Diagnosis and Management Diagnosis and Management of Inhalant Allergensof Inhalant Allergens

Steven T. Wright MDSteven T. Wright MD

Shawn Newlands MD, PhDShawn Newlands MD, PhD

June 11, 2003June 11, 2003

Diagnosis and Management of Diagnosis and Management of Inhalant AllergensInhalant Allergens

AnatomyAnatomy ImmunologyImmunology DiagnosisDiagnosis TreatmentTreatment

Environmental controlEnvironmental control PharmocotherapyPharmocotherapy ImmunotherapyImmunotherapy

Allergic EmergenciesAllergic Emergencies

Inhaled AllergensInhaled Allergens

5-22% annual prevalence of seasonal allergic 5-22% annual prevalence of seasonal allergic rhinitisrhinitis

9% of all visits to physicians9% of all visits to physicians

HistoryHistory

First described by John Bostock in 1819 as First described by John Bostock in 1819 as “seasonal catarrah”“seasonal catarrah”

1873, Blackley observed the first reaction by 1873, Blackley observed the first reaction by applying pollen to excoriated skinapplying pollen to excoriated skin

1911, treatment began by Leonard Noon on 1911, treatment began by Leonard Noon on the assumption of “antitoxins”the assumption of “antitoxins”

HistoryHistory

Cooke is said to have been the father of Cooke is said to have been the father of modern intradermal testing.modern intradermal testing.

French Hansel developed the optimal dose French Hansel developed the optimal dose concept by starting at lower concentrations.concept by starting at lower concentrations.

Herbert Rinkel first identified the “endpoint Herbert Rinkel first identified the “endpoint for titration”for titration”

Inhaled AllergensInhaled Allergens

Identified by their portal of entry via the Identified by their portal of entry via the respiratory tree which is richly supplied with respiratory tree which is richly supplied with IgE.IgE.

Essentially all inhalant allergy is IgE Essentially all inhalant allergy is IgE mediated, producing a Type I Gell and mediated, producing a Type I Gell and Coomb’s reaction.Coomb’s reaction.

Immune System ComponentsImmune System Components

Lymphocytes, Phagocytes, Complement, and Lymphocytes, Phagocytes, Complement, and mediator cells and their products.mediator cells and their products.

Functions to distinguish self from nonself.Functions to distinguish self from nonself.

Gell and Coomb’s reactionsGell and Coomb’s reactions

Type I- Immediate HypersensitivityType I- Immediate Hypersensitivity ImmediateImmediate Allergen binds 2 molecules of IgEAllergen binds 2 molecules of IgE Intracellular degranulation and immediate release Intracellular degranulation and immediate release

of productsof products Ex. Allergic rhinitis, anaphylactic shock, asthmaEx. Allergic rhinitis, anaphylactic shock, asthma

Gell and Coomb’sGell and Coomb’s

Type II- Cytotoxic reactionType II- Cytotoxic reaction ImmediateImmediate Binding of either IgM or IgG to cell bound antigen Binding of either IgM or IgG to cell bound antigen

and activation of complement cascade.and activation of complement cascade. Ex. Hemolytic anemia.Ex. Hemolytic anemia.

Gell and Coomb’sGell and Coomb’s

Type III- Immune complex reactionType III- Immune complex reaction DelayedDelayed Antigen-antibody complexes deposit on tissueAntigen-antibody complexes deposit on tissue

Gell and Coomb’sGell and Coomb’s

Type IV- Delayed hypersensitivyType IV- Delayed hypersensitivy DelayedDelayed Tissue injury involving presensitized T-Tissue injury involving presensitized T-

Lymphocytes.Lymphocytes.

Acute PhaseAcute Phase

Degranulation of preformed and newly Degranulation of preformed and newly synthesized mediators, most importantly, synthesized mediators, most importantly, Histamine.Histamine.

Sneezing, watery discharge, itchy eyes, nose Sneezing, watery discharge, itchy eyes, nose and throat.and throat.

Transitional PhaseTransitional Phase

AsymptomaticAsymptomatic Activation and recruitment of leukocytes into Activation and recruitment of leukocytes into

nasal tissue from the blood.nasal tissue from the blood.

Late PhaseLate Phase

Local Leukocyte infiltration.Local Leukocyte infiltration. 4-6hrs after allergen exposure.4-6hrs after allergen exposure. Nasal congestion is the most characteristic Nasal congestion is the most characteristic

symptom.symptom.

HistoryHistory

The most important method of establishing the The most important method of establishing the diagnosis of inhalant allergy.diagnosis of inhalant allergy.

What symptoms occur? What allergen What symptoms occur? What allergen exposure? When do they occur?exposure? When do they occur?

