Feature: How to Increase Your Patch Testing Efficacy - By Sharon E. Jacob, M.D., and Tace Steele, B.A. From Gold to Detergents, These experts identify top non-T.R.U.E. Test allergens. Further increase your chances of pinpointing your patients’ offending allergens by incorporating a supplemental panel based on their selections. In the 1980s the Food and Drug Administration (FDA) called for regulations on the sale and production of allergens in the United States. This mandate resulted in the approval of the German-based Hermal/Trolab 20 standard allergen test (Table I) and the 24-chamber Thin-layer Rapid-Use Epicutaneous test (T.R.U.E.) (Table II) in 1988 and 1997, respectively. The T.R.U.E test has emerged as the leader in basic “standard” patch testing evaluation for both dermatologists and allergists. One limitation of using only a “standard” screening panel is the low number of allergens and therefore the chance that an offending allergen will not be identified. With this in mind, dermatologists want to know: Will a supplemental panel of top relevant allergens used in conjunction with the T.R.U.E test further increase the efficacy of the T.R.U.E. test? This article will answer this question, identify top choice supplemental allergens to include, and offer practical information on how to obtain other allergens. But first, it is important to know the limitations of standard tests now commonly used. Limitations of Standard Screening Panels Cohen et al. investigated the efficacy of the Hermal 20 allergen standard in evaluating patients with allergic-type contact dermatitis and found that this screen adequately evaluated 15.7% of these patients.1 The T.R.U.E. test incorporated 18 of Hermal series compounds (with five mixes/mixtures) plus an additional 21 chemicals (with five new mixes/mixtures). Specifically, the T.R.U.E. test screens for 46 distinct allergens in addition to the more than 400 chemicals that comprise balsam of Peru. Even with this higher number of chemical allergens, the T.R.U.E test is believed to only identify an allergen in 24.5% of patients who have allergic contact dermatitis.2 This figure varies with the experience of the patch tester in selecting patients for testing and the skill level of the patch test evaluator in determining true-positive and true-negative reactions, as well as evaluating the relevance of the reactions. Over-reading false-positive reactions (e.g. punctuate purpura of cobalt) is also a common mistake. (See Figure 1.) Figure 1: An example of punctuate purpura of cobalt, a condition that is often overread as a false-positive reaction. In a head-to-head study done by Belsito and Suneja, the T.R.U.E test proved inferior to Finn chamber (comprehensive technique) in evaluating fragrance mix, balsam of Peru and thiuram mix. However, the T.R.U.E. Test was superior in detecting nickel, neomycin and methylchloroisothiazolinone/ methylisothiazolinone.3 The T.R.U.E. test utilizes hydroxypropyl cellulose, methylcellulose or polyvidone as vehicles and the preservatives BHT/BHA. It should be noted that while infrequent, methylcellulose and BHT/BHA have been known to cause allergic reactions, and should be considered in a patient with angry back syndrome following a T.R.U.E. test.4 Comprehensive testing, on the other hand, takes advantage of chemical solubility data, and it allows for testing both in aqueous and petrolatum-based formulations. The North American Contact Dermatitis Group (NACDG) tracks the group’s comprehensive patch test data and regularly updates the North American Standard, with the current guidelines to include 65 top relevant allergens.5,6 Despite these recommendations, comprehensive patch testing is not always available or accessible to patients. Because the art of patch testing involves patient-directed allergen selection, no absolute set list of allergens exists to suit every patient. There are, however, some allergens more likely to be culprits than others. Several allergens quickly make the list, as increasing sensitization rates have landed them on the Allergen of the Year list. (See Table III below.) Likewise, a number of allergens have repeatedly landed at the top of the NACDG prevalence data list, and so they may be prudent to include. Practical Top 25 Allergens to Consider as Supplements to the T.R.U.E. Test After much research, we have identified 25 top allergens to consider using in conjunction with the T.R.U.E. Test (see Table IV above for the full list). Here’s a look at these allergens in detail. I. Corticosteroids In 1959 the first case of corticosteroid allergy to topical hydrocortisone was reported in “a non-white 19-year-old garage boy”. The patient suffered from a thinner-induced hand and face dermatitis that was treated with a cream containing neomycin and hydrocortisone. After switching to an only hydrocortisone