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Skin or In Vitro Test for Food Allergy? Skin Test

Skin or In Vitro Test for Food Allergy? Skin Test. Linda Cox, FAAAI, FACAAI WAO 2011 Meeting Cancun, Mexico. Linda Cox, MD Disclosure. Allergist/Immunologist: solo private practice Associate Clinical Professor of Medicine Nova Southeastern University

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Skin or In Vitro Test for Food Allergy? Skin Test

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  1. Skin or In Vitro Test for Food Allergy?Skin Test Linda Cox, FAAAI, FACAAI WAO 2011 Meeting Cancun, Mexico

  2. Linda Cox, MD Disclosure • Allergist/Immunologist: solo private practice • Associate Clinical Professor of Medicine Nova Southeastern University • Medical advisory board/consultant: Stallergenes, Genentech/Novartis, ISTA • Speakers fee: Thermo Fisher, Baxter • Organizational interests: • FDA Allergenic Products Advisory Committee –consultant • AAAAI-Secretary/Treasurer • Joint Task Force on Practice Parameters-member • ABAI Board of Directors -member

  3. Skin or In Vitro Test for Food Allergy Learning Objectives • To recognize that, in general, allergy skin tests are the preferred tests for food allergy diagnosis for several reasons • Be able to discuss scenarios in which skin test may be superior to serum specific-IgE

  4. Significance Of Positive Allergy Skin Test ResultsFood Allergy Diagnostic TestingPearls, Pitfalls and the Gold Standard • Allergy tests yield information on sensitization, which is not always equivalent to clinical allergy. • Neither skin or serum sIgE have 100% sensitivity or specificity • The double-blind, placebo-controlled food challenge is the gold standard for food allergies but it is • a time-consuming procedure that is • limited to trained allergy specialists and • carries the risk of producing a severe reaction

  5. Negative test is not zero risk Food-specific IgE Antibody Concentrations or Skin Test Size Correlate with Risk of Clinical Reactivity • Curve varies by: • Food • Disease • Age • Assay (brand) At certain high IgE values, the chance of a clinical reaction approaches certainty One study, one test brand, children age 5: Egg- 7 kUa/L Milk 15 kIU/L, Peanut 14 kUa/L Sampson HA.. J Allergy Clin Immunol 2001;107:891-6.

  6. 50% and 95% Predictive Value have been Established for Food Specific-IgE and SPT Food specific-IgE measured with ImmunoCap™ and SPT with lancet (ref 17 & 21,) and bifurcated needle (ref 22) Nowak-WÄ et al, Work Group report: Oral food challenge testing. J Allergy Clin Immunol 2009; 123:S365-S83.

  7. Specificity of SPT in predicting positive open food challenges to milk, egg and peanut in children • Study: 555 challenges were undertaken in 467 children with suspected food allergy. Positive challenge if objective signs seen; negative, if the child could tolerate normal food daily, for 1 week. • Results: 55% were positive, 37% negative, and 8% inconclusive. • Possible to identify a SPT wheal at, and above, which negative reactions did not occur (100% specificity ): • cow milk, 8mm • egg, 7mm • peanut, 8mm • However positive reactions could occur with a SPT of 0 mm. Sporik et al, Clin Exp Allergy. 2000;30(11):1540-6.

  8. Positive open food challenges to milk, egg and peanut in children could occur with 0 mm SPT MILK PEANUT Sporik et al, Clin Exp Allergy. 2000;30(11):1540-6.

  9. Diagnostic accuracy of skin prick testing in children with tree nut allergy Study: 906 tree nut and peanut challenges in 680 child aged 4 month to 19 years Results : • 8 mm SPT weal diameters >95% accuracy in predicting a positive OFC for cashew, hazel nut, walnut, and sesame. • Using the predictive SPT decision points, the need for OFC was reduced by 33% (peanut), 56% (tree nuts), and 53% (sesame), • Not able to determine the 95% PPV for almond, pistachio, pecan, and brazilnut Ho et al J Allergy Clin Immunol 2006;117:1506-8

  10. The predictive value of the skin prick test weal size for the outcome of oral food challenges. • Study: 735 OFC in 385 children (median age 22 months), with cow's milk, hen's egg, wheat and soy. • Results: 312 (43%) OFC were assessed to be positive. • 95% and 99% predicted probabilities using logistic regression revealed predictive decision points of: • 13.0 and 17.8 mm for HE • 12.5 and 17.3 mm for CM Verstege et al. Clin Exp Allergy. 2005;35(9):1220-6.

