Contact Dermatitis

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

Each year, the American Contact Dermatitis Society names an Allergen of the Year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the Allergen of the Year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD).In 2020, the American Contact Dermatitis Society chose isobornyl acrylate as the Allergen of the Year.¹ Not only has isobornyl acrylate been implicated in an epidemic of contact allergy to diabetic devices, but it also illustrates the challenges of investigating contact allergy to medical devices in general.

What Is Isobornyl Acrylate?

Isobornyl acrylate, also known as the isobornyl ester of acrylic acid, is a chemical used in glues, adhesives, coatings, sealants, inks, and paints. Similar to other acrylates, such as those involved in gel nail treatments, it is photopolymerizable; that is, when exposed to UV light, it can transform from a liquid monomer into a hard polymer, contributing to its utility as an adhesive. Prior to its recent implication in diabetic device contact allergy, isobornyl acrylate was not thought to be a common skin sensitizer. In a 2013 Dutch study of patients with acrylate allergy, only 1 of 14 patients with a contact allergy to other acrylates had a positive patch test reaction to isobornyl acrylate, which led the authors to conclude that adding it to their acrylate patch test series was not indicated.²

Isobornyl Acrylate in Diabetic Devices

Devices such as glucose monitoring systems and insulin pumps are used by millions of patients with diabetes worldwide. Not only are continuous glucose monitoring devices more convenient than self-monitoring of blood glucose, but they also are associated with a reduction in hemoglobin A_1c levels and lower risk for hypoglycemia.³ However, these devices have been increasingly recognized as a source of irritant contact dermatitis and ACD.

Early cases of contact allergy to isobornyl acrylate in diabetic devices were reported in 1995 when 2 Belgian patients using insulin pumps developed ACD.⁴ The patients had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum and other allergens including acrylates. In addition, patch testing with plastic scrapings from their insulin pumps also was positive, and it was determined that the glue affixing the needle to the plastic had diffused into the plastic. The patients were switched to insulin pumps produced by heat staking instead of glue, and their symptoms resolved. In retrospect, this case series may seem prescient, as it was written 2 decades before isobornyl acrylate became recognized as a widespread cause of ACD in users of diabetic devices. Admittedly, other acrylate components of the glue also were positive on patch testing in these patients, so it was not until much later that the focus turned more exclusively to isobornyl acrylate.⁴

Similar to the insulin pumps in the 1995 Belgian series, diffusion of glue to other parts of modern glucose sensors also appears to cause isobornyl acrylate contact allergy. This theory was supported by a 2017 study from Belgian and Swedish investigators in which gas chromatography–mass spectrometry was used to identify concentrations of isobornyl acrylate in various components of a popular continuous glucose monitoring sensor.⁵ The concentration of isobornyl acrylate was approximately 100-fold higher at the site where the top and bottom plastic components of the sensor were joined as compared to the adhesive patch in contact with the patient’s skin. Therefore, the adhesive patch itself was not the source of the isobornyl acrylate exposure; rather, the isobornyl acrylate diffused into the adhesive patch from the glue used to join the components of the sensor together.⁵ One ramification is that patients with diabetic device contact allergy can have a false-negative patch test result if the adhesive patch is tested by itself, whereas they may react to patch testing with the whole sensor or an acetonic extract thereof.

Frequency of Sensitization to Isobornyl Acrylate

It is difficult to estimate the frequency of sensitization to isobornyl acrylate among users of diabetic devices, in part because those with mild allergy may not seek medical treatment. Nevertheless, there are studies that demonstrate a high prevalence of sensitization among users with suspected allergy. In a 2019 Finnish study of 6567 patients using an isobornyl acrylate–containing glucose sensor, 63 were patch tested for suspected ACD.⁶ Of these 63 patients, 51 (81%) had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum. These findings were consistent with the original 2017 study from Belgium and Sweden, in which 10 of 11 (91%) patients who used an isobornyl acrylate–containing glucose sensor and had suspected contact allergy had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum compared to no positive reactions in the 14 control patients.⁵ Given that there are more than 1.5 million users of this isobornyl acrylate–containing glucose sensor across 46 countries,⁷ it requires no stretch of the imagination to understand why investigators refer to isobornyl acrylate allergy as an epidemic, even if only a small percentage of users are sensitized to the device.

The Journey to Discover Isobornyl Acrylate as a Culprit Allergen

Similar to the discoveries of radiography and penicillin, the discovery of isobornyl acrylate as a culprit allergen in a modern glucose sensor was purely accidental. In 2016, a 9-year-old boy with diabetes presented to a Belgian dermatology department with ACD to a glucose sensor.¹ A patch test nurse serendipitously applied isobornyl acrylate—0.01%, 0.05%, and 0.1% in petrolatum—which was not intended to be applied as part of the typical acrylate series. The only positive patch test reactions in this patient were to isobornyl acrylate at all 3 concentrations. This lucky error inspired isobornyl acrylate to be tested at multiple other dermatology departments in Europe in patients with ACD to their glucose sensors, leading to its discovery as a culprit allergen.¹

One challenge facing investigators was obtaining information and materials from the diabetic device industry. Medical device manufacturers are not required to disclose chemicals present in a device on its label.⁸ Therefore, for patients or investigators to determine whether a potential allergen is present in a given device, they must request that information from the manufacturer, which can be a time-consuming and frustrating effort. Luckily, investigators collaborated with one another, and Belgian investigators suggested that Swedish investigators performing chemical analyses on a glucose monitoring device should focus on isobornyl acrylate, which enabled its detection in an extract from the device.⁵

Testing for Isobornyl Acrylate Allergy in Your Clinic

Patients with suspected ACD to a diabetic device—insulin pump or glucose sensor—should be patch tested with isobornyl acrylate, in addition to other previously reported allergens. The vehicle typically is petrolatum, and the commonly tested concentration is 0.1%. Testing with lower concentrations such as 0.01% can result in false-negative reactions,⁹ and testing at higher concentrations such as 0.3% can result in irritant skin reactions.² Isobornyl acrylate 0.1% in petrolatum currently is available from one commercial allergen supplier (Chemotechnique Diagnostics). A positive patch test reaction to isobornyl acrylate 0.1% in petrolatum is shown in the Figure.

Management of Diabetic Device ACD

For patients with diabetic device ACD, there are several strategies that can reduce direct contact between the device and the patient’s skin. Methods that have been tried with varying success to allow patients to continue using their glucose sensors include barrier sprays (eg, Cavilon [3M], Silesse Skin Barrier [ConvaTec]); barrier pads (eg, Compeed [HRA Pharma], Surround skin protectors [Eakin], DuoDERM dressings [ConvaTec], Tegaderm dressings [3M]); and topical corticosteroids, calcineurin inhibitors, and phosphodiesterase 4 inhibitors. Nevertheless, a 2019 Finnish study showed that only 14 of 63 (22%) patients with ACD to their isobornyl acrylate–containing glucose sensor were able to continue using the device, with all 14 requiring use of a barrier agent. Despite using the barrier agent, 13 (93%) of these patients had residual dermatitis.⁶ There also is concern that use of barrier methods might hamper the proper functioning of glucose sensors and related devices.

Patients with known isobornyl acrylate contact allergy also may switch to a different diabetic device. A 2019 German study showed that in 5 patients with isobornyl acrylate ACD, none had reactions to the one particular system that has been shown by gas chromatography–mass spectrometry to not contain isobornyl acrylate.¹⁰ However, as a word of caution, the same device also has been associated with ACD^11,12 but has been resolved by using heat staking during the production process.¹³ As manufacturers update device components, identification of other isobornyl acrylate–free devices may require a degree of trial and error, as neither isobornyl acrylate nor any other potential allergen is listed on device labels.

Final Interpretation

Isobornyl acrylate is not a common sensitizer in general patch test populations but is a recently identified major culprit in ACD to diabetic devices. Patch testing with isobornyl acrylate 0.1% in petrolatum is not necessary in standard screening panels but should be considered in patients with suspected ACD to glucose sensors or insulin pumps. If a patient with ACD wants to continue to experience the convenience provided by a diabetic device, options include using topical steroids or barrier agents and/or changing the brand of the diabetic device, though none of these methods are foolproof. Hopefully, the identification of isobornyl acrylate as a culprit allergen will help to improve the lives of patients who use diabetic devices worldwide.

Each year, the American Contact Dermatitis Society names an Allergen of the Year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the Allergen of the Year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD).In 2020, the American Contact Dermatitis Society chose isobornyl acrylate as the Allergen of the Year.¹ Not only has isobornyl acrylate been implicated in an epidemic of contact allergy to diabetic devices, but it also illustrates the challenges of investigating contact allergy to medical devices in general.

What Is Isobornyl Acrylate?

Isobornyl acrylate, also known as the isobornyl ester of acrylic acid, is a chemical used in glues, adhesives, coatings, sealants, inks, and paints. Similar to other acrylates, such as those involved in gel nail treatments, it is photopolymerizable; that is, when exposed to UV light, it can transform from a liquid monomer into a hard polymer, contributing to its utility as an adhesive. Prior to its recent implication in diabetic device contact allergy, isobornyl acrylate was not thought to be a common skin sensitizer. In a 2013 Dutch study of patients with acrylate allergy, only 1 of 14 patients with a contact allergy to other acrylates had a positive patch test reaction to isobornyl acrylate, which led the authors to conclude that adding it to their acrylate patch test series was not indicated.²

Isobornyl Acrylate in Diabetic Devices

Devices such as glucose monitoring systems and insulin pumps are used by millions of patients with diabetes worldwide. Not only are continuous glucose monitoring devices more convenient than self-monitoring of blood glucose, but they also are associated with a reduction in hemoglobin A_1c levels and lower risk for hypoglycemia.³ However, these devices have been increasingly recognized as a source of irritant contact dermatitis and ACD.

Early cases of contact allergy to isobornyl acrylate in diabetic devices were reported in 1995 when 2 Belgian patients using insulin pumps developed ACD.⁴ The patients had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum and other allergens including acrylates. In addition, patch testing with plastic scrapings from their insulin pumps also was positive, and it was determined that the glue affixing the needle to the plastic had diffused into the plastic. The patients were switched to insulin pumps produced by heat staking instead of glue, and their symptoms resolved. In retrospect, this case series may seem prescient, as it was written 2 decades before isobornyl acrylate became recognized as a widespread cause of ACD in users of diabetic devices. Admittedly, other acrylate components of the glue also were positive on patch testing in these patients, so it was not until much later that the focus turned more exclusively to isobornyl acrylate.⁴

Similar to the insulin pumps in the 1995 Belgian series, diffusion of glue to other parts of modern glucose sensors also appears to cause isobornyl acrylate contact allergy. This theory was supported by a 2017 study from Belgian and Swedish investigators in which gas chromatography–mass spectrometry was used to identify concentrations of isobornyl acrylate in various components of a popular continuous glucose monitoring sensor.⁵ The concentration of isobornyl acrylate was approximately 100-fold higher at the site where the top and bottom plastic components of the sensor were joined as compared to the adhesive patch in contact with the patient’s skin. Therefore, the adhesive patch itself was not the source of the isobornyl acrylate exposure; rather, the isobornyl acrylate diffused into the adhesive patch from the glue used to join the components of the sensor together.⁵ One ramification is that patients with diabetic device contact allergy can have a false-negative patch test result if the adhesive patch is tested by itself, whereas they may react to patch testing with the whole sensor or an acetonic extract thereof.

Frequency of Sensitization to Isobornyl Acrylate

It is difficult to estimate the frequency of sensitization to isobornyl acrylate among users of diabetic devices, in part because those with mild allergy may not seek medical treatment. Nevertheless, there are studies that demonstrate a high prevalence of sensitization among users with suspected allergy. In a 2019 Finnish study of 6567 patients using an isobornyl acrylate–containing glucose sensor, 63 were patch tested for suspected ACD.⁶ Of these 63 patients, 51 (81%) had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum. These findings were consistent with the original 2017 study from Belgium and Sweden, in which 10 of 11 (91%) patients who used an isobornyl acrylate–containing glucose sensor and had suspected contact allergy had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum compared to no positive reactions in the 14 control patients.⁵ Given that there are more than 1.5 million users of this isobornyl acrylate–containing glucose sensor across 46 countries,⁷ it requires no stretch of the imagination to understand why investigators refer to isobornyl acrylate allergy as an epidemic, even if only a small percentage of users are sensitized to the device.

The Journey to Discover Isobornyl Acrylate as a Culprit Allergen

Similar to the discoveries of radiography and penicillin, the discovery of isobornyl acrylate as a culprit allergen in a modern glucose sensor was purely accidental. In 2016, a 9-year-old boy with diabetes presented to a Belgian dermatology department with ACD to a glucose sensor.¹ A patch test nurse serendipitously applied isobornyl acrylate—0.01%, 0.05%, and 0.1% in petrolatum—which was not intended to be applied as part of the typical acrylate series. The only positive patch test reactions in this patient were to isobornyl acrylate at all 3 concentrations. This lucky error inspired isobornyl acrylate to be tested at multiple other dermatology departments in Europe in patients with ACD to their glucose sensors, leading to its discovery as a culprit allergen.¹

One challenge facing investigators was obtaining information and materials from the diabetic device industry. Medical device manufacturers are not required to disclose chemicals present in a device on its label.⁸ Therefore, for patients or investigators to determine whether a potential allergen is present in a given device, they must request that information from the manufacturer, which can be a time-consuming and frustrating effort. Luckily, investigators collaborated with one another, and Belgian investigators suggested that Swedish investigators performing chemical analyses on a glucose monitoring device should focus on isobornyl acrylate, which enabled its detection in an extract from the device.⁵

Testing for Isobornyl Acrylate Allergy in Your Clinic

Patients with suspected ACD to a diabetic device—insulin pump or glucose sensor—should be patch tested with isobornyl acrylate, in addition to other previously reported allergens. The vehicle typically is petrolatum, and the commonly tested concentration is 0.1%. Testing with lower concentrations such as 0.01% can result in false-negative reactions,⁹ and testing at higher concentrations such as 0.3% can result in irritant skin reactions.² Isobornyl acrylate 0.1% in petrolatum currently is available from one commercial allergen supplier (Chemotechnique Diagnostics). A positive patch test reaction to isobornyl acrylate 0.1% in petrolatum is shown in the Figure.

Management of Diabetic Device ACD

For patients with diabetic device ACD, there are several strategies that can reduce direct contact between the device and the patient’s skin. Methods that have been tried with varying success to allow patients to continue using their glucose sensors include barrier sprays (eg, Cavilon [3M], Silesse Skin Barrier [ConvaTec]); barrier pads (eg, Compeed [HRA Pharma], Surround skin protectors [Eakin], DuoDERM dressings [ConvaTec], Tegaderm dressings [3M]); and topical corticosteroids, calcineurin inhibitors, and phosphodiesterase 4 inhibitors. Nevertheless, a 2019 Finnish study showed that only 14 of 63 (22%) patients with ACD to their isobornyl acrylate–containing glucose sensor were able to continue using the device, with all 14 requiring use of a barrier agent. Despite using the barrier agent, 13 (93%) of these patients had residual dermatitis.⁶ There also is concern that use of barrier methods might hamper the proper functioning of glucose sensors and related devices.

Patients with known isobornyl acrylate contact allergy also may switch to a different diabetic device. A 2019 German study showed that in 5 patients with isobornyl acrylate ACD, none had reactions to the one particular system that has been shown by gas chromatography–mass spectrometry to not contain isobornyl acrylate.¹⁰ However, as a word of caution, the same device also has been associated with ACD^11,12 but has been resolved by using heat staking during the production process.¹³ As manufacturers update device components, identification of other isobornyl acrylate–free devices may require a degree of trial and error, as neither isobornyl acrylate nor any other potential allergen is listed on device labels.

