Microbes and mucosal immune responses in asthma.

Lancet. 2013 Feb 18;

Authors: Hansel TT, Johnston SL, Openshaw PJ

Abstract
The substantial increase in the worldwide prevalence of asthma and atopy has been attributed to lifestyle changes that reduce exposure to bacteria. A recent insight is that the largely bacterial microbiome maintains a state of basal immune homoeostasis, which modulates immune responses to microbial pathogens. However, some respiratory viral infections cause bronchiolitis of infancy and childhood wheeze, and can exacerbate established asthma; whereas allergens can partly mimic infectious agents. New insights into the host's innate sensing systems, combined with recently developed methods that characterise commensal and pathogenic microbial exposure, now allow a unified theory for how microbes cause mucosal inflammation in asthma. The respiratory mucosa provides a key microbial interface where epithelial and dendritic cells interact with a range of functionally distinct lymphocytes. Lymphoid cells then control a range of pathways, both innate and specific, which organise the host mucosal immune response. Fundamental to innate immune responses to microbes are the interactions between pathogen-associated molecular patterns and pattern recognition receptors, which are associated with production of type I interferons, proinflammatory cytokines, and the T-helper-2 cell pathway in predisposed people. These coordinated, dynamic immune responses underlie the differing asthma phenotypes, which we delineate in terms of Seven Ages of Asthma. An understanding of the role of microbes in the atopic march towards asthma, and in causing exacerbations of established asthma, provides the rationale for new specific treatments that can be assessed in clinical trials. On the basis of these new ideas, specific host biomarkers might then allow personalised treatment to become a reality for patients with asthma.

PMID: 23428115 [PubMed - as supplied by publisher]

Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency.

Respir Res. 2013 Feb 22;14(1):25

Authors: Korn S, Hübner M, Jung M, Blettner M, Buhl R

Abstract
ABSTRACT: BACKGROUND: Vitamin D has effects on the innate and adaptive immune system. In asthmatic children low vitamin D levels are associated with poor asthma control, reduced lung function, increased medication intake, and exacerbations. Little is known about vitamin D in adult asthma patients or its association with asthma severity and control. METHODS: Clinical parameters of asthma control and 25-hydroxyvitamin D (25(OH)D) serum concentrations were evaluated in 280 adult asthma patients (mean +/- SD: 45.0 +/- 13.8 yrs., 40% male, FEV1 74.9 +/- 23.4%, 55% severe, 51% uncontrolled). RESULTS: 25(OH)D concentrations in adult asthmatics were low (25.6 +/-11.8 ng/ml) and vitamin D insufficiency or deficiency (vitamin D <30 ng/ml) was common (67%). 25(OH)D levels were related to asthma severity (intermittent: 31.1 +/- 13.0 ng/ml, mild: 27.3 +/- 11.9 ng/ml, moderate: 26.5 +/- 12.0 ng/ml, severe: 24.0 +/- 11.8 ng/ml, p = 0.046) and control (controlled: 29.5 +/- 12.5 ng/ml, partly controlled 25.9 +/- 10.8 ng/ml, uncontrolled: 24.2 +/- 11.8 ng/ml, p = 0.030). The frequency of vitamin D insufficiency or deficiency was significantly higher in patients with severe or uncontrolled asthma and was associated with a lower FEV1 (vitamin D <30 vs. >=30 ng/ml 2.3 +/- 0.9 L vs. 2.7 +/- 1.0 L, p = 0.006), higher levels of exhaled NO (45 +/- 46 ppb vs. 31 +/- 37 ppb, p = 0.023), a higher BMI (28.3 +/- 6.2 vs. 25.1 +/- 3.9, p < 0.001), and sputum eosinophilia (5.1 +/- 11.8% vs. 0.5 +/- 1.0%, p = 0.005). The use of oral corticosteroids or sputum eosinophilia was associated with a 20% or 40% higher risk of vitamin D insufficiency or deficiency. CONCLUSIONS: 25(OH)D levels below 30 ng/ml are common in adult asthma and most pronounced in patients with severe and/or uncontrolled asthma, supporting the hypothesis that improving suboptimal vitamin D status might be effective in prevention and treatment of asthma.

PMID: 23432854 [PubMed - as supplied by publisher]

Exploring factors influencing asthma control and asthma-specific health-related quality of life among children.

Respir Res. 2013 Feb 23;14(1):26

Authors: Gandhi PK, Kenzik KM, Thompson LA, Dewalt DA, Revicki DA, Shenkman EA, Huang IC

Abstract
ABSTRACT: BACKGROUND: Little is known about factors contributing to children's asthma control status and health-related quality of life (HRQoL). The study objectives were to assess the relationship between asthma control and asthma-specific HRQoL in asthmatic children, and to examine the extent to which parental health literacy, perceived self-efficacy with patient-physician interaction, and satisfaction with shared decision making (SDM) contribute to children's asthma control and asthma-specific HRQoL. METHODS: This cross-sectional study utilized data collected from a sample of asthmatic children (n = 160) aged 8--17 years and their parents (n = 160) who visited a university medical center. Asthma-specific HRQoL was self-reported by children using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Asthma Impact Scale. Satisfaction with SDM, perceived self-efficacy with patient-physician interaction, parental health literacy, and asthma control were reported by parents using standardized measures. Structural equation modeling (SEM) was performed to test the hypothesized pathways. RESULTS: Path analysis revealed that children with better asthma control reported higher asthma-specific HRQoL (beta = 0.4, P < 0.001). Parents with higher health literacy and greater perceived self-efficacy with patient-physician interactions were associated with higher satisfaction with SDM (beta = 0.38, P < 0.05; beta = 0.58, P < 0.001, respectively). Greater satisfaction with SDM was in turn associated with better asthma control (beta = -0.26, P < 0.01). CONCLUSION: Children's asthma control status influenced their asthma-specific HRQoL. However, parental factors such as perceived self-efficacy with patient-physician interaction and satisfaction with shared decision-making indirectly influenced children's asthma control status and asthma-specific HRQoL.

PMID: 23432913 [PubMed - as supplied by publisher]

Redefining approaches to asthma: developing targeted biologic therapies.

Adv Pharmacol. 2013;66:1-49

Authors: Arron JR, Scheerens H, Matthews JG

Abstract
Asthma is a chronic respiratory disorder canonically associated with type 2 airway inflammation as characterized by elevated levels of eosinophils, immunoglobulin E, and cytokines including interleukin (IL) 4, IL5, IL9, and IL13 and tumor necrosis factor (TNF) α. However, mounting evidence has shown that considerable heterogeneity exists in human asthma in terms of the nature and intensity of airway inflammation. While many asthma patients achieve acceptable control of symptoms with standard-of-care therapies such as β(2)-adrenergic agonists and inhaled corticosteroids, a minority remains symptomatic despite maximal standard-of-care therapy and constitutes a significant unmet medical need. A growing number of investigational therapeutics under clinical development for asthma are biologic therapies that specifically target mediators of type 2 airway inflammation. In this chapter, we consider the biological functions of therapeutic targets in asthma and data from clinical trials of biologic agents directed against these targets. We discuss recent clinical trial results in terms of four key components of drug development: target selection, molecule selection, outcome selection, and patient selection, with particular attention paid to the emerging role of biomarkers in clinical development for asthma.

PMID: 23433454 [PubMed - in process]