Gaps in knowledge and in knowledge implementation for control of severe asthma

Ömer KALAYCI, MD

Turkish National Society of

Allergy and Clinical Immunology

Why is it important?

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

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

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

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

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

Bavbek S, Mısırlıgil Z. Allergy 2008 In press

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

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.

Hacettepe University Pediatric Asthma Registry

Severe

21

1.8

Total

1222

Moderate

223

18.2

Mild

978

80

N

%

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

Working definition of severe asthma

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

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.

Am J Respir Crit Care Med 2000;162:2341-51.

SARP CHILDREN

Fitzpatric AM J Allergy Clin Immunol 2006;118:1218-25

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

Miller MK et al. J Allergy Clin Immunol 2005;116:990-5.)

WHAT IS THE DEFINITION OF SEVERE ASTHMA?

For a global approach

a consensus is needed

SEVERE ASTHMA

SUBTYPESMECHANISMS BIOMARKERSGENETICS

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.

• 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

SARP CHILDREN

Fitzpatric AM J Allergy Clin Immunol 2006;118:1218-25

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

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.

Effect of Variation in CHI3L1 on Serum YKL-40 Level, Risk of Asthma, and Lung Function

N Engl J Med 2008;358:1682-91.

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

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.

J Allergy Clin Immunol 2005;115:963-72

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

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