Contact Dermatitis

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

The Diagnosis: Irritant Contact Dermatitis

The diagnosis of irritant contact dermatitis secondary to skateboarding is similar to pool palms, a benign, self-limiting irritant contact dermatitis.¹ We propose that contact with concrete surfaces during skateboarding can lead to a presentation similar to pool palms. In our case, it was likely that the finger pulpitis noted in the physical examination was due to daily skateboarding rather than once-weekly swimming. Furthermore, the fingertip contact with concrete in pool palms is similar to the rough surface exposure on the skateboard.

Pool palms is more commonly reported in children due to their participation in sports and other activities with recent exposure to rough surfaces, most commonly the floor of swimming pools.² The condition resolves after eliminating exposures.³ The frequency and duration of exposure to rough surfaces in swimming pools leading to development of this condition is unknown.

There have been mixed reports on the pathogenesis of pool palms. Some literature supports the idea that it is a wet dermatitis, a combination of prolonged water contact, friction, chemicals, and microbes leading to a chronic dermatitis. This theory states that the primary factor influencing the development of erythematous patches on the fingers, palms, and soles is the hyperhydration of the corneal layer at these sites.⁴ A different theory attributes pool palms to a mechanical origin, such as repeated microtrauma from contact with the rough concrete surfaces of swimming pools.⁵ This theory further states that the chemicals in pool water, such as chlorine and sodium hypochlorite, rarely produce irritant, allergic, or urticarial reactions.³

Based on these theories, we hypothesized that fingertip pulpitis can result from activities other than swimming (eg, skateboarding). Our case supports the latter theory on fingertip pulpitis in pool palms being a result of frictional dermatitis rather than wet dermatitis because we attributed our patient’s findings to contact with rough surfaces during skateboarding. Although the patient did swim, he only did so once weekly in the summer months, and the lesions had been persistent for 2 years consistently. His skateboarding hobby was more frequent, and he endorsed contact of the pads of the bilateral second to fifth fingers to the rough surfaces of the road and skateboard. The patient did not have lesions on the toes, further supporting the hypothesis that skateboarding led to the current presentation.

In children, hand-foot-and-mouth disease classically presents with oval-shaped, erythematous vesicles on the palmar surfaces of the hands and feet and generally is accompanied by fever and sore throat.⁶ Furthermore, unlike in our case, the viral exanthem usually would be present for up to 3 weeks and would not persist for more than 2 years. Erythema multiforme has an erythematous color and can present on the palms; however, the lesions have a classic targetoid appearance. It would be unique for erythema multiforme to present only on the fingertips rather than more diffusely on the palms or in other areas such as the face.⁷ Limited cutaneous sclerosis (scleroderma) initially can present with edematous pitted scars on the digital tips; however, with time the fingers will have a taut, white, shiny appearance that can develop into contractures and debilitating ulcerations.⁸ In our patient, the plaques did not advance to any further disease. Lastly, in contrast to our patient, punctate palmoplantar keratoderma presents as hyperkeratotic, firm, translucent, or opaque papules on the palms and soles. Over time, the papules can appear verrucous or callouslike.⁹ In our case, the plaques on the fingertips were erythematous rather than translucent or opaque papules.

Our case raises questions on whether prior reports of pool palms can be attributed to other activities involving contact with rough surfaces. More research is needed on the frequency and duration of rough surface exposure resulting in fingertip pulpitis.

The Diagnosis: Irritant Contact Dermatitis

The diagnosis of irritant contact dermatitis secondary to skateboarding is similar to pool palms, a benign, self-limiting irritant contact dermatitis.¹ We propose that contact with concrete surfaces during skateboarding can lead to a presentation similar to pool palms. In our case, it was likely that the finger pulpitis noted in the physical examination was due to daily skateboarding rather than once-weekly swimming. Furthermore, the fingertip contact with concrete in pool palms is similar to the rough surface exposure on the skateboard.

Pool palms is more commonly reported in children due to their participation in sports and other activities with recent exposure to rough surfaces, most commonly the floor of swimming pools.² The condition resolves after eliminating exposures.³ The frequency and duration of exposure to rough surfaces in swimming pools leading to development of this condition is unknown.

There have been mixed reports on the pathogenesis of pool palms. Some literature supports the idea that it is a wet dermatitis, a combination of prolonged water contact, friction, chemicals, and microbes leading to a chronic dermatitis. This theory states that the primary factor influencing the development of erythematous patches on the fingers, palms, and soles is the hyperhydration of the corneal layer at these sites.⁴ A different theory attributes pool palms to a mechanical origin, such as repeated microtrauma from contact with the rough concrete surfaces of swimming pools.⁵ This theory further states that the chemicals in pool water, such as chlorine and sodium hypochlorite, rarely produce irritant, allergic, or urticarial reactions.³

Based on these theories, we hypothesized that fingertip pulpitis can result from activities other than swimming (eg, skateboarding). Our case supports the latter theory on fingertip pulpitis in pool palms being a result of frictional dermatitis rather than wet dermatitis because we attributed our patient’s findings to contact with rough surfaces during skateboarding. Although the patient did swim, he only did so once weekly in the summer months, and the lesions had been persistent for 2 years consistently. His skateboarding hobby was more frequent, and he endorsed contact of the pads of the bilateral second to fifth fingers to the rough surfaces of the road and skateboard. The patient did not have lesions on the toes, further supporting the hypothesis that skateboarding led to the current presentation.

In children, hand-foot-and-mouth disease classically presents with oval-shaped, erythematous vesicles on the palmar surfaces of the hands and feet and generally is accompanied by fever and sore throat.⁶ Furthermore, unlike in our case, the viral exanthem usually would be present for up to 3 weeks and would not persist for more than 2 years. Erythema multiforme has an erythematous color and can present on the palms; however, the lesions have a classic targetoid appearance. It would be unique for erythema multiforme to present only on the fingertips rather than more diffusely on the palms or in other areas such as the face.⁷ Limited cutaneous sclerosis (scleroderma) initially can present with edematous pitted scars on the digital tips; however, with time the fingers will have a taut, white, shiny appearance that can develop into contractures and debilitating ulcerations.⁸ In our patient, the plaques did not advance to any further disease. Lastly, in contrast to our patient, punctate palmoplantar keratoderma presents as hyperkeratotic, firm, translucent, or opaque papules on the palms and soles. Over time, the papules can appear verrucous or callouslike.⁹ In our case, the plaques on the fingertips were erythematous rather than translucent or opaque papules.

Our case raises questions on whether prior reports of pool palms can be attributed to other activities involving contact with rough surfaces. More research is needed on the frequency and duration of rough surface exposure resulting in fingertip pulpitis.

The Diagnosis: Irritant Contact Dermatitis

The diagnosis of irritant contact dermatitis secondary to skateboarding is similar to pool palms, a benign, self-limiting irritant contact dermatitis.¹ We propose that contact with concrete surfaces during skateboarding can lead to a presentation similar to pool palms. In our case, it was likely that the finger pulpitis noted in the physical examination was due to daily skateboarding rather than once-weekly swimming. Furthermore, the fingertip contact with concrete in pool palms is similar to the rough surface exposure on the skateboard.

Pool palms is more commonly reported in children due to their participation in sports and other activities with recent exposure to rough surfaces, most commonly the floor of swimming pools.² The condition resolves after eliminating exposures.³ The frequency and duration of exposure to rough surfaces in swimming pools leading to development of this condition is unknown.

There have been mixed reports on the pathogenesis of pool palms. Some literature supports the idea that it is a wet dermatitis, a combination of prolonged water contact, friction, chemicals, and microbes leading to a chronic dermatitis. This theory states that the primary factor influencing the development of erythematous patches on the fingers, palms, and soles is the hyperhydration of the corneal layer at these sites.⁴ A different theory attributes pool palms to a mechanical origin, such as repeated microtrauma from contact with the rough concrete surfaces of swimming pools.⁵ This theory further states that the chemicals in pool water, such as chlorine and sodium hypochlorite, rarely produce irritant, allergic, or urticarial reactions.³

Based on these theories, we hypothesized that fingertip pulpitis can result from activities other than swimming (eg, skateboarding). Our case supports the latter theory on fingertip pulpitis in pool palms being a result of frictional dermatitis rather than wet dermatitis because we attributed our patient’s findings to contact with rough surfaces during skateboarding. Although the patient did swim, he only did so once weekly in the summer months, and the lesions had been persistent for 2 years consistently. His skateboarding hobby was more frequent, and he endorsed contact of the pads of the bilateral second to fifth fingers to the rough surfaces of the road and skateboard. The patient did not have lesions on the toes, further supporting the hypothesis that skateboarding led to the current presentation.