formulation, the patient’s dermatitis worsened. The patient was determined patch test positive to hydrocortisone.7 In general, corticosteroid allergy may either present as an unresponsive dermatitis or a worsening dermatitis with repeated use of topical corticosteroids within the same class. It is important to note that the inherent anti-inflammatory nature of corticosteroids may cause a delay in the appearance of a positive patch reaction and may ultimately lead to underreporting of contact sensitization.8 Screening for class A and B corticosteroids did not become commonplace until the 1990s. As the sensitization prevalence became more recognized, screening broadened to include components of the different structural classes, and cross-reactivities became further characterized. Accordingly, each of the five structural classes of steroids has a selected screening agent(s): tixocortol pivalate (class A), budesonide and triamcinolone acetate (class B), desoximethasone (class C), clobetasol-17-propionate (class D1) and hydrocortisone 17-butyrate (class D2). (See Table VI.) In 2005, corticosteroids became the Allergen of the Year, to commemorate the increased awareness of their role in causing allergic contact dermatitis. It is recommended that these allergens be added to a general screen, in addition to the corticosteroids in the patient’s therapeutic repertoire. II. Extended Fragrances Allergy to fragrance was first reported in the medical literature in 1957 and now accounts for approximately 23% of the relevant positive allergens detected by the NACDG.9 The increasing rates of sensitization to perfumes led to the establishment of fragrance identification measures in late ’70s.10 In 1977 Larsen proposed a mixture of eight ingredients (Fragrance Mix, FM) as a screening tool for fragrance contact allergy: isoeugenol, eugenol, cinnamic aldehyde, cinnamic alcohol, hydroxycitronellal, geraniol, a-amyl cinnamic aldehyde, and oak moss absolute.10,11 This composite is still used today for fragrance screening and in conjunction with balsam of Peru (BOP) detects 90% of fragrance allergies.12 The addition of ylang ylang oil, sandalwood, jasmine and lyral brings the fragrance allergy detection rate near to 100%.12 Furthermore, cinnamic aldehyde should be considered, as it is currently tested as a separate allergen on the NACDG standard in addition to FM and BOP. In a patient suspected of fragrance allergy, the addition of these chemicals would increase the ability to capture relevant allergens. III. Cocamidopropyl Betaine In 1967, the first “no tears” shampoo containing the “mildest” of detergents was introduced to the consumer market.13 The active ingredient responsible for the no tears claim was the amphoteric detergent, cocamidopropyl betaine (CAPB). This detergent was originally formulated in toothpaste preparations and shampoos, because it was less irritating to mucous membranes.14 In 1983, Van Haute and Dooms-Goossens reported the first case of CAPB allergy contained in a shampoo.15 Despite increasing reports of contact sensitization, an exponential increase in the number of products containing this allergen has occurred over the last 20 years, and today allergy to CAPB is common. For this reason, CAPB was designated the Allergen of the Year in 2004. The classic presentation of CAPB allergy is an eczematoid dermatitis involving the head, neck and dorsal hands, corresponding to common exposures through soaps and shampoos. CAPB has been reported to cause toothpaste-associated perioral dermatitis.16 This important allergen should be considered in the repertoire of additional allergens in a basic screen. IV. Bacitracin Bacitracin was first formulated in the 1950s, but renal toxicity limited its use as a systemic antibiotic. The therapeutic broad activity spectrum against gram-positive and gram-negative bacteria did not go unnoticed; however, and soon bacitracin became a superpotent topical salve. This antibiotic is used in a wide assortment of topical medications — for example, as a component of Neosporin, Polysporin and Betadine healing ointments and Ak-Tracin eyedrops. The NACDG tracked bacitracin as it climbed the top allergen rank list and landed as the ninth most common allergen. Ultimately, this rapid ascent, earned bacitracin the title of Allergen of the Year in 2003. Knowledge of sensitization to this antibiotic is paramount because more than 16 cases of near-death anaphylaxis have been reported to date. Allergic reactions are seen in as many as 2% of the patients who have used bacitracin post-operatively.17,18 It is recommended that this allergen be added to basic screening, but that care be taken not to apply this allergen to patients who have developed contact urticaria to bacitracin in the past (to minimize the possibility of a Type 1 immediate hypersensitivity reaction) and to