Defining and diagnosing severe asthma SY9 WAO WISC2010 Dubai December 2010 Eric D. Bateman MD, MBChB, FRCP, DCH Professor of Respiratory Medicine, University of Cape Town Director of University of Cape Town Lung Institute Head, Division of Pulmonology, Cape Town
Presenter Disclosures Eric D Bateman Lecture Fees: AstraZeneca, Alk Abello, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nycomed, Pfizer, TEVA Consultancy or Advisory Boards: Almirall, AlkAbello, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Forest, Hoffmann la Roche, GlaxoSmithKline, Merck, Morria Biopharmaceuticals, Novartis, Nycomed, Pfizer, ScheringPlough Industry-sponsored grants (Institution): Aeras, Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Chiesi, Hoffmann la Roche, GlaxoSmithKline, Merck, Morria Biopharmaceuticals, Novartis, Nycomed, Pfizer.
Defining and diagnosing severe asthma Learning objectives To review new definitions of severe asthma WHO ATS/ERS Task Force on Severity and Control ATS/ERS Task Force on Severe Asthma Consider the clinical implications of these definitions
Asthma is not a single disease! Asthma phenotypes The characteristics of an organism which develop as a consequence of interactions of the genetic background with the environment... Genotype Treatment Environment Pathobiology (marker/s) Clinical features responsiveness Natural history ATS/ERS Task Force on Severe Asthma 2009: Co-Chairs: Sally Wenzel & Fan Chung
Conceptual framework asthma and its management (ATS/ERS Task Force) Current control ASTHMA CONTROL Future risk TREATMENT ASTHMA SEVERITY ( difficulty in treating ) DISEASE ACTIVITY Genetic and environmental factors ASTHMA PHENOTYPES Taylor DR et al, ERJ 2008; 32:545-554 554
Severity Classification: Cockcroft Severity Very mild Mild Moderate Severe Very severe Treatment None or rare ß2-agonist Rare ß2-agonist +/- Lowdose ICS Moderate to high dose ICS + occasional OCS Responsiveness High- to very high-dose ICS + occasional OCS Very high dose ICS + Oral CS + additional therapies Level of control Mild infrequent Well controlled Well controlled Well controlled Well controlled Not well controlled Cockcroft DW, Swystun VA. JACI 1996; 98: 1016-8. Stoloff SW, Boushey HA. JACI 2006
SARP: Assessment of Asthma Phenotypes 628 variables from 726 patients 353 questionnaire data 197 Lung function 19 Atopy 59 Biomarkers Demographics 1 Sex 2 Race 3 BMI 4 Age 5 Onset of asthma 6 Asthma duration COMPOSITE VARIABLES: 14-17 medication use 18-19 Health care utilization 20-21 Symptoms 26-29 Asthma triggers 30 Co-morbidities 31-32 Family history 33 Tobacco exposure 34 Women/hormones Lung function 7-9 pre b.d. afo 10-12 post b.d. response to albuterol PC20 Meth 34 variables in cluster analysis 13 Skin tests Composite variables 22, 23 - Perennial allergens 24, 25 - Seasonal allergens IgE FeNO Sputum BAL 11 variables in discriminant analysis 3 variables in tree analysis Moore, WC et al, AJRCCM 2009: epub Severe Asthma Research Program (SARP)
Severe Asthma Research Programme: Phenotyping by Cluster Analysis Cluster 2 628 variables 34 core variables 726 patients Cluster 3 Cluster 1 Cluster 4 Branch based on treatment responsiveness Cluster 5 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.175 0.200 0.225 0.250 0.275 0.300 0.325 0.350 Semi-Partial R-squared Moore, WC et al, AJRCCM 2009: epub Severe Asthma Research Program (SARP)
SARP: Tree Performance Mild Atopic Asthma Mild-Moderate Moderate Atopic Asthma Late-onset Non-atopic Asthma Severe Atopic Asthma Severe Asthma with Fixed Airflow Using only pre- and post-bronchodilator FEV1% predicted and age of onset, 80% were correctly assigned % = percentage of patients from that cluster correctly assigned N = 728 Moore, WC et al, AJRCCM 2009: epub Severe Asthma Research Program (SARP)