In children, hand-foot-and-mouth disease classically presents with oval-shaped, erythematous vesicles on the palmar surfaces of the hands and feet and generally is accompanied by fever and sore throat.⁶ Furthermore, unlike in our case, the viral exanthem usually would be present for up to 3 weeks and would not persist for more than 2 years. Erythema multiforme has an erythematous color and can present on the palms; however, the lesions have a classic targetoid appearance. It would be unique for erythema multiforme to present only on the fingertips rather than more diffusely on the palms or in other areas such as the face.⁷ Limited cutaneous sclerosis (scleroderma) initially can present with edematous pitted scars on the digital tips; however, with time the fingers will have a taut, white, shiny appearance that can develop into contractures and debilitating ulcerations.⁸ In our patient, the plaques did not advance to any further disease. Lastly, in contrast to our patient, punctate palmoplantar keratoderma presents as hyperkeratotic, firm, translucent, or opaque papules on the palms and soles. Over time, the papules can appear verrucous or callouslike.⁹ In our case, the plaques on the fingertips were erythematous rather than translucent or opaque papules.

Our case raises questions on whether prior reports of pool palms can be attributed to other activities involving contact with rough surfaces. More research is needed on the frequency and duration of rough surface exposure resulting in fingertip pulpitis.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Postirradiation morphea (PIM) is a rare but well-documented phenomenon that primarily occurs in breast cancer patients who have received radiation therapy; however, it also has been reported in patients who have received radiation therapy for lymphoma as well as endocervical, endometrial, and gastric carcinomas.¹ Importantly, clinicians must be able to recognize and differentiate this condition from other causes of new-onset induration and erythema of the breast, such as cancer recurrence, a new primary malignancy, or inflammatory etiologies (eg, radiation or contact dermatitis). Typically, PIM presents months to years after radiation therapy as an erythematous patch within the irradiated area that progressively becomes indurated. We report an unusual case of PIM with a reticulated appearance occurring 3 weeks after radiotherapy, chemotherapy, and surgery for an infiltrating ductal carcinoma of the left breast.

A 62-year-old woman presented to the dermatology department with a stage IIA, lymph node–negative, estrogen and progesterone receptor–negative, human epidermal growth factor receptor 2–negative infiltrating ductal carcinoma of the left breast. She was treated with a partial mastectomy of the left breast followed by external beam radiotherapy to the entire left breast in combination with chemotherapy (doxorubicin, cyclophosphamide, paclitaxel). The patient received 15 fractions of 270 cGy (4050 cGy total) with a weekly 600-cGy boost over 21 days without any complications.

Three weeks after finishing radiation therapy, the patient developed redness and swelling of the left breast that did not encompass the entire radiation field. There was no associated pain or pruritus. She was treated by her surgical oncologist with topical calendula and 3 courses of cephalexin for suspected mastitis with only modest improvement, then was referred to dermatology 3 months later.

At the initial dermatology evaluation, the patient reported little improvement after antibiotics and topical calendula. On physical examination, there were erythematous, reticulated, dusky, indurated patches on the entire left breast. The area of most pronounced induration surrounded the surgical scar on the left superior breast. Punch biopsy for hematoxylin and eosin staining and tissue cultures was obtained at this appointment. The patient was started on doxycycline 100 mg twice daily and was instructed to apply triamcinolone ointment 0.1% twice daily to the affected area. After 1 month of therapy, she reported slight improvement in the degree of erythema with this regimen, but the involved area continued to extend outside of the radiation field to the central chest wall and medial right breast (Figure 1). Two additional biopsies—one from the central chest and another from the right breast—were then taken over the course of 4 months, given the consistently inconclusive clinicopathologic nature and failure of the eruption to respond to antibiotics plus topical corticosteroids.

Punch biopsy from the central chest revealed a sparse perivascular infiltrate comprised predominantly of lymphocytes with occasional eosinophils (Figure 2). There were foci suggestive of early dermal sclerosis, an increased number of small blood vessels in the dermis, and scattered enlarged fibroblasts. Metastatic carcinoma was not identified. Although the histologic findings were not entirely specific, the changes were most suggestive of PIM, for which the patient was started on pentoxifylline (400 mg 3 times daily) and oral vitamin E supplementation (400 IU daily). At subsequent follow-up appointments, she showed markedly decreased skin erythema and induration.

Morphea, also known as localized scleroderma, is an inflammatory skin condition characterized by sclerosis of the dermis and subcutis leading to scarlike tissue formation. Worldwide incidence ranges from 0.4 to 2.7 cases per 100,000 individuals with a predilection for white women.² Unlike systemic scleroderma, morphea patients lack Raynaud phenomenon and visceral involvement.^3,4

There are several clinical subtypes of morphea, including plaque, linear, generalized, and pansclerotic morphea. Lesions may vary in appearance based on configuration, stage of development, and depth of involvement.⁴ During the earliest phases, morphea lesions are asymptomatic, asymmetrically distributed, erythematous to violaceous patches or subtly indurated plaques expanding centrifugally with a lilac ring. Central sclerosis with loss of follicles and sweat glands is a later finding associated with advanced disease. Moreover, some reports of early-stage morphea have suggested a reticulated or geographic vascular morphology that may be misdiagnosed for other conditions such as a port-wine stain.⁵

Local skin exposures have long been hypothesized to contribute to development of morphea, including infection, especially Borrelia burgdorferi; trauma; chronic venous insufficiency; cosmetic surgery; medications; and exposure to toxic cooking oils, silicones, silica, pesticides, organic solvents, and vinyl chloride.^2,6,7

Radiation therapy is an often overlooked cause of morphea. It was first described in 1905 but then rarely discussed until a 1989 case series of 9 patients, 7 of whom had received irradiation for breast cancer.^8,9 Today, the increasing popularity of lumpectomy plus radiation therapy for treatment of early-stage breast cancer has led to a rise in PIM incidence.¹⁰Estimates have indicated an incidence among previously irradiated breast cancer patients as high as 1 in 500 individuals, appreciably higher than that seen in the general population.¹¹ Tissue changes occur as early as weeks or as late as 32 years after radiation treatment and are commonly mistaken for mastitis, such as in our case, as well as radiation dermatitis, radiation fibrosis, or malignant conditions.^1,11

In contrast to other radiation-induced skin conditions, development of PIM is independent of the presence or absence of adjuvant chemotherapy, type of radiation therapy, or the total radiation dose or fractionation number, with reported doses ranging from less than 20.0 Gy to up to 59.4 Gy and dose fractions ranging from 10 to 30. In 20% to 30% of cases, PIM extends beyond the radiation field, sometimes involving distant sites never exposed to high-energy rays.^1,10,11 This observation suggests a mechanism reliant on more widespread cascade rather than solely local tissue damage.

Prominent culture-negative, lymphoplasmacytic inflammation is another important diagnostic clue. Radiation dermatitis and fibrosis do not have the marked erythematous to violaceous hue seen in early morphea plaques. This color seen in early morphea plaques may be intense enough and in a geographic pattern, emulating a vascular lesion. However, a PubMed search of articles indexed for MEDLINE using the terms reticulate radiation morphea and livedo radiation morphea yielded no reports linking the reticulate erythema seen in our patient with early PIM. It is important to note that the histopathology findings in our patient were not entirely specific, and although there were some background changes that may have represented a sequela of radiation to the area (ie, the enlarged fibroblasts and increased number of vessels), there were foci suggestive of early sclerosing dermatitis. With clinical correlation, including the extension beyond the radiation field, these changes were best interpreted as early PIM. Therefore, our case demonstrated a novel presentation of a frequently underrecognized trigger for morphea. Although we favored a diagnosis of PIM, a fibrosing chronic radiation dermatitis could not be entirely excluded based on the clinical and histologic features.

