Allergies and AsthmaAllergies and AsthmaDouglas H. Jones, MD, FAAAAI, FACAAI
Unprecedented Patient Results
Learning ObjectivesLearning Objectives
1) Understand the key role that allergies play in asthma
2) Understand that treatment of allergies is part of the 2) Understand that treatment of allergies is part of the asthma treatment guidelines
3) Treating allergies will often reduce disease burden and 3) Treating allergies will often reduce disease burden and cost of asthma
What is asthma? NHLBI
Asthma is a chronic inflammatory disorder of the airways.
Features of asthma include inflammatory cell infiltration: — Neutrophils (fatal asthma exacerbations; occupational asthma; smokers) — Eosinophils (associated with allergies) — Mast cell activation (associated with allergies) Mast cell activation (associated with allergies) — Epithelial cell injury (may be due to allergens, toxins, or inflammation)
Inflammation leads to symptoms, hyperresponsiveness, and disease chronicity.
Gene-by-environment interactions are important to the expression of asthma.
Atopy, the genetic predisposition for the development allergies, is the strongest identifiable predisposing factor for developing asthma. g p p g p g
Viral respiratory infections are an important causes of asthma exacerbation
Airway Hyperresponsiveness Airway Obstruction
Clinical Symptoms
Overview of IgE-Mediated AsthmaInflammatory Cascade
B cell
T cell
IL-4, IL-13lgE production Mast cell
T cell
Mediator Airway
Antigen-presenting
cellActivated
B cell (plasma
Mediator release
wall
Allergen
B cell (plasma cell) Allergen cross-
linking
IgE FcRI
5 5Storms. Am J Respir Med. 2002:1:361.MacGlashan et al. J Immunol. 1997;158:1438.
g
Relationship Between Asthma and Serum IgE Levelg
Asthma Risk Versus Total Serum IgE Concentration
rati
o40
20
10
Odd
s r
5
2.5
10
0.32 1 3.2 10 32 100 320 1000 3200
Serum IgE level (IU/mL)
Data from a stratified cluster sample of 2657 patients from white non–Mexican-American households in which the association of self-reported asthma with serum IgE levels and skin-test reactivity to allergens was investigated. Blood samples were obtained from subjects, and serum IgE levels were measured.
6
The risk for allergic asthma starts with relatively low IgE levels.
Adapted from Burrows et al. N Engl J Med. 1989;320:271.
D i i h ll i hi i i Do patients with allergic rhinitis have pathophysiologic risk factors have pathophysiologic risk factors
for developing asthma?
Patients With Allergic Rhinitis Alone Have Abnormalities Of The Lower Airways
Pathologic abnormalities Eosinophilic inflammation
Basement membrane thickening
Bronchial hyperresponsiveness to nonspecific p p pstimuli
Bronchial Inflammation In Patients With Isolated Allergic Rhinitis vs. Asthmatics
100
7
8
Basement 5
6
7
Basement membranethickness
(μm)
Eosinophilsper mm2 10
3
4
5
1
2
1 0
controls isolated rhinitis asthmatics
Djukanovic R et al. Eur Respir J 1992;5:538
controls isolated rhinitis asthmatics
Comparative Histopathology Of Allergic Rhinitis (AR) vs. AR/Asthma
Bi di f l d b hi l i Biopsy studies of nasal and bronchial tissue
Difficult to distinguish AR/asthma from isolated AR on basis of: Nasal or bronchial eosinophils
Nasal or bronchial mast cells
Bronchial basement membrane thickeningg
Serum IL-5 or eotaxin levels
Braunstahl et al, Clin Exp Allergy, 2002;33:579-87
Correlation Between Nasal And Bronchial E i hil I A h iEosinophils In Asthmatics
35
40
phils
25
30
cosa
Eos
inop (n = 11)
15
20
Nas
al M
uc
0
5
10 r = 0.851, P<.001
00 5 10 15 20 25 30
Bronchial Mucosa Eosinophils
What’s the Risk of a Patient with Allergic Rhinitis Developing Allergic Rhinitis Developing
Asthma?
