Importance of Supplemental Patch Testing Beyond a Screening Series for Patients With Dermatitis: The North American Contact Dermatitis Group Experience

Key Points

Question  Do some patients with dermatitis have clinically relevant patch test reactions to supplemental allergens/materials not detected by a screening series of 65 to 70 allergens?

Findings  In this cross-sectional study including 43 417 patients with dermatitis, 22% had a currently relevant reaction to 1 or more supplemental allergens or substances. Of these patients, 26% had no currently relevant reactions to 65 to 70 screening allergens.

Meaning  These findings suggest that comprehensive patch testing with more than 70 allergens, including supplemental series and personal and work materials, is necessary for proper identification of allergens and successful management of allergic contact dermatitis.

Importance  Patch test screening series for patients with dermatitis are limited and may miss clinically relevant contact allergens.

Objective  To characterize individuals with dermatitis who showed clinically relevant patch test findings to supplemental (nonscreening) allergens or substances.

Design, Setting, and Participants  A 17-year, retrospective cross-sectional analysis (January 1, 2001, to December 31, 2018) of North American Contact Dermatitis Group (NACDG) data from multiple centers in North America was conducted. A total of 43 417 patients with dermatitis underwent patch testing to the NACDG screening series in a standardized manner with 65 to 70 allergens and supplemental allergens as clinically indicated. Patients with 1 or more clinically relevant reactions to a supplemental (nonscreening) allergen/substance were analyzed between November 18, 2020, and March 12, 2021.

Main Outcomes and Measures  The main outcomes were to assess the number of patients with clinically relevant reactions to supplemental (nonscreening) allergens and compare characteristics (including demographic characteristics and occupations) between patients with a clinically relevant patch test reaction to 1 or more supplemental allergens or substances (supplement-positive) and those without a reaction (supplement-negative) using odds ratios (ORs) and 95% CIs. Secondary outcomes included sources of allergic contact dermatitis and, for occupationally related cases, specific occupations and industries.

Results  Of 43 417 patients included in the study who underwent patch testing to the NACDG screening series (65-70 allergens), 9507 individuals (21.9%) had currently relevant reactions to 1 or more supplemental allergens or substances. Of these, 6608 were women (69.5%) and the mean (SD) age was 47.2 (0.54) years. Compared with patients who had supplement-negative results, patients with supplement-positive findings were significantly less likely to be male (OR, 0.90; 95% CI, 0.85-0.94; P < .001) and/or have atopic dermatitis (OR, 0.89; 95% CI, 0.84-0.93; P < .001). Common primary sites of dermatitis in 9499 patients with supplement-positive findings included the face (2856 [30.1%]), hands (2029 [21.4%]), and scattered/generalized distribution (1645 [17.3%]). Frequent sources of supplemental allergens in 9235 patients included personal care products (4746 [51.4%]) and clothing/wearing apparel (1674 [18.1%]). Of 9362 patients with available data, supplemental allergens/substances were occupationally related in 1580 (16.9%); of those with identified occupations, 25.1% (384 of 1529) were precision production, craft, or repair workers. Of 9507 patients with supplement-positive findings, 2447 (25.7%) had no currently relevant reactions to NACDG screening allergens.

Conclusions and Relevance  This cross-sectional study found that 21.9% of patients who underwent patch testing to an allergen screening series of 65 to 70 allergens had at least 1 relevant reaction to supplemental allergens/substances. Of these, one-quarter reacted only to a supplemental allergen/substance. Screening series include common, important allergens, but these findings suggest that the addition of specialty allergens and personal or work products is critical for the successful diagnosis and management of allergic contact dermatitis.

Epicutaneous patch testing is an important tool for investigating allergic contact dermatitis (ACD).¹ Screening series generally include common sensitizers and are not meant to be comprehensive. Additional specialty allergens (eg, cosmetics, textiles, dental, and adhesives) are typically applied at the same time as the screening series based on patient history, physical examination, and/or environmental/occupational exposure. In addition, personal products and work materials may be tested.

Most countries or regions have a recommended screening series (also referred to as baseline, standard, or core series). For example, the Korean Standard Screening Series contains 25 allergens² and the American Contact Dermatitis Society Core Allergen Series contains 90 allergens.³ In general, identification of allergens by a screening series is related to the number of allergens in that series. Patel and Belsito⁴ found that only 28.5% of patients with clinically relevant reactions had all reactions identified with a 28-allergen screening series, compared with 45.1% of patients with a 65-allergen screening series. Watts and colleagues⁵ found that adding 4 allergens to the British Standard Series (41 allergens) detected an additional 15.6% of contact allergy.