There is no standardized treatment of PIM, but traditional therapies for morphea may provide some benefit. Several randomized controlled clinical trials have shown success with pentoxifylline and oral vitamin E supplementation to treat or prevent radiation-induced breast fibrosis.¹² Extrapolating from this data, our patient was started on this combination therapy and showed marked improvement in skin color and texture.

To the Editor:

Postirradiation morphea (PIM) is a rare but well-documented phenomenon that primarily occurs in breast cancer patients who have received radiation therapy; however, it also has been reported in patients who have received radiation therapy for lymphoma as well as endocervical, endometrial, and gastric carcinomas.¹ Importantly, clinicians must be able to recognize and differentiate this condition from other causes of new-onset induration and erythema of the breast, such as cancer recurrence, a new primary malignancy, or inflammatory etiologies (eg, radiation or contact dermatitis). Typically, PIM presents months to years after radiation therapy as an erythematous patch within the irradiated area that progressively becomes indurated. We report an unusual case of PIM with a reticulated appearance occurring 3 weeks after radiotherapy, chemotherapy, and surgery for an infiltrating ductal carcinoma of the left breast.

A 62-year-old woman presented to the dermatology department with a stage IIA, lymph node–negative, estrogen and progesterone receptor–negative, human epidermal growth factor receptor 2–negative infiltrating ductal carcinoma of the left breast. She was treated with a partial mastectomy of the left breast followed by external beam radiotherapy to the entire left breast in combination with chemotherapy (doxorubicin, cyclophosphamide, paclitaxel). The patient received 15 fractions of 270 cGy (4050 cGy total) with a weekly 600-cGy boost over 21 days without any complications.

Three weeks after finishing radiation therapy, the patient developed redness and swelling of the left breast that did not encompass the entire radiation field. There was no associated pain or pruritus. She was treated by her surgical oncologist with topical calendula and 3 courses of cephalexin for suspected mastitis with only modest improvement, then was referred to dermatology 3 months later.

At the initial dermatology evaluation, the patient reported little improvement after antibiotics and topical calendula. On physical examination, there were erythematous, reticulated, dusky, indurated patches on the entire left breast. The area of most pronounced induration surrounded the surgical scar on the left superior breast. Punch biopsy for hematoxylin and eosin staining and tissue cultures was obtained at this appointment. The patient was started on doxycycline 100 mg twice daily and was instructed to apply triamcinolone ointment 0.1% twice daily to the affected area. After 1 month of therapy, she reported slight improvement in the degree of erythema with this regimen, but the involved area continued to extend outside of the radiation field to the central chest wall and medial right breast (Figure 1). Two additional biopsies—one from the central chest and another from the right breast—were then taken over the course of 4 months, given the consistently inconclusive clinicopathologic nature and failure of the eruption to respond to antibiotics plus topical corticosteroids.

Punch biopsy from the central chest revealed a sparse perivascular infiltrate comprised predominantly of lymphocytes with occasional eosinophils (Figure 2). There were foci suggestive of early dermal sclerosis, an increased number of small blood vessels in the dermis, and scattered enlarged fibroblasts. Metastatic carcinoma was not identified. Although the histologic findings were not entirely specific, the changes were most suggestive of PIM, for which the patient was started on pentoxifylline (400 mg 3 times daily) and oral vitamin E supplementation (400 IU daily). At subsequent follow-up appointments, she showed markedly decreased skin erythema and induration.

Morphea, also known as localized scleroderma, is an inflammatory skin condition characterized by sclerosis of the dermis and subcutis leading to scarlike tissue formation. Worldwide incidence ranges from 0.4 to 2.7 cases per 100,000 individuals with a predilection for white women.² Unlike systemic scleroderma, morphea patients lack Raynaud phenomenon and visceral involvement.^3,4

There are several clinical subtypes of morphea, including plaque, linear, generalized, and pansclerotic morphea. Lesions may vary in appearance based on configuration, stage of development, and depth of involvement.⁴ During the earliest phases, morphea lesions are asymptomatic, asymmetrically distributed, erythematous to violaceous patches or subtly indurated plaques expanding centrifugally with a lilac ring. Central sclerosis with loss of follicles and sweat glands is a later finding associated with advanced disease. Moreover, some reports of early-stage morphea have suggested a reticulated or geographic vascular morphology that may be misdiagnosed for other conditions such as a port-wine stain.⁵

Local skin exposures have long been hypothesized to contribute to development of morphea, including infection, especially Borrelia burgdorferi; trauma; chronic venous insufficiency; cosmetic surgery; medications; and exposure to toxic cooking oils, silicones, silica, pesticides, organic solvents, and vinyl chloride.^2,6,7

Radiation therapy is an often overlooked cause of morphea. It was first described in 1905 but then rarely discussed until a 1989 case series of 9 patients, 7 of whom had received irradiation for breast cancer.^8,9 Today, the increasing popularity of lumpectomy plus radiation therapy for treatment of early-stage breast cancer has led to a rise in PIM incidence.¹⁰Estimates have indicated an incidence among previously irradiated breast cancer patients as high as 1 in 500 individuals, appreciably higher than that seen in the general population.¹¹ Tissue changes occur as early as weeks or as late as 32 years after radiation treatment and are commonly mistaken for mastitis, such as in our case, as well as radiation dermatitis, radiation fibrosis, or malignant conditions.^1,11

In contrast to other radiation-induced skin conditions, development of PIM is independent of the presence or absence of adjuvant chemotherapy, type of radiation therapy, or the total radiation dose or fractionation number, with reported doses ranging from less than 20.0 Gy to up to 59.4 Gy and dose fractions ranging from 10 to 30. In 20% to 30% of cases, PIM extends beyond the radiation field, sometimes involving distant sites never exposed to high-energy rays.^1,10,11 This observation suggests a mechanism reliant on more widespread cascade rather than solely local tissue damage.

Prominent culture-negative, lymphoplasmacytic inflammation is another important diagnostic clue. Radiation dermatitis and fibrosis do not have the marked erythematous to violaceous hue seen in early morphea plaques. This color seen in early morphea plaques may be intense enough and in a geographic pattern, emulating a vascular lesion. However, a PubMed search of articles indexed for MEDLINE using the terms reticulate radiation morphea and livedo radiation morphea yielded no reports linking the reticulate erythema seen in our patient with early PIM. It is important to note that the histopathology findings in our patient were not entirely specific, and although there were some background changes that may have represented a sequela of radiation to the area (ie, the enlarged fibroblasts and increased number of vessels), there were foci suggestive of early sclerosing dermatitis. With clinical correlation, including the extension beyond the radiation field, these changes were best interpreted as early PIM. Therefore, our case demonstrated a novel presentation of a frequently underrecognized trigger for morphea. Although we favored a diagnosis of PIM, a fibrosing chronic radiation dermatitis could not be entirely excluded based on the clinical and histologic features.

There is no standardized treatment of PIM, but traditional therapies for morphea may provide some benefit. Several randomized controlled clinical trials have shown success with pentoxifylline and oral vitamin E supplementation to treat or prevent radiation-induced breast fibrosis.¹² Extrapolating from this data, our patient was started on this combination therapy and showed marked improvement in skin color and texture.

To the Editor:

Postirradiation morphea (PIM) is a rare but well-documented phenomenon that primarily occurs in breast cancer patients who have received radiation therapy; however, it also has been reported in patients who have received radiation therapy for lymphoma as well as endocervical, endometrial, and gastric carcinomas.¹ Importantly, clinicians must be able to recognize and differentiate this condition from other causes of new-onset induration and erythema of the breast, such as cancer recurrence, a new primary malignancy, or inflammatory etiologies (eg, radiation or contact dermatitis). Typically, PIM presents months to years after radiation therapy as an erythematous patch within the irradiated area that progressively becomes indurated. We report an unusual case of PIM with a reticulated appearance occurring 3 weeks after radiotherapy, chemotherapy, and surgery for an infiltrating ductal carcinoma of the left breast.

