Patch testing in Israeli children with suspected allergic contact dermatitis: A retrospective study and literature review

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1 DOI: /pde Patch testing in Israeli children with suspected allergic contact dermatitis: A retrospective study and literature review Yaron Zafrir MD 1 * Akiva Trattner MD 2,3 * Emmillia Hodak MD 2,3 Oren Eldar MD 2 Moshe Lapidoth MD 3,4 Dan Ben Amitai MD 3,5 1 Department of, Sheba Medical Center, Tel Hashomer, Israel 2 Department of, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Laser Unit, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel 5 Unit, Schneider Children s Medical Center of Israel, Petach Tikva, Israel Correspondence Dan Ben-Amitai, MD, Unit, Schneider Children s Medical Center of Israel, Petach Tikva, Israel. danb@clalit.org.il; benamitai.dan@gmail.com Abstract Background/objectives: Childhood allergic contact dermatitis is recognized as a significant clinical problem. The objective was to evaluate the rate of positive patch tests in Israeli children with clinically suspected allergic contact dermatitis, identify possible sex and age differences, compare results with those in Israeli adults, and review pediatric studies in the literature. Methods: The study sample included 343 children and adolescents (197 female, 146 male; 1-18 years of age, mean age 11.8 years) with clinically suspected allergic contact dermatitis who underwent patch testing with a standard pediatric series of 23 allergens at a tertiary medical center from 1999 to Data on clinical characteristics and test results were collected retrospectively from the medical files. Results: Ninety-eight subjects (28.6%) (75 girls [38.1%], 23 boys [15.8%]) had at least one positive reaction. The most frequent reactions were to nickel sulfate, followed by potassium dichromate and cobalt chloride. Nickel sulfate sensitivity was more common in girls, especially those younger than 3 years and older than 12 years. The prevalence of contact sensitization was similar in subjects with and without atopic dermatitis (50% and 51%, respectively). Conclusion: Nickel is the most common allergen in Israeli children, especially girls. Patch testing should be performed in children with clinically suspected allergic contact dermatitis regardless of atopic background. KEYWORDS allergic contact dermatitis, child, patch test 1 INTRODUCTION Allergic contact dermatitis (ACD) has been considered to affect mainly adults, based on the assumption that children have an immature immune system and are less frequently exposed to allergens, 1 but ACD is now recognized as a significant pediatric clinical problem, accounting for up to 20% of all forms of dermatitis in children. 2 In the few studies conducted of the prevalence of patch test proven contact allergy in asymptomatic children, the reported rates *Drs. Zafrir and Trattner contributed equally to this work. range from 13.3% 3 to 30.7%. 4 The real prevalence in symptomatic children with a clinical suspicion of ACD ranges from 14.5% 5 to 95.6%, 6 with relevance ranging from 21.4% 7 to 95.6%. 6 There has been a general increase in the rate of positive patch tests in recent decades. 8 This may reflect a true increase in the incidence of ACD, an increase in referrals of children for patch testing, variations in selection criteria for patch testing, regional and social variations in allergen exposure in younger age groups, or variations in the specific allergens tested. Early diagnosis of ACD is important, because by avoiding exposure to an allergen, patients can be spared the disease evolving to Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/pde. 2018;35:76 86.