Frequent Association of Upper and Lower Airway Diseasey
• Involvement of upper airway is very common in patients with asthma
• Of 478 patients w/ asthma, 99% of adults and 93% of adolescents reported concomitant AR¹p
• In patients with allergic rhinitis, asthma present in 19% - 40%²19% 40%
1. Busse W. Respir rev 1997; 7:284-5.2. Corren J. J Allergy Clin Immunol 1997;99:S781-6.
Allergic Rhinitis Symptoms Are Ubiquitous in Asthma
ADOLESCENTASTHMA STUDY
n = 125
ADULTASTHMA DATABASE
n = 348
COLLABORATIVESTUDIES FOR THE
GENETICS OF ASTHMAn = 168n = 168
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88.8% 94.3% 85.1%
rhinitis symptoms
no rhinitis symptoms
Patients With AR + Comorbid Conditions
67.5%
21.3% 20.8%
2.2%
Adapted from Schoenwetter WF et al. Curr Opin Med Res. 2004;20:305–317.
AR As A Risk Factor For The Development Of AsthmaIncidence of Asthma Over An 8-Year Period
20
25
30 OR: 46.5
10
15
20
% of subjectsOR: 8.2 OR: 18.9
0
5
10
pollen animal mite
no rhinitisat baseline
rhinitisat baseline
Linneberg et al. Allergy 2002;57:1048
Will Treatment Of Allergic Rhinitis Result In Improvements In Lower Result In Improvements In Lower
Airway Disease?
Rhinitis Therapies In AsthmaRhinitis Therapies In Asthma
Number of topical and oral rhinitis treatments have been evaluated in patients with both allergic rhinitis and mild asthma
All classes have been demonstrated to reduce lower airway symptoms
Variable effects on objective parameters (i.e., pulmonary function and BHR)pulmonary function and BHR)
How Does an Antihistamine-Decongestant Affect Asthma?
BaselineWeek
-0.5
01 2 3 4 5 6 .
Mean
Week
2
-1.5
-1
loratadine pluspseudophedrine
Change From Baseline InA th S
-3
-2.5
-2placebo
Asthma SxSeverity Score
-4
-3.5 P<.05
Corren J, et al. J Allergy Clin Immunol 1997;100:781-788.
Effect Of Cetirizine On Asthma Symptoms In P ti t With SAR A d Mild A thPatients With SAR And Mild Asthma
7
8 Placebo (n = 93) Cetirizine (10 mg/d) (n = 93)
5
6
7
ma
Scor
e
3
4
Tot
al A
sth
*P<0.05
0
1
2
0 1 2 3 4 5 6
Grant JA, et al, J Allergy Clin Immunol, 1995
Effect Of Loratadine+Pseudoephedrine On FEV1 inSAR & Mild AsthmaSAR & Mild Asthma
0.70Loratadine + Pseudoephedrine(5 /d 120 /d) ( 92)
Placebo( 92)
0 40
0.50
0.60 (5 mg/d + 120 mg/d) (n = 92)
m B
asel
ine
)
(n = 92)
*P 0 05
* *
*
*0 20
0.30
0.40
hang
e F
rom
in F
EV
1 (L
) *P<0.05
0 00
0.10
0.20
Mea
n C
h
0.00
Corren J, et al. J Allergy Clin Immunol, 1996
Effects Of Nasal Steroids On Nonspecific BHREffects Of Nasal Steroids On Nonspecific BHR
4 studies have examined effects of nasal steroids on nonspecific BHR: beclomethasone 2, fluticasone 1, triamcinolone 1
3 of 4 studies demonstrated statistically significant improvements in BHR with 2 to 4 wks of use
None of studies demonstrated improvements in pulmonary function (FEV1, PEFR)p y ( , )
Asthma PathophysiologyAsthma Pathophysiology
Smooth l Airway
before
muscle dysfunction
Airwayinflammation
after Edema
AirwayBronchoconstriction
remodeling
Adapted from Bousquet et al. Am J Respir Crit Care Med. 2000;161:1720-1745.
BronchospasmBronchospasm
Before
24Color Atlas of Respiratory Disease. Volume 2, 1995.
