Clinical Conference on Allergic Disease

Adrian Casillas, MD

Division of Clinical Immunology and Allergy

UCLA School of Medicine

ALLERGIC RHINITIS

• Affects 20-40 million Americans (15-20% of the

Population)

- Predominantly Older Adolescents and Young Adults

• 5th Most Common Chronic Illness

• Significant Impact on Quality of Life, Productivity,

Healthcare Costs

• Prevalence is Increasing

IMPACT OF ALLERGIC RHINITIS

• 28 Million Restricted Activity Days Each Year

• 6 Million Bedridden Days Each Year

• 2 Million Lost School Days Each Year

• 3.5 Million Lost Work Days Each Year

• Can Be a Factor in Other Illnesses

(Asthma, Chronic Sinusitis, Otitis Media with Effusion,

Nasal Polyposis, Upper Respiratory Infections)

Hypersensitivity States

The Allergic Response

• Susceptibility (approximately 25-30% of population)

• Allergen exposure

• IgE induction

• Effector cells of allergic inflammation: Mast cells, Basophils, and Eosinophils

Allergic Sensitization

Presentation ofAllergic Rhinitis: Clues

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

Nasal Nasal itchingitching

Mouth Mouth breathingbreathing

Repeated Repeated nose nose rubbing rubbing (“allergic (“allergic salute”)salute”)

AllergicAllergicshinersshiners

Classification of Rhinitis

• Allergic rhinitis– Seasonal– Perennial– Both

• Nonallergic rhinitis– Perennial nonallergic rhinitis

(idiopathic/vasomotor)– Infectious– Rhinitis medicamentosa– Hormonal– Anatomical

American Academy of Allergy, Asthma and Immunology. The Allergy Report. http://www.aaaai.org/. Accessed: April 13, 2000.

Prevalence of Allergic Rhinitisby Age Group

In Chronic Rhinitis, Nonallergic Rhinitis Is a Major Causative Factor

Pure Nonallergic RhinitisPure Nonallergic Rhinitis23%23%

Pure Allergic RhinitisPure Allergic Rhinitis43%43%

Mixture of Both Allergic andMixture of Both Allergic andNonallergic RhinitisNonallergic Rhinitis

34%34%

Settipane et al. In: Kaliner, ed. Current Review of Allergic Diseases. 2000.

National Rhinitis Classification Task Force Survey ResultsNational Rhinitis Classification Task Force Survey Results

Mast Cells and Basophils

Characteristic Mast Cells BasophilsOrigin CD34+

progenitorsCD34+progenitors

Maturation Connective tissue Bone MarrowCirculation No Yes

MajorDevelopmental.Factor

Stem Cell Factor IL3

Life Span Weeks to months Days

FcRI High High

EosinophilsCharacteristic Eosinophils

Origin CD34+ progentor

Maturation Bone marrow

Circulation Yes

MajorDevelopmentalFactor

IL5

Life span Days to weeks

FcRI Low levels

IgE-Dependent Mast Cell Activation

Ca++

Phosphodiesterase

Ca++

cAMP

AA

LTs PGs

Preformed MediatorsAg

Direct Activation of Mast Cells and Basophils (not dependent on

IgE)• Complement:C3a, C5a

• Neuropeptides

• Opiates:Morphine, codeine

• Radiocontrast dyes (ionic)

• Muscle relaxants

• Physical stimuli: vibration, light, temperature changes.

Major Biological Effects of Leukotrienes

LTC4, LTD4 and LTE4

• contraction of smooth muscle,bronchioles and coronary arteries• vasoconstriction with leakage from postcapillary venules and edema

formation• phospholipase A2 stimulation with subsequent prostaglandin and

thromboxane release• secretion of mucus in the respiratory tract

• potent chemotactic mediator that regulates leukocyte function• increases vascular permeability with exudation of plasma• induces lymphocyte transformation into suppressor or cytotoxic T cells

LTB4

Larsen,JS;Acosta,EP. Ann PharmacolJuly/Aug 1993

Mediators Eosinophils

Preformed Major basic protein, ECP,neurotoxin, EPO,lysophospholipase

Lipid mediators (newlyformed)

LTC4

Cytokines IL1a, IL2, IL3, IL4, IL5,IL6, IL8, IL10, GMCSF,TNFa, RANTES, MIP1a,etc

Allergic Mechanisms in Health and Disease

• Immediate hypersensitivity

• Late phase reactions-follows immediate reaction by about 4 to 8 hours and is characterized by swelling and leukocyte infiltration

