Defining and diagnosingsevere asthma

SY9

WAO – WISC2010Dubai December 2010

Eric D. BatemanEric D. BatemanMD, MBChB, FRCP, DCHMD, MBChB, FRCP, DCHProfessor of Respiratory Medicine, University of Cape TownProfessor of Respiratory Medicine, University of Cape TownDirector of University of Cape Town Lung InstituteDirector of University of Cape Town Lung InstituteHead, Division of Head, Division of PulmonologyPulmonology, , Cape TownCape Town

Presenter DisclosuresPresenter DisclosuresEric D Bateman

Lecture Fees: AstraZeneca, Alk Abello, BoehringerIngelheim, Chiesi, GlaxoSmithKline, Nycomed, Pfizer, TEVA

Consultancy or Advisory Boards: Almirall, AlkAbello, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Forest, Hoffmann la Roche, GlaxoSmithKline, Merck, MorriaBiopharmaceuticals, Novartis, Nycomed, Pfizer, ScheringPlough

Industry-sponsored grants (Institution): Aeras, Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Chiesi, Hoffmann la Roche, GlaxoSmithKline, Merck, MorriaBiopharmaceuticals, Novartis, Nycomed, Pfizer.

Learning objectivesLearning objectives

Defining and diagnosing severe asthmaDefining and diagnosing severe asthma

� 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

ATS/ERS Task Force on Severe Asthma 2009:Co-Chairs: Sally Wenzel & Fan Chung

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

Environment

Pathobiology(marker/s)

Clinical features

Treatmentresponsiveness

Natural history

ASTHMA CONTROLASTHMA CONTROLASTHMA CONTROLASTHMA CONTROL

Current controlCurrent controlCurrent controlCurrent control Future riskFuture riskFuture riskFuture risk

ASTHMA SEVERITYASTHMA SEVERITYASTHMA SEVERITYASTHMA SEVERITY

((((““““difficulty in treatingdifficulty in treatingdifficulty in treatingdifficulty in treating””””))))

Genetic and Genetic and Genetic and Genetic and environmental environmental environmental environmental

factorsfactorsfactorsfactors

Conceptual framework asthma and its managementConceptual framework asthma and its managementConceptual framework asthma and its managementConceptual framework asthma and its management((((ATS/ERS Task Force)ATS/ERS Task Force)ATS/ERS Task Force)ATS/ERS Task Force)

TREATMENTTREATMENTTREATMENTTREATMENT

DISEASE ACTIVITYDISEASE ACTIVITYDISEASE ACTIVITYDISEASE ACTIVITY

ASTHMA PHENOTYPESASTHMA PHENOTYPESASTHMA PHENOTYPESASTHMA PHENOTYPES

Taylor DR Taylor DR Taylor DR Taylor DR et al, ERJ et al, ERJ et al, ERJ et al, ERJ 2008; 32:5452008; 32:5452008; 32:5452008; 32:545----554554554554

Severity Classification: Cockcroft

Severity TreatmentLevel of control

Very mild None or rare ß2-agonistMild infrequent Well controlled

MildRare ß2-agonist +/- Low-dose ICS

Well controlled

ModerateModerate to high dose ICS + occasional OCS

Well controlled

SevereHigh- to very high-dose ICS + occasional OCS

Well controlled

Very severeVery high dose ICS + Oral CS + additional therapies

Not well controlled

Cockcroft DW, Swystun VA. JACI 1996; 98: 1016-8.

Stoloff SW, Boushey HA. JACI 2006

Responsiveness

SARP: Assessment of Asthma PhenotypesSARP: Assessment of Asthma PhenotypesSARP: Assessment of Asthma PhenotypesSARP: Assessment of Asthma Phenotypes

Moore , WC Moore , WC Moore , WC Moore , WC et al,et al,et al,et al, AJRCCM AJRCCM AJRCCM AJRCCM 2009: epub2009: epub2009: epub2009: epubSevere Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)