  11. SPT Wheal Size May Useful in Predicting Presence of Absence of Clinical Allergy • Study : Challenged 47 peanut-naïve children who had a positive SPT to peanut (smallpox needle) • Results: 49% of challenges were positive • Mean wheal: negative group 6.3 mm vs. positive group 10.3 mm • Using the cutoff of a > 5 mm wheal on PST, peanut challenge yielded • Sensitivity was 100% (no false -) • Specificity was 12.5% (high false+) • Negative predictive value was 100% • Positive predictive value was 52%. • Conclusion: These findings suggest peanut PST of 3 or 4 mm could undergo less resource-intensive, accelerated challenges. Kagan R et al., Ann Allergy Asthma Immunol  2003 Jun;90(6):640-5:

  12. Prediction of anaphylaxis during peanut food challenge: usefulness of peanut SPT & specific IgE • Study: 89 in-hospital challenges: positive in 56/89 (62.9%) patients: • In the 55 completed challenges: 28 no rx, 6 reaction without anaphylaxis, 21 had anaphylaxis • Mean peanut SPT wheal size and specific IgE level were associated with the severity of reactions on challenge Wainstein et al . 2010;21(4 Pt 1):603-11

  13. Allergy Skin Testing Advantages • In the allergist office, skin testing remains the central test to confirm allergic sensitivity.1 • Advantages: • Skin testing is fast (15-30 minutes), safe, sensitive and involves minimally invasive procedures • Can provide information on allergen sensitivity on initial clinic visit. • i.e., no trip to a busy lab for venipuncture • Cost-effective in terms of patient time & money • When performed correctly, skin testing is reproducible 1. Oppenheimer et al, Ann Allergy 2006;S1:6-122.

  14. Serological Evaluation for Sensitization to Food Adapted from : the Pearls & Pitfalls of Allergy Diagnostic Testing CME presentation at www.aaaai.org Limitations • Cost-patient time & money • Requires venipuncture/or other blood draw • Modest sensitivity/specificity lead to false positive and false negative • Although anyone can order still requires experienced clinician to optimally interpret data • Reactions could occur despite a “negative” test • Several studies show reaction rates over 20% in patients with “undetectable” food specific serum IgE (with suspected allergy by history) • Different Lab assay systems are not interchangeable

  15. Serum specific-IgE Antibody Laboratory ResultsInterassay Variability • Objective: compare results from CLIA-certified laboratories that used 3 common systems for sIgE antibody • Methods: 60 samples for peanut and 20 for soy and mouse-human chimeric IgE antibodies specific for the Bet v 1 and Der p 2 were submitted for sIgE measurement on 3 different systems: • ImmunoCAP, Immulite, and Turbo-RAST • Reference: total IgE = ChimericIgE Wood et al., Annals Allergy, Asthma & Immunol 2007; 99:34-41

  16. Poor Agreement of IgE Antibody Laboratory Results Results: Poor agreement among the 3 systems for soy and peanut • Using a cutoff of 0.35 kUa/L showed some differences in the ability to detect sIgE sensitization with Turbo RAST most variable • Studies suggest various assays measure different populations of IgE antibody. • Currently, it is not known which of the major assays provides the most accurate evaluation of allergen s-IgE in patients’ serum. Wood et al, Annals Allergy, Asthma & Immunol 2007; 99:34-41

  17. Interassay Variability of IgE Antibody Laboratory Results Immunlite ImmunoCAP Tubo RAST • Results: Chimeric antibodies: Widely disparate results amongst the 3 assays • Immunlite considerably overestimated sIgE • Turbo RAST underestimated sIgE Wood et al.,Annals Allergy, Asthma & Immunol 2007; 99:34-41

  18. Allergy Skin Testing Advantages & Diagnostic Utility in Comparison to Specific- IgE Antibody • SPT may be more sensitive in predicting who will react on challenge • In pts with low food sIgE, SPT may have diagnostic utility • SPT can identify sensitivity to labile food proteins

