Systematic Identification of Copositivity Groups in Standard Series Patch Testing Through Hierarchical Clustering

TAKE-HOME MESSAGE

• This retrospective cross-sectional analysis of patch test results from the 80-allergen Mayo Clinic Standard Series employed hierarchical clustering to identify copositivity groups, or allergens that are frequently positive together. The results not only showed copositivity groups that were well-known from prior research but also demonstrated novel associations, such as between benzalkonium chloride (an antiseptic) and topical antibiotics, specifically neomycin and bacitracin.
• This research adds to our knowledge of allergen relationships and contributes to optimizing the clinical application of patch testing results by guiding contact avoidance recommendations.

–  Ruth McTighe, MD

Written by

 

 

Yul W. Yang MD, PhD

In allergic contact dermatitis, patients are patch-tested to identify potential allergens to avoid. Yet, many patients react simultaneously to multiple related allergens during patch testing. Thus, when counseling patients, it is vital to avoid both patch-positive allergens and related allergens (called co-positivity groups). For example, patients allergic to nickel usually need to avoid cobalt (also found in costume jewellery).

The avoidance of co-positivity groups is a central foundation in patient-directed avoidance algorithms, including the American Contact Dermatitis Society's Contact Allergen Management Program (CAMP) and SkinSAFE. Both databases are designed to educate patients to avoid co-positivity groups based on any positive patch tests. However, both CAMP and SkinSAFE's co-positivity groups have been determined based on clinical experience, suspected chemical similarity, and/or review of small groups of allergen co-positivity rates, rather than systematic review.

In a Mayo Clinic study, we reviewed 10 years of patch tests, encompassing 5943 patients, 394,921 patch tests, distributed among 80 Standard Series allergens. After correcting for background positivity rates, we then systematically identified co-positivity groups in a blinded manner using hierarchical clustering. In addition to identifying 11 established co-positivity groups, we uncovered 4 new allergen associations to consider when counseling patients:

• Glutaraldehyde – sorbitan sesquioleate, resulting from contamination in the patch-test reagent itself. Dermatologists should avoid glutaraldehyde sources that contain sorbitan sesquioleate, as this may confound results.
• Bronopol – MCI/MI
• Benzoic acid – iodopropynyl butylcarbamate
• Benzalkonium chloride – neomycin/bacitracin. Many standard patch-test series only evaluate neomycin/bacitracin, but not benzalkonium chloride. We have found that benzalkonium chloride is the 10th most common allergen at Mayo Clinic,1 and is found ubiquitously, particularly in first-aid products. Patients allergic to neomycin/bacitracin, who have persistent rashes even with avoidance, should consider avoiding benzalkonium chloride also.

We hope that future research uses similar systematic approaches to define co-positivity groups and incorporate these results in patient-directed databases, such as CAMP and SkinSAFE.

Reference

1. Zawawi S, Yang YW, Cantwell HM, et al. Trends in Patch Testing With the Mayo Clinic Standard Series, 2017–2021. Dermatitis. 2023 May 6. doi:10.1089/derm.2023.0063. Online ahead of print. 

Abstract

IMPORTANCE

Patients are frequently copositive for multiple allergens simultaneously, either due to chemical similarity or simultaneous sensitization. A better understanding of copositivity groups would help guide contact avoidance.

OBJECTIVE

To use patient data to systematically determine copositivity groups in the Mayo Clinic Standard Series.

DESIGN, SETTING, AND PARTICIPANTS

In this retrospective cross-sectional analysis, the Mayo Clinic patch test database was queried for pairwise copositivity rates in the 80 allergen Mayo Clinic Standard Series between 2012 and 2021. Data were collected from 3 tertiary care sites of the Mayo Clinic Contact Dermatitis Group and a total of 5943 patients were included, comprising all patients undergoing patch testing to the Mayo Clinic Standard Series allergens.

MAIN OUTCOMES AND MEASURES

Copositivity rates between every 2 allergens in the 80-allergen Mayo Clinic Standard Series were estimated. After background correction, copositivity rates were analyzed using unsupervised hierarchical clustering to systematically identify copositivity groups in an unbiased manner.

RESULTS

Overall, 394 921 total patches were applied to 5943 patients (4164 [70.1%] women, 1776 [29.9%] men, with a mean [SD] age of 52.3 [18.8] years ), comprising 9545 positive reactions. After background correction based on overall positivity rates, hierarchical clustering revealed distinct copositivity groups. Many were supported by prior literature, including formaldehyde releasers, cobalt-nickel-potassium dichromate, acrylates, 3-dimethylaminopropylamine-amidoamine-oleamidopropyl dimethylamine, alkyl glucosides, budesonide-hydrocortisone-17-butyrate, certain fragrances, compositae-sesquiterpene lactone mix, mercapto mix-mercaptobenzothiazole, carba mix-thiuram mix, and disperse orange-p-phenylenediamine. However, novel associations were also found, including glutaraldehyde-sorbitan sesquioleate, benzalkonium chloride-neomycin-bacitracin, bronopol-methylchloroisothiazolinone-methylisothiazolinone, and benzoic acid-iodopropynyl butylcarbamate.

CONCLUSIONS AND RELEVANCE

This retrospective cross-sectional analysis found that copositivity rates varied between allergens; allergens with extremely high positivity rates demonstrated nonspecific copositivity to multiple other allergens. Background correction based on positivity rates followed by hierarchical clustering confirmed prior known copositivity groups, contaminants and/or excipients leading to copositivity, and novel associations to guide contact avoidance.

JAMA Dermatology

Systematic Identification of Copositivity Groups in Standard Series Patch Testing Through Hierarchical Clustering

JAMA Dermatol 2023 Aug 02;[EPub Ahead of Print], YW Yang, JA Yiannias, MM Voss, MR Hall, MJ Youssef, MDP Davis, DH Voelker, MC Klanderman, AR Mangold 

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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