628 variables from 726 patients

IgEFeNO

SputumBAL

Lung function

7-9 pre b.d. afo

10-12 post b.d. response to albuterol

PC20 Meth

Demographics1 Sex2 Race3 BMI4 Age5 Onset of asthma6 Asthma duration

COMPOSITE VARIABLES:14-17 medication use18-19 Health care utilization20-21 Symptoms26-29 Asthma triggers30 Co-morbidities31-32 Family history33 Tobacco exposure34 Women/hormones

34 variables in cluster analysis

11 variables in discriminantanalysis

3 variables in tree analysis

353 questionnaire data

197Lung function

59Biomarkers

19Atopy

13 Skin tests

Composite variables22, 23 -Perennial allergens24, 25 -Seasonal allergens

Severe Asthma Research Programme: Severe Asthma Research Programme: Severe Asthma Research Programme: Severe Asthma Research Programme: PhenotypingPhenotypingPhenotypingPhenotyping by Cluster Analysisby Cluster Analysisby Cluster Analysisby Cluster Analysis

Moore , WC Moore , WC Moore , WC Moore , WC et al,et al,et al,et al, AJRCCM AJRCCM AJRCCM AJRCCM 2009: epub2009: epub2009: epub2009: epubSevere Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)

628 variables34 core variables726 patients

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

Cluster 1

Semi-Partial R-squared

Cluster 4

Cluster 3

Cluster 5

Cluster 2

Branch based on treatment responsiveness

SARP: Tree PerformanceSARP: Tree PerformanceSARP: Tree PerformanceSARP: Tree Performance

Moore , WC Moore , WC Moore , WC Moore , WC et al,et al,et al,et al, AJRCCM AJRCCM AJRCCM AJRCCM 2009: epub2009: epub2009: epub2009: epubSevere Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)Severe Asthma Research Program (SARP)

Mild Atopic Mild Atopic Mild Atopic Mild Atopic Mild Atopic Mild Atopic Mild Atopic Mild Atopic AsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthma

MildMildMildMildMildMildMildMild--------Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Atopic AsthmaAtopic AsthmaAtopic AsthmaAtopic AsthmaAtopic AsthmaAtopic AsthmaAtopic AsthmaAtopic Asthma

LateLateLateLateLateLateLateLate--------onset onset onset onset onset onset onset onset NonNonNonNonNonNonNonNon--------atopic atopic atopic atopic atopic atopic atopic atopic

AsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthma

Severe Severe Severe Severe Severe Severe Severe Severe Atopic Atopic Atopic Atopic Atopic Atopic Atopic Atopic

AsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthmaAsthma

Severe Severe Severe Severe Severe Severe Severe Severe Asthma with Asthma with Asthma with Asthma with Asthma with Asthma with Asthma with Asthma with Fixed AirflowFixed AirflowFixed AirflowFixed AirflowFixed AirflowFixed AirflowFixed AirflowFixed Airflow

� Using only preUsing only preUsing only preUsing only pre---- and postand postand postand post----bronchodilator FEV1% predicted and age of onset, 80% bronchodilator FEV1% predicted and age of onset, 80% bronchodilator FEV1% predicted and age of onset, 80% bronchodilator FEV1% predicted and age of onset, 80% were were were were correctly assignedcorrectly assignedcorrectly assignedcorrectly assigned� % = percentage of patients from that cluster correctly assigne% = percentage of patients from that cluster correctly assigne% = percentage of patients from that cluster correctly assigne% = percentage of patients from that cluster correctly assignedddd� N = 728N = 728N = 728N = 728

Severe asthma requiring high intensity treatmentATS / ERS Task Force Asthma Control and Exacerbatio ns

Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice

Good control on high Good control on high intensity treatmentintensity treatment

Poor control despite high intensity treatment

Poor control Poor control despite despite high high intensity treatmentintensity treatment

Treatment responsive, but with persistent

problems e.g. poor adherence,

smoking

Treatment Treatment responsive, but responsive, but with persistent with persistent

problems e.g. poor problems e.g. poor adherence, adherence,

smokingsmoking

Persistent coPersistent co --morbidities e.g. morbidities e.g.