As summarized in Table 1, previous studies reported that screening series of 30 or fewer allergens identify all allergens in approximately 23% to 55% of patients tested; in other words, 45% to 77% of patients would have had at least 1 allergen missed if testing was limited to a screening series of 30 allergens or less.^4,6-10 Although larger screening series (>30 allergens) identify all allergens in more patients, 13% to 72% of patients would still have at least 1 allergen missed.^4,5,11-14 Most studies report only percentages of positive allergens (regardless of clinical relevance); proportions of clinically relevant allergens would be lower. Because relevance is assessed at the time of the final reading, most studies are also limited by lack of long-term follow-up.

Although proportions of patients with clinically relevant reactions to supplemental allergens/substances are reported periodically by the North American Contact Dermatitis Group (NACDG) and others,^4,15-23 detailed data are lacking. Herein, we describe specific factors of this population as well as sources of supplemental allergens and their association with occupation.

Between January 1, 2001, and December 31, 2018, the NACDG screening series consisted of 65 to 70 allergens, changing slightly in composition every 2 years (Chemotechnique Diagnostics AB and allergEAZE SmartPractice).^15-23 Additional supplemental patch tests were chosen based on clinical and occupational history. Supplemental allergens could include commercially available specialty series (>500 different commercial allergens are available from Chemotechnique Diagnostics AB or allergEAZE SmartPractice, which can be purchased in sets and series or as individual allergens) as well as personal and work substances (eg, personal care products [PCPs], hobby and work materials, glues, gloves, and shoes).

This cross-sectional analysis of deidentified data was approved by the Minneapolis Veterans Affairs Medical Center Subcommittee on Human Studies, waiving patient informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Patient data included demographic characteristics (age, sex, occupation), history of atopy (asthma, hay fever, atopic dermatitis), and anatomic sites of dermatitis (≤3 sites). Methods of patch testing, grading of reactions, and recording of data were performed according to the NACDG protocol.^18,22 Briefly, readings were performed at 48 hours and 72 to 168 hours after application. In addition to grading reactions to allergens on the NACDG screening series, the presence of at least 1 currently relevant supplemental allergen/substance was recorded (yes or no, with name of allergens not recorded); the source of that supplemental allergen/substance and its association with occupation were also recorded. Occupation was coded by a classification expert based on a standardized questionnaire using the 1990 US Department of Commerce Census Industrial & Occupational Classification Codes.²⁴

Only 1 supplemental allergen source was coded; if testing results for multiple allergens were positive, the most clinically relevant source was chosen. Supplemental allergens were recorded only if the screening series would have missed that clinically relevant allergen. For example, a reaction to isobornyl acrylate on the supplemental acrylate series in a patient with ACD resulting from use of a continuous glucose sensor would be recorded as a currently relevant supplemental allergen because it does not cross-react with acrylates on the screening series. Similarly, data from a patient with eyelid dermatitis, a positive patch test reaction to pimecrolimus (by testing the patient’s pimecrolimus, 1%, cream as is and negative patch test reactions to the inactive ingredients) would be recorded as a currently relevant supplemental substance because pimecrolimus is not an allergen included in the screening series. In contrast, a clinically relevant reaction to eugenol would not be recorded as a supplemental allergen if the patient had reacted to fragrance mix I, which contains eugenol and is present in the screening series. Reactions to supplemental allergens/substances with past or unknown clinical relevance were not recorded.

All patients tested in the NACDG screening series were included in this analysis. Study groups were defined as supplement-positive (patients with a clinically relevant patch test reaction to ≥1 supplemental allergen/substance) or supplement-negative (patients with no currently relevant reactions to supplemental allergens/substances).

All data were manually entered at a centralized location using Access 2010 software (Microsoft Corp) and Microsoft Excel 2019 (Microsoft Corp). Data analysis was conducted between November 18, 2020, and March 12, 2021. Demographic data are presented according to MOAHLFA guidelines (male sex, occupation, atopic, hand, leg, foot, and age >40 years).²⁵ Occupational relevance and the source of exposure are presented using descriptive analyses. Demographic characteristics were compared between patients with positive and negative screening results using GraphPad Prism software, version 8.2.1 (GraphPad Software) with a 2-sided χ² test, and P values <.05 were considered statistically significant.

