R. B. Vender, BSc, BMedSc, MD, FRCPC
Assistant Clinical Professor, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Allergic contact dermatitis (ACD) is more frequent in the pediatric population and in children with atopic dermatitis (AD) than has hitherto been appreciated. Patch testing, which is mediated by different immune mechanisms than prick skin testing, is both safe and diagnostically useful for individuals with AD. It may help to identify exacerbating allergens, e.g., constituents of topical treatments in refractory AD and to formulate treatment plans that feature preventive avoidance of the offending allergens.
atopic dermatitis, patch testing, contact dermatitis
The term “atopic dermatitis” was first used in the 1930s1 to denote the close association of this condition with the presence of respiratory allergies. Since the 1980s, the most frequently cited definition for atopic dermatitis (AD) is one by Hanifin and Rajka,2 who listed major and minor diagnostic criteria. However, a better understanding of the underlying pathophysiology of this condition has led some to argue that the criteria are due for re-evaluation.2
The precise role of allergies in the pathogenesis of AD has been debated for the last half-century. Out of that debate came the belief that when allergens are involved in AD, they provoke immediate (IgE-mediated) hypersensitivity reactions, but in contrast, AD patients have a reduced susceptibility to allergic contact dermatitis (ACD). Are these beliefs supported by current evidence? If they are, what is the role of patch testing for children with AD?
Patch testing has been reported to be an excellent evidencebased method for diagnosing ACD because it reproduces the identical disease using the putative offending allergen.3 Patients are generally tested with one of several available standard series of the most common allergens, sometimes augmented by other suspected allergens. After dilution in an appropriate vehicle, the allergens are applied to the skin of the back, either in metal chambers that are secured to the skin with tape, or in tapes that have been impregnated with the allergen.
In contrast, the technique of “atopy patch testing” (APT) is a questionable tool of clinical usefulness and may be best suited for use at a research level. This procedure relies on the epicutaneous application of aeroallergens by the usual patch test techniques applied to uninvolved skin. APT produces reactions in 30- 50% of patients with AD, and there is considerable variation in their performance and interpretation. The allergens used, e.g., molds and dust mites, have not been standardized.4 However, Ring et al, who performed several hundred of these procedures found that the morphology of the reactions of aeroallergens in the APT or classic contact patch test allergens were similar.5
It is important to distinguish between true allergic reactions, i.e., pruritic, erythematous, indurated and sometimes vesiculated lesions that persist for at least 5 days, from shorter-lived nonspecific irritant reactions that do not require an immunological response. This is particularly important in patients with active AD, whose skin is more susceptible to irritation6 and false-positive results, especially with metals.7 Another common error is to produce false-positive results by inadvertently testing two or more strong antigens too close together on the skin (“angry back syndrome”).8
There is a growing consensus that patch testing is safe for children and that the same series of antigens and the same concentrations can be used in children as well as adults. Children have more limited skin surface areas available for testing, shorter histories of antigenic exposures (therefore a shorter list of the “usual suspects”), and are more likely than adults to dislodge the patches. Hence, an abbreviated standard series is often sufficient. Some of the most common contact allergens relevant to children are listed in Table 1.
|Mercury||Thimerosal preservative in vaccines|
|Uroshiol||Poison ivy, oak, sumac|
|Fragrances||Wide variety of consumer products|
|Topical preparations||Topical antibiotics, cosmetics|
|Carba mix et al||Wide variety of rubber products|
|Wool alcohols (lanolin)||Emollients and soaps|
|Resins||Nail polishes, permanent press clothing|
Table 1: Most common allergens yielding positive patch tests in children.
What Are The Most Common Allergens?
The “standard series” of antigens contained in various commercially available patch test kits include many of the most common allergens. The North American Contact Dermatitis Group,9 after testing several thousand adult patients, noted that the 20 screening antigens included in a popular patch test kit detected ACD in only 54% of the patients, and missed a large number of allergic reactions that were deemed to be clinically relevant.
Of the positive reactions seen in adolescents who were patch tested (n=1146), 20 of 24 contact allergens were identified. Positive tests were most common to nickel (8.6%) and fragrance mix (1.8%). Significantly, more girls than boys were sensitized to nickel, whereas no sex difference was found for the other allergens.10
Apositive patch test for thimerosal, an organic mercurial that is widely used as a preservative in vaccines, eye drops and contact lens solutions, was reported in 5 infants with AD.11 Nummular eczema appeared on the trunk, limbs and face 2- 10 days after routine vaccinations. However, it is generally thought that if different needles are used to aspirate and to inject the vaccine, sensitivity to thimerosal should not prevent the completion of the routine vaccination series.