• Parasitic diseases-Trichinella spiralis and Strongyloides ratti infections are longer in mast cell deficient mice. Resolution of ectoparasite (i.e. ticks) infections also depend on basophil/mast cell activation

Induction of Allergic Sensitization

APC

APC

Allergen

IL-12, IFN-

Tnaive

IL4, IL10

T-1

T-2

B

IFN-

Mast

Mediators of allergic response

IgE

IL-4 IL-4

EosIL-5

IL-4

Role of IgE in Atopic Disease

AsthmaAdapted from Cochrane GM, Jackson WF, Rees PJ.

IgE PRODUCTION

Allergen

Second allergen

encounter

IgE

GranulesB-cell

Mast cellFirst exposure to antigen

MAST CELL SENSITIZATION

DEGRANULATION REACTION

Chemical mediators induce hay fever, eczema, asthma

Diagnosis of Allergic Rhinitis: History

Family history of atopy

Personal history of other allergenic conditions

– Asthma

– Atopic dermatitis

– Food hypersensitivity

Personal history of

– Long-lasting or recurrent colds

– Chronic sinusitis

– Frequent ear infections

– Chest symptoms (e.g., pain or wheezing)

Allergic Rhinitis: Physical Examination

Allergic facies (e.g., shiners, transnasal crease)

Pale, edematous nasal mucous membranes; clear, watery nasal discharge

Watery, swollen, red eyes

Wheezing, noticeable cough

Middle ear fluid, eustachian tube dysfunction

Tenderness over the sinuses

Eczema

Environment and Genetics in Allergic Disease

Genetic Factors

• Monozygous twins show a 70% concordance rate for an IgE response to any common allergen.

•Statistically significant genetic linkages identified for a number of genes, for example:

• IL-4 gene cluster (chr. 5) polymorphism related to high IgE production and asthma

•Variants of the high affinity IgE receptor (chr. 11) on mast cells and basophils

Why the increased prevalence?

Evidence for environmental effects on atopic disease

• Increase in levels of indoor allergen loads--”tighter” homes

• Dietary changes--too much controversy to accept

• Microbial exposure

Relationship between atopic state and

1. Lack of immunity to HAV

2. Vaccination to measles

3. Negative DTH reaction to TB

(these are all intracellular diseases which would stimulate a Th1 response and downregulate a Th2 (favoring atopy) response)

Other theories for increase in atopic disease prevalence

Diagnostic Tests for Allergic Disease

Allergic Rhinitis: Diagnostic Testing

Skin tests for specific IgE antibodies

– Confirm allergens suspected by history

Serum-specific IgE tests

– Correlate well with skin tests

– Not as sensitive as skin tests

Nasal cytology

– Eosinophils, basophils imply allergy or

NARES syndrome*

– Neutrophils suggest bacterial infection

*Nonallergenic rhinitis with eosinophilia syndrome.

•Rast Testing--detects the presence of preformed IgE in a patient’s serum

•Less sensitive than skin tests

•May take several days to get results

RAST or ELISA Tests

Rast Testing

• Use when it is not possible to skin test

Immobilized Ag + Patient’s

serum

+

Tagged anti-human IgE

Colorimetric assay

- RAST HONEY BEE VENOM IGE 144 count 0-500 - RAST PAPER WASP VENOM IGE ALL @ 808 count 0-500 - RAST WHITE-FACE HORNET VENOM 220 count 0-500 - RAST YELLOW HORNET VENOM IGE 212 count 0-500 - RAST YELLOW JACKET VENOM IGE @ 2739 count 0-500 - Allergen Interpretation Range - IgE counts Score Interpretation - 0-500 0 No antibodies detected - 501-750 0-1 Low equivocal - 751-1600 1 Equivocal - 1601-3600 2 - 3601-8000 3 Scores 2-6 indicate - 8001-18000 4 increasing levels - 18000-40000 5 of antibody - 40000+ 6

Skin testing• Quicker and cheaper that RAST

• A physiological test that detects the presence of sensitized mast cells within in a patient’s dermis

• Refer to experienced allergist

• Prick vs Intradermal--start with prick although less sensitive, it is safer since intradermal introduces 103 to 104 more antigen to the patient

Skin Testing

Photographs courtesy of Dr. Ed Philpot.