2 ZAFRIR ET AL. 77 the chronic phase. It may also improve patient compliance with treatment and quality of life and, in some cases, prevent patients from making inappropriate career choices. 9,10 The purpose of the present study was to determine the frequency of positive and significant patch tests in children and adolescents with suspected ACD in Israel and to compare the findings with those in Israeli adults. An extensive review of childhood ACD in the medical literature is presented. 2 METHODS Routine patch testing was performed in 6600 subjects who were referred to the Contact Dermatitis Clinic of Rabin Medical Center between 1999 and 2012; 343 age 18 years or younger formed the study group. All subjects were suspected to have ACD according to history, rash distribution, localization, or findings of uncontrolled or deteriorating dermatitis. Subjects with irritant reactions were excluded from the study, as were subjects who had applied topical corticosteroids to test sites or had been treated with oral corticosteroids within 2 weeks before the study. Data on demographic characteristics, personal and family history of atopy (according to the criteria of Hanifin and Rajka 11 ), and patch test results were collected retrospectively according to chart review. Findings were also compared with those from a historical cohort of adults from the same medical center. 12 The institutional review board of Rabin Medical Center approved the study protocol (6895/12). 2.1 Patch test procedure Subjects were tested using the European standard patch test series of 23 allergens (Chemotechnique Diagnostics, Malmo, Sweden) using Finn Chambers on Scanpor tape (Hermal, Reinbeck, Germany). The allergens were applied to patches placed on unaffected skin of the upper back for 2 days. Reactions were determined on days 2 and 3 according to the guidelines of the International Contact Dermatitis Research Group. 13 No delayed reactions, beyond day 3 were monitored. 2.2 Statistical analysis Statistical analyses were performed using BMDP software (Wilfrid Dixon,University of California, Los Angeles, Los Angeles, CA). Discrete variables were compared between groups using the Fisher exact test, chi-square test, or Pearson coefficient, as appropriate; continuous variables were compared using the t-test or nonparametric Mann Whitney test. P-values <.05 were considered statistically significant. 3 RESULTS The study group consisted of 197 girls (57.4%) and 146 boys (42.6%) with a mean age of 11.8 years (range 1-18 years). Ninety- TABLE 1 Positive reactions to standard patch test series, overall and according to sex (N = 343) Allergen Total, n (%) Female, n = 197 Male, n = 147 P-value Nickel sulfate 43 (12.5) 41 (20.8) 2 (1.4) <.001 Potassium dichromate 18 (5.2) 13 (6.6) 5 (3.4) NS Cobalt chloride 18 (5.2) 12 (6.1) 6 (4.1) NS Methylchloroisothiazolinone/methylisothiazolinone 13 (3.8) 10 (5.1) 3 (2.1) NS Fragrance mix 9 (2.6) 5 (2.5) 4 (2.7) NS Colophony 5 (1.5) 4 (2) 1 (0.7) NS Balsam of Peru 5 (1.5) 4 (2) 1 (0.7) NS 4-tert butylphenol formaldehyde 5 (1.5) 3 (1.5) 2 (1.4) NS Wool alcohols 4 (1.2) 3 (1.5) 1 (0.7) NS 4-phenylenediamine base 4 (1.2) 4 (2) 0 NS Thiuram mix 3 (0.9) 2 (1) 1 (0.7) NS Formaldehyde 3 (0.9) 1 (0.5) 2 (1.4) NS Neomycin sulfate 2 (0.6) 1 (0.5) 1 (0.7) NS Benzocaine 2 (0.6) 2 (1) 0 NS Mercaptobenzothiazole 2 (0.6) 2 (1) 0 NS Priman 2 (0.6) 1 (0.5) 1 (0.7) NS Quaternium 15 2 (0.6) 1 (0.5) 1 (0.7) NS Mercapto mix 1 (0.3) 1 (0.5) 0 NS N-isopropyl-N-phenyl-4-phenylenediamine 1 (0.3) 1 (0.5) 0 NS Total (78.2) 31 (21.8) <.001 NS, not significant.

