GP CME Allergy Diagnosis Workshop Waipuna Conference Center

GP CME Allergy Diagnosis Workshop Waipuna Conference Center Friday 13 August 2010 Vincent St Aubyn Crump

Plan for Talk n n n n Overview of Allergy Diagnosis Skin Prick Test & Prick-Prick Test Immuno. CAP Specific Ig. E Comparison of the two with emphasis on the diagnosis & follow-up of Food Allergy Penicillin Allergy Atopy Patch test Cases for Discussion

Clinical Assessment Pre-test Probability score Specific- Ig. E Tests ·Skin Prick Tests ·Prick-Prick Test ·Serum Ig. E levels Provocation Tests ·Oral Challenge · DBPCFC ·Nasal & Bronchial Challenges o. Immuno-CAP (RAST) Test for Delayed Hypersensitivity ·Patch Tests o. Contact Dermatitis o. Delayed food reactions o. Drug reactions

Pre-test probability In Allergy diagnosis Is defined as the probability of the allergic disorder being present, before a diagnostic test result is known n Is useful in interpreting the results of allergy tests n Is useful in deciding whether it's worth doing the allergy testing at all n

High Pre-probability score n n n n Anaphylaxis* after eating known food allergen Very good history temporally compatible with an Ig. E-mediated (Immediate) reaction Reliable witness for reaction Presence of objective signs of known Ig. Emediated reactions Presence of Atopy (Asthma, eczema & hay fever) 1 of the 8 common food allergen implicated No other non-allergic explanation for symptoms

Likelihood Ratio (LR) n n The Likelihood Ratio (LR) is the likelihood that a given test result would be expected in a patient with the target disorder compared to the likelihood that same result would be expected in a patient without the target disorder. LR positive = sensitivity / (1 - specificity) LR negative = (1 - sensitivity) / specificity LR is better than sensitivity & specificity because it is less likely to change with prevalence of disorder

Total Ig. E n n n Ig. E represents <0. 001% of total Igs Majority of Ig. Es are bound to surface of mast cells and basophils ~ 50% of patients with allergic rhinitis or asthma will have elevated Ig. E Total Ig. E more often elevated in AD, and correlates with severity of AD Total Ig. E also elevated in: – – Parasitic Infections Bronchopulmonary Aspergillosis Immunodefieciecy, such as HIV infections Cigarette smoking

Total Ig. E – Normal Reference Interval Age (years) Range (IU/ml) <1 1 -52 1 -4 0 -352 5 – 10 0 -393 11 – 15 2 – 170 >15 0 – 158 n Very high levels of total Ig. E can give false positive Specific Ig. E results (multiple allergens tested positive), due to nonspecific binding of Ig. E antibodies

Disease indications for skin prick testing n n n n n To confirm atopy, assisting in the diagnosis of asthma, eczema in infants – Especially differentiating transient wheezers in infancy from persistent / asthmatics Before initiating immunotherapy To monitor progress during immunotherapy Acute Urticaria & Anaphylaxis All asthmatics requiring therapy Occupational Diseases including latex allergy Eczema Some drug reactions: Penicillin, some herbals such as Echinacea. In an Australian study ~50 % of cases of allergy to Echinacea, were thought to be Ig. E-mediated, and skin prick testing was helpful in their diagnosis. Stinging insect anaphylaxis Rhinitis vs Sinusitis

Diagnosing Ig. E-mediated food: Skin Prick Test q Skin Prick Tests are used to screen patients for sensitivity to specific foods q Allergens eliciting a wheal of at least 3 mm greater than the negative control are considered positive q Overall positive predictive accuracy is < 50 % q Negative predictive accuracy > 95 % (negative skin test results essentially confirm the absence of Ig. E -mediated reactions)

Diagnosing Ig. E-mediated food hypersensitivity disorders with Immuno. CAP q Sensitivity similar to skin prick tests (slightly less) q Good correlation with other procedures q Efficiency: Depends on the allergen q Indicated if SPT are contraindicated (eg, skin disease, medications) q Useful if discrepancy exists between history and SPT q The use of quantitative measurements has shown to be predictive, for some allergens, of symptomatic Ig. Emediated food allergy

Comparison of in-vivo (SPT) with in-vitro Immuno CAP-RAST Feature Availability Speed of results Sensitivity Specificity Standardization Quantification of results Temp. Stability Reagent stability Drugs effects Educational Importance ++++ +++ ++++ SPT CAP-RAST ++++ ++ ++++ +++++ ++++ ++++ ++