Final Interpretation

Isobornyl acrylate is not a common sensitizer in general patch test populations but is a recently identified major culprit in ACD to diabetic devices. Patch testing with isobornyl acrylate 0.1% in petrolatum is not necessary in standard screening panels but should be considered in patients with suspected ACD to glucose sensors or insulin pumps. If a patient with ACD wants to continue to experience the convenience provided by a diabetic device, options include using topical steroids or barrier agents and/or changing the brand of the diabetic device, though none of these methods are foolproof. Hopefully, the identification of isobornyl acrylate as a culprit allergen will help to improve the lives of patients who use diabetic devices worldwide.

Each year, the American Contact Dermatitis Society names an Allergen of the Year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the Allergen of the Year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD).In 2020, the American Contact Dermatitis Society chose isobornyl acrylate as the Allergen of the Year.¹ Not only has isobornyl acrylate been implicated in an epidemic of contact allergy to diabetic devices, but it also illustrates the challenges of investigating contact allergy to medical devices in general.

What Is Isobornyl Acrylate?

Isobornyl acrylate, also known as the isobornyl ester of acrylic acid, is a chemical used in glues, adhesives, coatings, sealants, inks, and paints. Similar to other acrylates, such as those involved in gel nail treatments, it is photopolymerizable; that is, when exposed to UV light, it can transform from a liquid monomer into a hard polymer, contributing to its utility as an adhesive. Prior to its recent implication in diabetic device contact allergy, isobornyl acrylate was not thought to be a common skin sensitizer. In a 2013 Dutch study of patients with acrylate allergy, only 1 of 14 patients with a contact allergy to other acrylates had a positive patch test reaction to isobornyl acrylate, which led the authors to conclude that adding it to their acrylate patch test series was not indicated.²

Isobornyl Acrylate in Diabetic Devices

Devices such as glucose monitoring systems and insulin pumps are used by millions of patients with diabetes worldwide. Not only are continuous glucose monitoring devices more convenient than self-monitoring of blood glucose, but they also are associated with a reduction in hemoglobin A_1c levels and lower risk for hypoglycemia.³ However, these devices have been increasingly recognized as a source of irritant contact dermatitis and ACD.

Early cases of contact allergy to isobornyl acrylate in diabetic devices were reported in 1995 when 2 Belgian patients using insulin pumps developed ACD.⁴ The patients had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum and other allergens including acrylates. In addition, patch testing with plastic scrapings from their insulin pumps also was positive, and it was determined that the glue affixing the needle to the plastic had diffused into the plastic. The patients were switched to insulin pumps produced by heat staking instead of glue, and their symptoms resolved. In retrospect, this case series may seem prescient, as it was written 2 decades before isobornyl acrylate became recognized as a widespread cause of ACD in users of diabetic devices. Admittedly, other acrylate components of the glue also were positive on patch testing in these patients, so it was not until much later that the focus turned more exclusively to isobornyl acrylate.⁴

Similar to the insulin pumps in the 1995 Belgian series, diffusion of glue to other parts of modern glucose sensors also appears to cause isobornyl acrylate contact allergy. This theory was supported by a 2017 study from Belgian and Swedish investigators in which gas chromatography–mass spectrometry was used to identify concentrations of isobornyl acrylate in various components of a popular continuous glucose monitoring sensor.⁵ The concentration of isobornyl acrylate was approximately 100-fold higher at the site where the top and bottom plastic components of the sensor were joined as compared to the adhesive patch in contact with the patient’s skin. Therefore, the adhesive patch itself was not the source of the isobornyl acrylate exposure; rather, the isobornyl acrylate diffused into the adhesive patch from the glue used to join the components of the sensor together.⁵ One ramification is that patients with diabetic device contact allergy can have a false-negative patch test result if the adhesive patch is tested by itself, whereas they may react to patch testing with the whole sensor or an acetonic extract thereof.

Frequency of Sensitization to Isobornyl Acrylate

It is difficult to estimate the frequency of sensitization to isobornyl acrylate among users of diabetic devices, in part because those with mild allergy may not seek medical treatment. Nevertheless, there are studies that demonstrate a high prevalence of sensitization among users with suspected allergy. In a 2019 Finnish study of 6567 patients using an isobornyl acrylate–containing glucose sensor, 63 were patch tested for suspected ACD.⁶ Of these 63 patients, 51 (81%) had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum. These findings were consistent with the original 2017 study from Belgium and Sweden, in which 10 of 11 (91%) patients who used an isobornyl acrylate–containing glucose sensor and had suspected contact allergy had positive patch test reactions to isobornyl acrylate 0.1% in petrolatum compared to no positive reactions in the 14 control patients.⁵ Given that there are more than 1.5 million users of this isobornyl acrylate–containing glucose sensor across 46 countries,⁷ it requires no stretch of the imagination to understand why investigators refer to isobornyl acrylate allergy as an epidemic, even if only a small percentage of users are sensitized to the device.

The Journey to Discover Isobornyl Acrylate as a Culprit Allergen

Similar to the discoveries of radiography and penicillin, the discovery of isobornyl acrylate as a culprit allergen in a modern glucose sensor was purely accidental. In 2016, a 9-year-old boy with diabetes presented to a Belgian dermatology department with ACD to a glucose sensor.¹ A patch test nurse serendipitously applied isobornyl acrylate—0.01%, 0.05%, and 0.1% in petrolatum—which was not intended to be applied as part of the typical acrylate series. The only positive patch test reactions in this patient were to isobornyl acrylate at all 3 concentrations. This lucky error inspired isobornyl acrylate to be tested at multiple other dermatology departments in Europe in patients with ACD to their glucose sensors, leading to its discovery as a culprit allergen.¹

One challenge facing investigators was obtaining information and materials from the diabetic device industry. Medical device manufacturers are not required to disclose chemicals present in a device on its label.⁸ Therefore, for patients or investigators to determine whether a potential allergen is present in a given device, they must request that information from the manufacturer, which can be a time-consuming and frustrating effort. Luckily, investigators collaborated with one another, and Belgian investigators suggested that Swedish investigators performing chemical analyses on a glucose monitoring device should focus on isobornyl acrylate, which enabled its detection in an extract from the device.⁵

Testing for Isobornyl Acrylate Allergy in Your Clinic

Patients with suspected ACD to a diabetic device—insulin pump or glucose sensor—should be patch tested with isobornyl acrylate, in addition to other previously reported allergens. The vehicle typically is petrolatum, and the commonly tested concentration is 0.1%. Testing with lower concentrations such as 0.01% can result in false-negative reactions,⁹ and testing at higher concentrations such as 0.3% can result in irritant skin reactions.² Isobornyl acrylate 0.1% in petrolatum currently is available from one commercial allergen supplier (Chemotechnique Diagnostics). A positive patch test reaction to isobornyl acrylate 0.1% in petrolatum is shown in the Figure.

Management of Diabetic Device ACD

For patients with diabetic device ACD, there are several strategies that can reduce direct contact between the device and the patient’s skin. Methods that have been tried with varying success to allow patients to continue using their glucose sensors include barrier sprays (eg, Cavilon [3M], Silesse Skin Barrier [ConvaTec]); barrier pads (eg, Compeed [HRA Pharma], Surround skin protectors [Eakin], DuoDERM dressings [ConvaTec], Tegaderm dressings [3M]); and topical corticosteroids, calcineurin inhibitors, and phosphodiesterase 4 inhibitors. Nevertheless, a 2019 Finnish study showed that only 14 of 63 (22%) patients with ACD to their isobornyl acrylate–containing glucose sensor were able to continue using the device, with all 14 requiring use of a barrier agent. Despite using the barrier agent, 13 (93%) of these patients had residual dermatitis.⁶ There also is concern that use of barrier methods might hamper the proper functioning of glucose sensors and related devices.

Patients with known isobornyl acrylate contact allergy also may switch to a different diabetic device. A 2019 German study showed that in 5 patients with isobornyl acrylate ACD, none had reactions to the one particular system that has been shown by gas chromatography–mass spectrometry to not contain isobornyl acrylate.¹⁰ However, as a word of caution, the same device also has been associated with ACD^11,12 but has been resolved by using heat staking during the production process.¹³ As manufacturers update device components, identification of other isobornyl acrylate–free devices may require a degree of trial and error, as neither isobornyl acrylate nor any other potential allergen is listed on device labels.

Final Interpretation

Isobornyl acrylate is not a common sensitizer in general patch test populations but is a recently identified major culprit in ACD to diabetic devices. Patch testing with isobornyl acrylate 0.1% in petrolatum is not necessary in standard screening panels but should be considered in patients with suspected ACD to glucose sensors or insulin pumps. If a patient with ACD wants to continue to experience the convenience provided by a diabetic device, options include using topical steroids or barrier agents and/or changing the brand of the diabetic device, though none of these methods are foolproof. Hopefully, the identification of isobornyl acrylate as a culprit allergen will help to improve the lives of patients who use diabetic devices worldwide.

What is an essential oil?

An essential oil (EO) is defined by the International Organization for Standardization as a ‘‘product obtained from a natural raw material of plant origin, by steam distillation, by mechanical processes from the epicarp of citrus fruits, or by dry distillation, after separation of the aqueous phase—if any—by physical processes.’’¹ Steam distillation is the primary method used for the production of commercial EOs,² and believe it or not, most EOs contain 100 to 250 individual chemical components.³

The term essential oil often is incorrectly used for a variety of products obtained from plant material by methods other than distillation or cold-pressing, such as extraction. Products that are obtained via the extraction method include absolutes found in fine fragrances; hydrolates such as rose water; concretes such as jasmine or violet leaves; and vegetable oils including olive oil, coconut oil, and sesame oil.² These products are not true EOs.

Where do EOs come from?

Essential oils are produced in many countries around the world.⁴ Individual oils may be obtained from species of different plants, from different parts of the same plant, or from various cultivars (plants selectively bred to obtain desirable levels of chemical constituents such as monoterpenes or sesquiterpenes and biochemical properties such as antibacterial or antioxidant activities).^3,5 It is estimated that EOs can be obtained from approximately 30,000 plant species, but only 150 EOs are produced commercially.^2,6

Why are people using EOs? What is their claim to fame?

Essential oils are employed by the flavor, food (eg, soft drinks, milk, candies, chocolate, meats, sausages, alcoholic beverages, spices, herbs, tea, preservatives, animal foods), fragrance, cosmetic, tobacco, and pharmaceutical industries. They also are used in household products (eg, detergents, fabric softeners, air fresheners, candles, incense) and for medicinal purposes (eg, folk and traditional medicine, phytotherapy, balneotherapy, aromatherapy).² The oils usually are applied to the skin but also can be administered orally, inhaled, diffused through the air, or used by other means.⁴ One 2019 survey of Minnesota State Fair attendees (N=282) found the most common reasons for using EOs were a desire for alternative treatments (53.4%), the opinion that EOs are safer than traditional therapies (47.6%), and/or failure of standard medical treatments (10.7%). The survey results also indicated that 46.7% of EO users utilized EOs to treat medical conditions or symptoms.⁷ Of note, review of the website of an international company that produces EOs confirmed that EOs are marketed not only for adults but also for children to help them concentrate,⁸ sleep,⁹ improve the appearance of their skin,¹⁰ soothe upset stomachs,¹¹ and decrease sniffles due to colds.¹²

Why are people selling EOs to family and friends? They must be making major bucks!

In general, the cost of EOs depends on the complexity of cultivated plant species; the mode of harvesting, which is sometimes done by hand; and the yield of oil. Prices range from $4.50 to an incredible $150,000 per kilogram.² On average, one bottle containing 5 to 15 mL of an EO or oil blend can cost anywhere from $7 to $251.¹³ In the United States, the consumer EO market is partially composed of multilevel/network marketing companies in which direct consumer sales occur via a hierarchy of individual distributors. Goodier et al⁷ found that 36.4% of participants who obtained EOs from family and friends purchased them through multilevel/network marketing companies. In 2018, individual distributors of an international EO-producing company made on average anywhere from $4 to as much as $1.54 million annually by selling the company’s EO products and enrolling additional members/individual distributors to purchase or sell the company’s EO products.¹⁴

Sometimes EOs are described as natural and pure, but are they really?

Just because a product is labeled as “pure” or “natural” does not ensure that it is a good-quality EO. Organically produced (ie, grown without the use of herbicides or pesticides) plant material can include up to 30% of extraneous herbs and weeds, which can change the composition of the oil.²

Lesser-quality EOs are the result of adulteration, contamination, inadequate oil production, or aging.² Adulteration (eg, cutting, stretching, bouquetting) occurs when foreign substances are introduced into pure EOs for the benefit of a higher profit; to ensure a sufficient supply of oils; or to meet demands for cheaper oils by “stretching” a more expensive, pure oil by combining with a cheaper, less pure oil. Inadequate oil production leading to lower-quality oils can occur when a biomass is incorrectly distilled, either from too much steam or temperatures that are too high or due to lack of adequate cooling units. Aging occurs when the oils are not stored properly, resulting in a change in the chemical composition due to esterification, reduction, and oxidization of chemicals, which leads to the formation of peroxides and hydroperoxides that can be contact allergens.¹⁵

Can patients develop contact allergies to EOs?

The short answer is yes! Contact allergy to almost 80 EOs has been reported,¹⁵ including tea tree oil,^16,17 ylang-ylang oil,^17,18 lavender oil, peppermint oil,¹⁸ jasmine absolute,¹⁷ geranium oil, rose oil,¹⁸ turpentine oil,^19,20 and sandalwood oil.¹⁸ The recent increased prevalence of allergic reactions to EOs likely is due to increased consumer use as well as increased detection from availability of commercial patch-test preparations.

Essential oils have many common ingredients. De Groot and Schmidt³ documented that 14 of 23 chemicals present in more than 80% of EOs have been reported to cause contact allergy. Interestingly, allergic patients often react to more than one EO, which may be explained by the many shared chemical components in EOs.

Essential oils are “natural” so they must be safe?

In general, most safety profiles are good, but rare toxic reactions from EOs have been observed.⁴ A recent Australian study reviewed EO exposure calls to the New South Wales Poisons Information Centre.²¹ The majority of EO poisonings were accidental or the result of therapeutic error such as mistaking EOs for liquid pharmaceuticals. Additionally, this study found that from July 2014 to June 2018, there was a 5% increase in the number of calls per year. More than half of EO poisoning calls involved children, with toddlers being the most frequent cases, suggesting the need for child-resistant top closures. The most frequently involved EOs in poisonings were eucalyptus (46.4% [n=2049]), tea tree (17% [n=749]), lavender (6.1% [n=271]), clove (4.1% [n=179]), and peppermint (3.5% [n=154]).²¹ Essential oils do not come without potential pitfalls.

What is the clinical presentation and workup?

The workup of EO allergic contact dermatitis begins with obtaining a history to evaluate for use of EO diffusers, perfumes, hygiene products, cosmetics, massage oils, toothpastes, and/or pharmaceutical products. Exploration of potential exposures through occupation, environment, and hobbies also is indicated. Clinical presentation is dependent on the mechanism of exposure. Contact allergy may result from direct application of an allergen to the skin or mucous membranes, contact with a contaminated environmental item (eg, lavender oil on a pillow), contact with EOs used by partners or coworkers (consort dermatitis), airborne exposure (EO diffusers), or systemic exposure (flavorings). Airborne dermatitis from EO diffusers may involve the exposed areas of the face, neck, forearms, arms, behind the earlobes, bilateral eyelids, nasolabial folds, and under the chin. History and clinical presentation can raise suspicion for allergic contact dermatitis, and patch testing is necessary to confirm the diagnosis.

How do we patch test for EO contact allergy?