  19. The natural history of peanut allergy Study: 223 peanut allergic pts 4 to 20 yrs were evaluated by questionnaire, skin testing, & peanut sIgE • Reaction-free plus peanut sIgE ≤ 20 kUa/L challenged • Results: 85 pts underwent DBPC or open challenge • 48 (21.5%) patients passed challenge (‘outgrew allergy’) • 37 failed challenge: 8(21%) patients with negative peanut sIgE , 2 of which also had negative SPT Skolnick et al,J Allergy Clin Immunol. 2001;107(2):367-74

  20. SPT to egg white provides additional diagnostic utility to serum egg white-sIgE concentration in children • Study: Retrospective analysis to determine whether the size of the SPT to egg white adds diagnostic utility for children with low egg white–sIgE. • Results: Egg OFCs passed (n = 29) and failed (n = 45) • 9 (20%) failed OFCs had undetectable (<0.35 kIU/L) egg white–sIgE levels with egg SPT from 4.0 to 6.0 mm and egg/histamine SPT indices from 0.67 to 1.71 • Between failed/passed OFC: • No difference in age, clinical characteristics, or egg white-sIgE • Significant differences between both egg white SPT wheal and egg/histamine SPT wheal index. • 1 failed had negative SPT & sIgE -urticaria 2 hrs later during placebo phase Knight et al, J Allergy Clin Immunol. 2006;117(4):842-7

  21. SPT Is Superior To IgE CAPRAST For The Diagnosis Of Infantile Food Allergy • Study: Infants with suspected egg and milk allergy with negative specific-IgE at the time of first visit • Results: • Egg: 72/89 (80%) suspected-HE allergies with negative IgE CAPRAST, were diagnosed as HE allergy by the elimination and provocation tests . 39 had positive egg SPT • Milk: 42/125 (33%) suspected-CM allergy infants with negative IgE were diagnosed as CM allergy, and 21 (50%) had positive milk SPT • Authors’ Conclusions: “SPT seemed to be more useful than EW- or CM- IgE CAPRAST for the diagnosis of HE or CM allergies in early infantile period.” Ebisawa M et al, J Allergy Clin Immunol 2009;123(2):S23.

  22. When commercial extracts are just not good enough • Study: In 430 children with suspected food allergy-compared results obtained with SPT using commercial extracts and fresh foods, and labial and/or oral challenge • Results: egg, peanut, and cow's milk. • Cow's milk, wheal larger with commercial extracts(NS) • Conversely, wheal diameters were significantly larger with other fresh foods • SPT positive in 40% of commercial extracts and 81.3% with fresh foods. • Concordance with positive challenge & SPT: 58.8% with commercial extracts and 91.7% with fresh foods. • Results indicate that fresh foods may be more effective for detecting the sensitivity to food allergens. Rance et al, Allergy. 1997;52(10):1031-5.

  23. Diagnosing IgE-mediated hypersensitivity to sesame by an immediate-reading "contact test" with sesame oil • 3 cases of immediate reaction to sesame: • 42-yo man: 2 anaphylactic reactions after ingestion of breadsticks and candy, • 28-yo man : 2 urticaria/angioedema reactions within 10 minutes after ingesting bread containing sesame seeds. • 38-year-old man several urticaria/angioedema reactions within 30 minutes after ingesting sesame-containing foods • All 3 with negative SPT to commercial extract and none had detectable sesame-specific IgE • SPT to sesame oil and crushed sesame was negative: note oleosins are hydrophobic and can not be solubilized in saline Alonzi J Allergy Clin Immunol 2011;127:1627-9

  24. When Commercial Extracts, Prick to Prick & Serum IgE Antibody Test Fail to DiagnoseThe Skin “Contact Test “ • An immediate-reading ‘‘contact test’’ was performed by applying on the volar side of the forearm a square of filter paper (10 x 10 mm) dipped in sesame oil and removing it after 20 minutes. • Results: Patient 2 had wheal reaction the same size as the filter paper at contact site, whereas patients 1 and 3 had several 4-mm wheals also involving the surrounding area • Immediate-reading contact test with sesame oil was negative in 10 healthy subjects & 3 pts tolerated other oil contact tests Alonzi J Allergy Clin Immunol 2011;127:1627-9

  25. Allergy Skin Test vs. In Vitro TestsWhat about the side effects, risks and dangers?

  26. Reactions to prick and intradermal skin tests Methods: 12-month prospective study was conducted to evaluate SRs from ST in 1,456 patients Results: • Six patients (0.4%) had SRs during SPT. 1 reacted to aeroallergens alone, whereas the other 5 reacted to aeroallergens and food • No severe asthma, shock, hypotension, unconsciousness, or biphasic reactions occurred. • All 52 patients received epinephrine intramuscularly Bagg A, Chacko T, Lockey R. Ann Allergy Asthma Immunol. 2009;102(5):400-2.

