gaps in knowledge and in knowledge implementation for ... · of refractory asthma • an extension...
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Gaps in knowledge and in knowledge implementation for control of severe asthma
Ömer KALAYCI, MD
Turkish National Society of
Allergy and Clinical Immunology
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Why is it important?
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Overall costs of asthma are greatest with severe persistent asthma: Italy
*GINA 2002 classification Antonicelli L, et al. Eur Respir J 2004Asthma severity*
720
1,046
1,535
3,328
Intermittent Mild Moderate Severe persistent persistent persistent
Annual cost (€) per patient
3,500
3,000
2,500
2,000
1,500
1,000
500
0
IndirectED and hospitalizationPhysicianDrug
3
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Total costs increase with worseningasthma control: TENOR
Sullivan SD, et al. Allergy 2007
ATAQ = Asthma Therapy Assessment Questionnaire
0 1 2 3+
Medications
ER visits
Hospital nights
Physician visits
Work/school lost
10,000
8,000
6,000
4,000
2,000
0
ATAQ index score
$
p≤0.0001
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Dolan CM, et al. Ann Allergy Asthma Immunol 2004
Hospitalization
Patients (%)
Emergency department visit
Moderate (n=2,285)Severe (n=2,285)
Mild (n=219)25
20
15
10
5
0
5
TENOR
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The burden of asthma is greater for uncontrolled asthma than controlled asthma: TENOR
Mean†
Work dayslost
UncontrolledControlled
Sullivan SD, et al. Allergy 2007
14
12
10
8
6
4
2
0
**
*p<0.05; **p<0.01; ***p<0.001; †in previous year
*
***
School dayslost
Physicianvisits
Hospitalnights
EDvisits
** ***0 0
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Situation in Turkey
25 centers
GINA 4 or 5
Uncontrolled severe asthma
N=267
Controlled severe asthma
N=184
Bavbek S, Mısırlıgil Z. Allergy 2008 In press
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Bavbek S, Mısırlıgil Z. Allergy 2008 In press
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Severe asthma is importantBECAUSE
• It causes great impairment in patients’ lifestyles and makes them unhappy
• account for a disproportionate use of health-care resources through
• hospital admissions, • unscheduled doctors’ visits • use of emergency services
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What is the magnitude of the problem?
Severe asthma represents less than 10% of all asthma, but these patients are responsible for a
disproportionate share of the health care costs and morbidity associated with the disease.
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Hacettepe University Pediatric Asthma Registry
Severe
21
1.8
Total
1222
Moderate
223
18.2
Mild
978
80
N
%
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Severe Asthma Research Program
• 9 sites in the United States and 1 in the United Kingdom.
• From August 2003 to May 16, 2005– 204 subjects with severe asthma
Moore WC, J Allergy Clin Immunol 2007;119:405-13
Severe Asthma Research Program
Moore WC, J Allergy Clin Immunol 2007;119:405-13
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Working definition of severe asthma
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The Epidemiology andNatural History of Asthma: Outcomes and Treatment
Regimens (TENOR) study,
• Assessed by the physician as severe or ‘‘difficult-to-treat’’ asthma
– difficulty adhering to the regimen,
– requirement for multiple drugs,
– inability to avoid triggers,
– frequent or severe exacerbations,
– unresponsiveness to therapy.
Dolan CM, et al. Ann Allergy Asthma Immunol 2004
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Classification of SeverityClassification of Severity
CLASSIFY SEVERITYClinical Features Before Treatment
SymptomsSymptoms NocturnalNocturnalSymptomsSymptoms
FEVFEV1 1 or PEFor PEF
STEP 4STEP 4
Severe Severe PersistentPersistent
STEP 3STEP 3
Moderate Moderate PersistentPersistent
STEP 2STEP 2
Mild Mild PersistentPersistent
STEP 1STEP 1
IntermittentIntermittent
ContinuousContinuous
Limited physical Limited physical activityactivity
DailyDaily
Attacks affect activityAttacks affect activity
> 1 time a week > 1 time a week
but < 1 time a daybut < 1 time a day
< 1 time a week< 1 time a week
Asymptomatic Asymptomatic
and normal PEF and normal PEF
between attacksbetween attacks
FrequentFrequent
> 1 time week> 1 time week
> 2 times a month> 2 times a month
≤≤≤≤ 2 times a month≤≤≤≤ 2 times a month2 times a month
≤≤≤≤≤≤≤≤ 60% predicted60% predicted
Variability > 30%Variability > 30%
60 60 -- 80% predicted 80% predicted
Variability > 30%Variability > 30%
≥≥≥≥≥≥≥≥ 80% predicted80% predicted
Variability 20 Variability 20 -- 30%30%
≥≥≥≥≥≥≥≥ 80% predicted80% predicted
Variability < 20%Variability < 20%
The presence of one feature of severity is sufficient to place patient in that category.The presence of one feature of severity is sufficient to place patient in that category.