A 62-year-old woman presented to the dermatology department with a stage IIA, lymph node–negative, estrogen and progesterone receptor–negative, human epidermal growth factor receptor 2–negative infiltrating ductal carcinoma of the left breast. She was treated with a partial mastectomy of the left breast followed by external beam radiotherapy to the entire left breast in combination with chemotherapy (doxorubicin, cyclophosphamide, paclitaxel). The patient received 15 fractions of 270 cGy (4050 cGy total) with a weekly 600-cGy boost over 21 days without any complications.

Three weeks after finishing radiation therapy, the patient developed redness and swelling of the left breast that did not encompass the entire radiation field. There was no associated pain or pruritus. She was treated by her surgical oncologist with topical calendula and 3 courses of cephalexin for suspected mastitis with only modest improvement, then was referred to dermatology 3 months later.

At the initial dermatology evaluation, the patient reported little improvement after antibiotics and topical calendula. On physical examination, there were erythematous, reticulated, dusky, indurated patches on the entire left breast. The area of most pronounced induration surrounded the surgical scar on the left superior breast. Punch biopsy for hematoxylin and eosin staining and tissue cultures was obtained at this appointment. The patient was started on doxycycline 100 mg twice daily and was instructed to apply triamcinolone ointment 0.1% twice daily to the affected area. After 1 month of therapy, she reported slight improvement in the degree of erythema with this regimen, but the involved area continued to extend outside of the radiation field to the central chest wall and medial right breast (Figure 1). Two additional biopsies—one from the central chest and another from the right breast—were then taken over the course of 4 months, given the consistently inconclusive clinicopathologic nature and failure of the eruption to respond to antibiotics plus topical corticosteroids.

Punch biopsy from the central chest revealed a sparse perivascular infiltrate comprised predominantly of lymphocytes with occasional eosinophils (Figure 2). There were foci suggestive of early dermal sclerosis, an increased number of small blood vessels in the dermis, and scattered enlarged fibroblasts. Metastatic carcinoma was not identified. Although the histologic findings were not entirely specific, the changes were most suggestive of PIM, for which the patient was started on pentoxifylline (400 mg 3 times daily) and oral vitamin E supplementation (400 IU daily). At subsequent follow-up appointments, she showed markedly decreased skin erythema and induration.

Morphea, also known as localized scleroderma, is an inflammatory skin condition characterized by sclerosis of the dermis and subcutis leading to scarlike tissue formation. Worldwide incidence ranges from 0.4 to 2.7 cases per 100,000 individuals with a predilection for white women.² Unlike systemic scleroderma, morphea patients lack Raynaud phenomenon and visceral involvement.^3,4

There are several clinical subtypes of morphea, including plaque, linear, generalized, and pansclerotic morphea. Lesions may vary in appearance based on configuration, stage of development, and depth of involvement.⁴ During the earliest phases, morphea lesions are asymptomatic, asymmetrically distributed, erythematous to violaceous patches or subtly indurated plaques expanding centrifugally with a lilac ring. Central sclerosis with loss of follicles and sweat glands is a later finding associated with advanced disease. Moreover, some reports of early-stage morphea have suggested a reticulated or geographic vascular morphology that may be misdiagnosed for other conditions such as a port-wine stain.⁵

Local skin exposures have long been hypothesized to contribute to development of morphea, including infection, especially Borrelia burgdorferi; trauma; chronic venous insufficiency; cosmetic surgery; medications; and exposure to toxic cooking oils, silicones, silica, pesticides, organic solvents, and vinyl chloride.^2,6,7

Radiation therapy is an often overlooked cause of morphea. It was first described in 1905 but then rarely discussed until a 1989 case series of 9 patients, 7 of whom had received irradiation for breast cancer.^8,9 Today, the increasing popularity of lumpectomy plus radiation therapy for treatment of early-stage breast cancer has led to a rise in PIM incidence.¹⁰Estimates have indicated an incidence among previously irradiated breast cancer patients as high as 1 in 500 individuals, appreciably higher than that seen in the general population.¹¹ Tissue changes occur as early as weeks or as late as 32 years after radiation treatment and are commonly mistaken for mastitis, such as in our case, as well as radiation dermatitis, radiation fibrosis, or malignant conditions.^1,11

In contrast to other radiation-induced skin conditions, development of PIM is independent of the presence or absence of adjuvant chemotherapy, type of radiation therapy, or the total radiation dose or fractionation number, with reported doses ranging from less than 20.0 Gy to up to 59.4 Gy and dose fractions ranging from 10 to 30. In 20% to 30% of cases, PIM extends beyond the radiation field, sometimes involving distant sites never exposed to high-energy rays.^1,10,11 This observation suggests a mechanism reliant on more widespread cascade rather than solely local tissue damage.

Prominent culture-negative, lymphoplasmacytic inflammation is another important diagnostic clue. Radiation dermatitis and fibrosis do not have the marked erythematous to violaceous hue seen in early morphea plaques. This color seen in early morphea plaques may be intense enough and in a geographic pattern, emulating a vascular lesion. However, a PubMed search of articles indexed for MEDLINE using the terms reticulate radiation morphea and livedo radiation morphea yielded no reports linking the reticulate erythema seen in our patient with early PIM. It is important to note that the histopathology findings in our patient were not entirely specific, and although there were some background changes that may have represented a sequela of radiation to the area (ie, the enlarged fibroblasts and increased number of vessels), there were foci suggestive of early sclerosing dermatitis. With clinical correlation, including the extension beyond the radiation field, these changes were best interpreted as early PIM. Therefore, our case demonstrated a novel presentation of a frequently underrecognized trigger for morphea. Although we favored a diagnosis of PIM, a fibrosing chronic radiation dermatitis could not be entirely excluded based on the clinical and histologic features.

There is no standardized treatment of PIM, but traditional therapies for morphea may provide some benefit. Several randomized controlled clinical trials have shown success with pentoxifylline and oral vitamin E supplementation to treat or prevent radiation-induced breast fibrosis.¹² Extrapolating from this data, our patient was started on this combination therapy and showed marked improvement in skin color and texture.

Allergy testing typically refers to evaluation of a patient for suspected type I or type IV hypersensitivity.^1,2 The possibility of type I hypersensitivity is raised in patients presenting with food allergies, allergic rhinitis, asthma, and immediate adverse reactions to medications, whereas type IV hypersensitivity is suspected in patients with eczematous eruptions, delayed adverse cutaneous reactions to medications, and failure of metallic implants (eg, metal joint replacements, cardiac stents) in conjunction with overlying skin rashes (Table 1).^1-5 Type II (eg, pemphigus vulgaris) and type III (eg, IgA vasculitis) hypersensitivities are not evaluated with screening allergy tests.

Type I Sensitization

Type I hypersensitivity is an immediate hypersensitivity mediated predominantly by IgE activation of mast cells in the skin as well as the respiratory and gastric mucosa.¹ Sensitization of an individual patient occurs when antigen-presenting cells induce a helper T cell (T_H2) cytokine response leading to B-cell class switching and allergen-specific IgE production. Upon repeat exposure to the allergen, circulating antibodies then bind to high-affinity receptors on mast cells and basophils and initiate an allergic inflammatory response, leading to a clinical presentation of allergic rhinitis, urticaria, or immediate drug reactions. Confirming type I sensitization may be performed via serologic (in vitro) or skin testing (in vivo).^5,6

Serologic Testing (In Vitro)
Serologic testing is a blood test that detects circulating IgE levels against specific allergens.⁵ The first such test, the radioallergosorbent test, was introduced in the 1970s but is not quantitative and is no longer used. Although common, it is inaccurate to describe current serum IgE (s-IgE) testing as radioallergosorbent testing. There are several US Food and Drug Administration-approved s-IgE assays in common use, and these tests may be helpful in elucidating relevant allergens and for tailoring therapy appropriately, which may consist of avoidance of certain foods or environmental agents and/or allergen immunotherapy.

