Review of the 2021 ACDS Allergen of the Year: Acetophenone Azine

Allergic contact dermatitis (ACD) is a highly prevalent global disease estimated to affect more than 85 million Americans and roughly 20% of the general European population.^1,2 Constituting 4% to 7% of all dermatologic consultations, ACD has been placed among the top five most prevalent skin diseases in the United States.^1,3 As the incidence continues to rise with changes in the exposure to allergens, its economic burden is expected to follow suit.⁴ In 2013, contact dermatitis alone accounted for $1.5 billion in medical treatment costs and an estimated $699 million in loss of productivity costs. The combination of high clinical costs, weighty productivity loss, a high prevalence, and significant physical and emotional patient morbidity that accompanies ACD highlights its substantial impact within dermatology and health care beyond.⁵

ACD is an inflammatory disease of the skin that results from an immune-mediated delayed-type hypersensitivity reaction. In this context, the first contact with an allergenic hapten does not lead to a reaction but rather leads to sensitization, which involves dermal dendritic cell uptake of the antigen from the skin and migration to regional lymph nodes where the formation of sensitized T cells begins.^6,7 Subsequent exposure to said allergen would then cause activation of these T cells, resulting in a delayed inflammatory response and elicitation of the dermatitis.⁸ Classically thought as a T helper (T_H)1 dominant reaction, ACD is now known to involve the T_H17 pathway, with clinical data showing T_H2 inhibitors attenuating some ACD reactions.⁹ Compared with adults, this intricate process of sensitization was previously believed to be rare in children due to their immature immune systems. However, as the prevalence of ACD in children continues to rise, studies have suggested that sensitization and exposure to allergens may begin as early as the neonatal period and children are having similar sensitization rates as adults.^9-11 Hence, ACD is a pertinent dermatologic and immunologic condition for patients of all ages. The diagnosis of ACD can be tricky at times due to its clinical overlap with atopic and irritant contact dermatitis. Patch testing is the gold standard diagnostic tool for ACD.¹² Allergen exposure and relevance varies between patients, cities, and countries. This phenomenon likely results from exogenous factors, including legislative changes such as the nickel initiative in the European Union, cultural changes such as an increasing number of men wearing jewelry, and recent increases in the use of cosmetic products among children.^13-16

Since the year 2000, the American Contact Dermatitis Society (ACDS) has accentuated underrecognized and emerging sensitizers via the Allergen of the Year award.^17,18 In this section we examine the clinical significance of the ACDS 2021 Allergen of the Year, acetophenone azine (AA).

What is AA?

AA (CAS 729-43-1) holds the molecular formula C₁₆H₁₆N₂ and has been previously utilized as a biocide with broad-spectrum antimicrobial and antihelminth activity.^19,20 Although AA has been discovered as a component of ethylene vinyl acetate (EVA), its role in the production of EVA remains unclear. Theories suggest AA may not be an intended ingredient but rather a byproduct of reactions between additives during the processing of EVA.²¹

Reported AA ACD Cases

The first case of ACD associated with AA was identified in 2016 involving a 13-year-old boy who wore shin pads while playing soccer.²¹ He presented with progressively worsening contact dermatitis on his bilateral shins. Patch testing displayed an isolated positive finding from the foam of his shin guards. Through high-performance liquid chromatography, AA was unveiled as a component of EVA and as the culprit behind the ACD.²¹ Ensuing cases consequently followed a similar suit in patients after the use of EVA foam products such as shin pads, sports shoes, or flip-flops.^22,23 A total of 12 cases have been reported, with only one of these cases occurring in an adult.^18,22-26 A report by the French Agency for Food, Environmental and Occupational Health & Safety detected AA in 14% of their sample footwear, prompting a warning to check whether shoes contained EVA foam.²⁷ Other potential sources of AA exposure that should be on clinicians’ radars are ski boots, swimming goggles, and bike saddles.