There are many EOs commercially available for patch testing, and they typically are tested at 2% to 5% concentrations in petrolatum.¹⁵ A North American and European study of 62,354 patch-tested patients found that 7.4% of EO-positive individuals did not react to fragrance allergens in a standard screening series including fragrance mix I, fragrance mix II, and balsam of Peru, highlighting the importance of patch testing with specific EOs.²² Currently, only 3 EOs—tea tree oil, peppermint oil, and ylang-ylang oil—are included in the 2019-2020 North American Contact Dermatitis Group screening series, making supplemental testing for other EOs important if contact allergy is suspected; however, testing the patient’s own products is imperative, as there is strong variability in the composition of EOs. Additionally, aged oils may have been exposed to light, oxygen, or varying temperatures, which could result in the formation of additional allergenic chemicals not present in commercially available preparations.¹⁵ In addition to commercially available allergens, we test patient-provided EOs either as is in semi-open fashion (ie, EOs are applied to patient’s back with a cotton swab, allowed to dry, covered with adhesive tape, and read at the same interval as other patch tests²³) or occasionally dilute them to 1% or 10% (in olive oil or mineral oil).

How should I manage a positive patch-test reaction to EOs?

Patients should avoid relevant EO allergens in their products and environment, which can be easily achieved with the use of the American Contact Dermatitis Society’s Contact Allergen Management Program or similar databases.

Final Interpretation

We are ubiquitously exposed to EOs every day—through the products we use at home, at work, and in our environment. Essential oils make their place in the world by providing sweet-smelling aromas in addition to their alleged therapeutic properties; however, beware, EOs may be the culprit of your next patient’s allergic contact dermatitis.

What is an essential oil?

An essential oil (EO) is defined by the International Organization for Standardization as a ‘‘product obtained from a natural raw material of plant origin, by steam distillation, by mechanical processes from the epicarp of citrus fruits, or by dry distillation, after separation of the aqueous phase—if any—by physical processes.’’¹ Steam distillation is the primary method used for the production of commercial EOs,² and believe it or not, most EOs contain 100 to 250 individual chemical components.³

The term essential oil often is incorrectly used for a variety of products obtained from plant material by methods other than distillation or cold-pressing, such as extraction. Products that are obtained via the extraction method include absolutes found in fine fragrances; hydrolates such as rose water; concretes such as jasmine or violet leaves; and vegetable oils including olive oil, coconut oil, and sesame oil.² These products are not true EOs.

Where do EOs come from?

Essential oils are produced in many countries around the world.⁴ Individual oils may be obtained from species of different plants, from different parts of the same plant, or from various cultivars (plants selectively bred to obtain desirable levels of chemical constituents such as monoterpenes or sesquiterpenes and biochemical properties such as antibacterial or antioxidant activities).^3,5 It is estimated that EOs can be obtained from approximately 30,000 plant species, but only 150 EOs are produced commercially.^2,6

Why are people using EOs? What is their claim to fame?

Essential oils are employed by the flavor, food (eg, soft drinks, milk, candies, chocolate, meats, sausages, alcoholic beverages, spices, herbs, tea, preservatives, animal foods), fragrance, cosmetic, tobacco, and pharmaceutical industries. They also are used in household products (eg, detergents, fabric softeners, air fresheners, candles, incense) and for medicinal purposes (eg, folk and traditional medicine, phytotherapy, balneotherapy, aromatherapy).² The oils usually are applied to the skin but also can be administered orally, inhaled, diffused through the air, or used by other means.⁴ One 2019 survey of Minnesota State Fair attendees (N=282) found the most common reasons for using EOs were a desire for alternative treatments (53.4%), the opinion that EOs are safer than traditional therapies (47.6%), and/or failure of standard medical treatments (10.7%). The survey results also indicated that 46.7% of EO users utilized EOs to treat medical conditions or symptoms.⁷ Of note, review of the website of an international company that produces EOs confirmed that EOs are marketed not only for adults but also for children to help them concentrate,⁸ sleep,⁹ improve the appearance of their skin,¹⁰ soothe upset stomachs,¹¹ and decrease sniffles due to colds.¹²

Why are people selling EOs to family and friends? They must be making major bucks!

In general, the cost of EOs depends on the complexity of cultivated plant species; the mode of harvesting, which is sometimes done by hand; and the yield of oil. Prices range from $4.50 to an incredible $150,000 per kilogram.² On average, one bottle containing 5 to 15 mL of an EO or oil blend can cost anywhere from $7 to $251.¹³ In the United States, the consumer EO market is partially composed of multilevel/network marketing companies in which direct consumer sales occur via a hierarchy of individual distributors. Goodier et al⁷ found that 36.4% of participants who obtained EOs from family and friends purchased them through multilevel/network marketing companies. In 2018, individual distributors of an international EO-producing company made on average anywhere from $4 to as much as $1.54 million annually by selling the company’s EO products and enrolling additional members/individual distributors to purchase or sell the company’s EO products.¹⁴

Sometimes EOs are described as natural and pure, but are they really?

Just because a product is labeled as “pure” or “natural” does not ensure that it is a good-quality EO. Organically produced (ie, grown without the use of herbicides or pesticides) plant material can include up to 30% of extraneous herbs and weeds, which can change the composition of the oil.²

Lesser-quality EOs are the result of adulteration, contamination, inadequate oil production, or aging.² Adulteration (eg, cutting, stretching, bouquetting) occurs when foreign substances are introduced into pure EOs for the benefit of a higher profit; to ensure a sufficient supply of oils; or to meet demands for cheaper oils by “stretching” a more expensive, pure oil by combining with a cheaper, less pure oil. Inadequate oil production leading to lower-quality oils can occur when a biomass is incorrectly distilled, either from too much steam or temperatures that are too high or due to lack of adequate cooling units. Aging occurs when the oils are not stored properly, resulting in a change in the chemical composition due to esterification, reduction, and oxidization of chemicals, which leads to the formation of peroxides and hydroperoxides that can be contact allergens.¹⁵

Can patients develop contact allergies to EOs?

The short answer is yes! Contact allergy to almost 80 EOs has been reported,¹⁵ including tea tree oil,^16,17 ylang-ylang oil,^17,18 lavender oil, peppermint oil,¹⁸ jasmine absolute,¹⁷ geranium oil, rose oil,¹⁸ turpentine oil,^19,20 and sandalwood oil.¹⁸ The recent increased prevalence of allergic reactions to EOs likely is due to increased consumer use as well as increased detection from availability of commercial patch-test preparations.

Essential oils have many common ingredients. De Groot and Schmidt³ documented that 14 of 23 chemicals present in more than 80% of EOs have been reported to cause contact allergy. Interestingly, allergic patients often react to more than one EO, which may be explained by the many shared chemical components in EOs.

Essential oils are “natural” so they must be safe?

In general, most safety profiles are good, but rare toxic reactions from EOs have been observed.⁴ A recent Australian study reviewed EO exposure calls to the New South Wales Poisons Information Centre.²¹ The majority of EO poisonings were accidental or the result of therapeutic error such as mistaking EOs for liquid pharmaceuticals. Additionally, this study found that from July 2014 to June 2018, there was a 5% increase in the number of calls per year. More than half of EO poisoning calls involved children, with toddlers being the most frequent cases, suggesting the need for child-resistant top closures. The most frequently involved EOs in poisonings were eucalyptus (46.4% [n=2049]), tea tree (17% [n=749]), lavender (6.1% [n=271]), clove (4.1% [n=179]), and peppermint (3.5% [n=154]).²¹ Essential oils do not come without potential pitfalls.

What is the clinical presentation and workup?

The workup of EO allergic contact dermatitis begins with obtaining a history to evaluate for use of EO diffusers, perfumes, hygiene products, cosmetics, massage oils, toothpastes, and/or pharmaceutical products. Exploration of potential exposures through occupation, environment, and hobbies also is indicated. Clinical presentation is dependent on the mechanism of exposure. Contact allergy may result from direct application of an allergen to the skin or mucous membranes, contact with a contaminated environmental item (eg, lavender oil on a pillow), contact with EOs used by partners or coworkers (consort dermatitis), airborne exposure (EO diffusers), or systemic exposure (flavorings). Airborne dermatitis from EO diffusers may involve the exposed areas of the face, neck, forearms, arms, behind the earlobes, bilateral eyelids, nasolabial folds, and under the chin. History and clinical presentation can raise suspicion for allergic contact dermatitis, and patch testing is necessary to confirm the diagnosis.

How do we patch test for EO contact allergy?

There are many EOs commercially available for patch testing, and they typically are tested at 2% to 5% concentrations in petrolatum.¹⁵ A North American and European study of 62,354 patch-tested patients found that 7.4% of EO-positive individuals did not react to fragrance allergens in a standard screening series including fragrance mix I, fragrance mix II, and balsam of Peru, highlighting the importance of patch testing with specific EOs.²² Currently, only 3 EOs—tea tree oil, peppermint oil, and ylang-ylang oil—are included in the 2019-2020 North American Contact Dermatitis Group screening series, making supplemental testing for other EOs important if contact allergy is suspected; however, testing the patient’s own products is imperative, as there is strong variability in the composition of EOs. Additionally, aged oils may have been exposed to light, oxygen, or varying temperatures, which could result in the formation of additional allergenic chemicals not present in commercially available preparations.¹⁵ In addition to commercially available allergens, we test patient-provided EOs either as is in semi-open fashion (ie, EOs are applied to patient’s back with a cotton swab, allowed to dry, covered with adhesive tape, and read at the same interval as other patch tests²³) or occasionally dilute them to 1% or 10% (in olive oil or mineral oil).

How should I manage a positive patch-test reaction to EOs?

Patients should avoid relevant EO allergens in their products and environment, which can be easily achieved with the use of the American Contact Dermatitis Society’s Contact Allergen Management Program or similar databases.

Final Interpretation

We are ubiquitously exposed to EOs every day—through the products we use at home, at work, and in our environment. Essential oils make their place in the world by providing sweet-smelling aromas in addition to their alleged therapeutic properties; however, beware, EOs may be the culprit of your next patient’s allergic contact dermatitis.

What is an essential oil?

An essential oil (EO) is defined by the International Organization for Standardization as a ‘‘product obtained from a natural raw material of plant origin, by steam distillation, by mechanical processes from the epicarp of citrus fruits, or by dry distillation, after separation of the aqueous phase—if any—by physical processes.’’¹ Steam distillation is the primary method used for the production of commercial EOs,² and believe it or not, most EOs contain 100 to 250 individual chemical components.³

The term essential oil often is incorrectly used for a variety of products obtained from plant material by methods other than distillation or cold-pressing, such as extraction. Products that are obtained via the extraction method include absolutes found in fine fragrances; hydrolates such as rose water; concretes such as jasmine or violet leaves; and vegetable oils including olive oil, coconut oil, and sesame oil.² These products are not true EOs.

Where do EOs come from?

Essential oils are produced in many countries around the world.⁴ Individual oils may be obtained from species of different plants, from different parts of the same plant, or from various cultivars (plants selectively bred to obtain desirable levels of chemical constituents such as monoterpenes or sesquiterpenes and biochemical properties such as antibacterial or antioxidant activities).^3,5 It is estimated that EOs can be obtained from approximately 30,000 plant species, but only 150 EOs are produced commercially.^2,6

Why are people using EOs? What is their claim to fame?

Essential oils are employed by the flavor, food (eg, soft drinks, milk, candies, chocolate, meats, sausages, alcoholic beverages, spices, herbs, tea, preservatives, animal foods), fragrance, cosmetic, tobacco, and pharmaceutical industries. They also are used in household products (eg, detergents, fabric softeners, air fresheners, candles, incense) and for medicinal purposes (eg, folk and traditional medicine, phytotherapy, balneotherapy, aromatherapy).² The oils usually are applied to the skin but also can be administered orally, inhaled, diffused through the air, or used by other means.⁴ One 2019 survey of Minnesota State Fair attendees (N=282) found the most common reasons for using EOs were a desire for alternative treatments (53.4%), the opinion that EOs are safer than traditional therapies (47.6%), and/or failure of standard medical treatments (10.7%). The survey results also indicated that 46.7% of EO users utilized EOs to treat medical conditions or symptoms.⁷ Of note, review of the website of an international company that produces EOs confirmed that EOs are marketed not only for adults but also for children to help them concentrate,⁸ sleep,⁹ improve the appearance of their skin,¹⁰ soothe upset stomachs,¹¹ and decrease sniffles due to colds.¹²

Why are people selling EOs to family and friends? They must be making major bucks!

In general, the cost of EOs depends on the complexity of cultivated plant species; the mode of harvesting, which is sometimes done by hand; and the yield of oil. Prices range from $4.50 to an incredible $150,000 per kilogram.² On average, one bottle containing 5 to 15 mL of an EO or oil blend can cost anywhere from $7 to $251.¹³ In the United States, the consumer EO market is partially composed of multilevel/network marketing companies in which direct consumer sales occur via a hierarchy of individual distributors. Goodier et al⁷ found that 36.4% of participants who obtained EOs from family and friends purchased them through multilevel/network marketing companies. In 2018, individual distributors of an international EO-producing company made on average anywhere from $4 to as much as $1.54 million annually by selling the company’s EO products and enrolling additional members/individual distributors to purchase or sell the company’s EO products.¹⁴

Sometimes EOs are described as natural and pure, but are they really?

Just because a product is labeled as “pure” or “natural” does not ensure that it is a good-quality EO. Organically produced (ie, grown without the use of herbicides or pesticides) plant material can include up to 30% of extraneous herbs and weeds, which can change the composition of the oil.²

Lesser-quality EOs are the result of adulteration, contamination, inadequate oil production, or aging.² Adulteration (eg, cutting, stretching, bouquetting) occurs when foreign substances are introduced into pure EOs for the benefit of a higher profit; to ensure a sufficient supply of oils; or to meet demands for cheaper oils by “stretching” a more expensive, pure oil by combining with a cheaper, less pure oil. Inadequate oil production leading to lower-quality oils can occur when a biomass is incorrectly distilled, either from too much steam or temperatures that are too high or due to lack of adequate cooling units. Aging occurs when the oils are not stored properly, resulting in a change in the chemical composition due to esterification, reduction, and oxidization of chemicals, which leads to the formation of peroxides and hydroperoxides that can be contact allergens.¹⁵

Can patients develop contact allergies to EOs?

The short answer is yes! Contact allergy to almost 80 EOs has been reported,¹⁵ including tea tree oil,^16,17 ylang-ylang oil,^17,18 lavender oil, peppermint oil,¹⁸ jasmine absolute,¹⁷ geranium oil, rose oil,¹⁸ turpentine oil,^19,20 and sandalwood oil.¹⁸ The recent increased prevalence of allergic reactions to EOs likely is due to increased consumer use as well as increased detection from availability of commercial patch-test preparations.

Essential oils have many common ingredients. De Groot and Schmidt³ documented that 14 of 23 chemicals present in more than 80% of EOs have been reported to cause contact allergy. Interestingly, allergic patients often react to more than one EO, which may be explained by the many shared chemical components in EOs.

Essential oils are “natural” so they must be safe?

In general, most safety profiles are good, but rare toxic reactions from EOs have been observed.⁴ A recent Australian study reviewed EO exposure calls to the New South Wales Poisons Information Centre.²¹ The majority of EO poisonings were accidental or the result of therapeutic error such as mistaking EOs for liquid pharmaceuticals. Additionally, this study found that from July 2014 to June 2018, there was a 5% increase in the number of calls per year. More than half of EO poisoning calls involved children, with toddlers being the most frequent cases, suggesting the need for child-resistant top closures. The most frequently involved EOs in poisonings were eucalyptus (46.4% [n=2049]), tea tree (17% [n=749]), lavender (6.1% [n=271]), clove (4.1% [n=179]), and peppermint (3.5% [n=154]).²¹ Essential oils do not come without potential pitfalls.

What is the clinical presentation and workup?