only apply this allergen to intact, unbroken skin.4 V. Extended Preservatives Formaldehyde releasing preservatives FRPs are often used in cosmetic and personal hygiene formulations in lieu of formaldehyde. As they are commonly used in eyecare products and mascaras, allergy in the eye area can become problematic with continued use of these allergens. The sensitization may occur to these agents specifically or to the formaldehyde that they release.19 The basic T.R.U.E. test screens for only quaternium-15 — which is only one of the top five FRPs. While cross-reactivity occurs between the FRPs, a substantial number of allergic reactions are missed by not specifically screening for the other top FRPs.5 Inclusion of the additional top-four FRP allergens: bronopol, diazolidinyl urea, imidiazolidinyl urea, and DMDM hydantoin would render a higher screening sensitivity for these agents. The Methyldibromoglutaronitrile (MDBG)/Phenoxyethanol(PE) compound, marketed as Euxyl K400, is the most common sensitizing non-formaldehyde releasing preservative. While it was introduced in Europe in the 1980s, MDBG was not used by American manufacturers until the 1990s. It is commonly used in cosmetics and toiletry products. The classic presentation of MDBG/PE sensitization is a head and neck dermatitis, due to cosmetic creams. However, a number of reported cases are in the literature of perianal dermatitis to MDBG/PE, as these products are often used in moistened toilet paper.19,20 VI. Gold Prior to the 1980s, allergies to gold were thought to be rare, with only a few cases reported. Because it was thought to be immunologically inert, gold was rarely tested for among patch testers. This allowed gold allergy to go undetected, and it was therefore considered an insignificant allergen.4 Gold was added to the NACDG standard screening panel in the 1996-1998 series, and quickly became the sixth-most frequent allergen.6 The recognition as a significant sensitizer and second-most common metal allergy, led to the designation of gold as the Allergen of the Year in 2001.21 It is important to note that oftentimes gold does not cause a reaction under jewelry. Rather reactions are seen in the areas where the gold comes into contact with eye make-up, foundation, sunscreens, etc. — items that contain harder metals, such as titanium dioxide and zinc oxide. These harder metals abrade the gold, leading to the release of sensitizing gold particles.4 When patch testing, gold salts should be used, as gold leaf shavings rarely produce reactions in patients and may produce false negatives.4 It is important to note that both the dermatitis and the positive patch test reactions may persist for months after the exposure, with one case reporting that a reaction lasted for 18 months.4,22 The recent removal of gold from the NACDG standard series indicates that this chemical should be selectively tested when there is a high index of suspicion that this is a culprit allergen. VII. Disperse Blue 106 Disperse dyes (and specifically the color blue 106) have been reported to cause acute dermatitis and generalized pruritus.4 Since the increase in popularity of navy blue uniforms — with everyone from customs workers to postal workers to school children wearing them — the prevalence of allergic reactions to these dyes is also high. Reactions to disperse dyes may present as a dermatitis in the areas where textiles have frictional contact with the moist areas of the skin, such as the infra-axillary area (sparing the vault), inner thighs, the popliteal fossa and the buttocks.23 One study reported that 10% of the dye allergic patients presented with genital pruritus.24 It is important to note that disperse blue dye can also be used to create black, brown and green colors, especially in synthetic fabrics such as nylon and polyester blends.4 Additionally, disperse blue dye has been reported to cross-react with the hair dye paraphenylenediamine at a rate of 16%.25 Before testing for disperse dyes became commonplace in comprehensive testing, most textile allergies were blamed on the formaldehyde resins.26 An international board of experts was chosen by the American Journal of Contact Dermatitis to designate the first Allergen of the Year in 2000. The disperse dyes were bestowed the inaugural title, because of their “sudden emergence on the scene.”26 VIII. Caines Caine mix is one of the seven allergen mixes on T.R.U.E. test panel.27 The mix is comprised of two esters and one amide anesthetic: benzocaine, tetracaine and dibucaine. The component lacks specificity because it simultaneously screens for both ester and amide structural classes of anesthetics. Distinguishing between an ester and amide anesthetic allergy would be useful, as the esters commonly cross-react, precluding their use in an ester sensitized individual.4 Given that the esters anesthetics