3 78 eight children (28.6%; 75 girls, 23 boys) had at least one positive patch test. A total of 142 positive results to the tested allergens were documented: 66 subjects (67.3%) had one positive response, 22 (22.4%) had two positive responses, 8 (8.2%) had three positive responses, and 2 (2%) had four positive responses. Girls had a significantly higher rate of total positive patch tests than boys (38.1% vs 15.8%; P <.001). There was no significant difference in mean age between subjects with a positive or negative response, overall or according to sex. The frequencies of sensitization to allergens in boys and girls are listed in Table 1. The highest rates were documented for nickel sulfate, potassium dichromate, cobalt chloride, the combined formulation of methylchloroisothiazolinone and methylisothiazolinone (MCI/ MI), and fragrance mix 1. Nickel sulfate sensitization was significantly more common in girls than boys and this difference accounted for the overall difference in sensitivity between girls and boys. Subjects with a positive response to nickel sulfate were significantly older ( years) than those with a negative response ( years) (P <.001). Division of the cohort into three age groups (<3, 3-12, >12 years) revealed that the rate of sensitivity to nickel sulfate decreased from infancy to childhood in girls and then increased in adolescence (Table 2). This difference was statistically significant (P <.001). No such association with age was found in boys, apparently because of their very few positive responses to nickel sulfate. We have no data on piercing in our study population. The positive response rate for cobalt chloride was significantly higher in subjects who had a positive response to nickel sulfate (14%) than in those who did not (4%) (Table 3). There was no significant difference in the rate of positive responses to potassium TABLE 2 and sex Sensitivity incidence to nickel sulfate according to age Sex <3 y 3-12 y y P-value Male n Sensitivity incidence, n (%) Female 0 (0) 0 (0) 2 (2.8) Not significant n Sensitivity 2 (11.8) 4 (6.2) 35 (30.4) <.001 incidence, n (%) Nickel is associated with age group (P <.001). Nickel is associated with sex (P <.001). TABLE 3 Cobalt chloride sensitivity Potassium dichromate sensitivity Double sensitization of nickel-sensitive children No nickel sensitivity (n = 300) Nickel sensitivity (n = 43) P-value 12 (4) 6 (14) (4.3) 5 (11.6).06 ZAFRIR ET AL. dichromate between subjects with a positive (11.6%) or negative (4.3%) response to nickel sulfate (Table 3). There was no significant difference in the mean age of the subjects with a positive or negative response to cobalt chloride or potassium dichromate. Data on personal or familial history of atopy were available for 102 subjects. Sixty-one (59.8%) had a positive history (39 girls [63.9%], 22 boys [36.1%]). The positive patch test rate was similar in subjects with and without a personal or familial history of atopy, overall (50% and 51%, respectively) and according to allergen. In our previous study in Israeli adults, 12 nickel sulfate was the most common allergen, as in Israeli children, but the overall rate of positive findings was higher in the adults (17.4% vs 12.5%; Table 4). After nickel sulfate, the most common allergens were potassium dichromate and fragrance mix in the earlier study and potassium dichromate and cobalt chloride in the present study (Table 4). Men had a higher sensitivity to nickel sulfate than boys (Table 5). Adults had a higher sensitivity to potassium dichromate than children (Table 5). 4 DISCUSSION The realization is growing that children are exposed to a wide range of potential allergens in their environment and that these may play a part in the observed increase in the prevalence of childhood eczema. We reviewed 50 series from 48 studies 5 8,14 57 of children and adolescents referred for standard patch testing because of suspected ACD (total n = ; Table 6). The upper age limit was 18 years in all but three studies, in which the limit was 19 53,54 or 20 years. 55 Sample size ranged from 45 to 6708 subjects. Thirty-nine studies were performed in Europe, six in North America, and five in South America 46,47 or Asia There was some overlap of subjects between some of the series (17 and 22, 18 and 24, 26 and 32, 6 and 48, 16 and 21, 41, 47 and 57). Because we were unable to summarize or statistically evaluate all the published series, we concentrated on the three leading allergens in each (Table 6). Nickel sulfate was by far the main allergen during childhood, the most common allergen in 42 series, and one of the three leading allergens in 47 of the 50 series. It was followed in order by cobalt nitrate, thimerosal, fragrance mix, and potassium dichromate. A meta-analysis by Bonitsis and colleagues 58 published in 2011 found that the rate of positive patch tests in children was higher in studies published after In the present study, a positive patch test was documented in 28.5% of subjects. This rate falls within the reported global range of 14.5% 5 to 95.6%. 6 The most common allergens were nickel sulfate, potassium dichromate, cobalt chloride, MCI/MI, and fragrance mix. Three of these allergens were included in the top five allergens in children reported in the literature. Nickel sulfate accounted for 12.5% of the positive patch tests in our study, more than all the other allergens. In a study of Czech schoolchildren, Machovcova 4 reported a 15.6% rate of nickel allergy. Some authors have noted a particularly high rate (39%) in very