The workup of EO allergic contact dermatitis begins with obtaining a history to evaluate for use of EO diffusers, perfumes, hygiene products, cosmetics, massage oils, toothpastes, and/or pharmaceutical products. Exploration of potential exposures through occupation, environment, and hobbies also is indicated. Clinical presentation is dependent on the mechanism of exposure. Contact allergy may result from direct application of an allergen to the skin or mucous membranes, contact with a contaminated environmental item (eg, lavender oil on a pillow), contact with EOs used by partners or coworkers (consort dermatitis), airborne exposure (EO diffusers), or systemic exposure (flavorings). Airborne dermatitis from EO diffusers may involve the exposed areas of the face, neck, forearms, arms, behind the earlobes, bilateral eyelids, nasolabial folds, and under the chin. History and clinical presentation can raise suspicion for allergic contact dermatitis, and patch testing is necessary to confirm the diagnosis.

How do we patch test for EO contact allergy?

There are many EOs commercially available for patch testing, and they typically are tested at 2% to 5% concentrations in petrolatum.¹⁵ A North American and European study of 62,354 patch-tested patients found that 7.4% of EO-positive individuals did not react to fragrance allergens in a standard screening series including fragrance mix I, fragrance mix II, and balsam of Peru, highlighting the importance of patch testing with specific EOs.²² Currently, only 3 EOs—tea tree oil, peppermint oil, and ylang-ylang oil—are included in the 2019-2020 North American Contact Dermatitis Group screening series, making supplemental testing for other EOs important if contact allergy is suspected; however, testing the patient’s own products is imperative, as there is strong variability in the composition of EOs. Additionally, aged oils may have been exposed to light, oxygen, or varying temperatures, which could result in the formation of additional allergenic chemicals not present in commercially available preparations.¹⁵ In addition to commercially available allergens, we test patient-provided EOs either as is in semi-open fashion (ie, EOs are applied to patient’s back with a cotton swab, allowed to dry, covered with adhesive tape, and read at the same interval as other patch tests²³) or occasionally dilute them to 1% or 10% (in olive oil or mineral oil).

How should I manage a positive patch-test reaction to EOs?

Patients should avoid relevant EO allergens in their products and environment, which can be easily achieved with the use of the American Contact Dermatitis Society’s Contact Allergen Management Program or similar databases.

Final Interpretation

We are ubiquitously exposed to EOs every day—through the products we use at home, at work, and in our environment. Essential oils make their place in the world by providing sweet-smelling aromas in addition to their alleged therapeutic properties; however, beware, EOs may be the culprit of your next patient’s allergic contact dermatitis.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.

One of the perils of patch testing is fielding questions about which type of allergens will be used. Patients often ask if the patch test includes milk, foods, dander, mold, pets, and grass. Most patch testers spend a substantial amount of time explaining that the purpose of patch testing is to detect applied chemical allergens: It’s not what you eat; rather, it’s what touches your skin. However, the big caveat is that some oral, parenteral, inhaled, and even cutaneous allergens can produce systemic contact dermatitis (SCD), which represents a unique clinical scenario that we will review in this month’s Final Interpretation column.

There are many patterns of SCD. Familiarity with potential clinical presentations can aid in diagnosis and counseling. Systemic contact dermatitis tends to be symmetrical. Dyshidrotic hand dermatitis is a reported pattern for systemic metal allergy, most commonly nickel. Refractory eyelid or genital dermatitis can reflect a systemic exposure, particularly if the dermatitis is in areas not caused by direct skin contact with the allergen. Systemic drug-related intertriginous and flexural exanthema is, as the name describes, an eruption involving axillae, genital skin, and flexural sites. It usually is a type of drug reaction, but the culprit can be an ingested allergen. So-called baboon syndrome SCD can cause persistent genital and intertriginous dermatitis. Other clues to SCD include dermatitis flare at the patch test site and erythema multiforme. Some patients also describe systemic symptoms, including headache, fatigue, and malaise.

Rhus Dermatitis

Poison ivy is the most common cause of acute contact dermatitis but also can be a cause of SCD. From the family Anacardiaceae, this sneaky plant is common in many parts of the United States; most allergic patients are familiar with their allergy from prior exposure.

In 1982, 54 Little League baseball attendees developed diffuse vesicular dermatitis involving the flexures after ingesting packaged cashews contaminated with cashew shells.¹ In the same family as poison ivy, the cashew nut tree (Anacardium occidentale) produces a cashew apple containing the cashew nut. The cashew shell is the site that contains the allergenic oils. Typically, cashews are processed to remove the shell and oil prior to consumption. Ingestion of raw cashews is more likely to lead to SCD than roasted cashews because the heat in the roasting process can break down any allergenic oil.²

Metals

Systemic exposures to nickel usually are dietary. Clinically, SCD from nickel most commonly presents as refractory dyshidrotic hand eczema or papular elbow dermatitis.³ Nickel is commonly found in vitamins and supplements as well as certain whole grains, vegetables, beans, coffee, chocolate, and tea.⁴ Sometimes, cookware also can be a source of nickel exposure, particularly with steel cookware, from which nickel can leach into food.

In general, a diet lower than 150 μg/d is needed to prevent flares.⁵ A point-based diet is available for nickel-allergic patients.⁵ Patients should ingest a restricted amount of nickel (15 points daily); those who are extremely allergic might need to limit nickel ingestion to less than 5 points daily. Because of the challenges associated with maintaining a low-nickel diet, chelation therapy has been recommended to prevent nickel absorption. Disulfiram³ and ascorbic acid⁵ have been recommended, but larger studies are lacking.

Cobalt and chromium are other metals that, when ingested, can lead to SCD; both can be found in multivitamins. Other sources of dietary chromium include vegetables, coffee, beans, certain meats, and seafood.⁴ For cobalt, the dietary exposures are similar with the addition of nuts, apricots, and whole-grain flour. A point-based cobalt avoidance diet has been published. This diet recommends less than 12 μg of cobalt daily; patients can ingest up to 12 cobalt points daily.⁶

Likewise, gold has been reported to cause SCD, with one case attributed to gold in a homeopathic cardiac medication.⁷ Gold SCD also should be considered in the setting of ingested gold-containing alcoholic beverages and historically has been associated with intramuscular gold sodium thiomalate for the treatment of rheumatoid arthritis.⁸

Metal implants, including prosthetic joints, stents, and other devices, have been implicated in SCD. (More to come on this topic soon; yes, dear reader, that is a teaser!)

Fragrances

Balsam of Peru
Secreted by the tree Myroxylon balsamum var pereirae, balsam of Peru (BOP) contains several potential allergens, including cinnamon oils (eg, eugenol, vanillin, cinnamates), coniferin derivatives, and benzoic acid derivatives.⁹ Foods and beverages associated with BOP include citrus, pickled vegetables, chocolate, ice cream, chili, pizza, tomatoes, wine, beer, gin, vermouth, flavored tea, and soft drinks.¹⁰ Flavoring agents, spices (eg, cloves, curry, vanilla, cinnamon, allspice, ginger, anise), and condiments (eg, ketchup, barbeque sauce) are potential sources, as are cough medicines, lozenges, and flavored tobacco.

Salam and Fowler¹⁰ described BOP-allergic patients whose condition improved with dietary restriction of BOP. Avoidance of tomatoes, citrus, spices, and cola most commonly contributed to improvement.¹⁰ Scheman et al⁹ proposed BOP subgroups, including the eugenol, vanillin, cinnamate, benzoate, ferulic acid, and coniferin groups. Targeted patch testing can identify relevant subgroups, and patients can focus dietary restrictions by subgroup.

Plants
Systemic contact dermatitis has been reported in association with a number of plants and herbals, including chamomile in tea,¹¹ goldenrod in a medicated extract,¹²Hosta plantaginea roots,¹³ and garlic extract for hyperlipidemia.¹⁴ Many more have been described.

Propolis
Also known as bee glue, propolis comprises a mixture of balsams, resins, waxes, essential oils, pollen, cinnamic alcohol, and vitamins. It can be found in many cosmetic products, foods, and chewing gum.¹⁵ Propolis has been reported to be the source of SCD from ingestion of propolis capsules, which have been used to promote immune stimulation,¹⁵ and propolis solution as a natural tonic.¹⁶

Propylene Glycol

Propylene glycol (PG) can be found in (believe it or not) foods and medications. In foods, it typically is used for its softening, humectant, and preservative properties.¹⁷ Common food sources of PG include sauces, desserts, snack foods, and salad dressings.

Many topical prescription medications, including corticosteroids and newer nonsteroidal anti-inflammatory topicals, might contain PG; providers must specifically request PG-free products for PG-allergic patients. A detailed PG-avoidance diet lists products to avoid and products that are PG free.¹⁸

Preservatives

Sulfites
These compounds are preservatives found in cosmetics, hair dyes, and certain foods. Systemic contact dermatitis caused by sulfites in food has been described in numerous patients. One unfortunate vacationer developed axillary and groin dermatitis after ingesting large amounts of grapes, wine, shrimp, and french fries while vacationing in Italy.¹⁹ Among dietary sources, beer and wine contain higher levels of sulfites. Sulfites also can be found in some pickled foods; bottled citrus juice; dried fruits; and commercial prepared foods, such as powdered potatoes and gravy mixes. Other reports of SCD from sulfites include an enema preparation²⁰ and anesthetics²¹ as the source of the allergen.

Formaldehyde
Formaldehyde can cause SCD after ingestion of aspartame, which is hydrolyzed to phenylalanine, aspartic acid, and aspartic acid methyl ester in the intestine.²² The methyl ester is converted to methyl alcohol, which is transported to the liver and oxidized to formaldehyde, which is then converted to formic acid. Hill and Belsito²² reported a case of SCD presenting as eyelid dermatitis after ingestion of an aspartame-based artificial sweetener. A similar case of eyelid, neck, and leg dermatitis was reported after ingestion of drinks and candy sweetened with aspartame.²³

Parabens
Although parabens are rare contact sensitizers, there are a few reports of paraben SCD. Cases include a predominantly flexural pattern from ingestion of a mucolytic-containing methylparaben,²⁴ a generalized eczematous eruption after intramuscular injection of ampicillin preserved with methylparaben and propylparaben,²⁵ and diffuse dermatitis from methylparaben in a local anesthetic.²⁶

Sorbic Acid
Sorbic acid is utilized as a preservative in foods and occurs naturally in red fruit, such as strawberries and cranberries.²⁷ It is a rare allergen, but several cases of sorbic acid SCD have been reported, including perianal and buttock dermatitis,²⁷ hand dermatitis in an infant,²⁸ and hand-and-foot dermatitis in a storekeeper.²⁹

Carmine

Carmine, or cochineal extract, is a red dye derived from dried pulverized scale insects of the family Coccidae. This chemical can be used in a multitude of foods and medications, including candies, yogurt, red velvet items, popsicles, food coloring, frozen meat and fish, ice cream, syrups, ketchup, sausage, donuts, cake pops, applesauce, canned fruits, soups, and drinks.³⁰ Machler and Jacob³¹ described a child with recurrent episodes of erythroderma and periorbital edema in whom patch testing revealed a reaction to carmine. The patient’s mother connected the flares with ingestion of red velvet cupcakes.³¹ Ferris et al³² reported a likely case of SCD attributed to carmine in a multivitamin.

Steroids

Ingested and injected corticosteroids have been associated with SCD, which is illustrated by a case of a generalized cutaneous eruption several days after joint injection with triamcinolone acetonide.³³ In another report, a patient developed an eruption in the body folds, later generalized, after topical application of a corticosteroid, first in ear drops and later in nasal spray.³⁴ Traditional corticosteroid classification systems might be less reliable in predicting relevant allergens in corticosteroid SCD; comprehensive testing, including oral challenge, might be necessary to identify alternatives.³³

Ethylenediamine

Ethylenediamine is an uncommon allergen in patch test populations. It is present in aminophylline³⁵ and is utilized in the production of hydroxyzine³⁶ and other piperazine-derived medications, such as cetirizine, levocetirizine, meclizine, and olanzapine. Several cases of SCD caused by aminophylline,³⁵ cetirizine,³⁶ and hydroxyzine³⁷ have been reported, all in the setting of a positive patch test reaction to ethylenediamine.

When to Counsel About Systemic Exposures

In general, we usually do not counsel on systemic exposures to allergens at the final patch test reading unless the pattern of dermatitis or clinical history strongly suggests systemic exposure. In most cases, we find that counseling on topical allergen avoidance alone is sufficient to treat allergic contact dermatitis. Because of the restrictive nature of allergen-avoidance diets, counseling all patients on the potential for SCD might cause undue stress without much benefit. However, if a patient experiences persistent dermatitis on follow-up with topical avoidance alone, we often will delve into systemic exposures and counsel on further avoidance strategies, including medication and diet.

Final Interpretation

A multitude of chemicals have been reported as the source of SCD; these exposures can occur through ingestion, injection, and inhaled and cutaneous routes. Chemicals present in foods, medications, and beverages have been implicated. Systemic contact dermatitis is rare and should be considered when traditional avoidance of contact allergens is unsuccessful and the clinical pattern is consistent with SCD.

One of the perils of patch testing is fielding questions about which type of allergens will be used. Patients often ask if the patch test includes milk, foods, dander, mold, pets, and grass. Most patch testers spend a substantial amount of time explaining that the purpose of patch testing is to detect applied chemical allergens: It’s not what you eat; rather, it’s what touches your skin. However, the big caveat is that some oral, parenteral, inhaled, and even cutaneous allergens can produce systemic contact dermatitis (SCD), which represents a unique clinical scenario that we will review in this month’s Final Interpretation column.

There are many patterns of SCD. Familiarity with potential clinical presentations can aid in diagnosis and counseling. Systemic contact dermatitis tends to be symmetrical. Dyshidrotic hand dermatitis is a reported pattern for systemic metal allergy, most commonly nickel. Refractory eyelid or genital dermatitis can reflect a systemic exposure, particularly if the dermatitis is in areas not caused by direct skin contact with the allergen. Systemic drug-related intertriginous and flexural exanthema is, as the name describes, an eruption involving axillae, genital skin, and flexural sites. It usually is a type of drug reaction, but the culprit can be an ingested allergen. So-called baboon syndrome SCD can cause persistent genital and intertriginous dermatitis. Other clues to SCD include dermatitis flare at the patch test site and erythema multiforme. Some patients also describe systemic symptoms, including headache, fatigue, and malaise.

Rhus Dermatitis

Poison ivy is the most common cause of acute contact dermatitis but also can be a cause of SCD. From the family Anacardiaceae, this sneaky plant is common in many parts of the United States; most allergic patients are familiar with their allergy from prior exposure.

In 1982, 54 Little League baseball attendees developed diffuse vesicular dermatitis involving the flexures after ingesting packaged cashews contaminated with cashew shells.¹ In the same family as poison ivy, the cashew nut tree (Anacardium occidentale) produces a cashew apple containing the cashew nut. The cashew shell is the site that contains the allergenic oils. Typically, cashews are processed to remove the shell and oil prior to consumption. Ingestion of raw cashews is more likely to lead to SCD than roasted cashews because the heat in the roasting process can break down any allergenic oil.²

Metals

Systemic exposures to nickel usually are dietary. Clinically, SCD from nickel most commonly presents as refractory dyshidrotic hand eczema or papular elbow dermatitis.³ Nickel is commonly found in vitamins and supplements as well as certain whole grains, vegetables, beans, coffee, chocolate, and tea.⁴ Sometimes, cookware also can be a source of nickel exposure, particularly with steel cookware, from which nickel can leach into food.

In general, a diet lower than 150 μg/d is needed to prevent flares.⁵ A point-based diet is available for nickel-allergic patients.⁵ Patients should ingest a restricted amount of nickel (15 points daily); those who are extremely allergic might need to limit nickel ingestion to less than 5 points daily. Because of the challenges associated with maintaining a low-nickel diet, chelation therapy has been recommended to prevent nickel absorption. Disulfiram³ and ascorbic acid⁵ have been recommended, but larger studies are lacking.