Skin Testing (In Vivo)
Skin testing can be performed percutaneously (eg, percutaneous skin testing) or intradermally (eg, intradermal testing).⁶ Percutaneous skin testing is performed by placing a drop of allergen extract on the skin, after which a lancet is used to lightly scratch the skin; intradermal testing is performed by injecting a small amount of allergen extract into the dermis. In both cases, the skin is evaluated after 15 to 20 minutes for the presence and size of a cutaneous wheal. Medications with antihistaminergic activity must be discontinued prior to testing. Both s-IgE and skin testing assess for type I hypersensitivity, and factors such as extensive rash, concern for anaphylaxis, or inability to discontinue antihistamines may favor s-IgE testing versus skin testing. False-positive results can occur with both tests, and for this reason, test results should always be interpreted in conjunction with clinical examination and patient history to determine relevant allergies.

Type IV Sensitization

Type IV hypersensitivity is a delayed hypersensitivity mediated primarily by lymphocytes.² Sensitization occurs when haptens bind to host proteins and are presented by epidermal and dermal dendritic cells to T lymphocytes in the skin. These lymphocytes then migrate to regional lymph nodes where antigen-specific T lymphocytes are produced and home back to the skin. Upon reexposure to the allergen, these memory T lymphocytes become activated and incite a delayed allergic response. Confirming type IV hypersensitivity primarily is accomplished via patch testing, though other testing modalities exist.

Skin Biopsy
Biopsy is sometimes performed in the workup of an individual presenting with allergic contact dermatitis (ACD) and typically will show spongiosis with normal stratum corneum and epidermal thickness in the setting of acute ACD and mild to marked acanthosis and parakeratosis in chronic ACD.⁷ The findings, however, are nonspecific and the differential of these histopathologic findings encompasses nummular dermatitis, atopic dermatitis, irritant contact dermatitis, and dyshidrotic eczema, among others. The presence of eosinophils and Langerhans cell microabscesses may provide supportive evidence for ACD over the other spongiotic dermatitides.^7,8

Patch Testing
Patch testing is the gold standard in diagnosing type IV hypersensitivities resulting in a clinical presentation of ACD. Hundreds of allergens are commercially available for patch testing, and more commonly tested allergens fall into one of several categories, such as cosmetic preservatives, rubbers, metals, textiles, fragrances, adhesives, antibiotics, plants, and even corticosteroids. Of note, a common misconception is that ACD must result from new exposures; however, patients may develop ACD secondary to an exposure or product they have been using for many years without a problem.

Three commonly used screening series are the thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice), North American Contact Dermatitis Group screening series, and American Contact Dermatitis Society Core 80 allergen series, which have some variation in the type and number of allergens included (Table 2). The T.R.U.E. test will miss a notable number of clinically relevant allergens in comparison to the North American Contact Dermatitis Group and American Contact Dermatitis Society Core series, and it may be of particularly low utility in identifying fragrance or preservative ACD.⁹

Allergens are placed on the back in chambers in a petrolatum or aqueous medium. The patches remain affixed for 48 hours, during which time the patient is asked to refrain from showering or exercising to prevent loss of patches. The patient's skin is then evaluated for reactions to allergens on 2 separate occasions: at the time of patch removal 48 hours after initial placement, then the areas of patches are marked for delayed readings at day 4 to day 7 after initial patch placement. Results are scored based on the degree of the inflammatory reaction (Table 3). Delayed readings beyond day 7 may be necessary for metals, specific preservatives (eg, dodecyl gallate, propolis), and neomycin.¹⁰

There is a wide spectrum of cutaneous disease that should prompt consideration of patch testing, including well-circumscribed eczematous dermatitis (eg, recurrent lip, hand, and foot dermatitis); patchy or diffuse eczema, especially if recently worsened and/or unresponsive to topical steroids; lichenoid eruptions, particularly of mucosal surfaces; mucous membrane eruptions (eg, stomatitis, vulvitis); and eczematous presentations that raise concern for airborne (photodistributed) or systemic contact dermatitis.^11-13 Although further studies of efficacy and safety are ongoing, patch testing also may be useful in the diagnosis of nonimmediate cutaneous adverse drug reactions, especially fixed drug eruptions, acute generalized exanthematous pustulosis, systemic contact dermatitis from medications, and drug-induced hypersensitivity syndrome.³ Lastly, patients with type IV hypersensitivity to metals, adhesives, or antibiotics used in metallic orthopedic or cardiac implants may experience implant failure, regional contact dermatitis, or both, and benefit from patch testing prior to implant replacement to assess for potential allergens. Of the joints that fail, it is estimated that up to 5% are due to metal hypersensitivity.⁴

Throughout patch testing, patients may continue to manage their skin condition with oral antihistamines and topical steroids, though application to the site at which the patches are applied should be avoided throughout patch testing and during the week prior. According to expert consensus, immunosuppressive medications that are less likely to impact patch testing and therefore may be continued include low-dose methotrexate, oral prednisone less than 10 mg daily, biologic therapy, and low-dose cyclosporine (<2 mg/kg daily). Therapeutic interventions that are more likely to impact patch testing and should be avoided include phototherapy or extensive sun exposure within a week prior to testing, oral prednisone more than 10 mg daily, intramuscular triamcinolone within the preceding month, and high-dose cyclosporine (>2 mg/kg daily).¹⁴

An important component to successful patch testing is posttest patient counseling. Providers can create a safe list of products for patients by logging onto the American Contact Dermatitis Society website and accessing the Contact Allergen Management Program (CAMP).¹⁵ All relevant allergens found on patch testing may be selected and patient-specific identification codes generated. Once these codes are entered into the CAMP app on the patient's cellular device, a personalized, regularly updated list of safe products appears for many categories of products, including shampoos, sunscreens, moisturizers, cosmetic products, and laundry or dish detergents, among others. Of note, this app is not helpful for avoidance in patients with textile allergies. Patients should be counseled that improvement occurs with avoidance, which usually occurs within weeks but may slowly occur over time in some cases.

Lymphocyte Transformation Test (In Vitro)
The lymphocyte transformation test is an experimental in vitro test for type IV hypersensitivity. This serologic test utilizes allergens to stimulate memory T lymphocytes in vitro and measures the degree of response to the allergen. Although this test has generated excitement, particularly for the potential to safely evaluate for severe adverse cutaneous drug reactions, it currently is not the standard of care and is not utilized in the United States.¹⁶

Conclusion

Dermatologists play a vital role in the workup of suspected type IV hypersensitivities. Patch testing is an important but underutilized tool in the arsenal of allergy testing and may be indicated in a wide variety of cutaneous presentations, adverse reactions to medications, and implanted device failures. Identification and avoidance of a culprit allergen has the potential to lead to complete resolution of disease and notable improvement in quality of life for patients.

Acknowledgments
The author thanks Nina Botto, MD (San Francisco, California), for her mentorship in the arena of ACD as well as the Women's Dermatologic Society for the support they provided through the mentorship program.

Allergy testing typically refers to evaluation of a patient for suspected type I or type IV hypersensitivity.^1,2 The possibility of type I hypersensitivity is raised in patients presenting with food allergies, allergic rhinitis, asthma, and immediate adverse reactions to medications, whereas type IV hypersensitivity is suspected in patients with eczematous eruptions, delayed adverse cutaneous reactions to medications, and failure of metallic implants (eg, metal joint replacements, cardiac stents) in conjunction with overlying skin rashes (Table 1).^1-5 Type II (eg, pemphigus vulgaris) and type III (eg, IgA vasculitis) hypersensitivities are not evaluated with screening allergy tests.

Type I Sensitization

Type I hypersensitivity is an immediate hypersensitivity mediated predominantly by IgE activation of mast cells in the skin as well as the respiratory and gastric mucosa.¹ Sensitization of an individual patient occurs when antigen-presenting cells induce a helper T cell (T_H2) cytokine response leading to B-cell class switching and allergen-specific IgE production. Upon repeat exposure to the allergen, circulating antibodies then bind to high-affinity receptors on mast cells and basophils and initiate an allergic inflammatory response, leading to a clinical presentation of allergic rhinitis, urticaria, or immediate drug reactions. Confirming type I sensitization may be performed via serologic (in vitro) or skin testing (in vivo).^5,6

Serologic Testing (In Vitro)
Serologic testing is a blood test that detects circulating IgE levels against specific allergens.⁵ The first such test, the radioallergosorbent test, was introduced in the 1970s but is not quantitative and is no longer used. Although common, it is inaccurate to describe current serum IgE (s-IgE) testing as radioallergosorbent testing. There are several US Food and Drug Administration-approved s-IgE assays in common use, and these tests may be helpful in elucidating relevant allergens and for tailoring therapy appropriately, which may consist of avoidance of certain foods or environmental agents and/or allergen immunotherapy.

