Title: Allan T. Luskin, MD
1Asthma 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
2Asthma and HRQOL The Burden
147 million unhealthy functioning days/year
3Initial 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
b-agonists
4Current Symptoms and MD Severity Rating
31 Concordance
80
5Underlying Severity and Future HCU
Who are these Patients? Which Mild patients get
sick? Which Severe patients stay well?
6Asthmas 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
7Variability of Asthma Asthma is a syndrome, not
a disease
- Control How the disease affects the organism
- Severity The pathos of the illness in the organ
- Risk For adverse outcomes
- Response To various therapies
- Natural History Outgrow or not outgrow
8Dimensions 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 of
exacerbations) - Comorbidities
9Exacerbation Frequency in Mild AsthmaInner City,
Peds Clinic, 3 month parental Survey80
Persistent 20 Intermittent
10Exacerbations and Effect of Therapy
Different Exacerbations or Different People (not
all exacerbations and not all asthmatics are the
same)
11Exacerbations and ICSISOLDE Trial
Mean Exacerbations/year pts with 1
Exacerbations/year
12Asthma 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
13COPD Response to Tobacco Smoke
Atopy and hx of childhood illness showed
significant additive effect
14Health Status Effect of Exacerbations
15Phenotypes The visible effects of the
interaction between Genetic Makeup and the
Environment
Genetic Disposition
Target Organ Reactivity
Smooth Muscle Dysfunction
Homing of Immune Response
Inflammatory Cell Activation
Type of Immune Response
Degree of Immune Response
Airway Epithelial Dysfunction
Environmental Exposure
Adapted from Sicherer SH et al. J Allergy Clin
Immunol. 2000106S251-S257.
16Factors in Asthma Variability
Patient Display on One Day-One Time
Genetic
Disease Variability
Environment
Rx Variability
Phenotypes The visible effects of the
interaction between Genetic Makeup and the
Environment
Patient over Time
Patient Display on One Day-One Time
N.B. There are 21 arrows. Probability
combinations are 2121
17Infant Eczema CD14/-159 Dogs
18Total IgE CD14/-159 Animal Contact
19Patient Display on One Day-One Time
Genetic
Environment
variability
Disease Variability
Rx Variability
Patient over Time
Seasonal (allergens, virus) Triggers (allergens,
virus, ETS, cold air, pollutants) Upper
Respiratory (sinusitis, otitis) Adherence ???
20Obvious Factors in Variability
- Season
- Allergen exposure
- Air pollutants
- ETS
- Infection
- Concomitant disease
- Exertion
- Hormones
- Adherence
21Variability and Outcomes6 mo pre/post Guideline
Adherence Directed Therapy
22Infections 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
23Behavior and Development of WheezePsychologic
Factors at age 3 and Development of Late-Onset
Wheeze at age 5
Compared to Never wheezers
Esp Inattentive, Overactive Suggesting
physiologic component
Calem R. Am J Respir Crit Care Med.
2005171323-327
24Adherence and Outcomes
- Adherence/persistence rates range from 5-501
- 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 20041141288-1293
25Patterns of Medication Utilization
- Super Adherence 10-15
- Takes gt 90 of prescribed therapy
- Good Adherence 25-35
- Takes 50-90 of prescribed therapy
- Takes some medication most of the time
- Poor Adherence 40-45
- Takes 10-50 of prescribed therapy
- Takes some medication some of the time
- Fairly compliant for short periods, then a drug
holiday - Very Poor Adherence 10-15
- Takes lt 10 of prescribed therapy
26Adherence and Resource Utilization
Luskin AT, Bukstein DA. JACI, 2000 (abs)
27Adherence and Activity Limitations
Luskin AT, Bukstein DA. JACI, 2000 (abs)
28ICS Use and Risk of Hospitalization
Regular Use
29Use of Inhaled Corticosteroids
30Impact of Non-Adherence
31Hospitalization Season and Age
32eNO and Adherence to ICS
33Mortality Season and Age
34Asthma Control Days Effect of BMI6 week DBPC
adult asthmatics
Placebo-adjusted response
35Asthma Severity BMI and Menarche
BMI Quintiles
36Work Loss in Parents of AsthmaticsChildren 6-16
y/o with persistent asthma (GINA 2)
30 lost work days 13 lost gt 5 work days
Severity
Control
37Work Loss in Parents of AsthmaticsChildren 6-16
y/o with persistent asthma (GINA 2)
30 lost work days 13 lost gt 5 work days
Hospital
po CS
Antibiotic
38Work Loss in Parents of AsthmaticsChildren 6-16
y/o with persistent asthma (GINA 2)
30 lost work days 13 lost gt 5 work days
gt5 work days lost
39Severity 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
40Asthma 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
41Outcomes 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)
42Predicting Response
- Why predict response
- What are appropriate predictors of response
- What response is most important
43Evaluation of Control
Medical Outcomes
Humanistic Outcomes
Quality of Life Life satisfaction Social
role functioning Sense of community Spiritual
fulfillement Self-esteem Enjoyment
Pleasure Appreciation Patient satisfaction
With asthma control With Quality of Life
Economic Outcomes
Modified from BLAISS MS, JAMA 1997
44Targets and Assessment Response to Rx
- Functional
- Symptoms/Medication Use
- Exacerbation
- Global QOL, ADL
- Physiologic
- Lung function/BHR
- Progression
- Pathologic (Inflammation)
- Sputum eos/ eNO
45What is Control?