Cobalt and chromium are other metals that, when ingested, can lead to SCD; both can be found in multivitamins. Other sources of dietary chromium include vegetables, coffee, beans, certain meats, and seafood.⁴ For cobalt, the dietary exposures are similar with the addition of nuts, apricots, and whole-grain flour. A point-based cobalt avoidance diet has been published. This diet recommends less than 12 μg of cobalt daily; patients can ingest up to 12 cobalt points daily.⁶

Likewise, gold has been reported to cause SCD, with one case attributed to gold in a homeopathic cardiac medication.⁷ Gold SCD also should be considered in the setting of ingested gold-containing alcoholic beverages and historically has been associated with intramuscular gold sodium thiomalate for the treatment of rheumatoid arthritis.⁸

Metal implants, including prosthetic joints, stents, and other devices, have been implicated in SCD. (More to come on this topic soon; yes, dear reader, that is a teaser!)

Fragrances

Balsam of Peru
Secreted by the tree Myroxylon balsamum var pereirae, balsam of Peru (BOP) contains several potential allergens, including cinnamon oils (eg, eugenol, vanillin, cinnamates), coniferin derivatives, and benzoic acid derivatives.⁹ Foods and beverages associated with BOP include citrus, pickled vegetables, chocolate, ice cream, chili, pizza, tomatoes, wine, beer, gin, vermouth, flavored tea, and soft drinks.¹⁰ Flavoring agents, spices (eg, cloves, curry, vanilla, cinnamon, allspice, ginger, anise), and condiments (eg, ketchup, barbeque sauce) are potential sources, as are cough medicines, lozenges, and flavored tobacco.

Salam and Fowler¹⁰ described BOP-allergic patients whose condition improved with dietary restriction of BOP. Avoidance of tomatoes, citrus, spices, and cola most commonly contributed to improvement.¹⁰ Scheman et al⁹ proposed BOP subgroups, including the eugenol, vanillin, cinnamate, benzoate, ferulic acid, and coniferin groups. Targeted patch testing can identify relevant subgroups, and patients can focus dietary restrictions by subgroup.

Plants
Systemic contact dermatitis has been reported in association with a number of plants and herbals, including chamomile in tea,¹¹ goldenrod in a medicated extract,¹²Hosta plantaginea roots,¹³ and garlic extract for hyperlipidemia.¹⁴ Many more have been described.

Propolis
Also known as bee glue, propolis comprises a mixture of balsams, resins, waxes, essential oils, pollen, cinnamic alcohol, and vitamins. It can be found in many cosmetic products, foods, and chewing gum.¹⁵ Propolis has been reported to be the source of SCD from ingestion of propolis capsules, which have been used to promote immune stimulation,¹⁵ and propolis solution as a natural tonic.¹⁶

Propylene Glycol

Propylene glycol (PG) can be found in (believe it or not) foods and medications. In foods, it typically is used for its softening, humectant, and preservative properties.¹⁷ Common food sources of PG include sauces, desserts, snack foods, and salad dressings.

Many topical prescription medications, including corticosteroids and newer nonsteroidal anti-inflammatory topicals, might contain PG; providers must specifically request PG-free products for PG-allergic patients. A detailed PG-avoidance diet lists products to avoid and products that are PG free.¹⁸

Preservatives

Sulfites
These compounds are preservatives found in cosmetics, hair dyes, and certain foods. Systemic contact dermatitis caused by sulfites in food has been described in numerous patients. One unfortunate vacationer developed axillary and groin dermatitis after ingesting large amounts of grapes, wine, shrimp, and french fries while vacationing in Italy.¹⁹ Among dietary sources, beer and wine contain higher levels of sulfites. Sulfites also can be found in some pickled foods; bottled citrus juice; dried fruits; and commercial prepared foods, such as powdered potatoes and gravy mixes. Other reports of SCD from sulfites include an enema preparation²⁰ and anesthetics²¹ as the source of the allergen.

Formaldehyde
Formaldehyde can cause SCD after ingestion of aspartame, which is hydrolyzed to phenylalanine, aspartic acid, and aspartic acid methyl ester in the intestine.²² The methyl ester is converted to methyl alcohol, which is transported to the liver and oxidized to formaldehyde, which is then converted to formic acid. Hill and Belsito²² reported a case of SCD presenting as eyelid dermatitis after ingestion of an aspartame-based artificial sweetener. A similar case of eyelid, neck, and leg dermatitis was reported after ingestion of drinks and candy sweetened with aspartame.²³

Parabens
Although parabens are rare contact sensitizers, there are a few reports of paraben SCD. Cases include a predominantly flexural pattern from ingestion of a mucolytic-containing methylparaben,²⁴ a generalized eczematous eruption after intramuscular injection of ampicillin preserved with methylparaben and propylparaben,²⁵ and diffuse dermatitis from methylparaben in a local anesthetic.²⁶

Sorbic Acid
Sorbic acid is utilized as a preservative in foods and occurs naturally in red fruit, such as strawberries and cranberries.²⁷ It is a rare allergen, but several cases of sorbic acid SCD have been reported, including perianal and buttock dermatitis,²⁷ hand dermatitis in an infant,²⁸ and hand-and-foot dermatitis in a storekeeper.²⁹

Carmine

Carmine, or cochineal extract, is a red dye derived from dried pulverized scale insects of the family Coccidae. This chemical can be used in a multitude of foods and medications, including candies, yogurt, red velvet items, popsicles, food coloring, frozen meat and fish, ice cream, syrups, ketchup, sausage, donuts, cake pops, applesauce, canned fruits, soups, and drinks.³⁰ Machler and Jacob³¹ described a child with recurrent episodes of erythroderma and periorbital edema in whom patch testing revealed a reaction to carmine. The patient’s mother connected the flares with ingestion of red velvet cupcakes.³¹ Ferris et al³² reported a likely case of SCD attributed to carmine in a multivitamin.

Steroids

Ingested and injected corticosteroids have been associated with SCD, which is illustrated by a case of a generalized cutaneous eruption several days after joint injection with triamcinolone acetonide.³³ In another report, a patient developed an eruption in the body folds, later generalized, after topical application of a corticosteroid, first in ear drops and later in nasal spray.³⁴ Traditional corticosteroid classification systems might be less reliable in predicting relevant allergens in corticosteroid SCD; comprehensive testing, including oral challenge, might be necessary to identify alternatives.³³

Ethylenediamine

Ethylenediamine is an uncommon allergen in patch test populations. It is present in aminophylline³⁵ and is utilized in the production of hydroxyzine³⁶ and other piperazine-derived medications, such as cetirizine, levocetirizine, meclizine, and olanzapine. Several cases of SCD caused by aminophylline,³⁵ cetirizine,³⁶ and hydroxyzine³⁷ have been reported, all in the setting of a positive patch test reaction to ethylenediamine.

When to Counsel About Systemic Exposures

In general, we usually do not counsel on systemic exposures to allergens at the final patch test reading unless the pattern of dermatitis or clinical history strongly suggests systemic exposure. In most cases, we find that counseling on topical allergen avoidance alone is sufficient to treat allergic contact dermatitis. Because of the restrictive nature of allergen-avoidance diets, counseling all patients on the potential for SCD might cause undue stress without much benefit. However, if a patient experiences persistent dermatitis on follow-up with topical avoidance alone, we often will delve into systemic exposures and counsel on further avoidance strategies, including medication and diet.

Final Interpretation

A multitude of chemicals have been reported as the source of SCD; these exposures can occur through ingestion, injection, and inhaled and cutaneous routes. Chemicals present in foods, medications, and beverages have been implicated. Systemic contact dermatitis is rare and should be considered when traditional avoidance of contact allergens is unsuccessful and the clinical pattern is consistent with SCD.

One of the perils of patch testing is fielding questions about which type of allergens will be used. Patients often ask if the patch test includes milk, foods, dander, mold, pets, and grass. Most patch testers spend a substantial amount of time explaining that the purpose of patch testing is to detect applied chemical allergens: It’s not what you eat; rather, it’s what touches your skin. However, the big caveat is that some oral, parenteral, inhaled, and even cutaneous allergens can produce systemic contact dermatitis (SCD), which represents a unique clinical scenario that we will review in this month’s Final Interpretation column.

There are many patterns of SCD. Familiarity with potential clinical presentations can aid in diagnosis and counseling. Systemic contact dermatitis tends to be symmetrical. Dyshidrotic hand dermatitis is a reported pattern for systemic metal allergy, most commonly nickel. Refractory eyelid or genital dermatitis can reflect a systemic exposure, particularly if the dermatitis is in areas not caused by direct skin contact with the allergen. Systemic drug-related intertriginous and flexural exanthema is, as the name describes, an eruption involving axillae, genital skin, and flexural sites. It usually is a type of drug reaction, but the culprit can be an ingested allergen. So-called baboon syndrome SCD can cause persistent genital and intertriginous dermatitis. Other clues to SCD include dermatitis flare at the patch test site and erythema multiforme. Some patients also describe systemic symptoms, including headache, fatigue, and malaise.

Rhus Dermatitis

Poison ivy is the most common cause of acute contact dermatitis but also can be a cause of SCD. From the family Anacardiaceae, this sneaky plant is common in many parts of the United States; most allergic patients are familiar with their allergy from prior exposure.

In 1982, 54 Little League baseball attendees developed diffuse vesicular dermatitis involving the flexures after ingesting packaged cashews contaminated with cashew shells.¹ In the same family as poison ivy, the cashew nut tree (Anacardium occidentale) produces a cashew apple containing the cashew nut. The cashew shell is the site that contains the allergenic oils. Typically, cashews are processed to remove the shell and oil prior to consumption. Ingestion of raw cashews is more likely to lead to SCD than roasted cashews because the heat in the roasting process can break down any allergenic oil.²

Metals

Systemic exposures to nickel usually are dietary. Clinically, SCD from nickel most commonly presents as refractory dyshidrotic hand eczema or papular elbow dermatitis.³ Nickel is commonly found in vitamins and supplements as well as certain whole grains, vegetables, beans, coffee, chocolate, and tea.⁴ Sometimes, cookware also can be a source of nickel exposure, particularly with steel cookware, from which nickel can leach into food.

In general, a diet lower than 150 μg/d is needed to prevent flares.⁵ A point-based diet is available for nickel-allergic patients.⁵ Patients should ingest a restricted amount of nickel (15 points daily); those who are extremely allergic might need to limit nickel ingestion to less than 5 points daily. Because of the challenges associated with maintaining a low-nickel diet, chelation therapy has been recommended to prevent nickel absorption. Disulfiram³ and ascorbic acid⁵ have been recommended, but larger studies are lacking.

Cobalt and chromium are other metals that, when ingested, can lead to SCD; both can be found in multivitamins. Other sources of dietary chromium include vegetables, coffee, beans, certain meats, and seafood.⁴ For cobalt, the dietary exposures are similar with the addition of nuts, apricots, and whole-grain flour. A point-based cobalt avoidance diet has been published. This diet recommends less than 12 μg of cobalt daily; patients can ingest up to 12 cobalt points daily.⁶

Likewise, gold has been reported to cause SCD, with one case attributed to gold in a homeopathic cardiac medication.⁷ Gold SCD also should be considered in the setting of ingested gold-containing alcoholic beverages and historically has been associated with intramuscular gold sodium thiomalate for the treatment of rheumatoid arthritis.⁸

Metal implants, including prosthetic joints, stents, and other devices, have been implicated in SCD. (More to come on this topic soon; yes, dear reader, that is a teaser!)

Fragrances

Balsam of Peru
Secreted by the tree Myroxylon balsamum var pereirae, balsam of Peru (BOP) contains several potential allergens, including cinnamon oils (eg, eugenol, vanillin, cinnamates), coniferin derivatives, and benzoic acid derivatives.⁹ Foods and beverages associated with BOP include citrus, pickled vegetables, chocolate, ice cream, chili, pizza, tomatoes, wine, beer, gin, vermouth, flavored tea, and soft drinks.¹⁰ Flavoring agents, spices (eg, cloves, curry, vanilla, cinnamon, allspice, ginger, anise), and condiments (eg, ketchup, barbeque sauce) are potential sources, as are cough medicines, lozenges, and flavored tobacco.

Salam and Fowler¹⁰ described BOP-allergic patients whose condition improved with dietary restriction of BOP. Avoidance of tomatoes, citrus, spices, and cola most commonly contributed to improvement.¹⁰ Scheman et al⁹ proposed BOP subgroups, including the eugenol, vanillin, cinnamate, benzoate, ferulic acid, and coniferin groups. Targeted patch testing can identify relevant subgroups, and patients can focus dietary restrictions by subgroup.

Plants
Systemic contact dermatitis has been reported in association with a number of plants and herbals, including chamomile in tea,¹¹ goldenrod in a medicated extract,¹²Hosta plantaginea roots,¹³ and garlic extract for hyperlipidemia.¹⁴ Many more have been described.

Propolis
Also known as bee glue, propolis comprises a mixture of balsams, resins, waxes, essential oils, pollen, cinnamic alcohol, and vitamins. It can be found in many cosmetic products, foods, and chewing gum.¹⁵ Propolis has been reported to be the source of SCD from ingestion of propolis capsules, which have been used to promote immune stimulation,¹⁵ and propolis solution as a natural tonic.¹⁶

Propylene Glycol

Propylene glycol (PG) can be found in (believe it or not) foods and medications. In foods, it typically is used for its softening, humectant, and preservative properties.¹⁷ Common food sources of PG include sauces, desserts, snack foods, and salad dressings.

Many topical prescription medications, including corticosteroids and newer nonsteroidal anti-inflammatory topicals, might contain PG; providers must specifically request PG-free products for PG-allergic patients. A detailed PG-avoidance diet lists products to avoid and products that are PG free.¹⁸

Preservatives

Sulfites
These compounds are preservatives found in cosmetics, hair dyes, and certain foods. Systemic contact dermatitis caused by sulfites in food has been described in numerous patients. One unfortunate vacationer developed axillary and groin dermatitis after ingesting large amounts of grapes, wine, shrimp, and french fries while vacationing in Italy.¹⁹ Among dietary sources, beer and wine contain higher levels of sulfites. Sulfites also can be found in some pickled foods; bottled citrus juice; dried fruits; and commercial prepared foods, such as powdered potatoes and gravy mixes. Other reports of SCD from sulfites include an enema preparation²⁰ and anesthetics²¹ as the source of the allergen.

Formaldehyde
Formaldehyde can cause SCD after ingestion of aspartame, which is hydrolyzed to phenylalanine, aspartic acid, and aspartic acid methyl ester in the intestine.²² The methyl ester is converted to methyl alcohol, which is transported to the liver and oxidized to formaldehyde, which is then converted to formic acid. Hill and Belsito²² reported a case of SCD presenting as eyelid dermatitis after ingestion of an aspartame-based artificial sweetener. A similar case of eyelid, neck, and leg dermatitis was reported after ingestion of drinks and candy sweetened with aspartame.²³

Parabens
Although parabens are rare contact sensitizers, there are a few reports of paraben SCD. Cases include a predominantly flexural pattern from ingestion of a mucolytic-containing methylparaben,²⁴ a generalized eczematous eruption after intramuscular injection of ampicillin preserved with methylparaben and propylparaben,²⁵ and diffuse dermatitis from methylparaben in a local anesthetic.²⁶

Sorbic Acid
Sorbic acid is utilized as a preservative in foods and occurs naturally in red fruit, such as strawberries and cranberries.²⁷ It is a rare allergen, but several cases of sorbic acid SCD have been reported, including perianal and buttock dermatitis,²⁷ hand dermatitis in an infant,²⁸ and hand-and-foot dermatitis in a storekeeper.²⁹

Carmine

Carmine, or cochineal extract, is a red dye derived from dried pulverized scale insects of the family Coccidae. This chemical can be used in a multitude of foods and medications, including candies, yogurt, red velvet items, popsicles, food coloring, frozen meat and fish, ice cream, syrups, ketchup, sausage, donuts, cake pops, applesauce, canned fruits, soups, and drinks.³⁰ Machler and Jacob³¹ described a child with recurrent episodes of erythroderma and periorbital edema in whom patch testing revealed a reaction to carmine. The patient’s mother connected the flares with ingestion of red velvet cupcakes.³¹ Ferris et al³² reported a likely case of SCD attributed to carmine in a multivitamin.