Skin Testing (In Vivo)
Skin testing can be performed percutaneously (eg, percutaneous skin testing) or intradermally (eg, intradermal testing).⁶ Percutaneous skin testing is performed by placing a drop of allergen extract on the skin, after which a lancet is used to lightly scratch the skin; intradermal testing is performed by injecting a small amount of allergen extract into the dermis. In both cases, the skin is evaluated after 15 to 20 minutes for the presence and size of a cutaneous wheal. Medications with antihistaminergic activity must be discontinued prior to testing. Both s-IgE and skin testing assess for type I hypersensitivity, and factors such as extensive rash, concern for anaphylaxis, or inability to discontinue antihistamines may favor s-IgE testing versus skin testing. False-positive results can occur with both tests, and for this reason, test results should always be interpreted in conjunction with clinical examination and patient history to determine relevant allergies.

Type IV Sensitization

Type IV hypersensitivity is a delayed hypersensitivity mediated primarily by lymphocytes.² Sensitization occurs when haptens bind to host proteins and are presented by epidermal and dermal dendritic cells to T lymphocytes in the skin. These lymphocytes then migrate to regional lymph nodes where antigen-specific T lymphocytes are produced and home back to the skin. Upon reexposure to the allergen, these memory T lymphocytes become activated and incite a delayed allergic response. Confirming type IV hypersensitivity primarily is accomplished via patch testing, though other testing modalities exist.

Skin Biopsy
Biopsy is sometimes performed in the workup of an individual presenting with allergic contact dermatitis (ACD) and typically will show spongiosis with normal stratum corneum and epidermal thickness in the setting of acute ACD and mild to marked acanthosis and parakeratosis in chronic ACD.⁷ The findings, however, are nonspecific and the differential of these histopathologic findings encompasses nummular dermatitis, atopic dermatitis, irritant contact dermatitis, and dyshidrotic eczema, among others. The presence of eosinophils and Langerhans cell microabscesses may provide supportive evidence for ACD over the other spongiotic dermatitides.^7,8

Patch Testing
Patch testing is the gold standard in diagnosing type IV hypersensitivities resulting in a clinical presentation of ACD. Hundreds of allergens are commercially available for patch testing, and more commonly tested allergens fall into one of several categories, such as cosmetic preservatives, rubbers, metals, textiles, fragrances, adhesives, antibiotics, plants, and even corticosteroids. Of note, a common misconception is that ACD must result from new exposures; however, patients may develop ACD secondary to an exposure or product they have been using for many years without a problem.

Three commonly used screening series are the thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice), North American Contact Dermatitis Group screening series, and American Contact Dermatitis Society Core 80 allergen series, which have some variation in the type and number of allergens included (Table 2). The T.R.U.E. test will miss a notable number of clinically relevant allergens in comparison to the North American Contact Dermatitis Group and American Contact Dermatitis Society Core series, and it may be of particularly low utility in identifying fragrance or preservative ACD.⁹

Allergens are placed on the back in chambers in a petrolatum or aqueous medium. The patches remain affixed for 48 hours, during which time the patient is asked to refrain from showering or exercising to prevent loss of patches. The patient's skin is then evaluated for reactions to allergens on 2 separate occasions: at the time of patch removal 48 hours after initial placement, then the areas of patches are marked for delayed readings at day 4 to day 7 after initial patch placement. Results are scored based on the degree of the inflammatory reaction (Table 3). Delayed readings beyond day 7 may be necessary for metals, specific preservatives (eg, dodecyl gallate, propolis), and neomycin.¹⁰

There is a wide spectrum of cutaneous disease that should prompt consideration of patch testing, including well-circumscribed eczematous dermatitis (eg, recurrent lip, hand, and foot dermatitis); patchy or diffuse eczema, especially if recently worsened and/or unresponsive to topical steroids; lichenoid eruptions, particularly of mucosal surfaces; mucous membrane eruptions (eg, stomatitis, vulvitis); and eczematous presentations that raise concern for airborne (photodistributed) or systemic contact dermatitis.^11-13 Although further studies of efficacy and safety are ongoing, patch testing also may be useful in the diagnosis of nonimmediate cutaneous adverse drug reactions, especially fixed drug eruptions, acute generalized exanthematous pustulosis, systemic contact dermatitis from medications, and drug-induced hypersensitivity syndrome.³ Lastly, patients with type IV hypersensitivity to metals, adhesives, or antibiotics used in metallic orthopedic or cardiac implants may experience implant failure, regional contact dermatitis, or both, and benefit from patch testing prior to implant replacement to assess for potential allergens. Of the joints that fail, it is estimated that up to 5% are due to metal hypersensitivity.⁴

Throughout patch testing, patients may continue to manage their skin condition with oral antihistamines and topical steroids, though application to the site at which the patches are applied should be avoided throughout patch testing and during the week prior. According to expert consensus, immunosuppressive medications that are less likely to impact patch testing and therefore may be continued include low-dose methotrexate, oral prednisone less than 10 mg daily, biologic therapy, and low-dose cyclosporine (<2 mg/kg daily). Therapeutic interventions that are more likely to impact patch testing and should be avoided include phototherapy or extensive sun exposure within a week prior to testing, oral prednisone more than 10 mg daily, intramuscular triamcinolone within the preceding month, and high-dose cyclosporine (>2 mg/kg daily).¹⁴

An important component to successful patch testing is posttest patient counseling. Providers can create a safe list of products for patients by logging onto the American Contact Dermatitis Society website and accessing the Contact Allergen Management Program (CAMP).¹⁵ All relevant allergens found on patch testing may be selected and patient-specific identification codes generated. Once these codes are entered into the CAMP app on the patient's cellular device, a personalized, regularly updated list of safe products appears for many categories of products, including shampoos, sunscreens, moisturizers, cosmetic products, and laundry or dish detergents, among others. Of note, this app is not helpful for avoidance in patients with textile allergies. Patients should be counseled that improvement occurs with avoidance, which usually occurs within weeks but may slowly occur over time in some cases.

Lymphocyte Transformation Test (In Vitro)
The lymphocyte transformation test is an experimental in vitro test for type IV hypersensitivity. This serologic test utilizes allergens to stimulate memory T lymphocytes in vitro and measures the degree of response to the allergen. Although this test has generated excitement, particularly for the potential to safely evaluate for severe adverse cutaneous drug reactions, it currently is not the standard of care and is not utilized in the United States.¹⁶

Conclusion

Dermatologists play a vital role in the workup of suspected type IV hypersensitivities. Patch testing is an important but underutilized tool in the arsenal of allergy testing and may be indicated in a wide variety of cutaneous presentations, adverse reactions to medications, and implanted device failures. Identification and avoidance of a culprit allergen has the potential to lead to complete resolution of disease and notable improvement in quality of life for patients.

Acknowledgments
The author thanks Nina Botto, MD (San Francisco, California), for her mentorship in the arena of ACD as well as the Women's Dermatologic Society for the support they provided through the mentorship program.

Allergy testing typically refers to evaluation of a patient for suspected type I or type IV hypersensitivity.^1,2 The possibility of type I hypersensitivity is raised in patients presenting with food allergies, allergic rhinitis, asthma, and immediate adverse reactions to medications, whereas type IV hypersensitivity is suspected in patients with eczematous eruptions, delayed adverse cutaneous reactions to medications, and failure of metallic implants (eg, metal joint replacements, cardiac stents) in conjunction with overlying skin rashes (Table 1).^1-5 Type II (eg, pemphigus vulgaris) and type III (eg, IgA vasculitis) hypersensitivities are not evaluated with screening allergy tests.