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Am J Respir Crit Care Med 2000;162:2341-51.
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SARP CHILDREN
Fitzpatric AM J Allergy Clin Immunol 2006;118:1218-25
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ENFUMOSA
One asthma exacerbation in the last year despite treatment with 1,200 mg/day
budesonide or equivalent
Eur Respir J 2003; 22: 470–477
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Miller MK et al. J Allergy Clin Immunol 2005;116:990-5.)
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WHAT IS THE DEFINITION OF SEVERE ASTHMA?
For a global approach
a consensus is needed
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SEVERE ASTHMA
SUBTYPESMECHANISMS BIOMARKERSGENETICS
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Hypotheses Regarding the Pathologyof Refractory Asthma
• An extension of mild/moderate asthma, with ongoing Th2 predominant inflammation the persistence of eosinophilic inflammation seemingly unresponsive to treatment with high-dose corticosteroids
• A “different” inflammatory process from that seen in milder forms of asthma, i.e neutrophil predominance
• Structurally remodeled airways leading to fixed/irreversible obstruction
• On the basis of altered distribution of inflammation and/or structural abnormalities: more extensive involvement of the smaller airways
• One or more subtypes.Am J Respir Crit Care Med 2000;162:2341-51.
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• Prebronchodilator FEV1 % predicted • 36% increase in risk for every 5% fall in FEV1
• History of pneumonia (OR 3.30)
• Lower numbers of blood basophils (OR, 2.55)
• Asthma symptoms during routine physical activities (OR, 2.28)
• Lower numbers of allergy skin test reactions (OR, 1.11)
Severe Asthma Research ProgramRisk of severe asthma
Moore WC, J Allergy Clin Immunol 2007;119:405-13
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SARP CHILDREN
Fitzpatric AM J Allergy Clin Immunol 2006;118:1218-25
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SARP CHILDRENSevere asthma
• Significantly higher serum IgE
• More positive skin prick reactions to aeroallergens Repeated exacerbations
• Greater allergic sensitization,
• Airflow obstruction,
• FENO despite treatment with high-dose ICS
• The percentage of eosinophils in peripheral blood: No difference
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A Chitinase-like Protein in the Lung andCirculation of Patients with Severe Asthma
Chupp GR Et al. N Engl J Med 2007;357:2016-27.
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Effect of Variation in CHI3L1 on Serum YKL-40 Level, Risk of Asthma, and Lung Function
N Engl J Med 2008;358:1682-91.
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Oxidative stress and genetic and epidemiologicdeterminants of oxidant injury in childhood
asthma
Ercan H et al. J Allergy Clin Immunol 2006;118:1097-104.
Oxidative stress and genetic and epidemiologicdeterminants of oxidant injury in childhood
asthma
Ercan H et al. J Allergy Clin Immunol 2006;118:1097-104.
OR ,45, p<0.001
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0
10
20
30
40
50
60
70
Controls Mild asthma Moderate-severe asthma
Ile/Ile
Ile/Val
Val/Val
% genotype
P=0.007
Ercan H et al. J Allergy Clin Immunol 2006;118:1097-104.
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J Allergy Clin Immunol 2005;115:963-72
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Other genotypes that confer risks for moderate-severe asthma in children
• ALOX5 promoter Sp1-Egr binding sites tandem repeats (OR, 3.7)
• TLR-4 299 and TLR 399 polmorphisms (OR 4.1)
1. Allergy 2006:61;97-1032. Allergy 2005;60:1485-1492
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CONCLUSIONS
1. Severe asthma has important public health consequences
2. A consensus needs to be reached regarding its definition
3. Actual prevalence of severe asthma and its various phenotypes are mostly unknown
4. Phenotypic markers, biomarkers, and genotypic markers with highsensitivity are needed.
5. Collaboration in clinical and basic reserach is an absolute necessity to combat the burden of severe asthma