Steroids

Ingested and injected corticosteroids have been associated with SCD, which is illustrated by a case of a generalized cutaneous eruption several days after joint injection with triamcinolone acetonide.³³ In another report, a patient developed an eruption in the body folds, later generalized, after topical application of a corticosteroid, first in ear drops and later in nasal spray.³⁴ Traditional corticosteroid classification systems might be less reliable in predicting relevant allergens in corticosteroid SCD; comprehensive testing, including oral challenge, might be necessary to identify alternatives.³³

Ethylenediamine

Ethylenediamine is an uncommon allergen in patch test populations. It is present in aminophylline³⁵ and is utilized in the production of hydroxyzine³⁶ and other piperazine-derived medications, such as cetirizine, levocetirizine, meclizine, and olanzapine. Several cases of SCD caused by aminophylline,³⁵ cetirizine,³⁶ and hydroxyzine³⁷ have been reported, all in the setting of a positive patch test reaction to ethylenediamine.

When to Counsel About Systemic Exposures

In general, we usually do not counsel on systemic exposures to allergens at the final patch test reading unless the pattern of dermatitis or clinical history strongly suggests systemic exposure. In most cases, we find that counseling on topical allergen avoidance alone is sufficient to treat allergic contact dermatitis. Because of the restrictive nature of allergen-avoidance diets, counseling all patients on the potential for SCD might cause undue stress without much benefit. However, if a patient experiences persistent dermatitis on follow-up with topical avoidance alone, we often will delve into systemic exposures and counsel on further avoidance strategies, including medication and diet.

Final Interpretation

A multitude of chemicals have been reported as the source of SCD; these exposures can occur through ingestion, injection, and inhaled and cutaneous routes. Chemicals present in foods, medications, and beverages have been implicated. Systemic contact dermatitis is rare and should be considered when traditional avoidance of contact allergens is unsuccessful and the clinical pattern is consistent with SCD.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

Unless you have been living under a rock, you probably already know that the preservative methylisothiazolinone (MI) has caused an epidemic of allergic contact dermatitis (ACD) and was named the 2013 American Contact Dermatitis Society Allergen of the Year.¹ Methylisothiazolinone is not new on the market, but its solo use as a preservative is relatively new. In this article, we review the emergence of MI as a common allergen, discuss North American MI patch test results, and describe common and uncommon sources of MI exposure. We also explore the related isothiazolinones, benzisothiazolinone (BIT) and octylisothiazolinone (OIT).

Background

Methylchloroisothiazolinone (MCI) and MI have been utilized as a preservative in a 3:1 ratio since the 1980s. In 2005, MI was first used alone as a preservative in personal care products in concentrations of up to 100 ppm, which represented a 25-fold increase in exposure to MI in personal care products and thus unleashed an epidemic of ACD.¹ In the 2015 to 2016 cycle of the North American Contact Dermatitis Group (NACDG) patch testing results, MI was found to be positive in 13.4% of patch tested patients (N=5597) and also had the highest significance-prevalence index number, a calculation that represents the relevance of positive reactions in relationship to prevalence.² In Europe, MI is banned in leave-on products and is allowed in rinse-off products in concentrations of up to 15 ppm. In the United States, the Cosmetic Ingredient Review panel concluded that MI is safe at a maximum concentration up to 100 ppm in rinse-off products and safe in leave-on products when formulated to be nonsensitizing, which may be determined based on a quantitative risk assessment.³

It is recommended that MI be patch tested at a concentration of 2000 ppm (0.2% aqueous).⁴ Testing at lower concentrations may result in missed positives. In addition, it should be noted that MCI/MI is present in the T.R.U.E. Test (SmartPractice), but MI alone is not.

Sources of MI Exposure

The first few case reports of MI contact allergy were associated with occupational exposures. In 2004, Isaksson et al⁵ reported 2 cases of MI allergy following exposure to wallpaper glue and a chemical burn from a biocide, respectively. Soon after, Thyssen et al⁶ reported 4 occupational cases of MI allergy at a paint manufacturing plant.

An early case series of MI contact allergy associated with personal care products was published in 2010 in which the authors described adults with ACD from wet wipes and a makeup remover that contained MI.⁷ A more recent report indicated that MI is now an infrequent ingredient in wet wipes but is still found in a wide variety of household and personal care products.⁸ A 2017 query of the American Contact Dermatitis Society’s Contact Allergy Management Program (CAMP) database revealed that 12.9% of all products contained MI. Furthermore, CAMP data revealed that MI was the most commonly found preservative in both hair care and household products.⁹ An additional CAMP database study revealed that 53% of shampoos and 45% of conditioners contained MI, and it also was commonly found in hair dyes, soaps and cleansers, hand cleaners and sanitizers, vaginal hygiene products, sunscreens, and moisturizers.¹⁰

Household products represent an important source of MI exposure. A chemical analysis of water-based paints identified the presence of isothiazolinones. Contact allergy from isothiazolinones in paint can present as either direct or airborne-pattern contact dermatitis.¹¹ Sodium bisulfite has been used to inactivate MCI/MI in wall paint and could be utilized in severe cases of airborne contact dermatitis.¹² Off-gassing may take up to 5.5 weeks before the paint cures and the isothiazolinone level decreases.¹³ A 2016 analysis of household products in the CAMP database revealed that MI commonly was found in dishwashing soap (64%), followed by household cleaners (47%), laundry softeners/additives (30%), surface disinfectants (27%), and laundry detergents (13%).¹⁰ Because certain chemical ingredients are not always listed on household product labels, patients with MI contact allergy may be at higher risk for unanticipated exposure to this allergen.

Dear reader, we know that you know all of this. We know that you have been watching the MI epidemic and have followed its every turn. But something that may be new to you are the unique MI exposures identified over the last several years.

In 2017, MI was identified in the glue used to affix 3 layers of the upper portion of a shoe.¹⁴ In addition, a recent chemical analysis of US consumer adhesives confirmed the presence of isothiazolinones in 50% (19/38) of products; 44.7% (17/38) specifically contained MI.¹⁵ Slime, the sticky play substance that children concoct out of household materials, has caused ACD, and not surprisingly, MI has been identified as a culprit allergen. In one case report, contact allergy was caused by MI present in a slime mixture made up of laundry detergent, dish soap, shampoo, and hand cream.¹⁶ In another case series, 3 children with MI contact allergy had played with slime that included dishwashing liquid, which contained MI, along with polyvinyl acetate glue and liquid soap components.¹⁷ Another case report documented slime made from MI-containing school glue as the source of ACD.¹⁸ Isothiazolinones also have been identified as causative allergens in “noise putty,” another homemade play item.¹⁹

Additionally, there has been a report of contact allergy to MI in a designer eyeglass frame.²⁰ There also have been several documented cases of ACD to MCI/MI aerosolized from water used during ironing.^21,22

There also have been several reports of photoaggravated ACD and possible photoallergic contact dermatitis from MI.^23,24 In such cases, patients also may have transient photosensitivity even when MI exposure is discontinued; therefore, MI should be considered for inclusion in photopatch test panels when relevant.

Methylisothiazolinone contact allergy also should be considered for products that do not list MI on the label, which presents another potential exposure. In products that do not list MI as an ingredient on the label, its presence may be due to inclusion of the preservative in raw materials used in production. For example, a patient who reacted to a facial mask gel had a positive patch test reaction to MI, the facial mask gel, and sodium hyaluronate, the raw ingredient in the gel. Further analysis revealed that MI was unexpectedly present in the sodium hyaluronate.²⁵ Similar scenarios have been reported in association with facial wet wipes,²⁶ an exfoliating facial sponge,²⁷ and a polyurethane sponge from a wound vacuum pump,²⁸ among others.

Other Isothiazolinones

Other isothiazolinones also are known to cause ACD, albeit less commonly than MI. Benzisothiazolinone has been identified in glues, cleaning agents, paints, and industrial chemicals; unlike MI, the presence of BIT is infrequent in personal care products.^15,29 This chemical is not commonly included in patch test screening series in the United States but is currently present in the NACDG screening series as BIT 0.1% in petrolatum.

Octylisothiazolinone (OIT) has been reported in leather furniture, belts, shoes, and watchbands, as well as industrial chemicals.^30,31 Similar to BIT, OIT is not commonly tested in screening series in the United States; the NACDG tests this chemical as OIT 0.025% in petrolatum.

The cross-reaction patterns between the isothiazolinones remain uncertain. A study in mice supported cross-reactivity between MI, OIT, and BIT³²; however, several clinical epidemiologic studies suggested that although there is evidence that there may be cross-reactivity between OIT and MI, concomitant positive BIT and MI reactions more likely represent cosensitization.^33-35

Final Interpretation

Methylisothiazolinone continues to have high positive patch test rates in North American patch test populations and should be tested at a concentration of 2000 ppm (0.2% aqueous). Methylisothiazolinone may now be rare in wet wipes, but it is still present in numerous personal care products including hair care products, liquid soaps, and cleaning products. Novel exposures to MI include paint, slime, and glues. It also is important to remember that MI can cause photoaggravated or photoallergic contact dermatitis and might be a worthy addition to photopatch test trays. Finally, keep a look out for BIT and OIT, which may be present in industrial chemicals, glues, paints, cleaning products, and leather items.

Unless you have been living under a rock, you probably already know that the preservative methylisothiazolinone (MI) has caused an epidemic of allergic contact dermatitis (ACD) and was named the 2013 American Contact Dermatitis Society Allergen of the Year.¹ Methylisothiazolinone is not new on the market, but its solo use as a preservative is relatively new. In this article, we review the emergence of MI as a common allergen, discuss North American MI patch test results, and describe common and uncommon sources of MI exposure. We also explore the related isothiazolinones, benzisothiazolinone (BIT) and octylisothiazolinone (OIT).

Background

Methylchloroisothiazolinone (MCI) and MI have been utilized as a preservative in a 3:1 ratio since the 1980s. In 2005, MI was first used alone as a preservative in personal care products in concentrations of up to 100 ppm, which represented a 25-fold increase in exposure to MI in personal care products and thus unleashed an epidemic of ACD.¹ In the 2015 to 2016 cycle of the North American Contact Dermatitis Group (NACDG) patch testing results, MI was found to be positive in 13.4% of patch tested patients (N=5597) and also had the highest significance-prevalence index number, a calculation that represents the relevance of positive reactions in relationship to prevalence.² In Europe, MI is banned in leave-on products and is allowed in rinse-off products in concentrations of up to 15 ppm. In the United States, the Cosmetic Ingredient Review panel concluded that MI is safe at a maximum concentration up to 100 ppm in rinse-off products and safe in leave-on products when formulated to be nonsensitizing, which may be determined based on a quantitative risk assessment.³

It is recommended that MI be patch tested at a concentration of 2000 ppm (0.2% aqueous).⁴ Testing at lower concentrations may result in missed positives. In addition, it should be noted that MCI/MI is present in the T.R.U.E. Test (SmartPractice), but MI alone is not.

Sources of MI Exposure

The first few case reports of MI contact allergy were associated with occupational exposures. In 2004, Isaksson et al⁵ reported 2 cases of MI allergy following exposure to wallpaper glue and a chemical burn from a biocide, respectively. Soon after, Thyssen et al⁶ reported 4 occupational cases of MI allergy at a paint manufacturing plant.

An early case series of MI contact allergy associated with personal care products was published in 2010 in which the authors described adults with ACD from wet wipes and a makeup remover that contained MI.⁷ A more recent report indicated that MI is now an infrequent ingredient in wet wipes but is still found in a wide variety of household and personal care products.⁸ A 2017 query of the American Contact Dermatitis Society’s Contact Allergy Management Program (CAMP) database revealed that 12.9% of all products contained MI. Furthermore, CAMP data revealed that MI was the most commonly found preservative in both hair care and household products.⁹ An additional CAMP database study revealed that 53% of shampoos and 45% of conditioners contained MI, and it also was commonly found in hair dyes, soaps and cleansers, hand cleaners and sanitizers, vaginal hygiene products, sunscreens, and moisturizers.¹⁰

Household products represent an important source of MI exposure. A chemical analysis of water-based paints identified the presence of isothiazolinones. Contact allergy from isothiazolinones in paint can present as either direct or airborne-pattern contact dermatitis.¹¹ Sodium bisulfite has been used to inactivate MCI/MI in wall paint and could be utilized in severe cases of airborne contact dermatitis.¹² Off-gassing may take up to 5.5 weeks before the paint cures and the isothiazolinone level decreases.¹³ A 2016 analysis of household products in the CAMP database revealed that MI commonly was found in dishwashing soap (64%), followed by household cleaners (47%), laundry softeners/additives (30%), surface disinfectants (27%), and laundry detergents (13%).¹⁰ Because certain chemical ingredients are not always listed on household product labels, patients with MI contact allergy may be at higher risk for unanticipated exposure to this allergen.

Dear reader, we know that you know all of this. We know that you have been watching the MI epidemic and have followed its every turn. But something that may be new to you are the unique MI exposures identified over the last several years.

In 2017, MI was identified in the glue used to affix 3 layers of the upper portion of a shoe.¹⁴ In addition, a recent chemical analysis of US consumer adhesives confirmed the presence of isothiazolinones in 50% (19/38) of products; 44.7% (17/38) specifically contained MI.¹⁵ Slime, the sticky play substance that children concoct out of household materials, has caused ACD, and not surprisingly, MI has been identified as a culprit allergen. In one case report, contact allergy was caused by MI present in a slime mixture made up of laundry detergent, dish soap, shampoo, and hand cream.¹⁶ In another case series, 3 children with MI contact allergy had played with slime that included dishwashing liquid, which contained MI, along with polyvinyl acetate glue and liquid soap components.¹⁷ Another case report documented slime made from MI-containing school glue as the source of ACD.¹⁸ Isothiazolinones also have been identified as causative allergens in “noise putty,” another homemade play item.¹⁹

Additionally, there has been a report of contact allergy to MI in a designer eyeglass frame.²⁰ There also have been several documented cases of ACD to MCI/MI aerosolized from water used during ironing.^21,22

There also have been several reports of photoaggravated ACD and possible photoallergic contact dermatitis from MI.^23,24 In such cases, patients also may have transient photosensitivity even when MI exposure is discontinued; therefore, MI should be considered for inclusion in photopatch test panels when relevant.

Methylisothiazolinone contact allergy also should be considered for products that do not list MI on the label, which presents another potential exposure. In products that do not list MI as an ingredient on the label, its presence may be due to inclusion of the preservative in raw materials used in production. For example, a patient who reacted to a facial mask gel had a positive patch test reaction to MI, the facial mask gel, and sodium hyaluronate, the raw ingredient in the gel. Further analysis revealed that MI was unexpectedly present in the sodium hyaluronate.²⁵ Similar scenarios have been reported in association with facial wet wipes,²⁶ an exfoliating facial sponge,²⁷ and a polyurethane sponge from a wound vacuum pump,²⁸ among others.

Other Isothiazolinones

Other isothiazolinones also are known to cause ACD, albeit less commonly than MI. Benzisothiazolinone has been identified in glues, cleaning agents, paints, and industrial chemicals; unlike MI, the presence of BIT is infrequent in personal care products.^15,29 This chemical is not commonly included in patch test screening series in the United States but is currently present in the NACDG screening series as BIT 0.1% in petrolatum.

Octylisothiazolinone (OIT) has been reported in leather furniture, belts, shoes, and watchbands, as well as industrial chemicals.^30,31 Similar to BIT, OIT is not commonly tested in screening series in the United States; the NACDG tests this chemical as OIT 0.025% in petrolatum.