Severe asthma requiring high intensity treatment ATS / ERS Task Force Asthma Control and Exacerbations Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice Severe asthma is defined as the requirement for high intensity treatment after modifiable factors and comorbidites have been appropriately managed Good control on high intensity treatment Poor control despite high intensity treatment Treatment responsive, but with persistent problems e.g. poor adherence, smoking Persistent co- morbidities e.g. GE reflux, obesity Treatment resistant/ refractory asthma Reddel H, et al, Amer J Resp Crit Care Med 2009;180:59-99
WHO: Definition of Severe or Difficult to Manage Asthma All severe asthma requires confirmed diagnosis of asthma, compliance/adherence and co-morbidities addressed All severe asthma requires treatment with gold standard medication (for that age group) for 3 months by asthma specialist* to prevent patient from becoming uncontrolled or which remains uncontrolled. *Asthma specialist can vary from country to country and from children to adults. In adults, this is traditionally an allergist or pulmonologist/respirologist with advanced training and experience in asthma. In pediatric populations this may also include pediatricians with additional training and experience in severe asthma Bousquet J et al, JACI 2010
Definition of Severe or Difficult to Manage Asthma: Gold Standard Therapy High dose inhaled CS and LABA (or LT modifier) and / or systemic CS for >50% of the previous year. High dose ICS is fluticasone >1000 mcg/day (or equivalent) Bousquet J et al, JACI 2010
Failed Step 3
Levels of CONTROL achieved in GOAL Total or Well Controlled* at 52 weeks % of patients CONTROLLED 100 80 60 40 20 47% 62% 50% Fluticasone 500 Fluticasone 250 Fluticasone 100 Salm/FP 500 Salm/FP 250 Salm/FP 100 Severe asthma 50% *GOAL definitions of control 0 Previously uncontrolled on moderate doses of ICS n = 1155 Bateman ED et al. Am J Respir Crit Care Med 2004; 170: 836 844
Patients (% per week) achieving GINA Controlled or Partly Controlled weeks during Bud/Form M&R studies Bud/Form M&R vs High-dose ICS + SABA 1,2 Bud/Form M&R vs Same-dose ICS/LABA + SABA 1,3 Bud/Form M&R vs High-dose ICS/LABA + SABA 4,5 Controlled and Partly Controlled (%) 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week Controlled and Partly Controlled (%) 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week 56 Controlled and Partly Controlled (%) 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 Week Bateman ED et al, JACI 2010 1. O Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129 136 2. Scicchitano R, et al. Curr Med Res Opin 2004;20:1403 141 3. Rabe KF, et al. Lancet 2006;368:744 753 4. Kuna P, et al. Int J Clin Pract 2007;61:725 736 5. Bousquet J, et al. Respir Med 2007;101:2437 2446
Definition of Severe or Difficult to Manage Asthma Definition of Uncontrolled Asthma Any one of the following: Poor symptom control: ACQ consistently >1.5 (or not well controlled by NAEPP guidelines) Frequent exacerbations: 2 or more bursts of systemic CSs (>3 days each) in the previous year Severe exacerbations: at least one hospitalization, ICU stay or mechanical ventilation in the previous year Persistent airflow limitation: pre-short and long acting bronchodilator FEV1< 80% predicted (in the face of reduced FEV1/FVC) Bousquet J et al, JACI 2010
Future risk of exacerbations in relation FEV1 (pre-bronchodilator) 70 Incidence of asthma exacerbations over next 3 years 60 50 40 30 20 10 Netherlands United States 0 >100 90-100 80-89 70-79 60-69 50-59 <50 FEV1 % predicted Kitch BT et al, Chest 2004;126:1875-82. Fuhlbrigge AL et al, JACI 2001;107:61-7.