Hypertension
Pain
?
Risk
Symptoms
Asthma
46Ideal Measure of Asthma Control
- Simple and practical
- Meaningful
- Applicable to patients, clinicians, researchers
- Reflective of short and long-term control
- Discriminatory
- Responsive to change
47Question 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
48PEAK 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
49PEAK TrialChange 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
50Lung Function in Children Natural History
Childhood Asthma Research and Education Network.
Tucson Childrens Respiratory Study.
51Expression of Childhood Asthma at 42 years
Persistent
Frequent
Infrequent
No recent
MWB mild wheeze bronchitis WB Wheezy
bronchitis A Asthma
SA Severe Asthma
Phelan et al., JACI 2002109( 2)189-194
52Course of AsthmaChange in Severity after 5
years
53Who/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)
54Severe Asthmatic PhenotypesClinical,
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
55Mild-Moderate Asthma Phenotypes
- Differentiate on basis of eosinophils
- Eosinophilic relatively steroid responsive
- Non-eosinophilic steroid non-responsive
56Asthma Severity and FEV1Severity based on More
Severe of Symptoms and Medication Use
57Asthma Severity and FEV1/FVCSeverity based on
More Severe of Symptoms and Medication Use
Abnormal lt 5th percentile for age
58Consistence of Asthma SeverityModerate/Severe
Asthma b-agonist onlyb-agonist 5-6 ppd
FEV1 64
59Asthma VariabilityModerate-Severe Asthma on
b-Agonist Only12 week mean FEV1 64,
b-agonist 4-5/day
Intermittent, Mild, Mod-Severe Intermittent-Mil
d, Moderate, Severe
Albuterol 59 Symptoms 45
Weeks in Category
60Variability of HEDIS Enrollment
61Asthma Health-Care Utilization
The 20-80 Rule
2severe 25,000/yr 18episodic 2500/yr
20 of members
80 of costs
80healthy 250/yr
62Lack of Consistency in Utilization
- Pitfall of the 20-80 Rule
This Year
Next Year
2/3
20 of patients
80 of costs
High-cost member
Low-cost member
63Asthma Costs Effect of Disease Management
Variability
31
Intervention
49
64Asthma Severity and FEV1Severity based on More
Severe of Symptoms and Medication Use
65Responder and Non-Responder Dichotomy of
Outcomes Response
Responder
?
FEV1 Symptom Score
FEV1 Symptom Score
40
FEV1 Symptom Score
FEV1 Symptom Score
?
Non-Responder
Shingo S. Eur Respir J 200117220-224
66Patients Not Controlled on PRN Beta-Agonists
FEV1 Distribution of Individual Patient
Responses
34 of patients had no signif. Increase in FEV 1
30 25 20 15 10 5 0
Patients ()
lt-30
-30 to lt-20
-20 to lt-10
-10 to lt0
0 to lt10
10 to lt20
20 to lt30
40 to lt50
50
30 to lt40
FEV1 Percent Change From Baseline
- In this study, all patients benefited from
- mandatory use of spacers,
- enforced compliance, and
- rigorous monitoring of patients
Malmstrom et al. Ann Intern Med. 1999130487-495.
67Patients Not Controlled on PRN Beta-Agonists
FEV1 Distribution of Individual Patient
Responses
22 of patients had no signif. Increase in FEV 1
30 25 20 15 10 5 0
Patients ()
lt-30
-30 to lt-20
-20 to lt-10
-10 to lt0
0 to lt10
10 to lt20
20 to lt30
40 to lt50
50
30 to lt40
FEV1 Percent Change From Baseline
- In this study, all patients benefited from
- mandatory use of spacers,
- enforced compliance, and
- rigorous monitoring of patients
Malmstrom et al. Ann Intern Med. 1999130487-495.