Treatment

I. Avoidance

II. Pharmacotherapy

III. Immunotherapy

IV. Psychotherapy

I. AVOIDANCE

Environmental Control Measures

• Keep windows/doors closed during the allergy season

• Reduce outdoor activity during high pollen days

• Maintain a dust/allergen-free environment• Keep pets outdoors• Avoid smoke and strong odors• Use air conditioning and/or air filters

Druce. In: Middleton et al, eds. Allergy Principles & Practice. 1998.

Potentially Avoidable Environmental Allergens

– Molds

– Cockroaches

– Dust mites

– Pet dander

Dust Mites

Dust mites• Dust mite covers

• Wash sheets/covers in HOT water

• Diminish humidity

• Vacuum with HEPA filter

• Move to Taos, NM

Cats

•Keep out of bedroom

•Wash frequently

•Wash once (permanently)

Cat allergen--Fel D1saliva and skin, not hair

Compliance With Environmental Control Measures

•Response %

Dust my house frequently 34.1

Do not have pets inside my house 20.8

Avoid outdoor activities 18.7

Wash bedding in hot water 15.0

Wrap mattresses in plastic cover 6.0

Do not have carpeting (or rugs) in my house 2.1

No measures 25.4

Note: Respondents (481 patients with self-reported allergic rhinitis) were asked to check all items that apply.

II. PHARMACOTHERAPY

Allergic Rhinitis: Pharmacotherapy

OTC treatments• Intranasal cromolyn sodium• Intranasal decongestants• Intranasal saline• Oral antihistamines• Oral decongestants

Rx treatments• Antihistamines

– Intranasal– Systemic

• Decongestants– Systemic

• Corticosteroids– Intranasal– Systemic

• Anticholinergics– Intranasal

• LT receptor antagonists

This table lists the various classes of pharmacotherapy This table lists the various classes of pharmacotherapy available to treat allergic rhinitis.available to treat allergic rhinitis.

American Academy of Allergy, Asthma and Immunology. The Allergy Report. http://www.aaaai.org/. Accessed: April 13, 2000.

First-generation Antihistamines

H1 Sedative Anticholinergic GI Blockade Effects Effects Effects

Ethylenediamines +++ ++ ++ ++(tripelennamine)

Ethanolamines +++ +++ +++ +(diphenhydramine)

Alkylamines +++ + ++ + (chlorpheniramine)

Piperazines +++ ++ ++ +(hydroxyzine)

Piperidines +++ ++ ++ +(azatadine)

++++ Strongly positive effects

Second-generation Antihistamines

H1 Sedative Anticholinergic GI Blockade Effects Effects Effects

Fexofenadine +++ – – – (60 mg bid)

Astemizole ++++ – – – (10 mg qd)

Loratadine +++ – – – (10 mg qd)

Cetirizine +++ + – – (10 mg qd)

– Negative effect

++++ Strongly positive effect

Advantages of Second-generation Nonsedating Antihistamines

• Bind strongly to histamine (H1) receptors

• negligible affinity for nonhistamine receptors

• no anticholinergic effects

• Do not cross the blood-brain barrier• do not affect cognitive functions

or psychomotor performance

• do not potentiate impairment caused by alcohol or benzodiazepines

• do not impair driving skills

Decongestants

• Actions– Constrict mucous membranes: shrinkage promotes drainage,

improves ventilation, relieves nasal stuffiness

• Routes of administration– Systemic, topical

• Indications– Allergic rhinitis, vasomotor rhinitis, sinusitis, eustachian tube

congestion

• Side effects– Systemic: stimulation (CNS, cardiovascular)– Topical: rhinitis medicamentosa, CNS stimulation, local irritation

Primary CarePrimary Care(including Internal Medicine)(including Internal Medicine)

ENTENT

AllergistAllergist

PediatricianPediatrician

All OthersAll Others

PrescriptionPrescriptionAntihistaminesAntihistamines

72.2%72.2%

50.7%50.7%

63.5%63.5%

72.4%72.4%

73.9%73.9%

IntranasalIntranasalCorticosteroidsCorticosteroids

27.8%27.8%

49.3%49.3%

36.5%36.5%

27.6%27.6%

26.1%26.1%

IntranasalIntranasalCorticosteroidsCorticosteroids

10.8%10.8%

4.2%4.2%

4.9%4.9%

14.3%14.3%

9.8%9.8%

Source: SourceTM Prescription Audit (SPA). MAT August 2000. Scott-Levin, Inc.