GE reflux, obesityGE reflux, obesity

Treatment Treatment resistant/ resistant/

refractory asthmarefractory asthma

“Severe asthma is defined as the requirement for high intensity treatment after modifiable factors and comorbidites have been

appropriately managed”

Reddel H , et al, Amer J Resp Crit Care Med 2009;180:59-99

• 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

WHO: Definition of Severe or Difficult to Manage Asthma

Bousquet J et al, JACI 2010

High dose inhaled CS and LABA (or LT modifier) and / High dose inhaled CS and LABA (or LT modifier) and / or systemic CS for or systemic CS for >>50% of the previous year. 50% of the previous year.

High dose ICS is fluticasone High dose ICS is fluticasone >>1000 mcg/day 1000 mcg/day (or equivalent)(or equivalent)

Definition of Severe or Difficult to Manage Asthma:

Gold Standard TherapyGold Standard Therapy

Bousquet J et al, JACI 2010

FailedStep 3

Levels of CONTROL achieved in GOALTotal or Well Controlled* at 52 weeks

Salm/FP 500Fluticasone 500Salm/FP 250Fluticasone 250

Salm/FP 100Fluticasone 100

0

n = 1155

20

80

40

60

% o

f pat

ient

s C

ON

TR

OLL

ED

0

20

80

40

60

100

62%

47%

Bateman ED et al. Am J Respir Crit Care Med 2004; 170: 836–844*GOAL definitions of control

Previously uncontrolled on Previously uncontrolled on moderate doses of ICSmoderate doses of ICS

Severe asthmaSevere asthma50%50%50%

Week

Con

trol

led

and

Par

tly

Con

trol

led

(%)

0 4 8 12 16 20 24 28 32 36 40 44 48 52

10

0

20

30

40

50

56

60

1. O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129–1362. Scicchitano R, et al. Curr Med Res Opin 2004;20:1403–141

3. Rabe KF, et al. Lancet 2006;368:744–7534. Kuna P, et al. Int J Clin Pract 2007;61:725–736

5. Bousquet J, et al. Respir Med 2007;101:2437–2446

Patients (% per week) achieving GINA Controlled or Partly Controlled weeks during Bud/Form M&R studies

Bud/Form M&R Bud/Form M&R vsvsHighHigh --dose dose ICS/LABA ICS/LABA + SABA+ SABA 4,54,5

Week

0 4 8 12 16 20 24 28

10

0

20

30

40

50

60

Con

trol

led

and

Par

tly

Con

trol

led

(%)

Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52

10

0

20

30

40

50

56

60

Con

trol

led

and

Par

tly

Con

trol

led

(%)

Bud/Form M&R Bud/Form M&R vsvsSameSame--dose dose ICS/LABA ICS/LABA + SABA+ SABA 1,31,3

Bud/Form M&R Bud/Form M&R vsvsHighHigh --dose ICS dose ICS

+ SABA+ SABA 1,21,2

Bateman ED Bateman ED Bateman ED Bateman ED et alet alet alet al, , , , JACIJACIJACIJACI 2010 2010 2010 2010

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)

Definition of Severe or Difficult to Manage Asthma

Definition of Uncontrolled AsthmaDefinition of Uncontrolled Asthma

Bousquet J et al, JACI 2010

Future risk of exacerbations… in relation FEV 1(pre-bronchodilator)

Fuhlbrigge AL et al, JACI 2001;107:61-7.

7070

60

50

40

30

20

10

0

United States

Inci

denc

e of

ast

hma

exac

erba

tions

ov

er n

ext 3

yea

rs

>100 90-100 80-89 70-79 60-69 50-59 <50

FEV1 % predicted

Netherlands

Kitch BT et al, Chest 2004;126:1875-82.

• 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

Definition of Severe or Difficult to Manage Asthma

Bousquet J et al, JACI 2010

Historical = 0.40

Historical = 0.70

0.28

0.090.01

0.42

0.170.07

0.130.05 0.02

0.23 0.19 0.130

0.2

0.4

0.6

0.8

Stratum 1: ICS-naiveStratum 3: Moderate ICS

*Requiring either oral steroids or hospitalisation / emergency visitBateman ED, et al Am J Resp Crit Care 2004

Exacerbation rate in maintenance phase(according to control status achieved in phase I)