Symptoms include sneezing, itchy eyes/nose, Symptoms include sneezing, itchy eyes/nose, rhinnorhea, postnasal drip, congestion, rhinnorhea, postnasal drip, congestion, headache, loss or diminished smell or taste.headache, loss or diminished smell or taste.

Itching and Sneezing are the most distinctive Itching and Sneezing are the most distinctive complaints.complaints.

HistoryHistory

PMHx: Asthma, allergic reactions, eczema PMHx: Asthma, allergic reactions, eczema Hypertension, DepressionHypertension, Depression

Medications: B-Blockers, TCA, MAOi, OTC-Medications: B-Blockers, TCA, MAOi, OTC-antihistamines/nasal spraysantihistamines/nasal sprays

FH: Asthma, allergies, immune disordersFH: Asthma, allergies, immune disorders SH: Geographical area, Work environment, SH: Geographical area, Work environment,

smoker or smoker in the house, toxic/irritant smoker or smoker in the house, toxic/irritant exposuresexposures

Physical ExamPhysical Exam

Nasal mucosa tends to be pale/bluish, Nasal mucosa tends to be pale/bluish, congested, covered by watery mucosa.congested, covered by watery mucosa.

Infraorbital edema or “allergic shiner”Infraorbital edema or “allergic shiner” Open mouth breathing, nasal crease, Open mouth breathing, nasal crease,

infraorbital creaseinfraorbital crease Lymphoid hyperplasiaLymphoid hyperplasia

Physical ExamPhysical Exam

Also rule out anatomic factors aggravating the Also rule out anatomic factors aggravating the allergic condition.allergic condition. Septal deviationSeptal deviation Nasal Valve CollapseNasal Valve Collapse SinusitisSinusitis Choanal StenosisChoanal Stenosis

Nasal CytologyNasal Cytology

Anterior Inferior turbinate has shown to be the Anterior Inferior turbinate has shown to be the most representative.most representative.

5:1 Ratio of columnar to goblet cells in normal 5:1 Ratio of columnar to goblet cells in normal nasal epithelium.nasal epithelium.

1:4 Ratio in an allergic response.1:4 Ratio in an allergic response. 20% or more Eosinophils suggest inhalant 20% or more Eosinophils suggest inhalant

allergy.allergy.

Skin Endpoint Titration (SET)Skin Endpoint Titration (SET)

Intradermal skin test technique using 1:5 serial Intradermal skin test technique using 1:5 serial dilutions of allergenic extract.dilutions of allergenic extract. AdvantagesAdvantages

SafeSafe ReadableReadable StandardizationStandardization

SETSET

Intradermal injections of 0.01ml allergenic Intradermal injections of 0.01ml allergenic extract applied to the upper lateral arm.extract applied to the upper lateral arm.

Wheal and Flare beyond 5mm suggest positive Wheal and Flare beyond 5mm suggest positive response.response.

Maximal whealing occurs at 15 minutes.Maximal whealing occurs at 15 minutes.

SETSET

The endpoint is defined as the antigen dilution The endpoint is defined as the antigen dilution which yields a wheal at least 2mm larger than which yields a wheal at least 2mm larger than the preceding negative wheal, and which is the preceding negative wheal, and which is followed by a wheal at the next stronger followed by a wheal at the next stronger dilution.dilution.

The confirming wheal is important for The confirming wheal is important for determining the true endpoint.determining the true endpoint.

SET controlsSET controls

Negative ControlsNegative Controls DiluentDiluent Preservative (2% Glycerin)Preservative (2% Glycerin)

Positive ControlsPositive Controls No. 3 Histamine dilutionNo. 3 Histamine dilution

Abnormal WhealingAbnormal Whealing

Occur in 5-15% of tests appliedOccur in 5-15% of tests applied Most common include:Most common include:

Flash ResponseFlash Response HourglassHourglass PlateauPlateau

Flash ResponseFlash Response

Huge whealing response to a dilution that is Huge whealing response to a dilution that is weaker than the true endpoint.weaker than the true endpoint.

Day 1: 5-5-5-13-18-21Day 1: 5-5-5-13-18-21

Day 2: 5-5-5-5-7-9-11Day 2: 5-5-5-5-7-9-11

Plateau ResponsePlateau Response

A 7mm or larger wheal that is followed by the A 7mm or larger wheal that is followed by the same size wheal on progressively stonger same size wheal on progressively stonger dilutions until an additional 2mm increment is dilutions until an additional 2mm increment is observedobserved

7-7-7-7-9-9-11-117-7-7-7-9-9-11-11

Hourglass ResponseHourglass Response

A large response of an initial weak dilution A large response of an initial weak dilution that is followed by progressively smaller that is followed by progressively smaller reactions on stronger dilutions until a normal reactions on stronger dilutions until a normal reaction occurs.reaction occurs.