Interestingly, several authors have reported that the reproducibility of patch testing can be strongly affected by the nature of the antigen. Nickel in particular has been noted to produce discordant results in trials that double-tested patients.11,12 One reason for the apparent reported discrepancies in the incidence of ACD may be that the current antigen preparations yield intrinsically variable results.
Is ACD Common In Children With AD?
In recent years, the prevailing belief that ACD was very uncommon in children has been challenged. In fact, the true incidence of contact allergy and ACD in children and adolescents is unknown, partly because most studies examined referral populations, rather than unselected populations. Furthermore, they did not consider the clinical relevance of the contact allergic reactions that were noted, nor did they include follow-up data.13 However, ACD accounts for approximately 13.3%-23.3% of all the dermatitis seen in childhood.14-17
ACD has been observed in children under 3 years of age9 and even in neonates.7 In a large series of pediatric patients referred for patch testing to evaluate a variety of problems, the prevalence of positive patch test results is in the neighborhood of 40%.18 As previously noted, the standard series of antigens may miss a great many ACD patients, which may have contributed to the perception that it is not common in children.
The literature is extremely mixed with regard to whether ACD is less common in children with AD than in others. AD is one of the most frequent diagnoses among children who are referred for patch testing.19 In one recently reported series of 100 children, 87% had positive patch test reactions, and of these, 44.8% had AD.20 However, children with AD were reported to be somewhat underrepresented in a population of referred children whose patch tests were positive.21
Conversely, some investigators noted that the incidence of positive patch tests is lower in children with AD than in non-atopic children22 or in children with other types of dermatitis.23 A study of 499 adults reported that patients with atopy were significantly less likely to have a positive patch test result with a standard series of antigens.24 In contrast, a study of 670 referred children reported that atopy was a predisposing factor for contact hypersensitivity. Of the 42% with positive patch tests, 77% were atopic.25 Another sample of 410 patients found that the atopic subgroup had a significantly higher incidence of positive patch test results, although atopy also correlated with a higher incidence of nonspecific irritant reactions as well.26
A more recent report of patch testing in 1,146 adolescents with or without AD showed one or more positive reactions in 15.2% of subjects studied. Significantly more girls (19.4%) than boys (10.3%) (p< 0.001). Two or more positive reactions were seen in 14.9% of children. Of those with allergic contact dermatitis, 37% had a history of AD.10
Contact dermatitis can be of the irritant or the allergic types. The irritant type, which is more common, depends to some extent on disruption of the epidermal barrier, and is related to the concentration and the duration of exposure to the irritant. ACD, on the other hand, requires an initial exposure. On re-exposure, memory T-lymphocytes are activated and proceed to mediate the inflammatory processes that lead to the familiar clinical picture.19
The results of patch testing in AD patients can vary greatly, e.g., as previously mentioned, certain antigens are likely to yield discordant results. Patch testing invokes a delayed, Tlymphocyte- mediated immune response, and thus might be expected to yield different results from the prick skin test, which invokes immediate, antibody-mediated hypersensitivity. In a prospective open study of 33 children with AD who were tested for food allergens, there were discrepancies in the results given by patch-scratch testing, skin application food tests (SAFT), prick skin tests and delayed-type patch tests.27 Among 113 infants with atopic eczema, cow’s milk oral challenge was positive in 54 infants. This response correlated with prick skin testing in 36 infants and with patch testing in 18. However, 26% of the allergic infants were detected only with patch testing.28
Moreover, patients with active dermatitis, including AD, may have an intrinsic hyperreactivity of inflammatory cells which is shared with patients who have allergic rhinitis without dermatitis. This lower threshold may predispose them to the nonspecific “conditioned hyperirritability” that is often seen.29 In turn, the microscopic breaches of the epidermal barrier associated with skin irritation may allow specific antigens to penetrate more effectively and eventually to provoke the delayed immune responses that underlie the positive patch test result.
Recommendations: Should AD Patients Be Patch Tested?