are para-aminobenzoic acid (PABA) derivatives, there is a risk for cross-reactivity with other PABA derivatives, such as paraphenylenediamine (PPD), PABA sunscreens, parabens, hydrochlorothiazide and sulfonamides.4,28 An allergy to an amide, on the other hand, does not preclude the use of another amide, as cross-reactivity within the class is rare.29 Lidocaine allergy is very rare, and it is important to note that the lidocaine or paraben preservative may be the culprit allergen.30 Further delineation of the anesthetic allergy would provide invaluable information on which anesthetics could be used topically and/or systemically. Distinguishing the type of anesthetic allergy is an important distinction given that lidocaine and procainamide are both integral parts of the Advance Cardiac Life Support algorithm.4,31 A supplemental panel containing: lidocaine 5% in petrolatum and prilocaine 5% in petrolatum may be a useful adjuvant. IX. Benzalkonium Chloride Benzalkonium chloride is a surfactant that is often used as a preservative. It is the most common preservative in contact lens solutions and has been seen to cause both conjunctivitis and periorbital irritant and allergic contact dermatitis.19 Because it is a strong irritant, patch test reactions should be judiciously evaluated, and multiple tests with serial dilutions should be considered. X. Propylene Glycol Propylene glycol (PG) is a viscous dihydric alcohol widely used as a vehicle for topical medications and cosmetics. PG also has some innate antibacterial and antimycotic characteristics.32 Of late, PG has been used in corticosteroid creams at concentrations as high as 70%.4 Because of its emulsifying properties, the vehicle is often used in foods, such as Kraft Thousand Island salad dressing, Duncan Hines cake mixes and Wise butter flavored popcorn. It has been reported to cause both topical and systemic allergic contact dermatitis, in addition to irritant contact dermatitis.4,19 Contact dermatitis/reactions from PG may be of the irritant or allergic type. Due to the high irritant response from PG, some contact dermatitis specialists have suggested that a patient not be diagnosed with a PG allergy until after undergoing multiple tests with serial dilutions of PG.33 Figure 2A Figure 2B Figures 2A & 2B: Allergens are loaded onto test strips and then placed on a patient’s back for patch testing. Combining Panels to Enhance Allergen Detection First and foremost, patch testing is the gold standard measure for adequate evaluation of a patient with allergic contact dermatitis. Comprehensive testing provides a means to both test standardized allergens in appropriate vehicles and the patient’s own products. This allergen selection is based on a patient’s exposure history and clinical presentation. The patch test expert combines the information gathered from an extended history taking session with the clinical presentation to determine which allergens will be custom-prepared for testing the individual patient. Unfortunately, comprehensive patch testing is practiced by less than 1% of dermatologists.34 With its accessibility so highly limited, perhaps the time has come to call this art the Platinum Standard, and T.R.U.E testing with adjuvant chemicals the Gold Standard. To answer the question of whether a supplemental allergen panel could be created to use in conjunction with the T.R.U.E test — this can be done and may be of value in evaluating patients when comprehensive testing is unavailable. Dermatologists who wish to start a comprehensive patch test clinic (or acquire supplemental allergens) could purchase chemical supplies and IQ chambers from Dormer Chemicals at www.dormer.com. Likewise, Finn chambers may be purchased from Allerderm (www.allerderm.com). The selected chemicals or patient leave-on type products would then be loaded onto the chambers (see Figure 2A above) and then placed on a patient’s back (see Figure 2B above). As standard practice, the allergen patches are removed and evaluated at 48 hours, and re-read after 72 hours to identify delayed reactions.       References: 1. Saripalli YV, Achen F, Belsito DV. The detection of clinically relevant contact allergens using a standard screening tray of twenty-three allergens. J Am Acad Dermatol 2003;49:65-9. 2. Cohen DE, Brancaccio R, Andersen D, Belsito DV. Utility of a standard allergen series alone in the evaluation of allergic contact dermatitis: a retrospective study of 732 patients. J Am Acad Dermatol 1997;36:914-8. 3. Suneja T, Belsito DV. Comparative study of Finn Chambers and T.R.U.E. test methodologies in detecting the relevant allergens inducing contact dermatitis. J Am Acad Dermatol. 2001 Dec;45:836-9. 4. Nedorost S. Wagman A.  Positive patch-test reactions to gold: patients' perceptions of relevance and the role of titanium dioxide in cosmetics. Dermatitis. 