Type I Sensitization

Type I hypersensitivity is an immediate hypersensitivity mediated predominantly by IgE activation of mast cells in the skin as well as the respiratory and gastric mucosa.¹ Sensitization of an individual patient occurs when antigen-presenting cells induce a helper T cell (T_H2) cytokine response leading to B-cell class switching and allergen-specific IgE production. Upon repeat exposure to the allergen, circulating antibodies then bind to high-affinity receptors on mast cells and basophils and initiate an allergic inflammatory response, leading to a clinical presentation of allergic rhinitis, urticaria, or immediate drug reactions. Confirming type I sensitization may be performed via serologic (in vitro) or skin testing (in vivo).^5,6

Serologic Testing (In Vitro)
Serologic testing is a blood test that detects circulating IgE levels against specific allergens.⁵ The first such test, the radioallergosorbent test, was introduced in the 1970s but is not quantitative and is no longer used. Although common, it is inaccurate to describe current serum IgE (s-IgE) testing as radioallergosorbent testing. There are several US Food and Drug Administration-approved s-IgE assays in common use, and these tests may be helpful in elucidating relevant allergens and for tailoring therapy appropriately, which may consist of avoidance of certain foods or environmental agents and/or allergen immunotherapy.

Skin Testing (In Vivo)
Skin testing can be performed percutaneously (eg, percutaneous skin testing) or intradermally (eg, intradermal testing).⁶ Percutaneous skin testing is performed by placing a drop of allergen extract on the skin, after which a lancet is used to lightly scratch the skin; intradermal testing is performed by injecting a small amount of allergen extract into the dermis. In both cases, the skin is evaluated after 15 to 20 minutes for the presence and size of a cutaneous wheal. Medications with antihistaminergic activity must be discontinued prior to testing. Both s-IgE and skin testing assess for type I hypersensitivity, and factors such as extensive rash, concern for anaphylaxis, or inability to discontinue antihistamines may favor s-IgE testing versus skin testing. False-positive results can occur with both tests, and for this reason, test results should always be interpreted in conjunction with clinical examination and patient history to determine relevant allergies.

Type IV Sensitization

Type IV hypersensitivity is a delayed hypersensitivity mediated primarily by lymphocytes.² Sensitization occurs when haptens bind to host proteins and are presented by epidermal and dermal dendritic cells to T lymphocytes in the skin. These lymphocytes then migrate to regional lymph nodes where antigen-specific T lymphocytes are produced and home back to the skin. Upon reexposure to the allergen, these memory T lymphocytes become activated and incite a delayed allergic response. Confirming type IV hypersensitivity primarily is accomplished via patch testing, though other testing modalities exist.

Skin Biopsy
Biopsy is sometimes performed in the workup of an individual presenting with allergic contact dermatitis (ACD) and typically will show spongiosis with normal stratum corneum and epidermal thickness in the setting of acute ACD and mild to marked acanthosis and parakeratosis in chronic ACD.⁷ The findings, however, are nonspecific and the differential of these histopathologic findings encompasses nummular dermatitis, atopic dermatitis, irritant contact dermatitis, and dyshidrotic eczema, among others. The presence of eosinophils and Langerhans cell microabscesses may provide supportive evidence for ACD over the other spongiotic dermatitides.^7,8

Patch Testing
Patch testing is the gold standard in diagnosing type IV hypersensitivities resulting in a clinical presentation of ACD. Hundreds of allergens are commercially available for patch testing, and more commonly tested allergens fall into one of several categories, such as cosmetic preservatives, rubbers, metals, textiles, fragrances, adhesives, antibiotics, plants, and even corticosteroids. Of note, a common misconception is that ACD must result from new exposures; however, patients may develop ACD secondary to an exposure or product they have been using for many years without a problem.

Three commonly used screening series are the thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice), North American Contact Dermatitis Group screening series, and American Contact Dermatitis Society Core 80 allergen series, which have some variation in the type and number of allergens included (Table 2). The T.R.U.E. test will miss a notable number of clinically relevant allergens in comparison to the North American Contact Dermatitis Group and American Contact Dermatitis Society Core series, and it may be of particularly low utility in identifying fragrance or preservative ACD.⁹

Allergens are placed on the back in chambers in a petrolatum or aqueous medium. The patches remain affixed for 48 hours, during which time the patient is asked to refrain from showering or exercising to prevent loss of patches. The patient's skin is then evaluated for reactions to allergens on 2 separate occasions: at the time of patch removal 48 hours after initial placement, then the areas of patches are marked for delayed readings at day 4 to day 7 after initial patch placement. Results are scored based on the degree of the inflammatory reaction (Table 3). Delayed readings beyond day 7 may be necessary for metals, specific preservatives (eg, dodecyl gallate, propolis), and neomycin.¹⁰

There is a wide spectrum of cutaneous disease that should prompt consideration of patch testing, including well-circumscribed eczematous dermatitis (eg, recurrent lip, hand, and foot dermatitis); patchy or diffuse eczema, especially if recently worsened and/or unresponsive to topical steroids; lichenoid eruptions, particularly of mucosal surfaces; mucous membrane eruptions (eg, stomatitis, vulvitis); and eczematous presentations that raise concern for airborne (photodistributed) or systemic contact dermatitis.^11-13 Although further studies of efficacy and safety are ongoing, patch testing also may be useful in the diagnosis of nonimmediate cutaneous adverse drug reactions, especially fixed drug eruptions, acute generalized exanthematous pustulosis, systemic contact dermatitis from medications, and drug-induced hypersensitivity syndrome.³ Lastly, patients with type IV hypersensitivity to metals, adhesives, or antibiotics used in metallic orthopedic or cardiac implants may experience implant failure, regional contact dermatitis, or both, and benefit from patch testing prior to implant replacement to assess for potential allergens. Of the joints that fail, it is estimated that up to 5% are due to metal hypersensitivity.⁴

Throughout patch testing, patients may continue to manage their skin condition with oral antihistamines and topical steroids, though application to the site at which the patches are applied should be avoided throughout patch testing and during the week prior. According to expert consensus, immunosuppressive medications that are less likely to impact patch testing and therefore may be continued include low-dose methotrexate, oral prednisone less than 10 mg daily, biologic therapy, and low-dose cyclosporine (<2 mg/kg daily). Therapeutic interventions that are more likely to impact patch testing and should be avoided include phototherapy or extensive sun exposure within a week prior to testing, oral prednisone more than 10 mg daily, intramuscular triamcinolone within the preceding month, and high-dose cyclosporine (>2 mg/kg daily).¹⁴

An important component to successful patch testing is posttest patient counseling. Providers can create a safe list of products for patients by logging onto the American Contact Dermatitis Society website and accessing the Contact Allergen Management Program (CAMP).¹⁵ All relevant allergens found on patch testing may be selected and patient-specific identification codes generated. Once these codes are entered into the CAMP app on the patient's cellular device, a personalized, regularly updated list of safe products appears for many categories of products, including shampoos, sunscreens, moisturizers, cosmetic products, and laundry or dish detergents, among others. Of note, this app is not helpful for avoidance in patients with textile allergies. Patients should be counseled that improvement occurs with avoidance, which usually occurs within weeks but may slowly occur over time in some cases.

Lymphocyte Transformation Test (In Vitro)
The lymphocyte transformation test is an experimental in vitro test for type IV hypersensitivity. This serologic test utilizes allergens to stimulate memory T lymphocytes in vitro and measures the degree of response to the allergen. Although this test has generated excitement, particularly for the potential to safely evaluate for severe adverse cutaneous drug reactions, it currently is not the standard of care and is not utilized in the United States.¹⁶

Conclusion

Dermatologists play a vital role in the workup of suspected type IV hypersensitivities. Patch testing is an important but underutilized tool in the arsenal of allergy testing and may be indicated in a wide variety of cutaneous presentations, adverse reactions to medications, and implanted device failures. Identification and avoidance of a culprit allergen has the potential to lead to complete resolution of disease and notable improvement in quality of life for patients.

Acknowledgments
The author thanks Nina Botto, MD (San Francisco, California), for her mentorship in the arena of ACD as well as the Women's Dermatologic Society for the support they provided through the mentorship program.

