What Is New In Small Airways Research
By Ves Dimov, M.D.
Allergist/Immunologist, Assistant Professor of Medicine and Pediatrics, University of Chicago
Editor, WAO Small Airways Working Group Website
Posted 17 January 2012
Low Vitamin D Level at Age 6 Years is a Predictor of Atopy and Asthma at 14 Years of Age
Vitamin D has been linked in some studies with atopy and asthma in children with already established disease. The aim of this study was to investigate if vitamin D status can be used as a predictor of allergy and asthma development in children aged 6 and 14 years in Perth, Australia.
Serum vitamin D was assayed in 6 yr-old and 14 yr-old children from an unselected community birth cohort; 689 subjects were assessed at both ages.
Vitamin D levels were negatively associated with concurrent allergic phenotypes; and the association was restricted mainly to males. In addition, low vitamin D levels at age 6 years were significant predictors of subsequent atopy/asthma-associated phenotypes at age 14 years.
Children (particularly males) with inadequate vitamin D were at increased risk of developing atopy, and subsequently bronchial hyperresponsiveness (BHR) and asthma. Low vitamin D at age 6 years was a predictor of atopy and asthma at 14 years of age.
It would be interesting to evaluate if the addition of vitamin D level would improve the accuracy of the currently used modified Asthma Predictive Index (mAPI). The index applies to 3-year-old children with 4 wheezing episodes in the past year. If a child has 1 major criterion or 2 minor criteria, he or she has a 76% risk of having persistent asthma during school years. A major criterion would be one of the following: eczema; a family history or either parent with asthma (including during childhood); or sensitization to aeroallergens, such as house dust mites, dog, cat, or pollen. Minor criteria are wheezing other than with colds, food allergy to egg, milk, or peanut, and blood eosinophilia.
Source: Hollams EM, Hart PH, Holt BJ, Serralha M, Parsons F et al. Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study. European Respiratory Journal 2011; 38(6):1320-1327.
Sensitive Measures of Small-Airway Function (Scond and Sacin) May Be Useful in Monitoring the Response to Asthma Therapy
The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR). It improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations.
This study from Australia included 105 adult patients with asthma. The indices of ventilation heterogeneity were derived by using the multiple-breath nitrogen washout technique and included ventilation heterogeneity in convection-dependent airways (Scond) and ventilation heterogeneity in diffusion-dependent airways (Sacin).
Subjects with poorly controlled asthma had worse FEV(1), fraction of exhaled nitric oxide (FeNO), Scond, and Sacin values.
In the treatment group (n = 50) spirometric, FeNO, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma symptom control also improved. The independent predictors of a change in asthma control were changes in Scond and Sacin values.
Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function such as Scond and Sacin might be useful in monitoring the response to therapy in asthmatic subjects.
Source: Farah CS, King GG, Brown NJ, Downie SR, Kermode JA et al. The role of the small airways in the clinical expression of asthma in adults. Journal of Allergy and Clinical Immunology 2011; published online before print 22 December 2011, Article in Press.
Steroid Insensitivity in Severe Asthma Linked to Defect of Protein Phosphatase 2A (PP2A) Enzyme
Corticosteroid insensitivity is a major barrier of treatment of severe asthma, but the molecular mechanism of the insensitivity has not been fully elucidated. This UK study investigated the role of protein phosphate 2A (PP2A), a serine/threonine phosphatase.
Steroid sensitivity was determined by the dexamethasone ability to inhibit TNFα-induced IL-8 or LPS-induced TNFα production. The receptor expression and nuclear translocation were were analysed by Western-blotting.
A PP2A inhibitor reduced steroid sensitivity with reduced glucocorticoid receptor nuclear translocation and increased phosphorylation. PP2A knockdown by RNA interference showed similar effects. In peripheral blood mononuclear cells from severe asthma, the PP2A expression and activity were reduced. Conversely, PP2A overexpression increased steroid sensitivity.
The authors concluded that PP2A regulates glucocorticoid receptor nuclear translocation and corticosteroid sensitivity. This newly-discovered mechanism may provide further insight for the development of new therapy for severe asthma.
Source: Kobayashi Y, Mercado N, Barnes N, Barnes PJ, Ito K. Defects of Protein Phosphatase 2A Causes Corticosteroid Insensitivity in Severe Asthma. PLoS One. 2011;6(12):e27627. doi:10.1371/journal.pone.0027627. Epub 2011 Dec 19.
Full Text, Open Access
Posted 17 January 2012