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43530. ppt

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    3. Difficult asthma Defined as “asthma, poorly controlled in terms of chronic symptoms, with episodic exacerbations, persistent and variable airway obstruction and continued requirement for short-acting beta-2-agonists and a reasonable dose of inhaled corticosteroids” ERS definition-Eur Respir J 1999; 13:1198-208

    4. Refractory asthma Major criteria • Treatment with oral corticosteroids > 50% of the time • High doses inhaled corticosteroids (>1200 µg beclomethasone equivalent) Minor criteria • requirement for daily treatment with long-acting beta-agonists, theophylline or leukotriene antagonists • daily asthma symptoms requiring rescue medication • persistent airway obstruction (FEV1 < 80% predicted); diurnal PEF variability > 20% • 1 or more urgent care visits for asthma per year • 3 or more oral steroid bursts per year • prompt deterioration with < 25% reduction in oral or inhaled corticosteroid dose • near fatal asthma event in the past ATS Definition- Am J Respir Crit Care Med 2000; 162:2341-51.

    5. The term, “severe asthma” applies to patients who have refractory asthma who remain difficult to control despite an extensive re-evaluation of diagnosis, management, and following an observational period of at least 6 months by an asthma specialist. Chanez et al, JACI 2007

    6. Epidemiology Severe asthma is associated with an increased risk of hospitalization and death. The true prevalence of severe asthma is unknown Severe asthma in children, but not adults, is associated with elevated IgE. Female gender, obesity and smoking are associated with more severe asthma and a poor response to therapy.

    7. Severe and difficult to treat asthma 2-12% of asthmatic patients 50% of asthma costs Severe impact on health and QoL

    8. Poor asthma control contributes to substantial healthcare and societal costs

    9. Epidemiology-Genetics Genes and genetic-environmental interactions are associated with severity ADAM33 BHR, decline in lung function TGF-ß1 lower FEV1 IL-4 lower FEV1, severe exacerbations IL-4Ra lower FEV1, severe exacerbations Jongepier et al, Clin Exp Allergy 2004 Pulleyn et al, Hum Genet 2001 Sandford et al, JACI 2000 Lee et al Am J Respir Crit Care Med 2006

    10. Epidemiology-Allergens Atopy is less frequent in severe asthma as compared to mild to moderate asthma. Although allergen exposures are associated with allergic sensitization, the association with the inception and severity of asthma is weak Certain allergen exposures are associated with severe asthma (cockroach, Alternaria). ENFUMOSA ERJ 2001 Peat et al, Clin Exp Allergy 1993 Neukirch et JACI, 1999 Gruchalla et al JACI 2005 Teach et al, Pediatrics 2006 Lemanske et al, JACI 2006

    11. Epidemiology- Infections Respiratory viruses and some intracellular bacteria (Clamydia) contribute to severe exacerbations of asthma Viruses can persist in the airways for long periods after the exacerbation their role in the development of severe persistent asthma remains poorly understood Everard Curr Opin Allergy Clin Immunol 2006 Murray et al, Thorax 2006 Kraft et al, Chest, 2002 ten Brinke et al JACI 2001

    12. Epidemiology- Infections In a study of 198 children at high atopy risk, during respiratory episodes, viruses were detected in 69% of aspirates, most commonly rhinoviruses (48.3%) and RSV (10.9%). Kusel et al, JACI 2007 Bronchial epithelium in asthma has reduced ability to generate IFN-? This probably explains the reason why viruses continue to replicate and cause cytotoxic damage Viral exacerbations are poorly responsive to CS therapy. Chen et al, Am J Respir Cell Mol Biol 2006

    13. Occupational exposure Occupational sensitizers can induce persistent severe asthma, and are a common cause of new onset severe asthma in adults Lemiere et al, Am J Respir Crit Care Med 2000 Sayers et al, Thorax 2003 Le Moual et al, Am J Respir Crit Care Med

    15. Epidemiology-NSAIDs Prevalence 10-20% Exact cause of NSAID-induced asthma is not known increased urinary LTE4 excretion genetic defects in the leukotriene synthetic and receptor pathways ongoing disease chronicity and severity. More studies needed in Severe asthma

    16. Refractory asthma: defined on the basis of medication requirements, asthma symptoms, frequency of asthma exacerbations and degree of airflow limitation This definition is applicable only when other conditions have been excluded exacerbating factors have been optimally treated poor adherence does not appear to be a confounding issue.

    17. Trigger factors for asthma attacks Women

    18. Trigger factors for asthma attacks Men

    20. Influence of BMI on response to controller treatment in Asthma M Peters Golden et al ERJ 2006

    21. Interactions Genes and genetic-environmental interactions are associated with disease severity and poor response to treatment Wheezing lower respiratory illness in the first year of life and atopy are independently associated with increased risk for current asthma at the age of 6 yrs, suggesting that their effects are mediated via different causal pathways and that these risk factors are multiplicative when they operate concomitantly within individual children. Exclusive breastfeeding protects against asthma via effects on both these pathways, as well as through other as yet undefined mechanisms. Oddy et al, ERJ 2002

    22. TENOR study, risk score Age 3 Gender 1 Race 2 BMI 1 Lung Function 2 Previous history of pneumonia 1 Diabetes 1 Cataracts 1 Previous intubation 1 Steroid bursts 3 Nebuliser ipratropium bromide 1 Systemic corticosteroids 1

    25. Obesity is associated with increased risk of sleep apnea

    26. Obesity in severe asthma is associated with more symptoms and psychopathology

    27. Epidemiology - obesity Potential mechanisms Genetics of asthma and obesity ? Respiratory functional abnormalities ? Hormonal abnormalities ? Diet abnormalities ? A role for inflammation ?

    28. Conclusions The true prevalence of severe asthma is not yet defined The role of allergic sensitization, viral infections, gender, obesity, environmental exposure and their interactions need to be defined in studies focusing in severe asthma Defining severe asthma phenotypes and examining risk factors and outcomes in long term, prospective studies is needed

    29. Questions What is the incidence of severe asthma and does it develop differently in childhood as compared to adulthood? Does asthma that has been mild progress to severe asthma or does severe asthma develop very early in the course of the disease? What is the association to allergen, occupational and viral exposure and their interaction on chronicity, airway remodelling and response to therapy? What is the pathogenesis of NSAID-induced severe asthma?

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