9-7-5-5-7-9-119-7-5-5-7-9-11

Factors influencing SETFactors influencing SET

Volume injectedVolume injected Skin reactivitySkin reactivity Increased allergen exposureIncreased allergen exposure Food AllergensFood Allergens AntihistaminesAntihistamines AgeAge

Food IngestantsFood Ingestants

Ragweed: Milk, Melons, BananasRagweed: Milk, Melons, Bananas Sage: PotatoSage: Potato Grass: Beans, Peas, SoybeansGrass: Beans, Peas, Soybeans Cedar: BeefCedar: Beef Oak: EggOak: Egg

Antigen SelectionAntigen Selection

SeasonalsSeasonals Pollens- short ragweed most commonPollens- short ragweed most common Trees Trees GrassesGrasses WeedsWeeds

PerennialsPerennials Dust mitesDust mites Molds- Alternaria, HormodendrumMolds- Alternaria, Hormodendrum Cockroach allergensCockroach allergens Dog and Cat danderDog and Cat dander

SET ImmunotherapySET Immunotherapy

Individualized treatment sets are developed Individualized treatment sets are developed based on weak solutions of high sensitivities based on weak solutions of high sensitivities and stronger solutions of low sensitivities.and stronger solutions of low sensitivities.

Increased strengths until the patient has relief Increased strengths until the patient has relief of symptoms or serious local reactions occur.of symptoms or serious local reactions occur.

Length of treatment generally 3-5 years.Length of treatment generally 3-5 years.

In Vitro TestingIn Vitro Testing

Eliminates Variables associated with skin Eliminates Variables associated with skin testing.testing. non specific whealing, effects of medications, skin non specific whealing, effects of medications, skin

types.types. More specific but less sensitive.More specific but less sensitive.

Indications for In Vitro TestingIndications for In Vitro Testing

Impracticality of skin testingImpracticality of skin testing Skin disorder, drug inhibition, uncooperatvie Skin disorder, drug inhibition, uncooperatvie

patientspatients Clarification of skin test resultsClarification of skin test results

Bizarre or borderline reactionsBizarre or borderline reactions Prevention of systemic reactionsPrevention of systemic reactions

Prior history of anaphylactic reaction, severe Prior history of anaphylactic reaction, severe asthma, stinging hypersensitivityasthma, stinging hypersensitivity

ConvenienceConvenience

Inappropriate Use of In Vitro Inappropriate Use of In Vitro TestingTesting

Delayed food hypersensitivityDelayed food hypersensitivity Penicillin hypersensitivityPenicillin hypersensitivity Improper IndicationsImproper Indications

Routine screeningRoutine screening Patients who are not candidates for Patients who are not candidates for

immunotherapyimmunotherapy

Radioimmunosorbant Assay Radioimmunosorbant Assay (RAST)(RAST)

Allergen is couple to a paper disc and Allergen is couple to a paper disc and incubated with the patients serumincubated with the patients serum

Disc washed and radioactive IgE addedDisc washed and radioactive IgE added Gamma counters quantitates the radioactivity.Gamma counters quantitates the radioactivity.

Modified RASTModified RAST(MRT)(MRT)

Involves an additional washing procedure in Involves an additional washing procedure in order to reduce non immunologically bound order to reduce non immunologically bound radioactivity. radioactivity.

Increased sensitivity to RASTIncreased sensitivity to RAST

MRTMRT MRT system is divided into 5 classes from 1-5, each MRT system is divided into 5 classes from 1-5, each

representing approximately a fivefold increase in the representing approximately a fivefold increase in the amount of serum specific IgE antibody present in the amount of serum specific IgE antibody present in the sample.sample.

ClassClass CountsCounts 0.1ml0.1mlClass 1Class 1 751-1600751-1600 1:5001:500Class 2Class 2 1601-36001601-3600 1:25001:2500Class 3Class 3 3601-80003601-8000 1:125001:12500Class 4Class 4 8001-180008001-18000 1: 625001: 62500Class 5Class 5 18001-4000018001-40000 1: 312,5001: 312,500

MRT ImmunotherapyMRT Immunotherapy

Before starting immunotherapy, it is Before starting immunotherapy, it is mandatory that an intradermal skin challenge mandatory that an intradermal skin challenge of the initial vial be tested.of the initial vial be tested.

After the initial doses have been administered After the initial doses have been administered and tolerated, the injections are increased until and tolerated, the injections are increased until the dose reaches maximum level. the dose reaches maximum level.