When should skin prick tests not be done or should be done with extra caution? n n n n For mass screening in the general population. Up to 40% of adults will have positive skin prick tests to insect venoms, but only a small percent experience anaphylaxis to venoms. Having a positive skin prick test to a venom will not predict if that individual will get anaphylaxis, if stung by that insect In presence of dermographism Patient unable of unwilling to stop medications like antihistamines and some antidepressants Allergy to fruits & Vegetables. Do prick-prick test instead Within 6 weeks of an anaphylactic reaction. If therapy for anaphylaxis is not readily available Extreme caution in pregnancy

Drugs affecting Skin Prick Test Drug Degree of supression Duration of supression Loratidine ++ 3 – 5 days Cetirizine ++ 3 -5 days Phenergan + + 3 – 10 days Astemizole ++ >1 month Cimetidine 0 to + not significant Ranitidine + not significant Famotidine 0 to + probably not significant Ketotifen ++++ > 5 days Imipramines ++++ >10 days Phenothiazines ++ Nasal steroids 0 Topical steroids 0 to ++ Systemic steroids > 2 weeks & > 20 mg / day reduces wheal & flare Montelukast 0 Cyclosporin 0 EMLA cream reduces the flare but not the wheal

Skin Prick Test Form n Practice name / Ordering physician: Street address City Telephone Fax Patient name: _______________ Date of birth: __/__/__ n Testing Technician: ____________ n Last use of antihistamine (or other med affecting response to histamine): ___ days medication _________ n n n Testing Date (s) and Time: Percutaneous __/__/_______AM PM Intradermal __/__/_______AM PM General information about skin test protocol – Percutaneous reported as: Allergen: Testing concentration: Extract company (*see below) Location: back__ arm___ Device: _____Intradermal: 0. __ml injected, Location: arm Testing concentration: 1: ___ w/v or BAU or AU/ml, PNU Results Longest diameter (Left in this example ) or longest diameter and orthogonal diameter ( Right in this example) of wheal (W) and erythema (flare) (F) measured in millimeters at 15 minutes – Blank in results column indicates test was not performed, O=negative n * Extract manufacturer abbreviations: , STG= Stallergens, AK=ALK Abello, AD=ALK (Denmark), H=Hollister– Stier, Allergen: Concentration: Skin Prick Test. Extract Manufacturer. Wheal Flare *Extract Manufacturer. * Wheal Flare Allergens (W) (F) Allergens: (W) (F). n House dust mites Milk n Cat Egg n Dog Wheat –

Interpretation of Test Results n n n n The wheal & flare should be recorded in millimeters 3 mm is considered the cut-off for positive, but may overestimate clinical allergy! All results should be compared to the negative and positive control If negative control is positive the patient has dermographism, and entire test is invalid If histamine control is negative, the results are probably being inhibited by antihistamines (Patients do forget!) In hyperpigmented skin the indurations might have to be palpated Remember that sensitivity (positive skin prick tests) does not mean clinical reactivity or allergy.

Size of SPT wheal (mm) 100% likelihood of + Challenge Milk Egg Peanut >6 >5 >4 Children: all ages (medium =3 yrs) >8 >7 >8 Children: 0 -2 years of age Note: Results may vary widely due to lack of standardization of SPT (extracts, devices) (Clin Exp Allergy 200; 30: 1540 -1546)

Comparison of Skin Test (>3 mm) vs. DBPCFC NPV PPV Food High Risk Low Risk Egg 90 % 99% 85% 17% Milk 90% 99% 66% 2% Peanut 75% 99% 55% 15% Soy 84% 97% 35% 12% Wheat 94% 98% 35% 15% Fish 80% 99% 77% 30%

History of RAST n n n RAST (radioallergosorbent test) invented and marketed in 1974 The suspected allergen is bound to an insoluble material and the patient's serum is added If the serum contains antibodies to the allergen, those antibodies will bind to the allergen Radiolabeled anti-human Ig. E antibody is added where it binds to those Ig. E antibodies already bound to the insoluble material The unbound anti-human Ig. E antibodies are washed away. The amount of radioactivity is proportional to the serum Ig. E for the allergen

Immuno CAP Specific Ig. E In 1989, Pharmacia Diagnostics AB replaced RAST with a superior test named the Immuno. CAP Specific Ig. E blood test n Also describe as CAP RAST or CAP FEIA (fluoroenzymeimmunoassay) n

Immuno. CAP (RAST)