Regardless of whether ACD is more or less frequent among children with AD than among other children, the incidence of ACD among children with AD in these populations is in the range of 40%.30 Despite the differences in comparative findings, this substantial positive rate has led to a consensus among investigators that patch testing is a useful modality for children with AD. First, it helps to improve the accurate identification of allergens that may be exacerbating the condition. Second, one frequently finds that individuals with AD have a positive patch test reaction to constituents of frequently used topical treatments (such as antibiotics or emollients). Thus, patients whose AD is persistent or flares despite appropriate treatment should be patch tested. Third, systematic patch testing has been advocated for children with AD so that preventive avoidance (e.g., to perfumed cosmetics) can begin early and clinical exacerbations may be spared. Although the standard series and concentrations are safe for children, using an abbreviated series of antigens may be adequate.
Made possible through an unrestricted educational grant from LEO Pharma, Inc.
- Hill LW, Sulzberger MB. Yearbook of Dermatology and Syphilology. Chicago: Year Book Medical Publishers (1933).
- Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Dermatol Venereol Scand 92(Suppl):44-7 (1980).
- Weston WL, Bruckner A. Allergic contact dermatitis. Pediatr Clin North Am 47(4):897-907, vii (2000 Aug).
- Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol, 105(5):860-76 (2000 May).
- Ring J Darsow U Behrendt H. Role of aeroallergens in atopic eczema: proof of concept with the atopy patch test. J Am Acad Dermatol 45(1):S49-52 (2001 July).
- Loffler H, Effendy I. Skin susceptibility of atopic individuals. Contact Dermatitis 40(5):239-42 (1999 May).
- Roul S, Ducombs G, Taieb A. Usefulness of the European standard series for patch testing in children. A 3-year single-centre study of 337 patients. Contact Dermatitis 40(5):232-5 (1999 May).
- Brasch J, Henseler T, Aberer W, et al. Reproducibility of patch tests. A multicenter study of synchronous left- versus right-sided patch tests by the German Contact Dermatitis Research Group. J Am Acad Dermatol 31(4):584-91 (1994 Oct).
- Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Amer Acad Dermatol 38(6 Pt 1):911-8 (1998 Jun).
- Mortz CG, Lauristen JM, Bindslev-Jensen C, Andersen KE . Prevalence of atopic dermatitis, asthma, allergic rhinitis, and hand and contact dermatitis in adolescents. The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis. Br J Dermatol 144(3): 523-32 (2001 Mar).
- Patrizi A, Rizzoli L, Vincenzi C, Trevisi P, Tosti A. Sensitization to thimerosal in atopic children. Contact Dermatitis 40(2):94-7 (1999 Feb).
- Bourke JF, Batta K, Prais L, Abdullah A, Foulds IS. The reproducibility of patch tests. Br J Dermatol 140(1):102-5 (1999 Jan).
- Mortz CG, Andersen KE. Allergic contact dermatitis in children and adolescents. Contact Dermatitis 41(3):121-30 (1999 Sep).
- Friedlander SF. Contact dermatitis. Pediatr Rev 19(5):166-71 (1998 May).
- Dotterud LK, Falk ES. Contact allergy in relation to hand eczema and atopic diseases in north Norwegian schoolchildren. Acta Paediatr 84(4):402-6 (1995 Apr).
- Barros MA, Baptista A, Correia TM, Azevedo F. Patch testing in children: a study of 562 schoolchildren. Contact Dermatitis 25(3):156-9 (1991 Sep).
- Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children, and adolescents. Pediatrics 78(6):1070-4 (1986 Dec).
- Shah M, Lewis FM, Gawkrodger DJ. Patch testing in children and adolescents: five years’ experience and follow-up. J Am Acad Dermatol 37(6):929-34 (1997 Dec).
- Stables GI, Forsyth A, Lever RS. Patch testing in children. Contact Dermatitis 34(5):341-4 (1996 May).
- el Samahy MH, el-Kerdani T. Value of patch testing in atopic dermatitis. Am J Contact Dermat 8(3):154-7 (1997 Sep).
- Brasch J, Geier J. Patch test results in schoolchildren. Results from the Information Network of Departments of Dermatology (IVDK) and the German Contact Dermatitis Research Group (DKG). Contact Dermatitis 37(6):286-93 (1997 Dec).
- Cronin E, McFadden JP. Patients with atopic eczema do become sensitized to contact allergens. Contact Dermatitis 28(4):225-8 (1993 Apr).
- Whitmore SE. Should atopic individuals be patch tested? Dermatol Clin 12(3):491-9 (1994 Jul).
- De Groot AC. The frequency of contact allergy in atopic patients with dermatitis. Contact Dermatitis 22(5):273-7 (1990 May).
- Manzini BM, Ferdani G, Simonetti V, Donini M, Seidenari S. Contact sensitization in children. Pediatr Dermatol 15(1):12-7 (1998 Jan-Feb).
