has been recently described by international guidelines. A stepwise approach to diagnosis using usual features of both diseases is recommended although its clinical application is difficult.

Methods: In order to identify patients with ACOS, a cohort of well-characterized patients with COPD and up to one-year follow-up was analyzed. We evaluated the presence of specific characteristics associated to asthma in this COPD cohort, divided in major criteria (bronchodilator test greater than 400 ml and 15% and past medical history of asthma) and minor criteria (blood eosinophils greater than 5%, IgE>100 UI/ml, or two separate bronchodilator tests greater than 200 ml and 12%). We defined ACOS by the presence of one major criterion or two minor criteria. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between patients with and without criteria for ACOS.

Results: Out of 831 COPD patients included,125 (15%) fulfilled the criteria for ACOS, and 98.4% of them sustained these criteria after one year. Patients with ACOS were predominantly male (81.6%), with symptomatic mild to moderate disease (67%), and receiving inhaled corticosteroids (63.2%). There were no significant differences in baseline characteristics, and only survival was worse in non-ACOS COPD patients after one-year of follow-up (p <0.05).

Conclusions: The proposed ACOS criteria are present in 15% of a cohort of COPD patients and these patients show better one-year prognosis than clinically similar COPD patients with no ACOS criteria.

ClinicalTrials.gov Identifier: NCT01122758.

Novel glucocorticoid receptor agonists in the treatment of asthma.

Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index.

Areas covered: Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile.

Expert opinion: Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression 'fingerprints' produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.

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