68 Variability of ResponseFluticasone
FEV1
PC20
Szefler S. et al JACI 2002109410-8.
69Variability in FEV1 response BDP and FP
Szefler S. et al JACI 2002109410-8.
70Predictors of Response
- Change in FEV1 ?15 (n8)
- ? eNO ?17.6 ppb
- high BD reversibility ?25
- ? FEV1/FVC ratio 0.63
- Change in PC20 gt3 DD (n7)
- ? sputum eosinophils 3.6
- older onset of asthma 20-29 y
Szefler et al., J Allergy Clin Immunol
2002109410-418.
Not confirmed in PRICE
71Variability of Response ICSCorticotropin
Releasing Hormone Receptor 1 Polymorphism
72Smokings Effect on Response to CSOral
Corticosteroids (40mg) for 2 weeks
- Chaudrhuri R Am J Respir Crit Care Med
20031681308-1315
73Cigarette Smoking and ICS in Mild
AsthmaCrossover Study with FP 1000mcg for 3 Weeks
74SMOG Effect of Smoking on Therapy
P0.0019
P0.0006
P0.03
P0.19
75ICS in Smoking Dose Response
Decrease in Exacerbations 6 vs 1 No difference
in pm PEF, FEV1, Symptoms
76Race and Steroid Responsiveness
Plt0.01
P0.028
log10IC50
77Effect of Obesity on Response to Rx
78Response to LT InhibitionEffect of 5-LO
promoter gene mutation
Homozygous Wild Type 60
79BARGE Genetic effects on Response
Arg/Arg 15 (25 in people of color) Gly/Gly 33
80Exacerbations on LABA in Children
81SOCS Treatment Failures(Salmeterol and ICS had
equivalent improvement in lung function)
Not statistically different
ALA/ATS Conference 2000 Lazarus, JAMA
82CLIC 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 function Not mild symptoms
83CLIC FEV1 (7.5 ) Characterizing the Response
to a Leukotriene Receptor Antagonist and an
Inhaled Corticosteroid
Both
Montelukast only
17.5
5
55
23
Neither
Fluticasone only
? FEV1, ?BD response, ? eNO, ? ECP, ?BHR
Szefler S. JACI.2005115233-242
84Secondary Outcome Difference in Asthma-Free Days
No change
Participants,
Change in Asthma-Free Days/Week from Baseline
Ref. Szefler SJ and CARE Network. AAAAI 2004
85Secondary Outcome Asthma-Free Days Response
Concordance Correlation 0.70 (0.60, 0.78)
Both, n52 (42)
Mt alone n6 (5)
gt2-day Mt Response
Change in Asthma-Free Days/wk with Mt
FP alone n21 (17)
Line of identity
Neither n44 (36)
gt2-day FP Response
Ref. Szefler SJ and CARE Network. AAAAI 2004
Change in Asthma-Free Days/wk with FP
86Response to TherapyChildren with Mild Asthma
87Clinical Predictors of HRQL
88Asthma-Specific HRQL and CostsAsthma Costs over
a 12 month Follow-up
89Symptoms, FEV1, Inflammation and Asthma Control
Boulet L-P Chest 20021222217-2223
90eNO and FEV1 in Diagnosis
Adult
Children
91Correlation eNO, FEV1, and BHR
92Comparison of Tests in Asthma Diagnosis
93Upper and Lower Airway Inflammation
- Groups
- AR Asthma
- AR only (negative methacholine)
- Asymptomatic Atopic (SKT only)
- Non-Atopic
- Outcomes
- Clinical Scores, PFTs, PNIF
- Bx (bronchial and nasal)
- Atopy scores ( and size of SKT)
94Upper 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
95Upper and Lower Airway InflammationBottom Line
- Allergic inflammations and (?) its consequences
(increased BM thickening and epithelial
desquamation) are present in the lower airways
before onset of symptoms (which may or may never
occur) - The relationship between allergic inflammation
and clinical disease is not clearly established
96Inflammation 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.
1998157403-409 Van Den Toorn LM Am J Respir
Crit Care Med. 20011642107-2113 Braunstahl G
Clin Exp Allergy 200333379-387
97Remodeling and Asthma Correlations? Children
with Difficult Asthma (gt1600mcg/d)
No association with age, duration, PFT, (eos)
inflammation
Payne D. et al AJRCCM 200216778-82.
98Severity ClassificationGuidelines vs.
