Search

Background Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. Methods Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). Results For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10−11 and 5.4 × 10−4, respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10−4 and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10−6) but not in BAL. Conclusions Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.

Background Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. Methods A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. Results Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: −55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. Conclusions FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.

The links between asthma and rhinitis are well characterized. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines stress the importance of these links and provide guidance for their prevention and treatment. Despite effective treatments being available, too few patients receive appropriate medical care for both diseases. Most patients with rhinitis and asthma consult primary care physicians and therefore these physicians are encouraged to understand and use ARIA guidelines. Patients should also be informed about these guidelines to raise their awareness of optimal care and increase control of the two related diseases. To apply these guidelines, clinicians and patients need to understand how and why the recommendations were made. The goal of the ARIA guidelines is to provide recommendations about the best management options for most patients in most situations. These recommendations should be based on the best available evidence. Making recommendations requires the assessment of the quality of available evidence, deciding on the balance between benefits and downsides, consideration of patients’ values and preferences, and, if applicable, resource implications. Guidelines must be updated as new management options become available or important new evidence emerges. Transparent reporting of guidelines facilitates understanding and acceptance, but implementation strategies need to be improved.

Background: Uncontrolled asthma is characterized by variability. Current asthma guidelines recommend focussing on the achievement and maintenance of control but few studies have examined in detail, using composite measures of control, the stability and potential duration of control once achieved. In this post-hoc analysis of the results of the Gaining Optimal Asthma controL (GOAL) study, we examine the association between the level of asthma control achieved during the step-up phase of the study and the stability of control experienced during the maintenance phase. Methods: GOAL was a 1-year, randomized, stratified, double-blind study of 3421 patients with uncontrolled asthma, which compared salmeterol/fluticasone propionate combination with fluticasone propionate in achieving two composite, guideline-based measures of control: totally controlled and well-controlled asthma. We analysed the proportion and duration of time spent in control, the effect of treatment on asthma stability, and the impact of asthma control stability on unscheduled use of healthcare resources. Results: In patients achieving well-controlled or totally controlled asthma, at least well-controlled asthma was maintained for a median of almost 3 and 6 months, and for more than 85% and 95% of weeks of follow-up, respectively. A high level of stability was confirmed in a Markov analysis investigating transitional probability of change in control status. Variability in control was associated with increased probability of an unscheduled healthcare resource use (odds ratio: 1.06, P < 0.001). Conclusions: Most patients achieving guideline-defined control can maintain at least a similar level of control with regular, stable dosing, with little likelihood of losing control.

Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations. In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease. This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work. The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available. Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed. The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.

Background: The effector function of eosinophils involves their release of toxic granule proteins, reactive oxygen species, cytokines, and lipid mediators. Murine studies have demonstrated that eosinophils can also enhance T cell function. Whether human eosinophils, in particular, airway eosinophils, have similar immunoregulatory activity has not been fully investigated. The aim of this study was to determine whether human blood and airway eosinophils can contribute to Th1 and Th2 cytokine generation from CD4+ T cells stimulated with superantigen. Methods: Eosinophils were obtained from blood or bronchoalveolar lavage fluid 48 h after segmental allergen bronchoprovocation. Purified eosinophils were co-cultured with autologous CD4+ blood T cells in the presence of staphylococcal enterotoxin B (SEB). Cytokine levels in the supernatant fluid were determined by enzyme-linked immunosorbent assay (ELISA). Eosinophil expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules was assessed by flow cytometry before culture, 24 h after granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, and 24 h after co-culture with CD4+ T cells and SEB. Results: Interleukin (IL)-5, IL-13, and interferon (IFN)-γ generation increased when CD4+ T cells were co-cultured with either blood or airway eosinophils in the presence of SEB. The ability of eosinophils to enhance cytokine generation was independent of their source (blood vs airway), activation by GM-CSF, or detectable expression of human leukocyte antigen (HLA)-DR, CD80, or CD86. Conclusion: Our data demonstrate that SEB-induced generation of Th1 and Th2 cytokines is increased in the presence of human blood and airway eosinophils. Thus, eosinophils can have an immunoregulatory function in pathogen-associated allergic diseases such as atopic dermatitis, chronic sinusitis, and asthma exacerbations.

Summary From the above observations, it is apparent that many respiratory viruses causes a change in airway function such that bronchial obstruction is more likely to occur in patients with asthma. Furthermore, there is also evidence that viruses act through a number of pathways to enhance the likelihood of an inflammatory response. Subsequent observations must focus on the ability of viruses to stimulate cytokine production, which could then upregulate the allergic airway inflammatory response. With the unfolding of such observations, it is highly likely that greater insights into this major provoking factor in asthma will become more apparent as well as clearer insight into mechanisms of asthma.

The administration of Bordetella pertussis vaccine to mice has been associated with the development of an impaired beta-adrenoceptor responsiveness and in many respects has resembled human asthma. Trachea (n = 12) were isolated from Swiss-Webster mice 5 days following the intraperitoneal administration of 2 x 10(9) B. pertussis organisms. The tracheal smooth muscle response to carbachol was measured and compared with that found in trachea from unvaccinated mice (n = 15). The contractile response was similar in both groups. The tracheal smooth muscle relaxant effects of isoproterenol were measured in these two groups. The EC50 value for isoprenaline (6.5 x 10(-7) M) in trachea from B. pertussis treated mice was significantly (P < 0.05) greater than that noted in the control animals (2.3 x 10(-7) M). These studies demonstrated that in tracheal smooth muscle isolated from B. pertussis vaccinated mice, the relaxant effects of isoprenaline are impaired.

Intranasal flunisolide is an effective treatment for allergic rhinitis. Flunisolide has high bioavailability when administered to normal subjects (50% of an intranasal dose reaches the systemic circulation) with minimal systemic effects. Bioavailability in patients with active rhinitis averages 62.4 +/- 15.7%. The oral dose bioequivalent to 100 micrograms intranasally is 500 micrograms. To define the comparative trial and systemic effects of intranasal flunisolide in patients with active allergic rhinitis, a multicenter, randomized, double-blind, placebo-controlled study was conducted during the 1983 ragweed hayfever season. Ninety-nine patients with ragweed hayfever for greater than or equal to 2 years and positive prick skin tests to ragweed were randomly allocated to one of three treatment groups: 0 = oral flunisolide 500 micrograms b.i.d. and intranasal placebo b.i.d.; N = intranasal flunisolide 50 micrograms per nostril b.i.d. and oral placebo b.i.d.; P = intranasal and oral placebo b.i.d. Treatment continued for 4 weeks. Patients kept daily symptom scores. Patients were evaluated by a blinded observer every 2 weeks and were globally evaluated at the study's end. Data were analyzed for each center and pooled. There were no significant differences in symptom severity of sneezing, nasal congestion, and throat itch in the 0 (oral flunisolide) and P (placebo) groups. N (nasal flunisolide) was significantly more effective than O or P (P less than or equal to 0.005) for each symptom for at least one 2-week period. Global evaluation demonstrated control of overall hayfever severity for N (nasal flunisolide) but not for O (oral flunisolide). We conclude that the therapeutic efficacy of flunisolide is achieved by topical and not by systemic action.