Asthma: The Variability of Disease

Control, Severity, Outcomes and Treatment Response

Allan T. Luskin, MD
Associate Professor of Medicine, University of Wisconsin Director, Respiratory Institute, Dean Medical Center
Madison, Wisconsin

Past Chair, Patient and Public Education Committee, NAEPP Past Co-Chair, Managed Care Liaison, NAEPP Committee on Asthma Measures, AMA Asthma Expert Panel, JCAHO Respiratory Measurement Advisory Panel, HEDIS/NCQA

Initial Guideline Approach to Asthma

One Size Fits All
Only a cursory phenotyping by severity Most adverse outcomes due to poor diagnosis, poor prescribing, poor adherence Majority of asthmatics respond to CS and bagonists

Current Symptoms and MD Severity Rating

Mild Symptoms 70 60 50 40 30 20 10 0 Mild Moderate Severe Physician Rating of Underlying Severity
Diette GB Ann Allergy Asthma Immunol. 2004;93:546-552

Moderate Symptoms

Severe Symptoms

% of Patients

31% Concordance

Underlying Severity and Future HCU

Hospitalized 35 30 Cancelled Activities ED Visit

% of Pts

Who are these Patients? Which Mild patients get sick? 25 Which Severe patients stay well? 20
15 10 5 0 Mild Moderate Severe Physician Estimate of Underlying Severity

Diette GB Ann Allergy Asthma Immunol 2004;93:546-552

Asthmas are variable.

in control in severity in response to therapy in natural history in risk for adverse outcomes in the relationship among features of disease in the relationship between outcomes

Dimensions of Control
How the Disease Affects the Organism

Physiology Symptoms (nocturnal, exercise) Quality of life and Activities of Daily Living Medications (adverse events, adherence) Health Care Utilization (function of exacerbations) Comorbidities

Exacerbation Frequency in Mild Asthma

Inner City, Peds Clinic, 3 month parental Survey 80% Persistent 20% Intermittent
70 60 50 40 30 20 10 0 0 1 2 3 4 5 Red Zone Yellow Zone

Dinakar C J Asthma.2005;41:807-812

Exacerbations and Effect of Therapy

ICS 100 80 % 60 Exacerbations Prevented 40 20 0 COPD Asthma ICS + LABA

Different Exacerbations or Different People

(not all exacerbations and not all asthmatics are the same)

Calverley PMA Proc Am Thoracic Soc 2004;1:161-166

Exacerbations and ICS

ISOLDE Trial
Mean # Exacerbations/year
Place bo 2 FP
35

% pts with 1 Exacerbations/year

Place bo FP

30

1.5

25

20

1
15

10

0.5
5

0 Mild Mod-Se ve re

0 Mild Mod-Se ve re

Jones PW Eur Respir J 2003;21:68-73

Asthma is a syndrome, not a disease

The Asthma phenotype is highly variable
(clinically, pathologically and physiologically)

Response to ALL therapy is highly variable

BHR and Reversible airflow obstruction does not predict response to therapy

Outcomes do not necessarily correlate with each other There are Outcome phenotypes

COPD: Response to Tobacco Smoke

Atopy and hx of childhood illness showed significant additive effect

Patient Display on One Day-One Time Factors in Asthma Variability

Genetic Environment Rx Variability Disease Variability

Phenotypes: The visible effects of the interaction between Genetic Makeup and the Environment
PatientPatient Display on OneTime Day-One Time over
N.B.: There are 21 arrows. Probability combinations are 2121

Infant Eczema: CD14/-159 & Dogs

70 60 50 40 % Eczema 30 20 10 0 CC CT TT Dogs No dogs

Gern J JACI February 2004

Total IgE: CD14/-159 & Animal Contact

150 120 Geometric mean (IU/ml) 90 60 30 0 No animals Dog/Cat only Barn animals CC CT TT

Eder (in press)

Obvious Factors in Variability

Season Allergen exposure Air pollutants ETS Infection Concomitant disease Exertion Hormones Adherence

Infections and Asthma

Inception
RSV, PIV, Rhinovirus Lead to resolution or asthma (atopy)

Prevention
Early infection 1TH1 in most (protective) Asthma in those with TH1 defect

Exacerbation
Rhinovirus, Coronavirus, Influenza Childhood (80%), Adulthood (50%)

Persistence
Chlamydia, Mycoplasma ? Previous history of asthma

Behavior and Development of Wheeze

Psychologic Factors at age 3 and Development of Late-Onset Wheeze at age 5
Compared to Never wheezers

6 5 4 OR 3 2 1 0 Maternal Smoking Maternal Asthma Expressiveness ECBI Intensity

Esp: Inattentive, Overactive Suggesting physiologic component

Calem R. Am J Respir Crit Care Med. 2005;171:323-327

Adherence and Outcomes

Adherence/persistence rates range from 5-50%1 Use patterns tend to be sporadic2 Significant improvement in important outcomes may require ~50% adherence3 Non-adherence likely accounts for ~60% of hospitalizations4
1Luskin AT

Bukstein DA Ann Allergy 1999, 2001 Suissa S, Ernst Thorax 2002 2Bender B JACI 2003 3Luskin AT, Bukstein DA JACI 2001 4Williams LK JACI 2004;114:1288-1293

Hospitalization: Season and Age

Ages 5-34 20 15 10 5 0 -5 -10 -15 -20 Ages 35-64 Ages >65

Hospitalizations %

Ja n Fe b M ar A pr M ay Ju n

Weiss KB. JAMA 1990;263:2323-2328

Ju l A ug Se p O ct N ov D ec

eNO and Adherence to ICS

Asthma Severity: BMI and Menarche

4 3.5 3 2.5 Clinical Asthma 2 Severity Score 1.5 1 0.5 0 Men I II Women: no early menarche III IV V Women: early menarch

BMI Quintiles
Varraso R. Am J Respir Crit Care Med.2005;171:334-339

Work Loss in Parents of Asthmatics

Children 6-16 y/o with persistent asthma (GINA 2)
30% lost work days 13% lost > 5 work days
High
1 + Days 5 + Days

Severity

Moderate Low Poor

Control

Moderate Good
0.0 2.0 4.0 OR
Laforest L Ann Allergy Asthma Immunol 2004;93:265-271

6.0

8.0

10.0

Severity and Control (at one point in time) help determine Now therapy but only a portion of what we do later
Need understanding of the interaction between components of variability
Environment, genetics, response to therapy, relationship between outcomes

Need understanding of risk drivers Risk assessment (predictive modeling) Individualized control assessment

Asthma Management
Utilize characteristics, biomarkers, and genetics to profile asthma severity Select medications based on driving factors of disease presentation and predictors of response Monitor response and assess reasons for treatment failure Adjust therapy accordingly

Outcomes Variability in Management

There are multiple levels of response to therapy Variability of response to treatment is outcome parameter specific Adjustments in therapy (and in pharmacogenetics) should be related to response to each outcome parameter Important outcomes may differ from person to person and are also a function of perspective (society, payor, clinician, family, patient)

Predicting Response
Why predict response What are appropriate predictors of response What response is most important

Targets and Assessment: Response to Rx

Functional
Symptoms/Medication Use Exacerbation Global: QOL, ADL

Physiologic
Lung function/BHR

Progression Pathologic (Inflammation)

Sputum eos/ eNO

What is Control?
Hypertension Pain

Risk

?
Asthma

Symptoms

Ideal Measure of Asthma Control

Simple and practical Meaningful Applicable to patients, clinicians, researchers Reflective of short and long-term control Discriminatory Responsive to change

Question: Which outcomes measure is the Best one for us?

1) FEV1 at the routine office visit 2) BHR by methacholine challenge
(or by PF variability as an alternative)

3) Symptom score with particular attention to nocturnal symptoms 4) ER visits and hospitalizations 5) eNO (or other exhaled gas) 6) There is no single measure which is BEST

PEAK Trial: Can Therapy Change the Natural History

2-5 y/o at high risk for asthma (family history) 3 wheezing episodes in previous year 2 years of ICS or placebo Then off ICS for 1 year

PEAK Trial:
Change Therapy Change Natural History
At the end of 2 years of ICS
Better Control Fewer exacerbations

After 1 year off ICS (compared to placebo)

No difference in lung function or BHR 1 cm shorter

Course of Asthma
Change in Severity after 5 years
< 15 y/o Severe to Remission Severe to mild Severe to Not Severe Mild to Severe 0 20 40 60 80 100 > 15 y/o

Ernst P Am J Med 2002;112:44-48

Who/What are Severe Asthmatics?

Distal airway/lung involvement as targets
Diffuse airway wall thickening Structural changes not altered by current therapy

Immune activation (not necessarily IgE)

Altered GC receptors Impaired response to CS Persistent inflammation Fibrosis

Increased TGFb and Th1 mediators

?Response to anti-Th1 therapy (anti-TNF-a {infliximab/etanercept})

Severe Asthmatic Phenotypes

Clinical, Physiologic, Pathological Sub-Types

Brittle Asthma ASA-sensitive (overproduction of cysLT) Eosinophilia related

Relatively steroid resistant Thickened subepithelial BM Risk for near-fatal episodes

Neutrophilic related
Steroid non-responsive

Pauci-cellular

Asthma Variability:

Moderate-Severe Asthma on b-Agonist Only

12 week: mean FEV1: 64%, b-agonist: 4-5/day
Symptoms** 80 70 60 50 40 30 20 10 0 Intermittent Mild Moderate Weeks in Category Severe
Albuterol: 59% Symptoms: 45%

Albuterol**

PEF*

All Criteria
**Intermittent, Mild, Mod-Severe *Intermittent-Mild, Moderate, Severe

Calhoun WJ. J Allergy Clin Immunol. 2003;112:1088-1094

Lack of Consistency in Utilization

Pitfall of the 20-80 Rule
This Year
20% of patients

Next Year

2/3
High-cost member

80% of costs

Low-cost member
Luskin AT, Bukstein DA Dean Med Center, 1999

Asthma Costs: Effect of Disease Management

Asthma $400 $350 $300 $250 $200 $150 $100 $50 $0
Baseline

Non Asthma

31%

Variability

PMPM

49%

Intervention

Intervention

Baseline

Intervention

Intervention Group

Control Group

Tinkelman D Am J Managed Care. 2004;10:948-954

Responder and Non-Responder: Dichotomy of Outcomes Response

?
FEV1 Symptom Score

Responder
FEV1
Symptom Score

FEV1
Symptom Score FEV1 Symptom Score

Non-Responder
Shingo S. Eur Respir J 2001;17:220-224

Variability of Response:
Fluticasone
FEV1 PC20

33%

34%

19% 27%

>3 Doubling Doses of PC20

33%

>15% FEV1 Response <5% FEV1 Response 5-15% FEV1 Response

1-3 Doubling Doses of PC20

54%

<3 Doubling Doses of PC20

Szefler S. et al JACI 2002;109:410-8.

Variability in FEV1 response: BDP and FP

Szefler S. et al JACI 2002;109:410-8.

Predictors of Response
Change in FEV1 15% (n=8)
17.6 ppb* 25% 0.63 eNO high BD reversibility FEV1/FVC ratio

Change in PC20

>3 DD (n=7)
3.6% 20-29 y*
* Not confirmed in PRICE

sputum eosinophils older onset of asthma

Szefler et al., J Allergy Clin Immunol 2002:109:410-418.

Smokings Effect on Response to CS

Oral Corticosteroids (40mg) for 2 weeks
Smokers 0.5 0 -0.5 Change -1 Compared to Placebo -1.5 -2 -2.5 -3 FEV1 (l) Symptoms Asthma Control Ex-smokers Never Smokers

Chaudrhuri R Am J Respir Crit Care Med 2003;168:1308-1315

SMOG: Effect of Smoking on Therapy

Smokers 14 12 10 Change in am 8 PF (L/M) 6 4 2 0 Beclomethasone Montelukast
P=0.03 P=0.19

Non-Smokers
P=0.0019

P=0.0006

ICS in Smoking: Dose Response

Non-Smokers 20 15 10 Change am PEF 5 0 -5 -10 BDP 400 BDP 2000 Combined Smokers

Decrease in Exacerbations: 6 vs 1
No difference in pm PEF, FEV1, Symptoms
Tomlinson JEM. Thorax 2005;60:282-287

Race and Steroid Responsiveness

1.3 1.2
P<0.01 P=0.028

log10IC50

1.1 1 0.9 0.8 0.7 0.6 0.5

Black Caucasion

Asthma

No Asthma
Chest 2005;127:571-578

Effect of Obesity on Response to Rx

Normal 60 50 40 LS Mean % 30 ACD 20 10 0 Montelukast Beclomethasone Placebo Overweight Obese

Peters-Golden M Chest 2004 (abs)

BARGE: Genetic effects on Response

0.1 0.08 0.06 0.04 0.02 0 Symptoms -0.02 -0.04 -0.06 -0.08 -0.1 Regular

Arg/Arg Gly/Gly

Arg/Arg: 15% (25% in people of color) Gly/Gly: 33% Israel E Lancet 2004;364:1505-12

CLIC: Can biomarkers predict response?

Are responses independent? Can response be related to geno/phenotype? 6-17 y/o FEV1: 96% predicted Mild lung function AFD/week: 1day/week Not mild symptoms Crossover Fluticasone/Montelukast

Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid

CLIC: FEV1 (7.5% )

Montelukast only

Both
17.5% 23%
Fluticasone only
FEV1, BD response, eNO, ECP, BHR

5% 55% Neither
Szefler S. JACI.2005;115:233-242

Secondary Outcome: Difference in Asthma-Free Days

No change

18 16 14 12 10 8 6 4 2 0
<3 <2 to to to

Participants, %

FP (n=123) Mt (n=123)

-4

-3

Change in Asthma-Free Days/Week from Baseline

Ref. Szefler SJ and CARE Network. AAAAI 2004

-2

<-1 1 to <0 0 to <1 1 to <2 2 to <3 3 to <4 4 to <5 5 to <6 6 to 7

Secondary Outcome: Asthma-Free Days Response

>2-day Mt Response

Change in Asthma-Free Days/wk with Mt

Concordance Correlation 0.70 (0.60, 0.78)

Mt alone n=6 (5%) Both, n=52 (42%)

9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5

Neither n=44 (36%)

FP alone n=21 (17%)

>2-day FP Response

Ref. Szefler SJ -5 -4 and CARE Network. AAAAI 2004

-3 -2 -1 0 1 2 3 4 5 6 7 8 9 Change in Asthma-Free Days/wk with FP

Response to Therapy Children with Mild Asthma

Clinical Predictors of HRQL

Clinical Outcomes
FEV1 Rescue bagonist use

Mild Asthma
No correlation Some correlation

ModerateSevere Asthma
No correlation No correlation Some correlation

Symptom Some intensity (SOB) correlation

Moy M. Am J Resp Crit Care Med. 2000;:163:924-929

Symptoms, FEV1, Inflammation and Asthma Control

Boulet L-P Chest 2002;122:2217-2223

eNO and FEV1 in Diagnosis

Adult Children

Upper and Lower Airway Inflammation

No Significant Difference in AR and AR + Asthma
PNIF Nasal or Bronchial eosinophilia Bronchial epithelial shedding Reticular basement membrane thickness

AR + Asthma: increased blood eosinophils and SKT scores

Braunstahl G. Clin Exp Allergy 2003;33:379-387

Inflammation and Severity

Basic construct not supported
Asthma is an inflammatory disease Inflammation persists despite severity, treatment or (?) course
Biopsy + in mild intermittent asthma* Ongoing during clinical remission** Present in the absence of clinical disease or BHR***

There is lack of correlation between the clinical expression of disease and control and underlying pathology
*Vignola AM Am J Respir Crit Care Med. 1998;157:403-409 **Van Den Toorn LM Am J Respir Crit Care Med. 2001;164:2107-2113 ***Braunstahl G Clin Exp Allergy 2003;33:379-387

Add-On Therapy: MO vs. SMT

Asthma Exacerbations Same (~ 20%)
FEV1 pre-BD Salmeterol

Who are these people?

FEV1 post-BD

Same

Asthma Specific QOL Same

Nocturnal Awakening Same

Peripheral Eosinophils Montelukast
Bjermer L, Bisgaard H, Bousquet J. BMJ. 2003;327:891-896

Normal Lung Function and Protection Against a Subsequent Attack

80 70 Proportion of Observations Reporting an Asthma Attack Over Subsequent Year 60 50

<1%

25% have an attack WhoSelf-report are they?

Parental report

5.5% 50.9% 43.3%

40
30 20 10 0 <60

60-69 70-79 80-89 90-99 100-<119 120 FEV1 % Predicted Decile

Fuhlbrigge et al. J Allergy Clin Immunol. 2001;107:61-67.

Rates (Unadjusted) of Acute Asthma Events by Baseline Level of Asthma Control

Unscheduled Contacts Oral Steroid Bursts ER Visits Nights in Hospital 0 1000 2000 3000 4000 5000 6000 0 Barriers (n = 497) 1 Barrier (n = 581) 2 Barriers (n = 902) 3-4 Barriers (n = 938)

Rate per 1000 person-years

Sulivan SD ACAAI 2004

Asthma Severity: Patient Perception

Whos Wrong
Severe Symptoms None 4.8% Mild Moderate Severe NAEPP Guidelines Moderate Mild Intermittant

10.4%

13.1%
60.1%

48.6%
42.3%

31.9% 47.2%
41.3% 21.9% 36.3% 5.8%

22.1% 8.1% 4.5% 0.8%

Asthma in America, 2001

Asthma Severity by Method

80 70 60 50 40 30 20 10 0 Mild Moderate Severe 48 50 50 38 30 16 32 16 14 6 18 9 33 PPS OSS NSS ROS MDU 65 75

Lee S Ann Allergy Asthma Clin Immunol. 2003;91:449-454

Lessons about Asthma Control

Clinical, physiologic, and inflammatory markers are disparate and correlate poorly They reflect different expressions of disease Perspective determines weight of measures
Patient (adherence) will act on HRQofL (clinical)

Interventions have variable effects on outcomes

Clues to the Bad Actors

Can we identify patients at risk for adverse outcomes?

Risk Assessment
Obesity Race Depression Baseline disease severity Non-adherence Sub-optimal control

Mild Persistent Asthma:

Predictors of Poor Outcomes
BMI > 25 EIB uncontrolled with albuterol alone Asthma stress questionaire positive Parents with negative expectations

3 of 4 is strongly associated with poorer outcomes

Outcomes by Risk Group

16 14 12 10 8 6 4 2 0

High Risk: 3-4/4

Low Risk: 0-2/4

Hospitalization
(%)

Beta-agonist
Fills/year

Antibiotic
Fills/year

Bukstein DA, Luskin AT Annals Allergy Asthma Immunol. 2003

Asthma Flares:
Effect of Baseline Depression Score
50 40 30 20 12 10 0 None 1 to 3 4 to 6 >6 Number of Flares in 6 months 8 8 41 43 43

27 18 Positive Negative

No Difference or change in FEV1

Bukstein DA, Luskin AT. JACI, 1999

Risk of Hospitalization in Mod-Severe Asthma

Effect of Co-Morbidities
Number of Controllers Depression G-I Migraine Allergy Sinusitis 0 0.5 1 1.5 2 2.5

Rate Ratio Compared to Controls

Sullivan SD, Luskin AT J Manag Care Pharm 2004

Asthma is Not a Static Disease

Asthma Control may change day to day and month to month Asthma Severity depends on how it is defined Asthma Severity does not correlate well with other outcomes (exacerbations, inflammation, remodeling) A snapshot of control on one day is not very reliable as a gauge of long-term outcomes

Question: What is it we need to do and measure?

1) Use a single multifaceted measure 2) Stratify by control and medication use 3) Add comorbidities to control parameters 4) Continue to focus on the Guidelines staging (imperfect but the best we have) 5) Need more research on what is asthma control

Asthma is Well Controlled if in a week.

5 days with DSS 1 (0-6 scale) 5days with no rescue b-agonist PEFRam 80% every day

2 of 3

and
1 nocturnal awakening No exacerbations No ED visits No therapy related adverse events

all

AFD = DSS 1, no b-agonist, PEFR 80%, no noc awakening, no exacerbation, no ED

GOAL Study: Persistence of Control (of those who achieved Control)

N.B.: 19-36% never achieve control (89% adherence)
20-32% not persistent Lose Control
100 80 60 40 20 0 FP FP/SM Well Controlled Total Control

Bateman ED Am J Respir Crit Care Med 2004:170:836-844

Variable Therapy: Exacerbation Outcomes

BUD + SABA BUD/Form + SABA BUD/Form reg + prn

BUD + SABA BUD/Form + SABA BUD/Form reg + prn 300

600 500 400 Severe Asthma 300 Exacerbations 200 100 0

200

100

0 po CS

BUD + SABA 300

BUD/Form + SABA

BUD/Form reg + prn

BUD + SABA 50 40

BUD/Form + SABA

BUD/Form reg + prn

200

30
100

20 10

0 PEF fall

0 Hosp/ED

O'Byrne PM Am Rev Respir Crit Care Med. 2004;171:129-136

Goals of Therapy
Improve Lung Function Prevent exacerbations Reduce symptoms Improve QOL Reduce burden of disease and therapy Prevent progression

Asthma and Outcome Phenotypes: Whats Needed

Multi-faceted markers

treatment Not focus onWhich Lung Function Appreciate lack correlation between outcomes forof which asthma
Stratify by control and medication requirement for what outcome Focus on Co-morbidities and Risk Focus on adherence, depression, chronic disease Design (and give weight to) studies which consider these issues

Individual Treatment Plan

Evaluate the variability of therapy
Response (genetic and environmental factors) Outcome parameters

Determine the relationship of phenotypes (and genotypes) to course and response Develop systems to individualize therapy based on individual response parameters

Asthma Management
Utilize clinical, pathologic and physiologic features, with genetics to profile patient Selection of therapy and predictors of response based on driving factors of disease presentation Monitor response and assess reasons for treatment failure Adjust therapy accordingly

Asthma Management: Biomarker Application

(Steroid sensitive)
Airway Inflammation

Altered airway structure Obtain ENO Measure pulmonary function

(Steroid insensitive?)

Proceed with inhaled steroid trial

Assess pulmonary function response (% change in FEV1)

Interpretation and Application

High ENO + Low FEV1/FVC High ENO + Low FEV1/FVC Low ENO + High FEV1/FVC
Low steroid response (FEV1) Likely steroid-insensitive component

Good pulmonary function response to inhaled steroid Continue inhaled steroid therapy

Marginal improvement in pulmonary function

Assess etiology of poor response: Consider reducing or discontinuing If pulmonary function low, consider: Allergen sensitivity and exposure Cell response abnormality inhaled steroid therapy Environmental assessment Genetic polymorphism Evaluate efficacy of nonsteroid Test nonsteroid control therapy Consider high-dose steroid therapy long-term control therapy