Of 43 417 patients patch tested according to the NACDG screening series, 9507 individuals (21.9%) had 1 or more currently relevant reactions to a supplemental allergen/substance; of these, 2447 individuals (25.7%) with supplement-positive findings had no currently relevant reactions to allergens used in the NACDG screening series. A mean of 27.8% of supplement-positive patients (n = 1128) had no currently relevant reactions to a 65-allergen series (2001-2008) compared with 24.5% (n = 1319) to a 70-allergen series (2009-2018).

Of 30 313 patients with positive reactions to 1 or more screening and/or supplemental allergen, 20 806 individuals (68.6%) had positive reactions to only NACDG screening series allergens, 2447 patients (8.1%) had reactions that were positive to only a supplemental allergen/substance, and 7060 patients (23.3%) had positive reactions to both.

Of the 9507 patients with supplement-positive reactions, 6608 (69.5%) were women and 2899 (30.5%) were men; mean (SD) age was 47.2 (0.54) years. Patients with positive vs negative reactions were significantly less likely to be male (OR, 0.90; 95% CI, 0.85-0.94; P < .001), older than 40 years (OR, 0.95; 95% CI, 0.90-0.99; P = .03), and/or to have a history of atopic dermatitis (OR, 0.89; 95% CI, 0.84-0.93; P < .001). Patients with positive vs negative reactions were significantly less likely to be male (2899 [30.5%] vs 11 142 [32.9%]; P < .001), older than 40 years (6279 [66.1%] vs 22 794 [67.3%]; P = .03), and/or have a history of atopic dermatitis (2162 [22.9%] vs 8477 [25.1%]; P < .001), although absolute differences were small (Table 2).

In 9499 patients with supplement-positive results, the most common primary anatomic site of dermatitis was the face (2856 [30.1%]), followed by the hands (2029 [21.4%]), and scattered/generalized distribution (1645 [17.3%]) (Table 3). Compared with patients who had supplement-negative findings, those with supplement-positive results were significantly more likely to have facial dermatitis (2856 [30.1%] vs 9559 [28.2%]; P < .001) but significantly less likely to have hand dermatitis (2029 [21.4%] vs 7815 [23.1%], P < .001), although absolute differences were small (Table 2).

Sources of supplemental allergens/substances are presented in Table 4. Of all sources (n = 9235), most were PCPs (4746 [51.4%]). The most common subcategories were cosmetics (1542 [32.5%]), not otherwise specified PCPs (1375 [29.0%]), hair care products (743 [15.7%]), health aids (238 [5.0%]), and sunscreens (235 [5.0%]). The second most frequent category was clothing, wearing apparel, and protective equipment (1674 [18.1%]); common subcategories included clothing (966 [57.7%]) and jewelry (532 [31.8%]).

Compared with patients who had supplement-negative reactions, those with supplement-positive reactions had 1.87 times greater odds of having an occupationally related skin condition (1638 [17.3%] vs 3395 [10.0%]; odds ratio, 1.87; 95% CI, 1.76-1.99; P < .001) (Table 2). In the supplement-positive group, of 9362 patients with available data, supplemental allergens/substances were occupationally related in 1580 (16.9%). Top occupations in this subgroup included precision production/craft/repair occupations (especially mechanics/repairs), operators/fabricators/laborers (especially machine operators/assemblers/inspectors), and service occupations (especially hairdressers/cosmetologists) (Table 5). The most common sources of occupationally related supplemental allergens/substances in 1533 patients were chemicals and chemical products (622 [40.6%]), especially adhesives, glues, and bonding agents (240 of 349 with allergies to coatings, adhesives, dyes, inks, and photographic and copying chemicals [68.8%]), followed by PCPs (402 [26.2%]) (Table 4).

Among patients referred for patch testing, 21.9% had at least 1 relevant reaction to a supplemental allergen/substance; one-quarter of that subgroup did not have any relevant reactions to allergens in the NACDG screening series. More than half of supplemental allergen sources were PCPs, especially cosmetics. Supplement-positive reactions were related to occupation in 16.9% of the patients, especially precision production, craft, and repair workers, and operators, fabricators, and laborers. If only the NACDG screening series were tested; 31.4% of patients with positive reactions to screening and/or supplemental allergens would have had 1 or more clinically relevant allergens missed.