Specific Nasal ImmunotherapySpecific Nasal Immunotherapy(SNIT)(SNIT)

Applies the same principles as conventional Applies the same principles as conventional immunotherapy.immunotherapy.

Now listed by the WHO as an alternative Now listed by the WHO as an alternative therapeutic option to the subcutaneous or therapeutic option to the subcutaneous or intradermal route.intradermal route.

Data is still somewhat limited.Data is still somewhat limited.

Environmental controlEnvironmental control

Best treatment is prevention.Best treatment is prevention. Animal danderAnimal dander Dust mitesDust mites

High filtration air filtersHigh filtration air filters Hot water laundryHot water laundry Special beddingSpecial bedding

Pollen Pollen Pollen MasksPollen Masks

Avoiding irritants such as tobacco smoke.Avoiding irritants such as tobacco smoke.

Pharmacologic treatmentPharmacologic treatment

Alpha-adrenergic agonistsAlpha-adrenergic agonists Inhaled CromylynInhaled Cromylyn AntihistaminesAntihistamines LeukotrienesLeukotrienes Inhaled Nasal CorticosteroidsInhaled Nasal Corticosteroids Systemic and Intraturbinal Corticosteroid Systemic and Intraturbinal Corticosteroid

injectionsinjections

Alpha adrenergic agonistsAlpha adrenergic agonists

PseudoephedrinePseudoephedrine Vascular constrictionVascular constriction Wide variation of patient tolerance due to Wide variation of patient tolerance due to

insomnia and irritability.insomnia and irritability.

Cromolyn SodiumCromolyn Sodium

Inhibits the degranulation of sensitized mast Inhibits the degranulation of sensitized mast cells.cells.

Inhibits both the early and late phaseInhibits both the early and late phase Mainly prophylacticMainly prophylactic OTC- 4% Nasal spray four times dailyOTC- 4% Nasal spray four times daily Very safeVery safe

AntihistaminesAntihistamines

Currently the primary drug for treatment of nasal Currently the primary drug for treatment of nasal allergy.allergy.

Compete with Histamine for the H1 receptor.Compete with Histamine for the H1 receptor. Most effective when taken prophylacticallyMost effective when taken prophylactically Anticholinergic, antiserotatonergic, and anti alpha Anticholinergic, antiserotatonergic, and anti alpha

adrenergic. adrenergic. Lipid soluble and cross the Blood Brain BarrierLipid soluble and cross the Blood Brain Barrier Most effective at reducing symptoms of sneezing, Most effective at reducing symptoms of sneezing,

nasal itching, and rhinorrhea.nasal itching, and rhinorrhea.

Second generation AntihistaminesSecond generation Antihistamines

Loratidine, Fexofenadine, Cetrizine, and Loratidine, Fexofenadine, Cetrizine, and azelastine.azelastine.

Cross BBB less and have reduced CNS effects.Cross BBB less and have reduced CNS effects. Longer half livesLonger half lives

Antihistamine CostsAntihistamine Costs

AntihistamineAntihistamine Cost per monthCost per month

Allegra 60mgAllegra 60mg $47$47

Allegra 180mgAllegra 180mg $78$78

ClarinexClarinex $78$78

ZyrtecZyrtec $67$67

Leukotriene inhibitorsLeukotriene inhibitors

Act similar to antihistamines by competetive Act similar to antihistamines by competetive inhibition of the leukotriene receptor.inhibition of the leukotriene receptor.

SingularSingular Very successful in AsthmaVery successful in Asthma The data available to date do not clearly The data available to date do not clearly

support a unique role of leukotriene inhibitors support a unique role of leukotriene inhibitors in the treatment of allergic rhinitis.in the treatment of allergic rhinitis.

Intranasal CorticosteroidsIntranasal Corticosteroids

Primarily block the late phase reaction.Primarily block the late phase reaction. Only a small fraction is absorbed locallyOnly a small fraction is absorbed locally Side effectsSide effects

AtrophyAtrophy Epistaxis 5-8%Epistaxis 5-8%

Intranasal CorticosteroidsIntranasal Corticosteroids

Bedesonide, Mometasone, fluticasoneBedesonide, Mometasone, fluticasone Increased potencyIncreased potency Reduced systemic availability and activityReduced systemic availability and activity Quicker onset of actionQuicker onset of action

More effective than oral antihistamines at relieving More effective than oral antihistamines at relieving all nasal symptoms as well as improving the total all nasal symptoms as well as improving the total nasal symptom scorenasal symptom score

May be appropriate for replacing antihistamines as May be appropriate for replacing antihistamines as first line therapy for management of nasal allergy.first line therapy for management of nasal allergy.