  27. Systemic reactions to allergy skin tests Method: Retrospective study at the Mayo Clinic to identify patients who developed systemic reactions to skin tests Results:. 497,656 skin tests were performed : SPT 16,505 patients • 6 patients experienced SRs. All had asthma. • SPT SR rate was 15 or 23 reactions per 100,000 aeroallergen tests • “It is noteworthy that there were no systemic reactions to skin tests for foods or venoms” • Conclusion: SR to skin tests was very low. SRs were mild and all patients recovered fully within 1 hour. Valyasevi et al, Ann Allergy Asthma Immunol 1999;83:132–136.

  28. Risk of adverse reactions from SPT, venipuncture, and body measurements: NHANES II 1976-80 Study: 16,204 of the U.S. population , 6 to 74 yrs, examined with routine medical procedures, including SPT & venipuncture. • SPT to 8 FDA licensed unstandardized extracts Results: • SPT: No anaphylactic reactions after SPT were observed. • Venipuncture: One asthmatic reaction. Other AR limited to syncope, near syncope, and malaise. • Adverse reaction rates: • Venipuncture: 0.49% (95% CI, 0.38% to 0.60%); • SPT: 0.04% (95% CI, 0.01%-0.08%); • Age group 20 to 49 years had the highest occurrence of any AR to venipuncture (0.87%; 95% CI, 0.633% to 1.107%). Turkeltaub J Allergy Clin Immunol. 1989;84(6 Pt 1):886-90

  29. Allergy Skin Testing…moving into the future Molecular Allergy: Can allergy skin tests meet the challenge? Scarification Device Modified-Prick Puncture Multiplex Array • In 1930s, scarification - problem was a lack of uniformity in the abrasion AND there was the potential side effect of scarring. • Mueller device made six uniform abrasions 1-½ mm long and 15 mm apart • Pepys modified prick skin test method in 1968. • Studies comparing scarification to SPT showed increased false – and + • As a result, use of the scarification technique diminished in 1970’s • .

  30. Component-resolved diagnosis of pollen allergy based on SPT with profilin, polcalcin and LTP pan-allergens • Principle objective: evaluate a new diagnostic strategy - SPTs specific for 3 pan-allergens, together with an appropriate and complete panel of allergenic molecules. • Study :1329 pts with previous 2-year history of pollinosis, tested by vitro method to 13 purified allergen including pan-allergens & SPT to major allergens and pan-allergens • For SPT: • peach commercial extract adjusted to 30 mg/mL of Pru p 3, which is a LTP • date palm extract: natural profilin, Pho d 2 adjusted to 50 mg/mL & procalin

  31. Component-resolved diagnosis of pollen allergy based on SPT with profilin, polcalcin and LTP pan-allergens

  32. Concordance of SPT extracts and sIgE to the corresponding pan-allergens Results: • Concordance of SPT extracts and sIgE evaluated: high diagnostic value is observed for • Profilin SPT (positive and negative concordance 82.3% and 90.8%, respectively) • LTP-enriched SPT (positive and negative concordance 65% and 94.3% respectively ), • Polcalcin SPT performance lower (positive and negative concordance 50% and 90.4% respectively). • Authors’ conclusion: “ Novel diagnostic strategy has proven to be a valuable tool in daily clinical practice. Introduction of routine SPT to pan-allergens is a simple and feasible way of improving diagnostic efficacy.” Barber et al,Clin Exp Allergy 2009;39:1764-73

  33. Why Skin Testing is Superior to In Vivo Testing Because: • More cost and time efficient for patient • Results available on initial consultation allowed for development of specific treatment plan • Predictive value in terms of presence of clinical allergy and possible severity • In some cases greater predictive value than in vivo test • Ability to test to allergens that may be altered in extract preparation process e.g., natural foods • Can also be used in component-resolved diagnosis

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