Not TC or WC

Well controlled

Total control

Not TC or WC

Well controlled

Total control

Mean exacerbation rate per patient per year

Fluticasone

Salm-FP

HighHigh --dose ICS dose ICS + SABA + SABA vsvs Bud/Form M&RBud/Form M&R

Exa

cerb

atio

ns in

wee

k (%

)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

1.6

0.0

2.0

2.4

2.8

3.2

3.6

1.2

0.8

0.4

Week

SameSame--dose ICS/LABA dose ICS/LABA + SABA + SABA vsvs Bud/Form M&RBud/Form M&R

1.6

0.0

2.0

2.4

2.8

3.2

3.6

1.2

0.8

0.4

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56E

xace

rbat

ions

in w

eek

(%)

Week

HigherHigher --dose ICS/LABA dose ICS/LABA + SABA + SABA vs vs Bud/Form M&RBud/Form M&R

0 4 8 12 16 20 24 28

Week

1.6

0.0

2.0

2.4

2.8

3.2

3.6

1.2

0.8

0.4

Exa

cerb

atio

ns in

wee

k (%

)

Patients (% per week) experiencing exacerbations re quiring medical intervention

Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52

10

0

20

30

40

50

56

60

Con

trol

led

and

Par

tly

Con

trol

led

(%)

Week

Con

trol

led

and

Par

tly

Con

trol

led

(%)

0 4 8 12 16 20 24 28 32 36 40 44 48 52

10

0

20

30

40

50

56

60

Week

0 4 8 12 16 20 24 28

10

0

20

30

40

50

60

Con

trol

led

and

Par

tly

Con

trol

led

(%)

Increasing the dose of ICSIncreasing the dose of ICSIncreasing the dose of ICSIncreasing the dose of ICSin the combination inhalerin the combination inhalerin the combination inhalerin the combination inhaler

Bateman ED Bateman ED Bateman ED Bateman ED et al, JACI et al, JACI et al, JACI et al, JACI 2010201020102010

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

Severe and difficult to manage asthma

‘normal’

Mild asthmasteroid-responsive

Severe asthma‘steroid-dependent’

Steroid resistant

Corticosteroid refractoriness is not absolute

Dose of corticosteroidDose of corticosteroid

Improved Improved Improved Improved Improved Improved Improved Improved asthma asthma asthma asthma asthma asthma asthma asthma controlcontrolcontrolcontrolcontrolcontrolcontrolcontrol

Reduced Reduced Reduced Reduced Reduced Reduced Reduced Reduced airway airway airway airway airway airway airway airway

inflammation inflammation inflammation inflammation inflammation inflammation inflammation inflammation (%)(%)(%)(%)(%)(%)(%)(%)

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 and difficult to manage asthma

Severe /Difficult to manage asthma

Patients are not all the same !Patients are not all the same !

Revised NEO Personality InventoryRevised NEO Personality InventoryCosta PT & McCrae RR, 1992Costa PT & McCrae RR, 1992

Asthma Management and Prevention Programme

Component 1: Develop a doctor / patient partnership

DoctorDoctor --directed patient selfdirected patient self --managementmanagement

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

Bagby RM et al, J Pschosom Res 1994; 38: 23 Luminet O Bagby RM et al, J Pschosom Res 1994; 38: 23 Luminet O Bagby RM et al, J Pschosom Res 1994; 38: 23 Luminet O Bagby RM et al, J Pschosom Res 1994; 38: 23 Luminet O et alet alet alet al, J Pers Assess 1999; 73:345, J Pers Assess 1999; 73:345, J Pers Assess 1999; 73:345, J Pers Assess 1999; 73:345Serrano J Serrano J Serrano J Serrano J et alet alet alet al, ERJ 2006; 28: 296 Plaza V , ERJ 2006; 28: 296 Plaza V , ERJ 2006; 28: 296 Plaza V , ERJ 2006; 28: 296 Plaza V et alet alet alet al, J Asthma 2006; 43: 639, J Asthma 2006; 43: 639, J Asthma 2006; 43: 639, J Asthma 2006; 43: 639

Alexithymia more common in patients with near-fatal asthma episodes (36 versus 13%)

More severe asthma, and very severe near-fatal episodes

Severe and Difficult to Manage Asthma

� 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

Take home messages