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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The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again.

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The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again.

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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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