1

1

Allergic Disorders

Anne-Marie Irani, MDVirginia Commonwealth University

2

Allergic Disorders• IgE-mediated immune reactions• Clinical entities include:

– asthma– allergic rhinitis– atopic dermatitis– urticaria and angioedema– anaphylaxis (foods, drugs, venom,

idiopathic)

3IgE production

armmast cells

& basophils

triggermediatorrelease

clinical effects

Development of Immediate Hypersensitivity

TH

Be

APC

AnaphylaxisAnaphylaxisHivesHives

AsthmaAsthmaRhinitisRhinitis

ConjunctivitisConjunctivitis

processing

presentation

help

4

IgE-dependent Release of Inflammatory Mediators

IgEAllergens

FcεRI

Over MinutesLipid mediators: ProstaglandinsLeukotrienes

WheezingBronchoconstriction

Over HoursCytokine production:Specifically IL-4, IL-13

Mucus productionEosinophil recruitment

Immediate ReleaseGranule contents:Histamine, TNF-α, Proteases, Heparin

Sneezing Nasal congestionItchy, runny noseWatery eyes

5

Immediate and Late Reactions in IgE-mediated Hypersensitivity

Adapted from Hadley JA. Med Clin North Am. 1999;83(1):13-25.Dykewicz MS, et al. Ann Allergy Asthma Immunol. 1998;81:478-518.Squillance SP. Otolaryngol Head Neck Surg. 1992;107:831-834.Urval KR. Primary Care. 1998;25:649-662.Adapted from American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Vol 1. Milwaukee, Wis: 2000.

Immediate ReactionsImmediate Reactions

Late ReactionsLate Reactions

6

ILIL--22

INFINF--γγILIL--33

GMGM--CSFCSF

TNFTNF--αα

ILIL--4 (IL4 (IL--13)13)

ILIL--55ILIL--33

GMGM--CSFCSF

TNFTNF--αα

Delayed HypersensitivityDelayed Hypersensitivity Allergic InflammationAllergic Inflammation

TH1/TH2 Paradigm

TH1 TH2

BalanceBalance

IFNIFN--γγ

ILIL--1010

2

7

Why is the Prevalence of Asthma and Allergic Disorders Increasing Worldwide ?

8

TH1TH1

TH2TH2

IFNIFN--γγ

ILIL--4 4 ILIL--55

Cytokine Imbalance or Dysregulation

Cytokine Imbalance or Dysregulation

9

Developmental Component

? Normalize ? Normalize later in later in

ChildhoodChildhood

Delay in Delay in MaturationMaturation

Differences Differences at Birthat Birth

10

BirthBirthTh2Th2

AllergiesAllergiesStill Th2Still Th2

Only childOnly childFew infectionsFew infections

No allergiesNo allergiesTh1Th1

Older sibsOlder sibsMany infectionsMany infections

(Th1 stimuli)(Th1 stimuli)

The Hygiene Hypothesis

11

Diagnostic Testing: Allergen-specific IgE

• Total IgE level not diagnostic• Immediate Hypersensitivity Skin Tests

– epicutaneous (prick) /intradermal– results read within 15-20 minutes– more sensitive, less specific

• Serum Specific IgE Tests– less sensitive, more specific– RAST: radioallergosorbent test; qualitative– immunocap: quantitative

12

Allergy Skin Testing

3

13 14

Epidemiology, Diagnosis, and Pharmacologic Management of Allergic Rhinitis

15

AR and Comorbid Airway Disease

Spector, J Allergy Clin Immunol. 1997; 99: S773-S780.16

Allergic Rhinitis and Asthma:One Airway, One Disease

ARIA. J Allergy Clin Immunol. 2001;108:S148-61; Guerra et al. J Allergy Clin Immunol. 2002;109:419-25;

Asthmaalone

Allergicrhinitis

+ asthma

Allergic rhinitis alone

• Allergic rhinitis affects :– 25% of the general

population – 40% of children

• Of 478 patients with allergic asthma, 99% of adults and 93% of adolescents reported concomitant allergic rhinitis

• In patients with allergic rhinitis, asthma present in 19% - 40%

17

Nasalitching

Reprinted from:Skoner et al. In: Zitelli et al. Atlas of Pediatric Physical Diagnosis. 1997.By permission of the publisher Mosby-Wolfe.