Food Specific Ige (immuno-CAP RAST) values at /or above which there is a 95% risk of Clinical Allergy (no challenge necessary) Food___ n n n _Serum Ig. E (k. IU/L) for 95% PPV Egg (child) >7 Egg (age <2 yr) >2 Cow’s milk (child) >15 Cow’s milk (age <2 yr) >5 Peanut >14 Fish >20

Immuno. CAP Sensitivity compared to skin test and clinical diagnosis: Caveat For animal and mould allergens, a high proportion of positive skin test results were disregarded (i. e. considered as false positive) compared to Allergen Clinical diagnosis SPT n Cat 84% 66% Mould 79% 58%

Performance characteristics of diagnostic tests for peanut allergy Diagnostic test Sensitivity % Specificity % PPV % NPV % Skin Prick Test >95 30 -60 <50 >95 CAP-RAST 57 100 36 (If >15 k. U/L) Food Challenge ~100

Specific Ig. E level related to the probability of a food reaction Food-specific Ig. E level (measured by Immuno. CAP-specific Ig. E blood test) and probability of reacting to that food after challenge

Predicted relationship between specific Ig. E and challenge for peanuts

Predicted relationship between skin prick test result and challenge for peanuts.

Improved screening for peanut allergy by combining SPT to raw peanut & Immuno. CAP n n n SPT with raw peanut extract superior to commercial extract If SPT to raw extract <3 mm: 100% certainty child is not allergic to peanut If SPT to raw extract >3 mm: 74% certainty of allergy However, if raw extract > 16 mm: 100% certainty of peanut allergy If Immuno. CAP > 57 KU (A) / L = 100% positive predictive value DBPCFC can be avoided if: – SPT to raw extract <3 mm and Immuno. CAP <57 KU/L and also when – SPT to raw extract >16 mmm or CAP > 57 KU/L JACI Vol 109, 6, June 2002, Pg 1027 -33

Diagnosing food hypersensitivity disorders: Summary Skin tests ·Prick: Reproducible, sensitive, not irritant ·Prick-prick: Use raw or cooked food. Highly recommended for fruits and vegetables (commercially prepared extracts are generally inadequate because of the lability of the allergens, so the fresh food must be used for skin testing) ·CAP-RAST: Good for follow-up for out-grown allergy. ·Patch test: Atopic dermatitis, delayed reactions, fresh food is recommended

Immuno. CAP RAST for diagnosis of peanut, tree nut & seed allergy Patients referred for peanut or tree nut allergy

Organ system involvement with peanut, tree nut, and seed reactions.

A, Tree nut allergy and sensitization rates in patients with peanut allergy (n 5 234). B, Tree nut allergy rates in relation to peanut allergy for patients with tree nut allergy (n 5 128). TN, Tree nut. Peanut Tree Nut

Penicillin Skin Prick Test & Intradermal testing Benzyl Pennicillin n Penicillin Polylysine (major determinant) n Minor determinant mixture n Amoxycillin n Augmentin n Flucloxacillin n

Skin Testing in suspected penicillin allergy n In USA study: 566 history positive pts with negative SPT received penicillin: – 1. 2% had possible Ig. E rxn – None of the 568 history negative and SPT negative pts had any rxn – Of the 167 SPT positives, 9 received penicillin and only 2 had Ig. E-compatible rxn n Conclusion: Skin testing for penicillin is sensitive but not very specific

Penicillin skin testing contd. n Review by Weiss & Adkinson in 1988: – In pts with positive history & positive SPT only a 50 – 70% risk of drug rxn – Benzylpennicilloyl –specific Ig. E detetcted in 6095% of pts with positive SPT to peniilloylpolylysine n 1983 -90, 175 pts referred by GPS to allergy clinic, with h/o immediate rxn to penicillin. – – 132 tested & 4 had positive Immuno. Cap RAST The 128 that tested negative challenged with oral penicillin and none reacted – So, Clinical sensitivity is good

Immuno CAP vs SPT to penicillin n Specificity of CAP RAST to Pen G, Pen V, Ampicillin and amoxil was 89% when compared to negative SPT in 105 pts with positive history

Penicillin allergy: Incidence of positive SPT & Immuno. CAP 300 children with suspected penicillin allergy evaluated in OPD: SPT with Benzylpennicilloyl-polylysine (Major determinant) & Minor determinant mixture (MDM) RAST performed with Benzylpennicilloyl and phenoxymethylpenicilloyl conjugated on disc Procedure Children with positive results Skin Tests 48 (16) * – Major determinant 30 – Minor determinant 11 – Both 7 RAST 42 (14) SPT & RAST 33 (11) Skin Test only 15 (5) 57 (19) RAST only 9 (3) *% of total number of children

