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.)
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
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.
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.)
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
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.
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.)
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
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.