Specialist Judgment
99Add-on TherapyEffect of Salmeterol or
Montelukast
100Add-On Therapy MO vs. SMT
Who are these people?
101Asthma Severity and HCU and QOLSeverity Gauged
on Short-Term Symptoms
Note gt25 of Patients with Mild Intermittent
Asthma had a significant exacerbation over 1 year
102Normal Lung Function and Protection Against a
Subsequent Attack
25 have an attack Who are they?
80
lt1
Self-report Parental report
70
60
Proportion of Observations Reporting an Asthma
Attack Over Subsequent Year
5.5
50
50.9
40
43.3
30
20
10
0
lt60
60-69
70-79
80-89
90-99
100-lt119
?120
FEV1 Predicted Decile
Fuhlbrigge et al. J Allergy Clin Immunol.
200110761-67.
103Rates (Unadjusted) of Acute Asthma Events by
Baseline Level of Asthma Control
104 Assessment by Patients and Physicians
Boulet L-P, Phillips R, OByrne PM, Becker A. Can
Respir J 2002 9417-23
Physicians assessment l
Patients assessment
Patients assessment
105Asthma Severity Patient Perception
Whos Wrong
NAEPP Guidelines
Patient Self-Classification
Asthma in America, 2001
106Defining Asthma Severity
- Patient Perceived Severity
- how severe do you think your asthma is?
- Symptom Derived Severity
- Overall and Nocturnal
- In the past 4 weeks how often?
- Medication Derived Severity
- Reliever and Oral Steroid use
- Multi-Drug Use Method
Lee S Ann Allergy Asthma Clin Immunol.
200391449-454
107Asthma Severity by Method
Lee S Ann Allergy Asthma Clin Immunol.
200391449-454
108Agreement Between Methods
Lee S Ann Allergy Asthma Clin Immunol.
200391449-454
109Asthma Control Test In the last 4 weeks.
- Asthma keep you from getting as much done at
work, school or home - 1) all 2) most 3) some 4) a little 5) none of the
time - How often have you had shortness of breath
- 1) gt1/day 2) once/day 3) 3-6X/wk 4) 1-2X/wk 5)
Not at all - Asthma symptoms wake you up at night or earlier
than usual - 1) ? 4 nights/wk 2) 2-3 nights/wk 3) once a week
4) 1-2 times 5) Not at all - Used your rescue inhaler or neb medication
- 1) ?3X/day 2) 1-2X/day 3) 2-3X/wk 4) once a wk or
less 5) Not at all - Rate your asthma control
- 1) not 2) poorly 3) somewhat 4) well 5)
completely controlled
Well controlled is a score of 20 or higher
110Asthma Control Test
- Asthma keep you from getting as much done at work
or home - 1) none 2) a little 3) some 4) most 5) all the
time - Rate your asthma control
- 1) not 2) poorly 3) somewhat 4) well 5)
completely controlled - How often have you had shortness of breath
- 1) not 2) 1-2 X/wk 3) 3-6X/wk 4) 1-2X/day 5)
?3X/day - Asthma symptoms wake you up at night or earlier
than usual - 1) not 2) 1-2X/mo 3) once a week 4) 2-3 nights/wk
5) ?3nights/wk - Used your rescue inhaler or nebulizer medication
- 1) not 2) once a wk or less 3) few X/wk 4)
1-2X/day 5) ?3X/day
ACT correlates modestly with PFT and well (75)
with specialists assessment
Bold 1 point well controlled is a score of 4
or higher
111Lessons 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
112Management Guidelines or Eosinophils74
Mod-Severe Asthmatics treated for 1 year
Average daily dose of CS similar Symptoms, QOL,
b-agonist use, peak flow, FEV1(p-bd) similar
113BHR Treatment Strategy first mild asthma
exacerbations
114Variability of Therapy and Course
- ICS LABA (Symbicort)
- 2 puffs bid (80mcg) or
- 1 puff bid and temporary increase to 4 puffs bid
with exacerbations
115Control and Amount of Therapy
No difference in HRQL
116Clues to the Bad Actors
- Can we identify patients at risk for adverse
outcomes?