Definition of Severe or Difficult to Manage Asthma Controlled asthma on these high doses of inhaled corticosteroids or systemic CS (or additional biologics) places a patient at high future risk for side effects from medications Bousquet J et al, JACI 2010
Exacerbation rate in maintenance phase (according to control status achieved in phase I) Mean exacerbation rate per patient per year 0.8 0.6 Fluticasone Salm-FP Historical = 0.40 Historical = 0.70 0.4 0.2 0 0.13 0.28 0.09 0.05 0.02 0.01 0.42 0.23 0.19 0.17 0.13 0.07 Not TC or WC Well controlled Total control Not TC or WC Well controlled Total control Stratum 1: ICS-naive Stratum 3: Moderate ICS *Requiring either oral steroids or hospitalisation / emergency visit Bateman ED, et al Am J Resp Crit Care 2004
Patients (% per week) experiencing exacerbations requiring medical intervention Exacerbations in week (%) Controlled and Partly Controlled (%) 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 60 50 40 30 20 10 High-dose ICS + SABA vs Bud/Form M&R 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week Bateman ED et al, JACI 2010 Exacerbations in week (%) Controlled and Partly Controlled (%) 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 60 50 40 30 20 10 0 Same-dose ICS/LABA + SABA vs Bud/Form M&R 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week Higher-dose ICS/LABA + SABA vs Bud/Form M&R Exacerbations in week (%) 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 50 40 30 20 10 0 4 8 12 16 20 24 28 Week Increasing 60the dose of ICS Increasing the dose of ICS in the combination inhaler Controlled and Partly Controlled (%) 0 0 4 8 12 16 20 24 28 Week
Severe and difficult to manage asthma Disease factors: Wrong diagnosis: Functional upper airway problems, heart disease Unrecognised trigger factors: drugs, occupational agents Associated disease: GORD, sinusitis, thyrotoxicosis Corticosteroid refractoriness or resistance Health system factors: Inadequate or inappropropriate treatment Failed patient / physician partnership Patient factors: Poor adherence Psychological / personality Socio-behavioural
Corticosteroid refractoriness is not absolute Improved asthma control normal Mild asthma steroid-responsive Reduced airway inflammation (%) Severe asthma steroid-dependent Steroid resistant Dose of corticosteroid
Severe and difficult to manage asthma Disease factors: Wrong diagnosis: Functional upper airway problems, heart disease Unrecognised trigger factors: drugs, occupational agents Associated disease: GORD, sinusitis, thyrotoxicosis Corticosteroid refractoriness or resistance Health system factors: Inadequate or inappropropriate treatment Failed patient / physician partnership Patient factors: Poor adherence Psychological / personality Socio-behavioural / economic considerations
Severe /Difficult to manage asthma Patients are not all the same! Revised NEO Personality Inventory Costa PT & McCrae RR, 1992
Asthma Management and Prevention Programme Component 1: Develop a doctor / patient partnership Doctor-directed patient self-management Written self-management plans are associated with improved asthma outcomes
Alexithymia
Alexithymia = difficulty in perceiving and expressing emotions and body sensations Prevalence: 8-19% of males in general population Toronto Alexithymia Score Correlates with neuroticism Negative correlation with Extraversion and Openness Alexithymia more common in patients with near-fatal asthma episodes (36 versus 13%) More severe asthma, and very severe near-fatal episodes Bagby RM et al, J Pschosom Res 1994; 38: 23 Luminet O et al,, J Pers Assess 1999; 73:345 Serrano J et al,, ERJ 2006; 28: 296 Plaza V et al,, J Asthma 2006; 43: 639
Severe and Difficult to Manage Asthma Take home messages Severe asthma is common! Definition is clinical Consider domains to establish cause In real life practice, patient factors are most common Resistance to treatment is relative and seldom complete New second/third line (targeted) controllers are needed