4 ZAFRIR ET AL. 79 TABLE 4 Most-common allergens in Israeli children and adults % (order of prevalence of allergen in each population) Allergen Children Adults a Nickel sulfate 12.5 (1) 17.4 (1) Potassium dichromate 5.2 (2) 10.6 (2) Cobalt chloride 5.2 (3) 7.5 (4) Methylchloroisothiazolinone/methylisothiazolinone 3.8 (4) Fragrance mix 2.6 (5) 8.5 (3) Colophony 1.5 Balsam of Peru (5) 4-tert-butylphenol formaldehyde 1.5 a Adult data derived from our earlier study. 72 TABLE 5 to sex Allergen Nickel sulfate Potassium dichromate Cobalt chloride Allergy to metals in Israeli children and adults according Female Male Adults, Children, Adults, Children, % % P-value % % P-value >.99 young patients (<3 years) 29,41 and speculated that the practice in Europe of using the adult concentration of nickel sulfate in pediatric patch testing may yield a high proportion of false positives. 29 Others suggested that nickel reactivity may be increasing because of the earlier, more extensive exposure of children in contemporary society. 59 Studies have shown that 34.4% of children s toys release nickel, 60 and zippers, snaps, buckles, and other metal components have become common parts of children s clothing. Nickel sensitivity is statistically associated with piercing and increases with an increase in the number of piercings. 61 Children are also starting to wear jewelry at a younger age; one group reported that the prevalence of nickel allergy was 13% in girls with pierced ears compared with 1% in girls without pierced ears. 62 Additionally, more and more children have their own cell phone, which can also be a source of sensitization and ACD. 63 In 1992, to reduce the risk of nickel allergy, the Danish Ministry of the Environment limited the use of nickel in objects that come into direct and prolonged contact with the skin. 64 The European Union has since adopted this legislation. 65 There is no nickel exposure regulation in Israel. Potassium dichromate and cobalt chloride were the second most frequent allergens in our study (5.2% for both). In the literature review, cobalt chloride was the second most frequent allergen in childhood and one of the top three allergens in 20 of 50 series, and potassium dichromate was the fifth most frequent allergen (Table 6). Both these metals are commonplace in the modern industrialized environment. 66 Furthermore, in our cohort, rates of cobalt chloride and potassium dichromate sensitivity were higher in subjects with a nickel sulfate sensitivity than in those without, supporting the long-recognized association between nickel sensitivity and sensitivities to other metals. Already in the 1930s, studies suggested that, given the similar atomic structure of nickel and cobalt, concomitant nickel and cobalt allergy was probably a result of cross-sensitivity rather than dual sensitization, 67,68 although allergies to two distinct metals may also result from two unrelated processes of sensitization after separate or coupled exposures to both antigens. 69 Although cobalt sensitization is often related to identifiable occupational exposures in adults, children may be exposed to cobalt in jewelry, belts, makeup, tattoo ink, braces, school chairs, cleaners, and detergents. 67,69 They may also be exposed to potassium dichromate in detergent or chrometanned leather (shoes). The latter is a high risk in Israel, where it is hot and humid and children tend to wear leather footwear without socks. The higher sensitivity to potassium dichromate in adults (both sexes) than in children in Israel 12 is probably due to the higher exposure of adults to cleaning materials in the workplace. Contact allergy to MCI/MI, a preservative used in cosmetics and hygienie materials, has increased significantly in recent years, with a frequency as high as 11.1% in patients with dermatitis. 70 In our series, 13 subjects (3.8%; 10 girls, 3 boys) tested positive for MCI/MI. Rates of MCI/MI sensitivity in other studies ranged from 2.4% in asymptomatic infants 71 to 11.7% in children referred for patch testing, 40 but it was not among the top five allergens in our literature review (Table 6). MCI/MI is the sixth leading allergen in adults in Israel. 12 Recent regulations by the European Commission have banned MCI/MI in all leave-on body products. 70 There is no MCI/MI exposure regulation in Israel. The prevalence of MI dermatitis may be underestimated because of the lower detection of MI when tested in the combination preservative MCI/MI than when tested alone. An estimated 40% of patients with contact allergy to MI could have been missed in testing with MCI/MI. 72 MI alone at concentrations of 2000 ppm was added to the European baseline series in During the study period, MI was not included in standard patch tests.