The cross-reaction patterns between the isothiazolinones remain uncertain. A study in mice supported cross-reactivity between MI, OIT, and BIT³²; however, several clinical epidemiologic studies suggested that although there is evidence that there may be cross-reactivity between OIT and MI, concomitant positive BIT and MI reactions more likely represent cosensitization.^33-35

Final Interpretation

Methylisothiazolinone continues to have high positive patch test rates in North American patch test populations and should be tested at a concentration of 2000 ppm (0.2% aqueous). Methylisothiazolinone may now be rare in wet wipes, but it is still present in numerous personal care products including hair care products, liquid soaps, and cleaning products. Novel exposures to MI include paint, slime, and glues. It also is important to remember that MI can cause photoaggravated or photoallergic contact dermatitis and might be a worthy addition to photopatch test trays. Finally, keep a look out for BIT and OIT, which may be present in industrial chemicals, glues, paints, cleaning products, and leather items.

Unless you have been living under a rock, you probably already know that the preservative methylisothiazolinone (MI) has caused an epidemic of allergic contact dermatitis (ACD) and was named the 2013 American Contact Dermatitis Society Allergen of the Year.¹ Methylisothiazolinone is not new on the market, but its solo use as a preservative is relatively new. In this article, we review the emergence of MI as a common allergen, discuss North American MI patch test results, and describe common and uncommon sources of MI exposure. We also explore the related isothiazolinones, benzisothiazolinone (BIT) and octylisothiazolinone (OIT).

Background

Methylchloroisothiazolinone (MCI) and MI have been utilized as a preservative in a 3:1 ratio since the 1980s. In 2005, MI was first used alone as a preservative in personal care products in concentrations of up to 100 ppm, which represented a 25-fold increase in exposure to MI in personal care products and thus unleashed an epidemic of ACD.¹ In the 2015 to 2016 cycle of the North American Contact Dermatitis Group (NACDG) patch testing results, MI was found to be positive in 13.4% of patch tested patients (N=5597) and also had the highest significance-prevalence index number, a calculation that represents the relevance of positive reactions in relationship to prevalence.² In Europe, MI is banned in leave-on products and is allowed in rinse-off products in concentrations of up to 15 ppm. In the United States, the Cosmetic Ingredient Review panel concluded that MI is safe at a maximum concentration up to 100 ppm in rinse-off products and safe in leave-on products when formulated to be nonsensitizing, which may be determined based on a quantitative risk assessment.³

It is recommended that MI be patch tested at a concentration of 2000 ppm (0.2% aqueous).⁴ Testing at lower concentrations may result in missed positives. In addition, it should be noted that MCI/MI is present in the T.R.U.E. Test (SmartPractice), but MI alone is not.

Sources of MI Exposure

The first few case reports of MI contact allergy were associated with occupational exposures. In 2004, Isaksson et al⁵ reported 2 cases of MI allergy following exposure to wallpaper glue and a chemical burn from a biocide, respectively. Soon after, Thyssen et al⁶ reported 4 occupational cases of MI allergy at a paint manufacturing plant.

An early case series of MI contact allergy associated with personal care products was published in 2010 in which the authors described adults with ACD from wet wipes and a makeup remover that contained MI.⁷ A more recent report indicated that MI is now an infrequent ingredient in wet wipes but is still found in a wide variety of household and personal care products.⁸ A 2017 query of the American Contact Dermatitis Society’s Contact Allergy Management Program (CAMP) database revealed that 12.9% of all products contained MI. Furthermore, CAMP data revealed that MI was the most commonly found preservative in both hair care and household products.⁹ An additional CAMP database study revealed that 53% of shampoos and 45% of conditioners contained MI, and it also was commonly found in hair dyes, soaps and cleansers, hand cleaners and sanitizers, vaginal hygiene products, sunscreens, and moisturizers.¹⁰

Household products represent an important source of MI exposure. A chemical analysis of water-based paints identified the presence of isothiazolinones. Contact allergy from isothiazolinones in paint can present as either direct or airborne-pattern contact dermatitis.¹¹ Sodium bisulfite has been used to inactivate MCI/MI in wall paint and could be utilized in severe cases of airborne contact dermatitis.¹² Off-gassing may take up to 5.5 weeks before the paint cures and the isothiazolinone level decreases.¹³ A 2016 analysis of household products in the CAMP database revealed that MI commonly was found in dishwashing soap (64%), followed by household cleaners (47%), laundry softeners/additives (30%), surface disinfectants (27%), and laundry detergents (13%).¹⁰ Because certain chemical ingredients are not always listed on household product labels, patients with MI contact allergy may be at higher risk for unanticipated exposure to this allergen.

Dear reader, we know that you know all of this. We know that you have been watching the MI epidemic and have followed its every turn. But something that may be new to you are the unique MI exposures identified over the last several years.

In 2017, MI was identified in the glue used to affix 3 layers of the upper portion of a shoe.¹⁴ In addition, a recent chemical analysis of US consumer adhesives confirmed the presence of isothiazolinones in 50% (19/38) of products; 44.7% (17/38) specifically contained MI.¹⁵ Slime, the sticky play substance that children concoct out of household materials, has caused ACD, and not surprisingly, MI has been identified as a culprit allergen. In one case report, contact allergy was caused by MI present in a slime mixture made up of laundry detergent, dish soap, shampoo, and hand cream.¹⁶ In another case series, 3 children with MI contact allergy had played with slime that included dishwashing liquid, which contained MI, along with polyvinyl acetate glue and liquid soap components.¹⁷ Another case report documented slime made from MI-containing school glue as the source of ACD.¹⁸ Isothiazolinones also have been identified as causative allergens in “noise putty,” another homemade play item.¹⁹

Additionally, there has been a report of contact allergy to MI in a designer eyeglass frame.²⁰ There also have been several documented cases of ACD to MCI/MI aerosolized from water used during ironing.^21,22

There also have been several reports of photoaggravated ACD and possible photoallergic contact dermatitis from MI.^23,24 In such cases, patients also may have transient photosensitivity even when MI exposure is discontinued; therefore, MI should be considered for inclusion in photopatch test panels when relevant.

Methylisothiazolinone contact allergy also should be considered for products that do not list MI on the label, which presents another potential exposure. In products that do not list MI as an ingredient on the label, its presence may be due to inclusion of the preservative in raw materials used in production. For example, a patient who reacted to a facial mask gel had a positive patch test reaction to MI, the facial mask gel, and sodium hyaluronate, the raw ingredient in the gel. Further analysis revealed that MI was unexpectedly present in the sodium hyaluronate.²⁵ Similar scenarios have been reported in association with facial wet wipes,²⁶ an exfoliating facial sponge,²⁷ and a polyurethane sponge from a wound vacuum pump,²⁸ among others.

Other Isothiazolinones

Other isothiazolinones also are known to cause ACD, albeit less commonly than MI. Benzisothiazolinone has been identified in glues, cleaning agents, paints, and industrial chemicals; unlike MI, the presence of BIT is infrequent in personal care products.^15,29 This chemical is not commonly included in patch test screening series in the United States but is currently present in the NACDG screening series as BIT 0.1% in petrolatum.

Octylisothiazolinone (OIT) has been reported in leather furniture, belts, shoes, and watchbands, as well as industrial chemicals.^30,31 Similar to BIT, OIT is not commonly tested in screening series in the United States; the NACDG tests this chemical as OIT 0.025% in petrolatum.

The cross-reaction patterns between the isothiazolinones remain uncertain. A study in mice supported cross-reactivity between MI, OIT, and BIT³²; however, several clinical epidemiologic studies suggested that although there is evidence that there may be cross-reactivity between OIT and MI, concomitant positive BIT and MI reactions more likely represent cosensitization.^33-35

Final Interpretation

Methylisothiazolinone continues to have high positive patch test rates in North American patch test populations and should be tested at a concentration of 2000 ppm (0.2% aqueous). Methylisothiazolinone may now be rare in wet wipes, but it is still present in numerous personal care products including hair care products, liquid soaps, and cleaning products. Novel exposures to MI include paint, slime, and glues. It also is important to remember that MI can cause photoaggravated or photoallergic contact dermatitis and might be a worthy addition to photopatch test trays. Finally, keep a look out for BIT and OIT, which may be present in industrial chemicals, glues, paints, cleaning products, and leather items.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Metal allergy in patients with orthopedic implants can cause serious problems including dermatitis and implant failure.¹ As life expectancy increases, the general population ages, and more metallic orthopedic implants are placed,² allergy to these implants is expected to be a problem of greater significance. Uncertainty remains regarding best practice for patients with suspected metal implant allergy.¹ The major questions are: Who should be tested? When should they be tested? What are the optimal tests to diagnose metal allergy?^3-8

We report the case of a patient with vanadium allergy who developed a diffuse eczematous dermatitis and implant failure after receiving a vanadium-containing titanium alloy orthopedic implant in the left foot. This case is remarkable because hypersensitivity reactions to titanium-based hardware are rare, as they traditionally have not been thought to provoke allergic reactions.⁹

Case Report

A 62-year-old woman who was otherwise healthy presented with an eruption of more than 80 pruritic, nummular, eczematous plaques on the arms, legs, back, and buttocks of 3 weeks’ duration (Figure 1). She had a history of allergy to metal used in costume jewelry. Six weeks prior, the patient underwent implantation of a titanium alloy plate in the left foot for surgical repair of painful deforming osteoarthritis. A radiograph of the foot showed appropriate placement. According to the manufacturer, the plate was composed of the compound Ti6Al4V, which contained 90% titanium, 6% aluminum, and 4% vanadium. The lesions developed on the skin close to but not directly over the surgical site.

A punch biopsy of one of the lesions on the shoulder showed lymphoeosinophilic spongiosis consistent with a delayed hypersensitivity reaction (Figure 2). There was mild clinical improvement of the eruption with topical steroids. A course of prednisone for systemic effect resulted in clearing of the eruption, but it promptly recurred on cessation of the steroids. The patient was then patch tested using the North American 80 Comprehensive Series, with an additional 59 common textile, shampoo, fragrance, and several metal allergens, all of which were negative.

After the hardware was removed, it was analyzed to determine the elemental composition of the plate and screws, and the patient was then patch tested with the major metal components of the implant: aluminum chloride hexahydrate 2.0% pet, elemental titanium 10.0% pet, titanium dioxide 10.0% pet, titanium (III) nitride 5.0% pet, titanium (III) oxalate decahydrate 5.0% pet, elemental vanadium 5.0% pet, and vanadium (III) chloride 1.0% pet. She demonstrated a 1+ reaction (erythema and induration) to vanadium trichloride at 72 and 96 hours.

The plate and screws removed from the patient were sterilized and submitted for analysis. Electron microprobe analysis confirmed that the major elemental composition of the plate and screws essentially matched the manufacturer’s listing (Table 1). The trace elements were determined using laser ablative inductively coupled mass spectroscopy, which demonstrated that the screws were of different metal composition from the plate (Table 2). Electron microprobe analysis also was used to determine the microstructure of the plate and screws. The plate had 2 distinct phases consisting of a titanium-aluminum phase and a vanadium phase, whereas the screw was much more homogeneous. Basic electrochemical studies were performed in a salt solution replicating the tissue of the foot. These studies showed that galvanic corrosion could have occurred between the plate and screws due to the differences of composition.

Comment

Titanium is an attractive metal to use in orthopedic implants. It has a high strength-to-weight ratio, a low modulus of elasticity, and good resistance to corrosion. Titanium can be categorized as either commercially pure titanium (cp-Ti) or a titanium alloy. Colloquially, both cp-Ti and titanium alloys are often referred to simply as titanium, but the distinction is important when it comes to medical implants and devices. Commercially pure titanium is more than 99% pure titanium, but up to 1% of its volume can be comprised of impurities.¹⁰ In titanium alloys, the alloy elements are intentionally added to create a material with optimal properties. The 2 most common types of titanium that are used for orthopedic implants are cp-Ti and Ti6Al4V, a titanium alloy containing approximately 90% titanium, 6% aluminum, and 4% vanadium. Similar to cp-Ti, titanium alloys also can contain impurities such as aluminum, beryllium, cobalt, chromium, iron, nickel, and palladium, among many others. Although these impurities often are considered negligible from a metallurgy perspective, as they do not change the properties of the material, these trace elements may be present in large enough quantities to cause hypersensitivity reactions.¹¹

Several weeks after implantation of a titanium alloy metal plate in the left foot, a widespread eczematous eruption developed in our patient who had no prior skin disease. The eruption was steroid responsive but did not clear until the plate was removed. Detailed metallurgy analysis confirmed that vanadium was present and was not homogeneously distributed in the plate. The plate also was different in composition from the screws. Additional studies showed that galvanic corrosion between the plate and the chemically different screws might have contributed to the release of vanadium in the tissue.

Vanadium is known to be allergenic, especially in the presence of implant failure.^12,13 In our patient, patch testing with more than 100 allergens was negative, except for vanadium trichloride 1%. Our patient’s presentation strongly suggested that she developed a vanadium allergy manifesting as systemic allergic contact dermatitis. She demonstrated no history of skin disease, a widespread eczematous eruption after exposure, histology consistent with systemic contact allergy, a positive patch test to vanadium, and clearance of the eruption on removal of the antigen, which have been proposed as objective criteria that support a diagnosis of metal implant allergy.¹⁴ She refused our suggestion to reimplant a portion of the remaining plate under the skin without screws and monitor for recurrence of the eruption. She did not have a lesion overlying the surgical site, but she did develop lesions near the surgical scar. The literature indicates that cutaneous manifestations of allergy to metallic implants can be both localized and generalized.¹⁴

Although reports are rare, other researchers have found vanadium allergy in patients with metal orthopedic implants.^5,12,13,15 The scarcity of literature on vanadium allergy seems to suggest that it is a rare entity, but we believe that it may be more common. Vanadium allergy may be underdiagnosed because it is not a standard patch test allergen. Furthermore, many of those who do choose to test for it use what we believe to be ineffective formulas of vanadium when patch testing patients. Our patient demonstrated a positive patch test reaction only to vanadium trichloride and not to pure vanadium, which is consistent with the small number of other studies that investigated vanadium allergy.^5,12,13,15 We believe that vanadium trichloride is more water soluble than elemental vanadium,¹⁶ and thus more likely to identify true vanadium allergy than other test materials.

Although reports of vanadium allergy in patients with metal implants are rare in the medical literature, the material science literature clearly states that vanadium is toxic and that vanadium-containing implants are problematic.^17-20 It has been shown that although Ti6Al4V implants are considered highly resistant to corrosion, they will slowly and continuously corrode in a physiologic environment and release titanium, aluminum, and vanadium ions, both systemically and into the peri-implant space.¹¹ To address these problems with vanadium, vanadium-free titanium alloys such as Ti6Al7Nb have specifically been developed for medical use to address the problems caused by vanadium. Ti6Al7Nb contains 7% niobium rather than vanadium and appears to have some improved qualities in surgical implants.¹⁷

There is still a great deal of uncertainty around metal implant allergy. Allergy to metal implants can be difficult to diagnose for several reasons. Some metals are not conducive to patch testing because of their low bioavailability. Additionally, we lack validated and standardized patch test formulas for metals that can be diagnosed by patch testing. Furthermore, there is uncertainty about what to do after allergy to a metal implant is diagnosed; in some cases (eg, with more extensive procedures such as total joint replacements), removal or replacement of the implant may be associated with increased risk of further complications.^6,21

Conclusion

We suggest that manufacturers consider vanadium-free alloys such as Ti7Al6Nb, which contains niobium instead of vanadium, in their surgical implants,²² and if surgeons have a choice, they should consider using titanium implants with niobium rather than vanadium.¹⁰ We suggest that clinicians consider vanadium allergy in patients with Ti6Al4V surgical implants and signs of a hypersensitivity reaction, and include vanadium trichloride 1% when patch testing.