The majority (69.5%) of supplement-positive patients were women. This percentage is consistent with a 2013 study on PCPs that found the percentage of female users was higher compared with male users for all PCP categories (overall P < .05), with the exception of shaving products.²⁶ In addition, PCP-related contact allergy most commonly affects the face and hands,²⁷ which were the most frequently involved sites of dermatitis in our cohort. Comparison of our study demographics with others is limited because these involved selected populations (Table 1) in contrast to all patients presenting for patch testing (routine testing).

Our study found that 21.9% of all patients referred for patch testing and 31.4% of patients with positive reactions had relevant allergic patch test reactions to at least 1 supplemental allergen/substance, and 8.1% of supplement-positive patients had reactions only to supplemental allergens/substances. Smaller studies reported similar findings for the NACDG screening series of 9.2% (among 590 patients with a positive reaction to a patch-tested allergen or supplemental allergen; relevance not reported)¹³ and 14.7% (of 1206 patients; clinically relevant only).⁴ Studies evaluating other screening series, such as the Australian Baseline¹² and an Extended British Standard⁵ series, found approximately 13% of patients would have had missed allergens if supplemental series were not tested. In addition, smaller screening series, such as T.R.U.E. (Thin-Layer Rapid-Use Epicutaneous Test) panels, miss 1 or more clinically relevant positive reactions in 72% of patients identified by supplemental testing.^4,9

Previous studies reported that 26% to 50% of allergens responsible for occupational contact dermatitis are missed by a screening series alone.^9,28 Screening series are meant for screening a general population. Because workplace exposures and culprit allergens vary widely among occupational groups, patch testing with supplemental allergen series (eg, metalworking fluids, hairdresser series) or workplace materials is indicated. Accordingly, it was not surprising that patients with clinically relevant supplemental allergens were significantly more likely to have occupationally related skin disease.

There were 1580 patients with supplemental allergens deemed occupationally relevant; the most common were precision production, craft, and repair personnel (25.1%, especially mechanics and repairers [n = 91]), followed by operators, fabricators, and laborers (24.0%, especially machine operators, assemblers, and inspectors [n = 228]). These results might be expected since mechanics and machine operators are at high risk of developing occupational contact dermatitis given the variety of irritant and allergenic substances encountered (eg, adhesives, rubber chemicals, metals, and preservatives).^29,30 Many of these materials contain undisclosed ingredients. An Australian occupational clinic reported that 20% of their patients (especially machine operators) had reactions only to their work products.³¹ Schubert et al³² evaluated 652 patients with suspected occupational dermatitis and found that mechanics showed the greatest diversity of occupationally relevant sensitizers (including metalworking fluids, epoxy, rubber components, leave-on products, and miscellaneous lubricants); of 143 clinically relevant reactions to workplace materials, 23 were not accompanied by corresponding reactions to commercial patch test preparations.

Of 1533 occupationally related supplemental allergen sources identified in our study, 40.6% were attributed to chemicals and chemical products, most commonly adhesives, glues, and bonding agents. The NACDG screening series has included the following adhesive allergens: colophony, epoxy resin, p-tert butylphenol formaldehyde resin, methyl methacrylate, ethyl acrylate, 2-hydroethylmethacrylate and/or ethyl cyanoacrylate (some allergens were tested only in certain cycles). Additional important allergens in this group include bis(2-dimethylaminoethyl) ether, 2-hydroxymethyl methacrylate, 2-hydroxyethyl acrylate, and ethylene glycol dimethacrylate.³³

Sources of supplemental allergens were commonly PCPs, especially cosmetics (n = 1542) and hair care products (n = 743). The value of testing patients with suspected cosmetic allergy to a supplemental cosmetic series is well described.^34-36 A study of 945 US patients with suspected cosmetic allergy found that the T.R.U.E. Test would have missed 1 or more allergens in 22.5% of patients with preservative allergy, 11.3% with fragrance allergy, and 17.3% with excipient allergy.³⁴ Similarly, Ada and Seçkin³⁵ reported that 30% of 93 patients would have had 1 or more cosmetic series allergens missed if only the European Standard Series was used.

Although commercially available patch test materials (standard and supplementary series) provide the foundation of patch testing, many experts emphasize the necessity of testing PCPs.^36-38 A European analysis of 5911 patients with cosmetic allergy found that one-third reacted only to 1 or more PCPs and no other allergen.³⁶ Our study underscores the importance of testing with personal and workplace materials.