5 80 ZAFRIR ET AL. TABLE 6 Literature review of standard patch test in children and adolescents with suspected allergic contact dermatitis Series Author (ref) Year Country Patients, n Age Antigen tested (no. of antigens) Positive patch test, n (%) Top three allergens prevalence in total study population (%) Relevance, % Europe 1 Velen et al. (14) 2 Pevny et al. (15) 3 Romaguera et al. (16) 1982 Denmark 168 <14 y STD + AS () 77 (45.8) Nickel sulfate (19) Potassium dichromate (10) Wood tar (10) 1984 Germany y STD (25) 104 (70.7) Nickel sulfate 5% (20.4) Cobalt nitrate (14.3) p-aminodiphenylamine (12.2) 1985 Spain 1023 <14 y STD + AS () 318 (31) Nickel sulfate (5.5) Thimerosal (1.9) Mercapto mix (1.9) Rudzki et al. (17) 1987 Poland y () 109 (54.5) Nickel sulfate () 5 Balato et al. (5) 1989 Italy mo-14 y PSPT (32) 85 (14.5) Nickel sulfate 5% (3.8) Cobalt nitrate (1.3) Ethylened iamine (1.3) 6 Rademaker and Forsyth (18) 7 Pambor et al. (7) 8 Goncßalo et al. (19) 9 Ayala et al. (20) 10 Sevila et al. (21) 11 Rudzki and Rebandel (22) 12 Katsarou et al. (23) 13 Stables et al. (24) 14 Wantke et al. (25) 1989 UK 125 <12 y STD (36) + AS 60 (48) Nickel sulfate (14.4) Cobalt nitrate (5.6) Potassium dichromate (4.8) 1992 Germany y (11) 81 (22.1) Nickel sulfate 5% (6.1) Cobalt nitrate (3.2) Turpentine (2.7) 1992 Portugal 329 <14 y STD + AS () 170 (51.7) Nickel sulfate 5% (21.6) Thimerosal (11.2) Cobalt nitrate (7.3) 1992 Italy mo-14 y PSPT (28) + AS 114 (35.3) Nickel sulfate 5%, 2.5% (12.4) Neomycin (3.4) Thimerosal (3.1) 1994 Spain y STD + AS () 101 (37.1) Nickel sulfate 1% (12.1) Mercuric chloride (7) Cobalt salts (6.6) 1996 Poland y 267 (42.7) Nickel sulfate (10) Potassium dichromate (5.4) Cobalt nitrate (4.8) 1996 Greece mo-16 y STD + AS () 101 (43.5) Nickel sulfate 5% (16.3) Cobalt nitrate (8.6) Fragrance mix (7.3) 1996 UK y STD + AS () 33 (35.9) Nickel sulfate (10.9) Fragrance mix (6.5) Thimerosal (4.3) Neomycin (4.3) 1996 Austria 72 <7 y STD () 40 (55.6) Thimerosal (31.9) Ethylmercuric chlioride (26.4) Nickel sulfate 5% (22.2) y STD () 75 (46.3) Thimerosal (28.4) Nickel sulfate 5% (20.4) Ethylmercuric chloride (14.3) (Continues)

6 ZAFRIR ET AL. 81 TABLE 6 (Continued) Series Author (ref) Year Country Patients, n Age Antigen tested (no. of antigens) Positive patch test, n (%) Top three allergens prevalence in total study population (%) Relevance, % 16 Brasch and Geier (26) 1997 Germany y STD + AS () 170 (40.9) Nickel sulfate 5% (15.9) Thimerosal (11.3) Benzoyl peroxide (8.9) 17 Shah et al. (27) 1997 UK y STD + AS () 41 (49.4) Nickel sulfate 5% (14.5) Fragrance mix (7.2) Cobalt chloride (3.6) Neomycin (3.6) Manzini et al. (28) 1998 Italy mo-12 y STD (47) + PSPT 282 (42.1) Thimerosal (12.2) Nickel sulfate (7.8) Kathon CG (5.7) 19 Roul et al. (29) 1999 France y STD (34) + AS 226 (67) Nickel sulfate 5% (23.7) Fragrance mix (9.5) Wool wax alcohol (8.6) Most 20 Wohrl et al. (30) 21 Lewis et al. (31) 22 Heine et al. (32) 2003 Austria y STD (34) 49 (62) Nickel sulfate 5% (34.2) Ethylmercury (25.3) Thimerosal (17.7) 2004 UK 191 <16 y STD () 78 (41) Nickel sulfate (13) Fragrance (9) Thiuram (9) Cobalt (8) 2004 Germany y STD + AS () 150 (52.6) Thimerosal (18.2) Benzoyl peroxide (16.5) Phenylmercuric acetate (13.1) y STD + AS () 1081 (49.7) Nickel sulfate 5% (16.7) Thimerosal (14.3) Benzoyl peroxide (8) 24 Fernandez Vozmediano and Armario Hita (33) 2005 Spain 96 <15 y STD + AS () 52 (54.2) Thimerosal (18.8) Mercury (16.7) Nickel sulfate 5% (14.6) Seidenari et al. (34) 