Rising Popularity of EVA

The use of sporting equipment dates back as far as ancient Greece. As the ancient Olympic games were approaching, players prepared their equipment, including greaves, an early version of shin guards made of bronze and other hefty material.^28,29 As time progressed into the 18th century, sporting wear remained limited and restrictive relative to today. Take soccer for example. During the 18th century, many people wore hard work boots to their games. As the sport developed, these boots slowly evolved into metal-studded, steel-capped, thick-leathered high tops. An emphasis on protection can be seen; however, this was at the cost of mobility. These shoes could weigh as much as
18 oz and would double in weight in the rain.³⁰ The call for greater mobility changed the status quo. The discovery of EVA in the 19th century brought this possibility to reality and offered a means of bridging this demand.²⁹

EVA is the thermoplastic resins produced through the copolymerization of ethylene and vinyl acetate monomer. This elastomeric polymer is soft and holds a unique rubber-like physique that allows it to be light, flexible, and resilient,³¹ hence earning itself the more popular terms foam or expanded rubber. These qualities produce a sturdy and flexible shock absorber, making EVA a much-desired material for sporting equipment such as paddings, sports shoes, and ski boots.³² Although this innovation now allows for both protection and mobility, it seems as though this may come alongside a new expense, a potential for ACD.

Byproducts of AA

Since the rise of AA-associated ACD cases involving sporting wear, the role of perspiration in sensitization has been questioned. As in cases of atopic dermatitis, flexural areas that are predisposed to rubbing and sweating are at an increased risk of skin breakdown and allergic hapten penetration to induce sensitization.³³ Athletes in motion have increased friction and perspiration at the junction of their skin and athletic gear, which potentially increases their risk of sensitization to AA. Moreover, a key function in this context is sweat’s role in the hydrolysis of debris and allergens.³⁴ This chemical reaction involves the use of water to cleave biomolecular bonds and in the case of AA, the formation of byproducts, acetophenone and hydrazine.³⁵ Currently, there have been no reported cases demonstrating any positive reactions to these byproducts. Furthermore, the scarce number of studies have only demonstrated the hydrolysis of AA in the presence of strong acids.²¹ While this may be reassuring, one should still be cautious when managing of EVA products with acidic appliances such as hydrochloric acid-derived cleaners.

Diagnosing AA and Clinical Pearls

Patch testing is the gold standard diagnostic tool to diagnose ACD. The first diagnosis of AA ACD in 2016 was accomplished by patch testing with AA identified from the patient’s shin guards. As AA allergen was and is still not commercially available, the authors obtained its crude form from chemical retailers and prepared it manually for patch testing.^21,23 Through various formulations, acetone or petrolatum was soon identified as a preferred vehicle for AA ACD patch testing preparations. Specifically, a concentration of 0.1% AA in these vehicles was recommended, with positive findings identified in cases where AA in acetone was utilized in as low as 0.001% concentrations.^24-26 While the standard for the concentration and delivery of AA in patch testing has yet to be identified, the establishment of a standardized testing kit may expedite this process. Due to the current lack of standardized screening, we recommend conservative management for patients with highly suspected AA ACD. This would include avoidance of the suspected allergen as well as emollients and topical steroids. In cases where contact with EVA/AA may be unavoidable, the use of adhesives or other barriers would be beneficial.

AA and SARS-CoV-2

With the rise of the COVID-19 pandemic, the use of personal protective equipment (PPE) was swiftly normalized and cases of occupational contact dermatitis to PPE increased.³⁶ As the general public was urged to “mask-up,” masks, face shields, and gloves became part of normal wear for many. As the pandemic progressed over the last 2 years, so did fatigue and the increasing weariness of individuals to wearing PPE.^37,38 While there are many contributing factors to this phenomenon, an important one to note is the lack of comfort, prompting some to use padding commonly made of EVA foam as a solution.^39-41 This can be seen specifically in forehead padding for face shields.^39,40 Considering EVA foam is easily accessible, many people, especially the do-it-yourself (DIY) community, have taken it a step further by customizing or hand-crafting PPE with these materials.^42-44 The accessibility of EVA foam padding, coupled with the early scarcity of PPE, promoted DIY initiatives (eg, the popularization of readily available face shield templates) that have since lingered from the early pandemic days.^45,46 Hence, exposure and sensitization to AA may increase as the use of PPE becomes a long-lasting cultural and societal norm, especially as prolonged wear is accompanied by increased sweating, friction and rubbing.

Mr Mai is a medical student at the Western University of Health Sciences, College of Osteopathic Medicine of the Pacific, in Pomona, CA. Dr Goldenberg is director of the Contact Dermatitis Clinic at Dermatologist Medical Group of North County, Inc., in San Diego, CA.

Disclosure: The authors report no relevant financial conflicts of interest.

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