Approximately one-fifth (18.1%) of patients with supplement-positive findings had reactions to allergens in clothing/wearing apparel. Allergic contact dermatitis due to clothing and/or shoe wear can result from exposure to a variety of agents, including textile dyes, fabric finishes, biocides, metals, rubber additives, glues, or tanning agents.^39,40 In patients with suspected ACD caused by clothing, patch testing with a specialized textile series is often necessary.^41,42 An Italian study of 100 patients sensitized to textile dyes found that 24% of patients would have been missed by a screening series that included 4 disperse dyes (disperse blue 124, disperse red 1, disperse orange 3, and disperse yellow 3); testing with an additional 12 textile dyes helped to identify 23% of the cases.⁴³ There are numerous commercial patch test textile dye series available, although testing a patient’s personal garments may also be of use, especially when particular dyes are undeclared or proprietary. Specific allergens reported in footwear dermatitis are variable depending on fashion styles, manufacturing processes, climate, and geographic conditions.⁴⁴ A previous analysis of NACDG data revealed that 29.8% of patients with shoe contact allergy had positive patch test reactions to supplemental allergens and the screening series did not identify the specific shoe allergen in 12.2% of the cases.⁴⁵ Similar to clothing, patch testing for suspected shoe allergy often involves patch testing with samples of patients’ own footwear. To avoid false-negative results, it is important to use large pieces of shoes and clothing, moisten with water, and reapply if the result is negative at 48 hours.^46,47 Extracts of solid objects may also be tested.⁴⁸

There are several limitations to this study. First, the source of only 1 supplemental allergen/substance was recorded per patient; if multiple findings were positive, only the most clinically relevant source was coded. Second, specific names of supplemental allergens are not collected in the NACDG database. Third, our data do not specify whether supplemental allergens were obtained from commercial sources or personal or work products. There is also variability in the methods for patch testing PCPs (eg, dilution, vehicle, and occlusion vs semiocclusion), which may influence detection. Fourth, although most (>90%) patients were tested for allergic reactions to supplemental series/substances, in some cases, only the NACDG screening series was tested or patients chose not to bring personal items for testing; this information was not recorded; thus, our numbers represent underestimates. Fifth, the study sample was drawn from patients who were referred for patch testing; as such, they are representative of neither the general population nor the general dermatology population.

Our study found that 21.9% of patients with suspected ACD undergoing patch testing had a relevant reaction to at least 1 supplemental allergen/substance; of these, one-quarter had no currently relevant reactions to the NACDG screening series. These findings highlight the limitations of testing in a screening series alone. Based on exposure and occupational history, comprehensive patch testing includes testing not only supplemental allergens but also PCPs and workplace materials. These results suggest that comprehensive patch testing would be useful for the diagnosis and management of contact allergy.

Accepted for Publication: August 23, 2021.

Published Online: November 3, 2021. doi:10.1001/jamadermatol.2021.4314

Corresponding Author: Michele Buonomo, BA, Department of Dermatology, Park Nicollet Health Services, 7550 34th Ave S, Ste #101, Minneapolis, MN 55450 (buono004@umn.edu).

Author Contributions: Dr Warshaw had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Warshaw, Buonomo, Maibach, Houle, Dunnick.

Acquisition, analysis, or interpretation of data: Warshaw, Buonomo, DeKoven, Pratt, Reeder, Silverberg, Belsito, Maibach, Atwater, Houle, Taylor, Zug, DeLeo.

Drafting of the manuscript: Warshaw, Buonomo.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Warshaw.

Administrative, technical, or material support: Warshaw, Buonomo, Pratt, Atwater.

Supervision: Warshaw, Silverberg, Maibach, Houle.

Conflict of Interest Disclosures: Dr Warshaw reported receiving an investigator-initiated grant from and serving as a paid consultant for Wen by Chaz Dean. She also reported serving as a paid consultant for Noven Pharmaceuticals. Dr Atwater reported receiving a Pfizer Independent Grants for Learning & Change and serving as a paid consultant for Henkel. Dr Taylor reported owning noncontrolling shares of stock in AstraZeneca, Cigna, Merck, Johnson & Johnson, and Opko Health. He also reported serving as a paid consultant for Kao Brands and Monsanto (Bayer), being a nonpaid member of the Cosmetic Ingredient Review Steering Committee, and having a nondependent child employed by Pfizer. No other disclosures were reported.

Funding/Support: This study was supported by resources and use of facilities at the Minneapolis Veterans Affairs Medical Center.

Role of the Funder/Sponsor: The Minneapolis Veterans Affairs Medical Center had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The contents of this article do not represent the views of the US Department of Veterans Affairs or the US government.