- Klas PA, Corey G, Storrs FJ, Chan SC, Hanifin JM. Allergic and irritant patch test reactions and atopic disease. Contact Dermatitis 34(2):121-4 (1996 Feb).
- Oranje AP, Bruynzeel DP, Stenveld HJ, Dieges PH. Immediate- and delayedtype contact hypersensitivity in children older than 5 years with atopic dermatitis: a pilot study comparing different tests. Pediatr Dermatol 11(3):209-15 (1994 Sep).
- Kekki OM, Turjanmaa K, Isolauri E. Differences in skin-prick and patch test reactivity are related to the heterogeneity of atopic eczema in infants. Allergy 52(7):755-9 (1997 Jul).
- Nassif A, Chan SC, Storrs FJ, Hanifin JM. Abnormal skin irritancy in atopic dermatitis and in atopy without dermatitis. Arch Dermatol 130(11):1402-7 (1994 Nov).
- Giordano-Labadie F, Rance F, Pellegrin F, Bazex J, Dutau G, Schwarze HP. Frequency of contact allergy in children with atopic dermatitis: results of a prospective study of 137 cases. Contact Dermatitis 40(4):192-5 (199 Apr).
Dermatologists Increase Their Use of Patch Testing in US
The standard for diagnosing delayed-type hypersensitivity reactions of the skin is considered to be patch testing, and according to a survey published in the June issue of the American Journal of Contact Dermatitis, its use is on the rise.
E.M. Warshaw and D. Nelson from the Minneapolis VA Medical Center and the University of Minnesota surveyed one-third of US Fellows of the American Academy of Dermatology in 1997, and the responses were compared with a survey of dermatologists done in 1990. They reported that 83% of those responding use patch testing in their practice, which is a significant increase over those using this test in 1990 (P<.0001).
Fifty-two percent used a 48-hour, 96-hour patch test reading schedule, and 26% carried out a single reading after 48 hours or 72 hours. Seventyfour percent of the dermatologists who use this test reported that they use the T.R.U.E. test® (Allerderm), which was approved in July 1995, by the US FDA. Many (46%) said they were patch testing more patients now than when the T.R.U.E. test® was not available. Forty-four percent use the T.R.U.E. test® because it is less time consuming for their staff. Only 11% of dermatologists who patch test also use photopatch testing.
Source: Am J Contact Dermat 13(2):58-8 (2002 Jun).
New Policy on Pharmacy Compounding Set by the US FDA
A recent US Supreme Court decision invalidated the compounding provisions contained in the US FDA Modernization Act of 1997, because they contained unconstitutional restrictions on commercial speech. As a result, the US FDA issued new guidelines for pharmacists in June 2002, which were published on their website on June 4, 2002.
These new guidelines are not directed toward the traditional activity of extemporaneously compounding drugs when they are manipulated in a reasonable quantity upon receipt of a valid prescription from a licensed practitioner for one identifiable patient. These guidelines are instead directed at an increasing number of establishments with retail pharmacy licenses that are engaged in manufacturing and distributing these compounds in a manner that is clearly outside the bounds of traditional pharmacy practice.
Generally, the US FDA will continue to defer to state authorities with regard to less significant violations to the Act relating to pharmacy compounding of human drugs. However, when the scope and nature of a pharmacy’s activities raise the kinds of concerns that are normally associated with a drug manufacturer and result in significant violations of the new drug, adulterations, or misbranding provisions of the Act, then the FDA will seriously consider enforcement action. In order to determine whether such action is necessary, they will consider whether the pharmacy engages in any of the following acts:
- Compounding drugs in anticipation of receiving prescriptions, except in very limited quantities.
- Compounding drugs that were withdrawn or removed from the market for safety reasons.
- Compounding finished drugs from bulk active ingredients that are not components of FDA approved drugs without an FDA sanctioned investigational new drug application (IND).
- Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility.
- Receiving, storing, or using drug components that are not guaranteed.
- Using commercial scale manufacturing or testing equipment.
- Compounding drugs for third parties who resell to individual patients, or offering compounded drug products at wholesale cost to other state licensed persons or commercial entities for resale.
- Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products.
- Failing to operate in conformance with applicable state laws that regulate the practice of pharmacy.
FDA-initiated regulatory action may include issuing a warning letter, seizure, injunction, and/or prosecution.
Source: US FDA Compliance Policy Guide, Sec. 460.200 Pharmacy Compounding