Acknowledgment

The authors would like to thank Nicholas R. Krasnow, PhD (Tucson, Arizona), for his invaluable help coordinating, performing, and interpreting the metal analyses.

Metal allergy in patients with orthopedic implants can cause serious problems including dermatitis and implant failure.¹ As life expectancy increases, the general population ages, and more metallic orthopedic implants are placed,² allergy to these implants is expected to be a problem of greater significance. Uncertainty remains regarding best practice for patients with suspected metal implant allergy.¹ The major questions are: Who should be tested? When should they be tested? What are the optimal tests to diagnose metal allergy?^3-8

We report the case of a patient with vanadium allergy who developed a diffuse eczematous dermatitis and implant failure after receiving a vanadium-containing titanium alloy orthopedic implant in the left foot. This case is remarkable because hypersensitivity reactions to titanium-based hardware are rare, as they traditionally have not been thought to provoke allergic reactions.⁹

Case Report

A 62-year-old woman who was otherwise healthy presented with an eruption of more than 80 pruritic, nummular, eczematous plaques on the arms, legs, back, and buttocks of 3 weeks’ duration (Figure 1). She had a history of allergy to metal used in costume jewelry. Six weeks prior, the patient underwent implantation of a titanium alloy plate in the left foot for surgical repair of painful deforming osteoarthritis. A radiograph of the foot showed appropriate placement. According to the manufacturer, the plate was composed of the compound Ti6Al4V, which contained 90% titanium, 6% aluminum, and 4% vanadium. The lesions developed on the skin close to but not directly over the surgical site.

A punch biopsy of one of the lesions on the shoulder showed lymphoeosinophilic spongiosis consistent with a delayed hypersensitivity reaction (Figure 2). There was mild clinical improvement of the eruption with topical steroids. A course of prednisone for systemic effect resulted in clearing of the eruption, but it promptly recurred on cessation of the steroids. The patient was then patch tested using the North American 80 Comprehensive Series, with an additional 59 common textile, shampoo, fragrance, and several metal allergens, all of which were negative.

After the hardware was removed, it was analyzed to determine the elemental composition of the plate and screws, and the patient was then patch tested with the major metal components of the implant: aluminum chloride hexahydrate 2.0% pet, elemental titanium 10.0% pet, titanium dioxide 10.0% pet, titanium (III) nitride 5.0% pet, titanium (III) oxalate decahydrate 5.0% pet, elemental vanadium 5.0% pet, and vanadium (III) chloride 1.0% pet. She demonstrated a 1+ reaction (erythema and induration) to vanadium trichloride at 72 and 96 hours.

The plate and screws removed from the patient were sterilized and submitted for analysis. Electron microprobe analysis confirmed that the major elemental composition of the plate and screws essentially matched the manufacturer’s listing (Table 1). The trace elements were determined using laser ablative inductively coupled mass spectroscopy, which demonstrated that the screws were of different metal composition from the plate (Table 2). Electron microprobe analysis also was used to determine the microstructure of the plate and screws. The plate had 2 distinct phases consisting of a titanium-aluminum phase and a vanadium phase, whereas the screw was much more homogeneous. Basic electrochemical studies were performed in a salt solution replicating the tissue of the foot. These studies showed that galvanic corrosion could have occurred between the plate and screws due to the differences of composition.

Comment

Titanium is an attractive metal to use in orthopedic implants. It has a high strength-to-weight ratio, a low modulus of elasticity, and good resistance to corrosion. Titanium can be categorized as either commercially pure titanium (cp-Ti) or a titanium alloy. Colloquially, both cp-Ti and titanium alloys are often referred to simply as titanium, but the distinction is important when it comes to medical implants and devices. Commercially pure titanium is more than 99% pure titanium, but up to 1% of its volume can be comprised of impurities.¹⁰ In titanium alloys, the alloy elements are intentionally added to create a material with optimal properties. The 2 most common types of titanium that are used for orthopedic implants are cp-Ti and Ti6Al4V, a titanium alloy containing approximately 90% titanium, 6% aluminum, and 4% vanadium. Similar to cp-Ti, titanium alloys also can contain impurities such as aluminum, beryllium, cobalt, chromium, iron, nickel, and palladium, among many others. Although these impurities often are considered negligible from a metallurgy perspective, as they do not change the properties of the material, these trace elements may be present in large enough quantities to cause hypersensitivity reactions.¹¹

Several weeks after implantation of a titanium alloy metal plate in the left foot, a widespread eczematous eruption developed in our patient who had no prior skin disease. The eruption was steroid responsive but did not clear until the plate was removed. Detailed metallurgy analysis confirmed that vanadium was present and was not homogeneously distributed in the plate. The plate also was different in composition from the screws. Additional studies showed that galvanic corrosion between the plate and the chemically different screws might have contributed to the release of vanadium in the tissue.

Vanadium is known to be allergenic, especially in the presence of implant failure.^12,13 In our patient, patch testing with more than 100 allergens was negative, except for vanadium trichloride 1%. Our patient’s presentation strongly suggested that she developed a vanadium allergy manifesting as systemic allergic contact dermatitis. She demonstrated no history of skin disease, a widespread eczematous eruption after exposure, histology consistent with systemic contact allergy, a positive patch test to vanadium, and clearance of the eruption on removal of the antigen, which have been proposed as objective criteria that support a diagnosis of metal implant allergy.¹⁴ She refused our suggestion to reimplant a portion of the remaining plate under the skin without screws and monitor for recurrence of the eruption. She did not have a lesion overlying the surgical site, but she did develop lesions near the surgical scar. The literature indicates that cutaneous manifestations of allergy to metallic implants can be both localized and generalized.¹⁴

Although reports are rare, other researchers have found vanadium allergy in patients with metal orthopedic implants.^5,12,13,15 The scarcity of literature on vanadium allergy seems to suggest that it is a rare entity, but we believe that it may be more common. Vanadium allergy may be underdiagnosed because it is not a standard patch test allergen. Furthermore, many of those who do choose to test for it use what we believe to be ineffective formulas of vanadium when patch testing patients. Our patient demonstrated a positive patch test reaction only to vanadium trichloride and not to pure vanadium, which is consistent with the small number of other studies that investigated vanadium allergy.^5,12,13,15 We believe that vanadium trichloride is more water soluble than elemental vanadium,¹⁶ and thus more likely to identify true vanadium allergy than other test materials.

Although reports of vanadium allergy in patients with metal implants are rare in the medical literature, the material science literature clearly states that vanadium is toxic and that vanadium-containing implants are problematic.^17-20 It has been shown that although Ti6Al4V implants are considered highly resistant to corrosion, they will slowly and continuously corrode in a physiologic environment and release titanium, aluminum, and vanadium ions, both systemically and into the peri-implant space.¹¹ To address these problems with vanadium, vanadium-free titanium alloys such as Ti6Al7Nb have specifically been developed for medical use to address the problems caused by vanadium. Ti6Al7Nb contains 7% niobium rather than vanadium and appears to have some improved qualities in surgical implants.¹⁷

There is still a great deal of uncertainty around metal implant allergy. Allergy to metal implants can be difficult to diagnose for several reasons. Some metals are not conducive to patch testing because of their low bioavailability. Additionally, we lack validated and standardized patch test formulas for metals that can be diagnosed by patch testing. Furthermore, there is uncertainty about what to do after allergy to a metal implant is diagnosed; in some cases (eg, with more extensive procedures such as total joint replacements), removal or replacement of the implant may be associated with increased risk of further complications.^6,21

Conclusion

We suggest that manufacturers consider vanadium-free alloys such as Ti7Al6Nb, which contains niobium instead of vanadium, in their surgical implants,²² and if surgeons have a choice, they should consider using titanium implants with niobium rather than vanadium.¹⁰ We suggest that clinicians consider vanadium allergy in patients with Ti6Al4V surgical implants and signs of a hypersensitivity reaction, and include vanadium trichloride 1% when patch testing.

Acknowledgment

The authors would like to thank Nicholas R. Krasnow, PhD (Tucson, Arizona), for his invaluable help coordinating, performing, and interpreting the metal analyses.

Metal allergy in patients with orthopedic implants can cause serious problems including dermatitis and implant failure.¹ As life expectancy increases, the general population ages, and more metallic orthopedic implants are placed,² allergy to these implants is expected to be a problem of greater significance. Uncertainty remains regarding best practice for patients with suspected metal implant allergy.¹ The major questions are: Who should be tested? When should they be tested? What are the optimal tests to diagnose metal allergy?^3-8

We report the case of a patient with vanadium allergy who developed a diffuse eczematous dermatitis and implant failure after receiving a vanadium-containing titanium alloy orthopedic implant in the left foot. This case is remarkable because hypersensitivity reactions to titanium-based hardware are rare, as they traditionally have not been thought to provoke allergic reactions.⁹

Case Report

A 62-year-old woman who was otherwise healthy presented with an eruption of more than 80 pruritic, nummular, eczematous plaques on the arms, legs, back, and buttocks of 3 weeks’ duration (Figure 1). She had a history of allergy to metal used in costume jewelry. Six weeks prior, the patient underwent implantation of a titanium alloy plate in the left foot for surgical repair of painful deforming osteoarthritis. A radiograph of the foot showed appropriate placement. According to the manufacturer, the plate was composed of the compound Ti6Al4V, which contained 90% titanium, 6% aluminum, and 4% vanadium. The lesions developed on the skin close to but not directly over the surgical site.

A punch biopsy of one of the lesions on the shoulder showed lymphoeosinophilic spongiosis consistent with a delayed hypersensitivity reaction (Figure 2). There was mild clinical improvement of the eruption with topical steroids. A course of prednisone for systemic effect resulted in clearing of the eruption, but it promptly recurred on cessation of the steroids. The patient was then patch tested using the North American 80 Comprehensive Series, with an additional 59 common textile, shampoo, fragrance, and several metal allergens, all of which were negative.

After the hardware was removed, it was analyzed to determine the elemental composition of the plate and screws, and the patient was then patch tested with the major metal components of the implant: aluminum chloride hexahydrate 2.0% pet, elemental titanium 10.0% pet, titanium dioxide 10.0% pet, titanium (III) nitride 5.0% pet, titanium (III) oxalate decahydrate 5.0% pet, elemental vanadium 5.0% pet, and vanadium (III) chloride 1.0% pet. She demonstrated a 1+ reaction (erythema and induration) to vanadium trichloride at 72 and 96 hours.

The plate and screws removed from the patient were sterilized and submitted for analysis. Electron microprobe analysis confirmed that the major elemental composition of the plate and screws essentially matched the manufacturer’s listing (Table 1). The trace elements were determined using laser ablative inductively coupled mass spectroscopy, which demonstrated that the screws were of different metal composition from the plate (Table 2). Electron microprobe analysis also was used to determine the microstructure of the plate and screws. The plate had 2 distinct phases consisting of a titanium-aluminum phase and a vanadium phase, whereas the screw was much more homogeneous. Basic electrochemical studies were performed in a salt solution replicating the tissue of the foot. These studies showed that galvanic corrosion could have occurred between the plate and screws due to the differences of composition.

Comment

Titanium is an attractive metal to use in orthopedic implants. It has a high strength-to-weight ratio, a low modulus of elasticity, and good resistance to corrosion. Titanium can be categorized as either commercially pure titanium (cp-Ti) or a titanium alloy. Colloquially, both cp-Ti and titanium alloys are often referred to simply as titanium, but the distinction is important when it comes to medical implants and devices. Commercially pure titanium is more than 99% pure titanium, but up to 1% of its volume can be comprised of impurities.¹⁰ In titanium alloys, the alloy elements are intentionally added to create a material with optimal properties. The 2 most common types of titanium that are used for orthopedic implants are cp-Ti and Ti6Al4V, a titanium alloy containing approximately 90% titanium, 6% aluminum, and 4% vanadium. Similar to cp-Ti, titanium alloys also can contain impurities such as aluminum, beryllium, cobalt, chromium, iron, nickel, and palladium, among many others. Although these impurities often are considered negligible from a metallurgy perspective, as they do not change the properties of the material, these trace elements may be present in large enough quantities to cause hypersensitivity reactions.¹¹

Several weeks after implantation of a titanium alloy metal plate in the left foot, a widespread eczematous eruption developed in our patient who had no prior skin disease. The eruption was steroid responsive but did not clear until the plate was removed. Detailed metallurgy analysis confirmed that vanadium was present and was not homogeneously distributed in the plate. The plate also was different in composition from the screws. Additional studies showed that galvanic corrosion between the plate and the chemically different screws might have contributed to the release of vanadium in the tissue.

Vanadium is known to be allergenic, especially in the presence of implant failure.^12,13 In our patient, patch testing with more than 100 allergens was negative, except for vanadium trichloride 1%. Our patient’s presentation strongly suggested that she developed a vanadium allergy manifesting as systemic allergic contact dermatitis. She demonstrated no history of skin disease, a widespread eczematous eruption after exposure, histology consistent with systemic contact allergy, a positive patch test to vanadium, and clearance of the eruption on removal of the antigen, which have been proposed as objective criteria that support a diagnosis of metal implant allergy.¹⁴ She refused our suggestion to reimplant a portion of the remaining plate under the skin without screws and monitor for recurrence of the eruption. She did not have a lesion overlying the surgical site, but she did develop lesions near the surgical scar. The literature indicates that cutaneous manifestations of allergy to metallic implants can be both localized and generalized.¹⁴

Although reports are rare, other researchers have found vanadium allergy in patients with metal orthopedic implants.^5,12,13,15 The scarcity of literature on vanadium allergy seems to suggest that it is a rare entity, but we believe that it may be more common. Vanadium allergy may be underdiagnosed because it is not a standard patch test allergen. Furthermore, many of those who do choose to test for it use what we believe to be ineffective formulas of vanadium when patch testing patients. Our patient demonstrated a positive patch test reaction only to vanadium trichloride and not to pure vanadium, which is consistent with the small number of other studies that investigated vanadium allergy.^5,12,13,15 We believe that vanadium trichloride is more water soluble than elemental vanadium,¹⁶ and thus more likely to identify true vanadium allergy than other test materials.

Although reports of vanadium allergy in patients with metal implants are rare in the medical literature, the material science literature clearly states that vanadium is toxic and that vanadium-containing implants are problematic.^17-20 It has been shown that although Ti6Al4V implants are considered highly resistant to corrosion, they will slowly and continuously corrode in a physiologic environment and release titanium, aluminum, and vanadium ions, both systemically and into the peri-implant space.¹¹ To address these problems with vanadium, vanadium-free titanium alloys such as Ti6Al7Nb have specifically been developed for medical use to address the problems caused by vanadium. Ti6Al7Nb contains 7% niobium rather than vanadium and appears to have some improved qualities in surgical implants.¹⁷

There is still a great deal of uncertainty around metal implant allergy. Allergy to metal implants can be difficult to diagnose for several reasons. Some metals are not conducive to patch testing because of their low bioavailability. Additionally, we lack validated and standardized patch test formulas for metals that can be diagnosed by patch testing. Furthermore, there is uncertainty about what to do after allergy to a metal implant is diagnosed; in some cases (eg, with more extensive procedures such as total joint replacements), removal or replacement of the implant may be associated with increased risk of further complications.^6,21

Conclusion

We suggest that manufacturers consider vanadium-free alloys such as Ti7Al6Nb, which contains niobium instead of vanadium, in their surgical implants,²² and if surgeons have a choice, they should consider using titanium implants with niobium rather than vanadium.¹⁰ We suggest that clinicians consider vanadium allergy in patients with Ti6Al4V surgical implants and signs of a hypersensitivity reaction, and include vanadium trichloride 1% when patch testing.

Acknowledgment

The authors would like to thank Nicholas R. Krasnow, PhD (Tucson, Arizona), for his invaluable help coordinating, performing, and interpreting the metal analyses.