Mouth breathing

Repeated nose rubbing

(“allergic salute”)

Allergicshiners

Allergic Rhinitis: Clues

18

Normal Nasal Cytology

4

19

Eosinophilic Rhinitis

↑

↑

↑20

Pharmacotherapy for Rhinitis• Oral

– antihistamines– decongestants– combination drugs– leukotriene

modifiers– corticosteroids

• Subcutaneous– anti-IgE antibody

• Intranasal– corticosteroids– antihistamines– anticholinergics– decongestants– saline– cromolyn sodium

21

Medications: Targeting Symptoms

++++++Intranasal corticosteroids

++––Topical anticholinergics

+++Intranasal mast cell stabilizers

–++–Intranasal decongestants

–+–Oral decongestants

++/–+Nasal antihistamines

+++/–++Oral antihistamines

RhinorrheaRhinorrheaCongestionCongestionSneezingSneezingAgent Agent

– = provides no benefit+/– = provides little or minimal benefit+ = provides modest benefit++ = provides substantial benefitAmerican Academy of Allergy, Asthma, and Immunology. The Allergy Report. Vol 1. Milwaukee, Wis: 2000. 22

Intranasal Corticosteroids in Allergic Rhinitis: An Overview

Intranasal Intranasal CorticosteroidsCorticosteroids

• Require careful patient instruction to ensure proper use

• May cause nasal dryness, irritation, and/or bleeding

• Reports of nasal septal perforation and limited suppression of bone growth

• Most effective medication class for controlling symptoms of allergic rhinitis

• Relieve sneezing, rhinorrhea, and mucosal edema leading to nasal congestion

• Associated with minimal side effects

DrawbacksBenefits

Physicians should routinely monitor the growth of children taking nasal corticosteroids and weigh the benefits of corticosteroid therapy against the possibility of effects on growth velocity.

23

Total Systemic Exposure

LiverLiver

Post First-Pass Metabolism

GI Tract Absorption

NASAL CORTICOSTEROIDNasal Absorption

Excretion

Adapted from Pedersen S, et al. Allergy. 1997;52(suppl 39):1-34. 24

First and Second generation H1 Histamine Receptor Antagonists

• Minimal effect on rhinorrhea

• Higher costs

• Reduce itching, sneezing, rhinorrhea

• Some effect on nasal congestion

• Non-sedating• Minimal

anticholinergicactivity

• Once daily dose

Second Second GenerationGeneration

• Have little effect on nasal congestion

• Can cause sedation• Anticholinergic activity• Short duration of action

• Reduce itching, sneezing, rhinorrhea

• Lower costs

First First GenerationGeneration

DrawbacksBenefits

5

25

Immunotherapy for Allergic Rhinitis: An Overview

• Must be administered in facilities equipped to handle adverse reactions (urticaria, laryngeal edema, bronchospasm, and anaphylaxis)

• Requires high level of patient compliance

• Especially effective for grass pollen, ragweed pollen, and house-dust mites

• Improvement of childhood allergies in children

• May prevent progression of rhinitis to asthma

• May reduce need for symptomatic pharmacotherapy

DrawbacksBenefits

Report of BSACI Working Party. Clin Exp Allergy. 1993;23(suppl 3):1-44.Canonica GW, et al. Allergy. 1998;53(suppl 41):7-31. Report of BSACI Working Party. Clin Exp Allergy. 1993;23(suppl 3):1-44.Canonica GW, et al. Allergy. 1998;53(suppl 41):7-31. 26

Atopic Dermatitis“Chronic relapsing, highly pruritic,

inflammatory skin disease.”

27

Diagnostic Features of AD Clinical

• Atopy– personal Hx / FHx

of eczema, hay fever, asthma.

• Pruritus• Eczema

(Spongiosis)– acute– subacute– chronic

• (Vascular instability)

• Xerosis• Keratosis pilaris• Pityriasis alba• Allergic shiners• Morgan-Dennie lines • Palmar / plantar

hyperlinearity• Anterior Capsular

Cataracts• Keratoconus

Essential Essential NonessentialNonessential

28

Immunologic pathways involved in the progression of AD. LC,Langerhans cells; MC, mast cells; CLA, cutaneous lymphoid antigen.

29

Food Allergy and AtopicDermatitis• Children:

– moderate - Severe AD (33%) have food allergy

– increasing severity of AD ~ increasing risk of FA

• Adults:– low incidence (< 2%)

• Foods responsible (~ 85% of cases): – outgrown: milk, egg, soy, wheat– persistent: peanut, nuts, fish, shellfish 30

Evaluation of Food Allergy in AD

• Allergy prick skin tests:Negative is very reliablePositive carries 50-80% false positive rate

• Laboratory studies:– specific IgE (pharmacia immunoCAP-RAST

system)• predictive value (> 95% reaction rate) in

children –egg, milk, peanut, codfish

6

31

Evaluation of Food Allergy in AD

• Clinical evaluation:– elimination diets– oral food challenges

• physician supervised• open, single blind, double-blind, placebo-

controlled

32

Treatment

• Skin hydration & moisturizers• Avoidance of irritants• Avoidance of allergens• Topical corticosteroids• Topical calcineurin inhibitors

33

Incidence of different types of atopy. AD peaks in the first years of life and declines after that time. Asthma and allergic rhinitis increase over time as sensitization develops.