% of Use% of Use

Intranasal Corticosteroid Use Is Increasing

% incr vs% incr vs previous yrprevious yr

Absence of red-Absence of red-stained cells is stained cells is evidence of a evidence of a reduction in reduction in mast-cell mast-cell infiltration after infiltration after 1 year of therapy 1 year of therapy with fluticasone.with fluticasone.

Before TreatmentBefore TreatmentAfter 52 weeks After 52 weeks

of Treatmentof Treatment

The direct relationship of these findings to long-term symptom relief is unknown.The direct relationship of these findings to long-term symptom relief is unknown.

[Magnification: x100][Magnification: x100]

Reduction in the Infiltration of Mast Cells

The Fate of Intranasal Steroids

Adapted from: Allen. J Allergy Clin Immunol. 2000.

Allen. J Allergy Clin Immunol. 2000.

Fate of Intranasal Steroids• Majority of nasal steroid administered is

swallowed• Systemic bioavailability is determined primarily

by the amount of swallowed drug — not inactivated by first-pass hepatic inactivation — that subsequently reaches the circulation

• Factors such as lipophilicity affect the amount of drug that is absorbed across the nasal mucosa– Drugs with higher lipophilicity have lower absorption

The esterified The esterified carbothioate carbothioate

moleculemoleculefluticasone fluticasone propionatepropionate

The major metabolite of fluticasone propionate, 17ß-carboxylic acid, wich is devoid of glucocorticoid activity because of the loss of ester at C17ß.

Fluticasone propionate undergoes first-pass metabolism in the liver, being rapidly hydrolysed to the corresponding 17ß-carboxylic acid (GR36264).

III. IMMUNOTHERAPY

HISTORY OF ALLERGEN IMMUNOTHERAPY

1819: Bostock described his personal experience of having hayfever.

1889: Seventy years later, Wyman identified pollen as a cause of fall hayfever.

1890: Blackley identified grass pollen as the cause of his seasonal rhinitis.

1900: Curtis reported beneficial effects from the injection of aqueous pollen extracts for rhinitis and asthma.

1911: Freeman published data suggesting decreased symptoms in patients with allergic rhinitis treated with grass extract--“desensitization.”

Immunological Changes in Allergen Immunotherapytherapy • Diminished leukocyte histamine release

sensitivity with allergen challenge

• Diminished lymphoproliferative response to allergen

• Stimulation of Allergen specific CD8+ lymphocytes

• Decreased tissue CD4+ lymphocytes

Immunological Changes (cont)

• Blunted IL2 production to antigen

• Increased IFN g production

• Down regulation of the low affinity IgE receptor

• Decreased recruitment and activation of tissue eosinophils

DISEASES IN WHICHIMMUNOTHERAPY IS EFFECTIVE

1. Allergic Rhino-Conjunctivitis

2. Allergic Asthma

3. Hymenoptera Hypersensitivity

Some patients have unrealistic expectations from treatment.

IV. PSYCHOTHERAPY

Key Points

• Allergic (atopic) disease is one type of hypersensitivity state that depends on IgE production

• AR and asthma are characterized by early and late phase reactions due to rapidly released medators and newly formed AA metabolites.

• Th cell differentiation along a Th2 pathway favors allergic disease development

Key Points(cont.)

• Diagnostic tests for atopic deseases can be physiologic or simply measure preformed IgE

• IT is effective in part due to alterations in allergen specific antibody formation

*P < 0.01 for prednisone vs placebo, FP ANS 200 mcg QD, and FP ANS 400 mcg QD

Vargas et al. J Allergy Clin Immunol. 1998.

Pre-Infusion 2 4 6 Post-Infusion

0

10

20

30

40

Placebo Fluticasone 200 mcg QD

Fluticasone 400 mcg BID

Prednisone 7.5 mg QD

Prednisone 15 mg QD

Cosyntropin Infusion Time (hr)

Mea

n P

lasm

a C

ort

iso

l (m

cg/d

l)Stimulation Challenge

After 4 Weeks of Therapy

*

****

**

Cortisol Levels Comparable to Vehicle Placebo After Treatment With Futicasone