2005 Jun; 16(2):67-70. 5. Pratt MD, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI, Marks JG, Mathias CG, Rietschel RL, Sasseville D, Sherertz EF, Storrs FJ, Taylor JS, Zug K. North American Contact Dermatitis Group patch-test results, 2001-2002 study period. Dermatitis. 2004 Dec;15:176-83. 6. Marks JG, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI, Mathias CG, Nethercott JR, Rietschel RL, Sherertz EF, Storrs FJ, Taylor JS. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol 1998;38:911-8. 7. Kooij R. Hypersensitivity to hydrocortisone. Br J Dermatol 1959;71:392–394. 8. Villara MA, Escribano JM, Lopez-Sanchez JD, Iniesta JF and Pagan-Aleman JA. Corticosteroid-induced contact dermatitis. Clinical management Alergol Inmunol Clin 1999;14:152-155. 9. Chatard H. Case of sensitization to perfumes with cutaneous and general reactions. Bull Soc Fr Dermatol Syphiligr 1957;64:323. 10. Larsen WG. Perfume dermatitis. A study of 20 patients. Arch Dermatol 1977;113:623-6. 11. Johansen JD. Fragrance contact allergy: a clinical review. Am J Clin Dermatol 2003;4:789-98. 12. Militello G, James W. Lyral: a fragrance allergen. Dermatitis 2005;16:41-4. 13. Begoun P. Baby Shampoo. Hair-Care Formulations in: Don’t go shopping for hair-care products without me. Beginning Press 3rd Ed. 2004;Sep:80. 14. Mowad CM. Cocamidopropyl betaine allergy. Am J Contact Dermat 2001:12:223-4. 15. Van Haute N, Dooms-Goossens A. Shampoo dermatitis due to cocobetaine and sodium lauryl ether sulphate. Contact Dermatitis 1983 Mar;9(2):169. 16. Agar N, Freeman S. Cheilitis caused by contact allergy to cocamidopropyl betaine in '2-in-1 toothpaste and mouthwash'. Australas J Dermatol 2005;46:15-7. 17. Jacob SE, James WD.From road rash to top allergen in a flash: bacitracin. Dermatol Surg 2004;30:521-4. 18. Gette MT, Marks JG, Maloney ME. Frequency of Postoperative Allergic Contact Dermatitis to Topical Antibiotics. Arch Dermatol 1992;128:365-367. 19. Marks JG, Elsner P, DeLeo VA. Contact and Occupational Dermatology. 3rd ed. Mosby; St Louis, Missouri: 2002. 20. DeGroot AC, et al. Frequency of allergic reactions to methyldibromoglutaronitrile in the Netherlands. Contact Dermatitis 1991;25:270. 21. Marks JG, Belsito DV, DeLeo VA. North American contact dermatitis group patch-test results, 1998 2000. Am J Contact Dermatitis 2003;14:59 62. 22. Rytter M, Schubert H. Allergy due to a golden ring by primary epicutaneous sensitization. Dermatologica 1971;142:209. 23. Seidenari S, Giusti F, Massone F, Mantovani L. Sensitization to disperse dyes in a patch test population over a five-year period. Am J Contact Dermatitis 2002;13:101-108. 24. Pratt M, Taraska V. Disperse blue dyes 106 and 124 are common causes of textile dermatitis and should serve as screening allergens for this condition. Am J Contact Dermat 2000;11:30-41. 25. Seidenari S, Mantovani L, Manzini BM, Pignatti M. Cross-sensitizations between azo dyes and para-amino compound. A study of 236 azo-dye-sensitive subjects. Contact Dermatitis 1997;36:91-6. 26. Storrs FJ. Contact allergen of the year: Disperse blue dyes. Am J Contact Dermatitis 2000;11:1–2. 27. T.R.U.E. Test. Allergen Components. Accessible on the Internet at: http://www.truetest.com/physician/comp.htm (February 2006). 28. Sidhu SK, Shaw S, Wilkinson JD. A 10-Year Retrospective Study on Benzocaine Allergy in the United Kingdom. Am J Contact Dermat 1999;10:57- 61. 29. Suhonen R, Kanerva L.Contact allergy and cross-reactions caused by prilocaine. Am J Contact Dermat 1997;8:231-5. 30. Luebke NH, Walker JA. Discussion of sensitivity to preservatives in anesthetics. J Am Dent Assoc 1978;97:656-7. 31. American Heart Association. Ventricular Fibrillation/Pulseless Ventricular Tachycardia Algorithm. Accessible on the Internet at: http://www.ace.cc/images/VF.jpg (February 2006). 32. Fransway AF. The problem of preservation in the 1990s: Agents with preservation function independent of formaldehyde release. Am J Contact Dermatitis 199 1;22:734. 33. Rycroft RJG, Menne T, Frosch PJ, Lepoittevin JP. Eds Textbook of Contact Dermatitis. 3rd ed. Springer; New York: 2001. 34. Farrel AL et al. Prevalence and methodology of patch testing by allergists in the United States: results of a cross-sectional survey. Am J Contact Dermat 2002;13:157-63.41. 35. Jadassohn J: A Contribution to the Study of Dermatoses Produced by Drugs. Verh Deutsch Derm Ges 1896:103-129. 36. Davis MDP, Farmer S. Results of patch testing to a corticosteroid series: experience with 1000 patients at Mayo Clinic. Oral presentation at the 17th Annual American Contact Dermatitis Society Meeting, March 2, 2006, San Francisco, CA. 37. Orion Health. T.R.U.E. Test Panel 3. Accessible on the Internet at: http://www.orion-health.co.nz/TT%20Panel%203.htm (February 2006). Skin & Aging - ISSN: 1096-0120 - Volume 14 - Issue 5_2006 - May 2006 - Pages: 34 - 44