2005 Italy mo-12 y PSPT (7 mo-10 y, 30; >10 y, 36) 570 (52.1) Neomycin (13.2) Nickel sulfate 5% (10.9) Wool alcohol (10.1) Thimerosal (10.1) Clayton et al. (35) 27 Beattie et al. (36) 28 Onder and Adisen (37) 29 de Ward-van der Spek and Oranje (38) 30 Milingou et al. (8) 2006 UK y STD + AS () 133 (27) Nickel sulfate 5% (8.8) Fragrance mix (4.8) Cobalt chloride (3) 2006 UK y STD + AS () 58 (52) Nickel sulfate 5% (20) Rubber chemicals (10) Fragrance mix (7.2) 2008 Turkey y STD (24) + AS 118 (33) Nickel sulfate 5% (15.8) Cobalt chloride (3) p-phenylendiamine (3) Neomycin (2.5) 2009 Netherlands y STD (24) + AS 40 (51) Nickel sulfate (21.5) Potassium dichromate (6.3) p-tetra-butylphenol Formaldehyde resin (3.8) Formaldehyde (3.8) 2010 Greece 255 <16 y STD + AS () 153 (60) Nickel sulfate 5% (21.6) Thimerosal (18) Cobalt nitrate (12.9) (Continues)

7 82 ZAFRIR ET AL. TABLE 6 (Continued) Series Author (ref) Year Country Patients, n Age Antigen tested (no. of antigens) Positive patch test, n (%) Top three allergens prevalence in total study population (%) Relevance, % 31 Moustafa et al. (39) 32 Toledo et al. (40) 33 Belloni Fortina et al. (41) 34 Darling et al. (42) 35 Schena et al. (43) 36 Vongyer and Green (44) 2011 UK y PSPT (30) 48 (43.6) Nickel sulfate 5% (7.3) Amerchol (6.4) Neomycin (6.4) 2011 Spain y STD () 52 (46.8) Nickel sulfate (14.4) MCI/MI (11.7) Fragrance mix (9.9) 2011 Italy mo-3 y PSPT (30) 200 (62.3) Nickel sulfate 5% (26.8) Potassium dichromate (9) Cocamidopropyl betaine (7.2) 2012 UK y STD () 29 (70.7) Mercaptobenzothiazole (12.2) Mercapto mix (9.8) Potassium dichromate (9.8) 2012 Italy 349 <15 y STD () 242 (69.3) Nickel sulfate (16.3) Cobalt nitrate (6.9) Kathon CG (5.4) 2015 UK y STD (21) + AS 50 (36.5) Nickel sulfate 5% (7.2) Potassium dichromate (7.2) Wool alcohols (6.5) Belloni Fortina et al. (45) European countries y STD () + AS 2476 (36.9) Nickel sulfate (16.9) Cobalt chloride (7.9) Potassium dichromate (6.9) 38 Smith et al. (46) 39 Belloni Fortina et al. (47) North America 40 Jacob et al. (48) 41 Hogeling and Pratt (49) 2016 UK 500 <17 y STD (23) + AS 134 (27) Nickel sulfate 5% (4.8) Fragrance mix (4.6) p-phenylendiamine (4.2) 2016 Italy 2614 <11 y PSPT (30) 1220 (46.7) Nickel sulfate 5% (22.7) Cobalt chloride (11.1) Potassium dichromate (9.9) 2008 USA y STD + AS () 54 (83.1) Nickel sulfate 5% (21.5) Thimerosal (15.4) Balsam of Peru (13.8) Cocamidopropyl betaine (13.8) Neomycin (13.8) 2008 Canada y STD + AS () 75 (75) Nickel sulfate (26) Cobalt Chloride (14) Fragrance mix (7) Neomycin (7) Zug et al. (50) 2008 USA + Canada 391 <18 y STD (65) + AS 257 (65.7) Nickel sulfate 2.5% (28.3) Cobalt chloride (17.9) Thimerosal (15.3) Hammonds et al. (51) 2009 USA y STD + AS (25-185) 83 (61) Nickel sulfate (22.2) Cobalt Chloride (16.9) Gold (11.8) Jacob et al. (6) 2010 USA mo-16 y () 43 (95.6) Nickel sulfate 2.5% (23.3) Cocamidopropyl betaine (23.3) Balsam of Peru (18.6) Zug et al. (52) 2015 USA + Canada 883 <18 y STD (65 or 70) + AS 550 (62.3) Nickel sulfate (28.1) Cobalt chloride (12.3) Neomycin (7.1) 56.7 (Continues)