Intranasal Corticosteroid CostsIntranasal Corticosteroid Costs

SteroidSteroid Cost per monthCost per month

FlonaseFlonase $72$72

NasonexNasonex $87$87

Rhinocort AQRhinocort AQ $79$79

Systemic CorticosteroidsSystemic Corticosteroids

The most potent agents for relieving the The most potent agents for relieving the symptoms of allergic rhinitis.symptoms of allergic rhinitis.

Because of the side effects, they are reserved Because of the side effects, they are reserved for severe or chronic symptoms.for severe or chronic symptoms.

Intraturbinal injectionIntraturbinal injection

Concern over vasospasm or retrograde Concern over vasospasm or retrograde embolization of the retinal vasculature.embolization of the retinal vasculature.

Now considered safe and effective with proper Now considered safe and effective with proper procedure.procedure.

Side effects:Side effects: 2% nasal bleeding2% nasal bleeding Facial flushing occurs the following day due to Facial flushing occurs the following day due to

steroid induce vasodilation.steroid induce vasodilation.

Pregnancy and Allergic Rhinitis Pregnancy and Allergic Rhinitis TherapyTherapy

Increased levels of progesterone lead to Increased levels of progesterone lead to exacerbations of nasal congestion.exacerbations of nasal congestion.

Astemizole and CromolynAstemizole and Cromolyn Intranasal steroidsIntranasal steroids

SurgerySurgery

Minor roleMinor role SeptoplastySeptoplasty Partial Turbinate resectionsPartial Turbinate resections The effects of submucosal fibrosis on allergic The effects of submucosal fibrosis on allergic

rhinitis is still unproven.rhinitis is still unproven.

Allergic EmergenciesAllergic Emergencies

ImmediateImmediate DelayedDelayed

LocalLocal SystemicSystemic

Allergic EmergenciesAllergic EmergenciesDelayedDelayed

Local reactions range on a spectrum of pain Local reactions range on a spectrum of pain and indurationand induration

Systemic reactions usually manifest as Systemic reactions usually manifest as exacerbation of the patients symptomsexacerbation of the patients symptoms

Treatment consists of antihistamines and Treatment consists of antihistamines and reassurance, with steroids for more severe reassurance, with steroids for more severe symptoms.symptoms.

Allergic EmergenciesAllergic EmergenciesDiagnosisDiagnosis

VasovagalVasovagal Most commonMost common Slow pulse, normal BP, pale cool skinSlow pulse, normal BP, pale cool skin

AnaphylacticAnaphylactic Involvement of more than one organ system, Involvement of more than one organ system,

always including the cardiovascular systemalways including the cardiovascular system Rapid pulse, low BP, increased secretions/nasal Rapid pulse, low BP, increased secretions/nasal

congestion/hoarseness or wheezing, Flushed warm congestion/hoarseness or wheezing, Flushed warm skin.skin.

Allergic EmergenciesAllergic EmergenciesManagementManagement

Keep patient recumbent, loosen tight clothingKeep patient recumbent, loosen tight clothing Oxygen as neededOxygen as needed Check pulse and BPCheck pulse and BP Get Help and call ambulanceGet Help and call ambulance Place touniquet above the injection site (loosen every 20min)Place touniquet above the injection site (loosen every 20min) Epinephrine (1:1000) 0.3ml in the opposite arm, may repeat in 10 min intervals up Epinephrine (1:1000) 0.3ml in the opposite arm, may repeat in 10 min intervals up

to 1mlto 1ml Assess airway- more deaths result from airway obstruction than from Assess airway- more deaths result from airway obstruction than from

cardiovascular collapsecardiovascular collapse Oral airwayOral airway Inhaled albuterolInhaled albuterol Intubate or sugical airway if glottic obstruction threatensIntubate or sugical airway if glottic obstruction threatens

Start IVStart IV Diphenhydramine 50mg IVDiphenhydramine 50mg IV Dexamethasone 4mg IVDexamethasone 4mg IV Transport to Hospital ASAPTransport to Hospital ASAP

ConclusionConclusion

Allergic Rhinitis is very common.Allergic Rhinitis is very common. Thorough history and physical examination Thorough history and physical examination

including visualization of the nasal anatomy.including visualization of the nasal anatomy. Approach to therapyApproach to therapy

Environmental controlEnvironmental control First line pharmacotherapyFirst line pharmacotherapy Nasal Steroids, systemic steroidsNasal Steroids, systemic steroids ImmunotherapyImmunotherapy

Adequate counseling of the patientAdequate counseling of the patient