Relationship of positive penicillin test to time elapsed since adverse reaction Time interval (months) % with pos results 1 – 3 18. 6 4 – 12 9. 3 13 – 60 4. 5 > 60 1. 9 Archives of Childhood Disease, 1980, 55, 857 -860

Relationship of positive result to speed of adverse reaction Duration of Rx with Pen % with positive results Before rxn (hrs) ________________________ <12 21. 2 13 – 24 11. 9 25 – 48 6. 3 49 – 72 2. 1 >72 1. 9 Archives of Childhood Disease, 1980, 55, 857 -860

Relationship of positive results to the type of adverse rxn Manifestation % with positive results Accelerated skin rash* 25 Delayed skin rash** 5. 6 Urticaria 36. 7 Angioedema 54. 4 Serum Sickness 100 Anaphylaxis 100 *Skin rash appearing within 24 hrs of Rx ** Skin rash observed >24 hrs after starting pen

Steroid Testing: Skin Prick & I/D (or Patch Test) Prednisolone n Triamcinaline n Methylprednisolone n Hydrocortisone n Dexamethasone n

Other Drug Tested (Immuno. CAP & skin testing) Cefaclor n Insulin (Bovine, human, Porcine) n Isocyanate (painters) n Local Anaesthetic n General Anaesthetic n Gelatin (vaccine rxn) n (Venoms intradermal testing) n

Recommended interpretation of food allergen-specific Ig. E levels (k. U/L) in the diagnosis of food allergy Egg Milk Peanut Fish Soy Wheat 7 15 14 20 65 80 Reactive if > (no challenge needed) Possible reactive ( MD challenge*) (values between) Unlikely reactive If < (home challenge) 0. 35 0. 35

Uses of skin prick tests (SPT) and radioallergosorbent testing (RAST) Things SPT/RAST can tell us n That a patient is sensitised to an allergen n The likelihood of reacting after a food challenge (restricted range of foods) n That a patient is not sensitised to an allergen and therefore an Ig. E-mediated reaction to that allergen is very unlikely Things SPT/RAST cannot tell us n The severity of a reaction if a sensitised patient were exposed n Whether the patient’s symptoms are caused by the allergen

Mast cell Tryptase The increased levels of tryptase can normally be detected up to three to six hours after the anaphylactic reaction. Levels return to normal within 12 - 14 hours after release n Normal <11. 4

Types of challenge testing n Double -blind n Single-Blind n Open n Double-blind placebo controlled (DBPCFC) n Exercise + oral challenge n Inhalation challenge

Indications for Patch Test Atypical Eczema & non-immediate skin reactions n Allergic Contact Dermatitis n Occupational asthma & dermatitis n Drug Reactions, especially delayed n Non-immediate Food Reactions n

Predictive values of SPT & APT vs DBPCFC in patients with AD Technique PPA NPA SPT (early reaction) 9% 95% SPT (late-phase reaction) 41% 81% APT 81% 93% NPA = Negative predictive accuracy PPA = Positive predictive accuracy Niggemann et al, Allergy 2000; 55: : 281 -285

Food Protein-Induced Enterocolitis Syndrome (F Pies) n Profuse vomiting & diarrhea-> dehydrated Presents in 1 st weeks or months or later in exclusively breast fed child upon introducing solids or formulae Often misdiagnosed as “tummy bug” Triggers: n Diagnosis: n n n – Cow’s milk, soy – Oats, rice, Barley – Negative SPT & RAST – Atopy Patch Test: milk, soy, oats, wheat, barley, rice

Eosinophilic Esophagitis (EE) n n Presents as reflux Poor response to omeprazole Atopic Diagnosed with: – – n SPT, RAST & APT Biopsy of esophagus: High eosinophils >15/hpv Triggers: – milk, eggs, peanuts, shellfish, peas, beef, chicken, fish, rye, corn, soy, potatoes, oats, tomatoes and wheat n Rx: Swallowed Fluticasone

Unproven (useless) Tests widely available in NZ Ig. G antibody tests (Great Smokies lab) n Applied kinesiology (Muscle Testing) n Hair analysis n Electrodermal Tests (Vega Testing) n Iridology n Cytotoxic Test (Changes in WBC) n