8 ZAFRIR ET AL. 83 TABLE 6 (Continued) Series Author (ref) Year Country Patients, n Age Antigen tested (no. of antigens) Positive patch test, n (%) Top three allergens prevalence in total study population (%) Relevance, % South America 46 Duarte et al. (53) 2003 Brazil y () 64 (56) Nickel sulfate (31) Tosylamide-formaldehyde resin (12) 47 Rodrigues and Goulart (54) 2015 Brazil y STD (20-40) + AS 74 (59.2) Nickel sulfate 5% (36.8) Thimerosal (18.4) Neomycin (6.4) 77 Asia 48 Goon and Goh (55) 49 Sarma and Ghosh (56) 50 Mortazavi et al. (57) 2006 Singapore y STD (35) + AS 1063 (45.4) Nickel sulfate (40) Thimerosal (15) Colophony (9) 2010 India y STD (27) 56 (80) Paraben (43) Potassium dichromate (27) Fragrance mix (26) 2016 Iran 109 <18 y STD (24) 51 (46.8) Nickel sulfate 5% (19.3) Cobalt chloride (10.1) Methylisothiazolinone (6.4) STD, standard patch test; AS, additional series;, not defined; PSPT, pediatric standard patch test; mo, months, y, years. Thimerosal was the third top allergen in the literature review (Table 6). Thimerosal is used as a preservative in vaccines and has not been approved for use in Israel. Fragrance mix 1 induced a positive response in 2.6% of our cohort considerably lower than the 21.8% reported in the literature, 31 making it the fourth most common allergen overall. Adults in Israel were found to have a high rate of allergy to fragrance mix and balsam of Peru. 12 The increasing prevalence of fragrance mix 1 allergy in children may be attributable to its increasing use in cosmetic materials and the increasing use of cosmetics earlier in life. Even the youngest children may be prone to contact allergy and react to cosmetics or fragrances used for their own skin care or transmitted by adults who are in close contact with them (proxy dermatitis). Follow-up studies are needed to determine the persistence of sensitization throughout life and its effect on quality of life. 73 Our analysis of positive patch tests according to age in the pediatric literature yielded varied findings, with reports of a generally increasing prevalence through adolescence, 21,22,25,35 an early peak in prevalence in children younger than 3 years, 23,28,29,34 or no change with age. 32 In the present study there was no statistically significant difference in mean age between subjects with positive and negative patch tests, although we found a significantly higher prevalence of sensitivity in girls than in boys (Table 1). Some previous pediatric studies reported a similar sex bias, 8,26,33,37 whereas others did not. 18 Although it has been suggested that women are sensitized at a lower exposure than men, 74 nickel was the only allergen that had a significantly higher rate of positivity in girls than boys, and it was apparently the reason for the overall difference between the sexes. Nickel accounted for 95.3% of the positive findings in the girls, similar to other studies. 35,36 We speculate that this may be attributable to the younger age at which girls pierce their ears 75 than boys, who tend not to start piercing until their late teens. 55 In the European Union, after limitations were placed on the use of nickel, the male to female prevalence of nickel allergy equalized. 76 We found a higher prevalence of sensitivity to nickel in very young girls (Table 2). Others noted a high prevalence in children younger than 3 years of age. 41 Recently, researchers evaluated fasteners from children s clothing snaps on onesies, pajamas, and bodysuits as possible sources of releasable nickel ions. 77 The early exposure to nickel is sufficient to result in cutaneous sensitization reactions. The early exposure to nickel in girls may also explain the lack of a significant difference in the prevalence of nickel sensitivity between women and girls. 