10 Min After Ag Challenge
Airway Morphology in AsthmaAirway Morphology in Asthma
Epithelialdamage
Goblet cellhyperplasiayp p
Increasedpermeability/i l
Increasedsmoothmuscle mass
Inflammatorycell
microvascularleakage
Mucus
muscle mass
infiltration
Angiogenesis
Mucus
Collagendepositionp
Adapted from National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the
25
p g p pDiagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute. National Institutes of Health; August 1991.
Cost of asthma careCost of asthma care
NY Ti 10/10/13 NY Times 10/10/13 The Soaring Cost of a Simple Breath
The Centers for Disease Control and Prevention puts the annual cost of asthma in the United States at more than $56 billion, including millions of potentially avoidable hospital visits and more than 3,300 deaths, many involving patients
h ki d di i did i hwho skimped on medicines or did without.
NHLBI: Asthma Control Assessment (Adults and Youths ≥12 Years of Age)
Components of Control Classification of Asthma Control
Well Controlled Not Well Controlled Very Poorly Controlled
Symptoms ≤2 days/week >2 days/week Throughout the dayNighttime awakenings ≤2x/month 1x-3x/week ≥4x/weekInterfering with normal activity None Some limitation Extremely limitedShort-acting 2-agonist use for symptom control (not prevention ≤2 days/week >2 days/week Several times per day
Impairment
y p ( pof EIB)
y y p y
FEV1 or peak flow >80% predicted/ personal best
60%-80% predicted/ personal best
<60% predicted/ personal best
Validated questionnairesATAQ 0 1-2 3-4ACQACT
≤0.75*≥20
≥1.516-19
N/A≤15
Risk
Exacerbations† requiring oral systemic corticosteroids
0-1/year ≥2/year (see notes)Consider severity and interval since last exacerbation
Progressive loss of lung function Evaluation requires long term follow up careRisk Progressive loss of lung function Evaluation requires long-term follow-up care
Treatment-related adverse effectsMedication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk.
ACQ = Asthma Control Questionnaire; ACT = Asthma Control Test; ATAQ = Asthma Therapy Assessment Questionnaire; EIB = exercise-induced bronchospasm;
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FEV1 = forced expiratory volume. *ACQ values of 0.76 to 1.4 are indeterminate regarding well-controlled asthma. †Exacerbations of asthma are episodes of progressive worsening in symptoms and reductions in lung function that interfere with the ability to perform usual activities unless quick-relief therapy, such as SABA and additional corticosteroid treatment, is used. NHLBI. J Allergy Clin Immunol. 2007;120:S94.
Stepwise Approach for Managing Asthma in Youths 12 Years of Age and Adults
S if
IntermittentAsthma
Persistent Asthma: Daily MedicationConsult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.
Step 1P f d
Step 2Preferred:
Step 3Preferred:Low-dose
Step 4Preferred:
Medium-dose ICS + LABA
Step 5Preferred:High-dose
ICS + LABA
Step up if needed
(first, check adherence,
environmental control and
Step 6Preferred:
High-dose ICS + LABA + oral corticosteroid
Preferred:SABA PRN
Low-dose ICS
Alternative: Cromolyn,
LTRA, Nedocromil, or
ICS + LABAOR Medium-
dose ICSAlternative:
Low-dose ICS + either LTRA,
Alternative:Medium-dose ICS + either
LTRA, Theophylline, or
Zileuton
AND
Consider Omalizumab*
for patients who
control, and comorbid
conditions)
Step down if
AND
Consider Omalizumab*†
for patients who
Assess Control
Quick Relief Medication for All Patients
Nedocromil, or Theophylline
either LTRA, Theophylline, or
Zileuton
Zileutonhave allergies Step down if
possible(and asthma is well controlled
at least 3 months)
phave allergies
Each step: Patient education, environmental control, and management of comorbidities.Steps 2–4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma (see notes).
*The safety and efficacy of omalizumab used concomitantly with long acting beta agonists have not been established
Quick-Relief Medication for All Patients• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute
intervals as needed. Short course of oral systemic corticosteroids may be needed.• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the
need to step up treatment.
months)
28
*The safety and efficacy of omalizumab used concomitantly with long-acting beta2-agonists have not been established.†Reductions in exacerbations were not seen in patients who required oral steroids as maintenance therapy.NHLBI. J Allergy Clin Immunol. 2007;120:S94.
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