117Risk Assessment
- Obesity
- Race
- Depression
- Baseline disease severity
- Non-adherence
- Sub-optimal control
118Mild Persistent AsthmaPredictors of Poor
Outcomes
- BMI gt 25
- EIB uncontrolled with albuterol alone
- Asthma stress questionaire positive
- Parents with negative expectations
3 of 4 is strongly associated with poorer outcomes
119Outcomes by Risk Group
()
Fills/year
Fills/year
120Asthma Flares Effect of Baseline Depression
Score
No Difference or change in FEV1
121Risk of Hospitalization in Mod-Severe
AsthmaEffect of Co-Morbidities
Rate Ratio Compared to Controls
122Mental Distress and HRQOLPrevalence Rates in
Adult Asthmatics
19 in Asthmatics 9 in Non-Asthmatics
Associated with Obesity, Smoking, Inactivity
123Asthma 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
124Question 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
125Asthma 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
- 1 nocturnal awakening
- No exacerbations
- No ED visits
- No therapy related adverse events
2 of 3
and
all
AFD DSS 1, no b-agonist, PEFR 80, no noc
awakening, no exacerbation, no ED
126GOAL Study Are Guideline Goals for Control
Achievable?
- Uncontrolled asthmatics
- Three stratum
- No ICS, Low-dose ICS, Mod-dose ICS
- Similar at baseline (PFT (77), b-agonist (1.8),
noc awakenings (0.5), exacerbation rate (0.5) - FP vs. FP/SM for 1 year
- Step-up to max 500mgm BID
- Well or Total Control
Bateman ED Am J Respir Crit Care Med
2004170836-844
127Goal StudyExacerbation Rate (HCU or Burst CS)
Bateman ED Am J Respir Crit Care Med
2004170836-844
128GOAL Study Proportion of Patients Achieving
Well-Controlled
Bateman ED Am J Respir Crit Care Med
2004170836-844
129Goal Study Control
19-36 NOT controlled
Adherence 89
Lowest Dose Well-45-60
Total-40-53 Max Dose 57-87
Bateman ED Am J Respir Crit Care Med
2004170836-844
130GOAL Study Persistence of Control(of those who
achieved Control)
N.B. 19-36 never achieve control (89 adherence)
20-32 not persistent Lose Control
Bateman ED Am J Respir Crit Care Med
2004170836-844
131Variability of Therapy and Course
- ICS LABA (Symbicort)
- 2 puffs bid (80mcg) or
- 1 puff bid and temporary increase to 4 puffs bid
with exacerbations
132Control and Amount of Therapy
No difference in HRQL
133Variable Therapy Exacerbation Outcomes
134Goals of Therapy
- Improve Lung Function
- Prevent exacerbations
- Reduce symptoms
- Improve QOL
- Reduce burden of disease and therapy
- Prevent progression
135Asthma and Outcome PhenotypesWhats Needed
Which treatment for which asthma for what
outcome ?
- Multi-faceted markers
- Not focus on Lung Function
- Appreciate lack of correlation between outcomes
- Stratify by control and medication requirement
- Focus on Co-morbidities and Risk
- Focus on adherence, depression, chronic disease
- Design (and give weight to) studies which
consider these issues
136Asthma is variable.
Which treatment for which asthma for what outcome
- 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
137Global Severity
Level of Control
Outcomes HCU QOL ADL
Medical Therapy
Self Management
Individual Factors Genetics Co-Morbidities
Environmental Exposures
Modified from Vollmer WM Annals Allergy Asthma
Clin Immunol.200493409-414
138Individual 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
139Asthma 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
140Asthma Management Biomarker Application
Airway Inflammation
(Steroid insensitive?)
Altered airway structure
(Steroid sensitive)
Obtain ENO Measure pulmonary function
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
Marginal improvement in pulmonary function
Good pulmonary function response to inhaled
steroid
Continue inhaled steroid therapy
- Assess etiology of poor response
- Allergen sensitivity and exposure
- Cell response abnormality
- Genetic polymorphism
- Consider high-dose steroid therapy
Consider reducing ordiscontinuing inhaled
steroid therapy
- If pulmonary function low, consider
- Environmental assessment
- Test nonsteroid control therapy
Evaluate efficacy of nonsteroid long-term control
therapy
141Environmental Factors
Allergen
Genetic Factors (gene)
APC
I Antigen Recognition
Antigen-presenting HLA-Pep-TCR
IL-18 IL-12
T helper cells
Downregulation IL-12Rb2 IL-18Ra
IFN-gR1 Upregulation IL-4Ra IL-13
VDJ-Ce FceRIb
Th2
II IgE Production
Th1
INF-g
B cells
IL-4 IL-13
IL-2
DH
Allergen
IgG IgM IgA
IgE
Eos Mast cell et al
III Production of Mediators
Arachidonic cascade LT synthase
b2-adrenergic R IL-13R
Histamine Leukotriene Thromboxane
IV Target Organ
Symptoms Asthma, Rhinitis, Eczema
Kondo, N Allergology International 20045377-85