12 In Israeli men and boys, the significantly higher rate in adults than in children 12 is probably due to the high rate of occupational exposure of adults. The relationship between ACD and atopic dermatitis is complex and controversial. Some authors claim that atopy may be a predisposing factor for the development of ACD. 78,79 Atopic skin is more susceptible to allergens because its barrier function is disturbed and patients with atopy tend to use a wide variety of topical ointments and creams that contain allergens 28 ; patients with atopic dermatitis were significantly more likely to be allergic to fragrances, including balsam of Peru, than patients with nonatopic dermatitis. 80 Paradoxically, several clinical and experimental studies have reported a lower risk of ACD in individuals with atopic dermatitis. 37,81 83 We did not find a higher incidence of positive patch tests in subjects with an atopic background, in agreement with Milingou and colleagues. 8 The present study has several limitations. First, the number of patients was small, limiting the statistical analysis. Second, owing to the retrospective design, data on personal or family

9 84 atopic background, history of ear piercing, and dermatitis distribution and flare during patch testing were partially or completely lacking. Third, a standard screen with the same 23 allergens was used for every child, regardless of history, and without testing personal products. In the future, we will use the new European baseline series with 30 allergens, including methyldibromo glutaronitrile, fragrance mix 2, hydroxymethylpentylcyclohexenecarboxaldehyde, MI, textile dye mix, budesonide, and tixocortol-21- pivalate. Assessing the relevance of a positive patch test reaction is complex and involves many confounding factors, particularly in children, because it is difficult to know what materials they come into contact with during daily activities. Although we did not determine the relevance of the positive reactions, Jacob and colleagues, 48 in a study of pediatric allergic dermatitis, noted that 77% of patch test reactions in the children were clinically relevant. 5 CONCLUSION ACD is highly prevalent in children referred for suspected contact dermatitis in Israel. The allergen with the highest reactivity in the standard patch test series is nickel sulfate. Girls have a higher sensitivity to nickel sulfate than boys. Patch testing should be performed in all children and adolescents with a chronic inflammatory process of unknown etiology that does not respond well to standard therapy, regardless of atopic background. ORCID Dan Ben Amitai REFERENCES 1. Cronin E. Contact Dermatitis. London: Churchill Livingstone; Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children, and adolescents. s. 1986;78: Barros MA, Baptista A, Correia TM, et al. 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11 Herro EM, Matiz C, Sullivan K, et al. Frequency of contact allergens in pediatric patients with atopic dermatitis. J Clin Aesthet Dermatol. 2011;4: Uehara M, Sawai T. A longitudinal study of contact sensitivity in patients with atopic dermatitis. Arch Dermatol. 1989;125: Jones HE, Lewis CW, McMarlin SL. Allergic contact sensitivity in atopic dermatitis. Arch Dermatol. 1973;107: de Groot AC. The frequency of contact allergy in atopic patients with dermatitis. Contact Dermatitis. 1990;22: ZAFRIR ET AL. How to cite this article: Zafrir Y, Trattner A, Hodak E, Eldar O, Lapidoth M, Ben Amitai D. Patch testing in Israeli children with suspected allergic contact dermatitis: A retrospective study and literature review. Pediatr Dermatol. 2018;35: