Asthma Variability-WSAAI Syllabus

7/28/2019 Asthma Variability-WSAAI Syllabus

1/80

Allan T. Luskin, MD

Associate Professor of Medicine, University of WisconsinDirector, 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

Asthma: The Variability of DiseaseControl, Severity, Outcomes and

Treatment Response


2/80

Initial Guideline Approach to Asthma

Only a cursory phenotyping by severity

Most adverse outcomes due to poor

diagnosis, poor prescribing, poor adherence

Majority of asthmatics respond to CS and b-agonists

One Size Fits All


3/80

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

Current Symptoms and MD Severity Rating

010

20

30

40

50

60

70

%o

fPatie

Mild Moderate Severe

Physician Rating of Underlying Severity

Mild Symptoms Moderate Symptoms Severe Symptoms

31% Concordance


4/80

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

Underlying Severity and Future HCU

05

10

15

20

25

30

35

% of Pts

Mild Moderate Severe

Physician Estimate of Underlying Severity

Hospitalized Cancelled Activities ED Visit

Who are these Patients?

Which Mild patients get sick?Which Severe patients stay well?


5/80

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


6/80

Dimensions of ControlHow 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 ofexacerbations)

Comorbidities


7/80

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

Exacerbation Frequency in Mild AsthmaInner City, Peds Clinic, 3 month parental Survey

80% Persistent 20% Intermittent

0

10

20

30

40

50

60

70

0 1 2 3 4 5

Red Zone

Yellow Zone


8/80

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

Exacerbations and Effect of Therapy

0

20

40

60

80

100

%

Exacerbations

Prevented

COPD Asthma

ICS ICS + LABA

Different

Exacerbations

or Different People(not all exacerbations

and not all asthmaticsare the same)


9/80

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

Exacerbations and ICSISOLDE Trial

0

0.5

1

1.5

2

Mild Mod-Severe

Place bo FP

0

5

10

15

20

25

30

35

Mild Mod-Severe

Placebo FP

Mean # Exacerbations/year % pts with 1 Exacerbations/year


10/80

Asthma is a syndrome, not a disease

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

Response to ALL therapy is highly variableBHR and Reversible airflow obstruction does not predictresponse to therapy

Outcomes do not necessarily correlate witheach other

There are Outcome phenotypes


11/80

COPD: Response to Tobacco Smoke

Atopy and hx of childhood illness

showed significant additive effect


12/80

Factors in Asthma Variability

Genetic

Environment

Disease Variability

Rx Variability

Patient Display on One Day-One Time

N.B.: There are 21 arrows. Probability combinations are 2121

Phenotypes: The visible effects of the interaction

between Genetic Makeup and the Environment

Patient Display on One Day-One Time

Patient over Time


13/80

Gern J JACI February 2004

Infant Eczema: CD14/-159 & Dogs

0

10

20

30

40

50

60

70

% Eczema

CC CT TT

Dogs

No dogs


14/80

Eder (in press)

Total IgE: CD14/-159 & Animal Contact

0

30

60

90

120

150

Geometric

mean (IU/ml)

No animals Dog/Cat only Barn animals

CC

CT

TT


15/80

Obvious Factors in Variability

Season Allergen exposure

Air pollutants

ETS

Infection

Concomitant disease

Exertion

Hormones

Adherence


16/80


17/80

Behavior and Development of WheezePsychologic Factors at age 3 and Development of

Late-Onset Wheeze at age 5

0

1

2

3

4

5

6

OR

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

Compared to

Never wheezers


18/80

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 20022Bender B JACI 2003

3Luskin AT, Bukstein DA JACI 20014Williams LK JACI2004;114:1288-1293


19/80

Weiss KB. JAMA 1990;263:2323-2328

Hospitalization: Season and Age

-20

-15

-10

-5

0

5

10

15

20

Hospitalization

Jan

Feb

Mar Ap

rM

ay Jun Ju

lAu

gSep

Oct

Nov

Dec

Ages 5-34 Ages 35-64 Ages >65


20/80

eNO and Adherence to ICS


21/80

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

Asthma Severity: BMI and Menarche

0

0.5

1

1.5

2

2.5

3

3.5

4

Clinical

Asthma

Severity Score

Men Women: no early

menarche

Women: early

menarch

I II III IV V

BMI Quintiles


22/80


23/80

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 variabilityEnvironment, genetics, response to therapy,

relationship between outcomes

Need understanding of risk drivers Risk assessment (predictive modeling)

Individualized control assessment


24/80

Asthma Management

Utilize characteristics, biomarkers, andgenetics to profile asthma severity

Select medications based on driving factorsof disease presentation and predictors ofresponse

Monitor response and assess reasons fortreatment failure

Adjust therapy accordingly


25/80

Outcomes Variability in Management

There are multiple levels of response to therapy

Variability of response to treatment is outcomeparameter 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)


26/80

Predicting Response

Why predict response

What are appropriate predictors of response

What response is most important


27/80

Targets and Assessment: Response to Rx

FunctionalSymptoms/Medication Use

Exacerbation

Global: QOL, ADL Physiologic

Lung function/BHR

Progression Pathologic (Inflammation)

Sputum eos/ eNO


28/80

Hypertension Pain

Risk Symptoms

What is Control?

Asthma

?


29/80


30/80

Question: Which outcomes

measure is the Bestone 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


31/80

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


32/80

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


33/80

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

Course of Asthma

Change in Severity after 5 years

0 20 40 60 80 100

Mild to Severe

Severe to Not

Severe

Severe to mild

Severe to

Remission

< 15 y/o > 15 y/o


34/80

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})


35/80

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:


36/80

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

Asthma Variability:

Moderate-Severe Asthma on b-Agonist Only12 week: mean FEV

1

: 64%, b-agonist: 4-5/day

0

1020

30

40

50

60

70

80

Intermittent Mild Moderate Severe

Symptoms** Albuterol** PEF* All Criteria

**Intermittent, Mild, Mod-Severe

*Intermittent-Mild, Moderate, SevereAlbuterol: 59%

Symptoms: 45%

Weeks in Category


37/80

Luskin AT, Bukstein DA Dean Med Center, 1999

Lack of Consistency in Utilization

Pitfall of the 20-80 Rule

Low-cost

member

This Year Next Year

High-cost

member

2/320%of patients

80%

of costs


38/80

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

Asthma Costs: Effect of Disease Management

$0$50

$100

$150

$200

$250

$300

$350

$400

PMP

Baseline Intervention Baseline Intervention

Intervention Group Control Group

Asthma Non Asthma

49%31%

Variability

Intervention


39/80

Responder and Non-Responder:Dichotomy of Outcomes Response

FEV1

Symptom Score

FEV1

Symptom Score

FEV1

Symptom Score FEV1Symptom Score

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

Responder

Non-Responder

?

?


40/80

Variability of Response:Fluticasone

Szefler S. et alJACI2002;109:410-8.

34%

33%

33%

>15% FEV1 Response3 Doubling Doses of

PC20

1-3 Doubling Doses ofPC20


41/80

Szefler S. et alJACI2002;109:410-8.

Variability in FEV1 response: BDP and FP


42/80

Predictors of Response

Change in FEV1 15% (n=8) eNO 17.6 ppb*

high BD reversibility 25% FEV1/FVC ratio 0.63

Change in PC20

>3 DD (n=7)

sputum eosinophils 3.6%older onset of asthma 20-29 y*

Szefler et al., J Allergy Clin Immunol 2002:109:410-418. * Not confirmed in PRICE


43/80

Smokings Effect on Response to CS

Oral Corticosteroids (40mg) for 2 weeks

-3

-2.5

-2

-1.5

-1

-0.50

0.5

Change

Compared to

Placebo

FEV1 (l) Symptoms Asthma Control

Smokers Ex-smokers Never Smokers

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


44/80

SMOG: Effect of Smoking on Therapy

0

24

6

8

10

12

14

Change in am

PF (L/M)

Beclomethasone Montelukast

Smokers Non-Smokers

P=0.03

P=0.0006

P=0.19

P=0.0019


45/80

Tomlinson JEM. Thorax 2005;60:282-287

ICS in Smoking: Dose Response

-10

-5

0

5

10

15

20

Change am

PEF

BDP 400 BDP 2000 Combined

Non-Smokers Smokers

Decrease in Exacerbations: 6 vs 1No difference in pm PEF, FEV1, Symptoms


46/80

Chest 2005;127:571-578

Race and Steroid Responsiveness

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

Asthma No Asthma

Black

Caucasionlog10

IC

50

P=0.028

P


47/80

Peters-Golden M Chest 2004 (abs)

Effect of Obesity on Response to Rx

0

10

20

30

40

50

60

LS Mean %

ACD

Montelukast Beclomethasone Placebo

Normal Overweight Obese


48/80

Israel E Lancet 2004;364:1505-12

BARGE: Genetic effects on Response

-0.1-0.08

-0.06

-0.04

-0.02

0

0.020.04

0.06

0.08

0.1

Symptoms

Regular

Arg/Arg

Gly/Gly

Arg/Arg: 15% (25% in people of color)

Gly/Gly: 33%


49/80

CLIC: Can biomarkers predict response?Are responses independent?

Can response be related to geno/phenotype?

6-17 y/o

FEV1: 96% predicted AFD/week: 1day/week

Crossover Fluticasone/Montelukast

Mild lung functionNot mild symptoms


50/80

CLIC: FEV1 (7.5% )Characterizing the Response to a Leukotriene

Receptor Antagonist and an Inhaled Corticosteroid

5% 17.5%

55% 23%

Both

Neither

Montelukast only

Fluticasone only

FEV1, BD response, eNO,

ECP, BHRSzefler S. JACI.2005;115:233-242

Secondar O tcome:


51/80

No

change

0

2

4

6

8

10

1214

16

18

-4to

Date post:	03-Apr-2018
Category:	Documents
Upload:	minervastanciu
View:	218 times
Download:	0 times

Asthma Variability-WSAAI Syllabus

Documents