The Diagnosis: Black-Spot Poison Ivy

Due to the detailed account of the patient's history including acuity of current presentation, history of recent activities, travel history, and recent exposures, as well as a thorough skin examination, a diagnosis of black-spot poison ivy was made. In this case, the linear distribution of the lesions with overlying black pigment that could not be removed (Figures 1 and 2) provided important clues to diagnosis.

Poison ivy is an allergic contact dermatitis that affects an estimated 25 to 40 million Americans annually who are exposed to its resin. Poison ivy is a plant from the Toxicodendron genus, and an estimated 85% of the North American population report sensitivity to these plants, of which poison ivy (Toxicodendron radicans) is the most common.¹ Other related plants include poison sumac and poison oak. Poison ivy and other Toxicodendron plants produce urushiol, the oleoresin responsible for one of the most common allergic contact dermatitides in the United States.² Black-spot poison ivy is an uncommon presentation following exposure to urushiol or oleoresin,³ as sufficient concentration of urushiol on the skin rarely is achieved.^3,4 This plant's resin oxidizes and turns coal black when exposed to air.⁵ Contact with enough of this oleoresin will produce black-spot poison ivy.⁶ Patients with sufficient concentrations of oleoresin on their skin to cause this black oxidation usually have similar black spots on their clothing.⁷ Interestingly, some Toxicodendron species, such as the Japanese lacquer tree, Toxicodendron vernicifluum, have a black lacquer sap that was historically used as ink.⁸ This ink was used on Chinese and Japanese jars and has caused contact dermatitis hundreds of years after they were created.⁷

Poison ivy is characterized by a generalized, pruritic, erythematous rash with vesicles and papules in a linear distribution.⁹ Black-spot poison ivy presents the same with the addition of black lacquer-like macules with surrounding erythema.¹⁰ The skin lesions usually appear on exposed areas 24 to 48 hours after contact.¹¹ Histology of black-spot poison ivy lesions should reveal yellow material in the stratum corneum with epidermal necrosis, in addition to classic features of acute allergic contact dermatitis.³ Interestingly, because these lesions occur with the first exposure to poison ivy, a patient may not develop the typical itchy eczematous eruption characteristic of poison ivy dermatitis. Differential diagnosis includes superficial purpura; exogenous pigment such as marker, ink, or tattoo pigment; tinea nigra; purpuric allergic contact dermatitis to resins or dyes; arthropod assault; irritant contact dermatitis; and infectious and noninfectious vasculitis.¹¹

Similar to poison ivy, treatment of black-spot poison ivy involves oral and topical steroids combined with antihistamines if the patient continues to experience pruritus.^6,12 It was recommended to our patient to apply cool compresses with water or Burow solution to alleviate itching and promote drying of the lesions. Calamine lotion can provide similar outcomes.¹³ Once the oleoresin is oxidized and bound to skin, the black spots cannot be removed with soap, water, or alcohol. The black spots gradually desquamate 1 to 2 weeks after formation without scarring,¹¹ and patients do not require further monitoring.¹ Patients should clean or discard clothing and evaluate for possible sources of poison ivy exposure. Because this type of poison ivy dermatitis is rare, most health care workers likely have never seen black-spot poison ivy, and it is an important diagnosis to consider.¹³

The Diagnosis: Black-Spot Poison Ivy

Due to the detailed account of the patient's history including acuity of current presentation, history of recent activities, travel history, and recent exposures, as well as a thorough skin examination, a diagnosis of black-spot poison ivy was made. In this case, the linear distribution of the lesions with overlying black pigment that could not be removed (Figures 1 and 2) provided important clues to diagnosis.

Poison ivy is an allergic contact dermatitis that affects an estimated 25 to 40 million Americans annually who are exposed to its resin. Poison ivy is a plant from the Toxicodendron genus, and an estimated 85% of the North American population report sensitivity to these plants, of which poison ivy (Toxicodendron radicans) is the most common.¹ Other related plants include poison sumac and poison oak. Poison ivy and other Toxicodendron plants produce urushiol, the oleoresin responsible for one of the most common allergic contact dermatitides in the United States.² Black-spot poison ivy is an uncommon presentation following exposure to urushiol or oleoresin,³ as sufficient concentration of urushiol on the skin rarely is achieved.^3,4 This plant's resin oxidizes and turns coal black when exposed to air.⁵ Contact with enough of this oleoresin will produce black-spot poison ivy.⁶ Patients with sufficient concentrations of oleoresin on their skin to cause this black oxidation usually have similar black spots on their clothing.⁷ Interestingly, some Toxicodendron species, such as the Japanese lacquer tree, Toxicodendron vernicifluum, have a black lacquer sap that was historically used as ink.⁸ This ink was used on Chinese and Japanese jars and has caused contact dermatitis hundreds of years after they were created.⁷

Poison ivy is characterized by a generalized, pruritic, erythematous rash with vesicles and papules in a linear distribution.⁹ Black-spot poison ivy presents the same with the addition of black lacquer-like macules with surrounding erythema.¹⁰ The skin lesions usually appear on exposed areas 24 to 48 hours after contact.¹¹ Histology of black-spot poison ivy lesions should reveal yellow material in the stratum corneum with epidermal necrosis, in addition to classic features of acute allergic contact dermatitis.³ Interestingly, because these lesions occur with the first exposure to poison ivy, a patient may not develop the typical itchy eczematous eruption characteristic of poison ivy dermatitis. Differential diagnosis includes superficial purpura; exogenous pigment such as marker, ink, or tattoo pigment; tinea nigra; purpuric allergic contact dermatitis to resins or dyes; arthropod assault; irritant contact dermatitis; and infectious and noninfectious vasculitis.¹¹

Similar to poison ivy, treatment of black-spot poison ivy involves oral and topical steroids combined with antihistamines if the patient continues to experience pruritus.^6,12 It was recommended to our patient to apply cool compresses with water or Burow solution to alleviate itching and promote drying of the lesions. Calamine lotion can provide similar outcomes.¹³ Once the oleoresin is oxidized and bound to skin, the black spots cannot be removed with soap, water, or alcohol. The black spots gradually desquamate 1 to 2 weeks after formation without scarring,¹¹ and patients do not require further monitoring.¹ Patients should clean or discard clothing and evaluate for possible sources of poison ivy exposure. Because this type of poison ivy dermatitis is rare, most health care workers likely have never seen black-spot poison ivy, and it is an important diagnosis to consider.¹³

The Diagnosis: Black-Spot Poison Ivy

Due to the detailed account of the patient's history including acuity of current presentation, history of recent activities, travel history, and recent exposures, as well as a thorough skin examination, a diagnosis of black-spot poison ivy was made. In this case, the linear distribution of the lesions with overlying black pigment that could not be removed (Figures 1 and 2) provided important clues to diagnosis.

Poison ivy is an allergic contact dermatitis that affects an estimated 25 to 40 million Americans annually who are exposed to its resin. Poison ivy is a plant from the Toxicodendron genus, and an estimated 85% of the North American population report sensitivity to these plants, of which poison ivy (Toxicodendron radicans) is the most common.¹ Other related plants include poison sumac and poison oak. Poison ivy and other Toxicodendron plants produce urushiol, the oleoresin responsible for one of the most common allergic contact dermatitides in the United States.² Black-spot poison ivy is an uncommon presentation following exposure to urushiol or oleoresin,³ as sufficient concentration of urushiol on the skin rarely is achieved.^3,4 This plant's resin oxidizes and turns coal black when exposed to air.⁵ Contact with enough of this oleoresin will produce black-spot poison ivy.⁶ Patients with sufficient concentrations of oleoresin on their skin to cause this black oxidation usually have similar black spots on their clothing.⁷ Interestingly, some Toxicodendron species, such as the Japanese lacquer tree, Toxicodendron vernicifluum, have a black lacquer sap that was historically used as ink.⁸ This ink was used on Chinese and Japanese jars and has caused contact dermatitis hundreds of years after they were created.⁷

Poison ivy is characterized by a generalized, pruritic, erythematous rash with vesicles and papules in a linear distribution.⁹ Black-spot poison ivy presents the same with the addition of black lacquer-like macules with surrounding erythema.¹⁰ The skin lesions usually appear on exposed areas 24 to 48 hours after contact.¹¹ Histology of black-spot poison ivy lesions should reveal yellow material in the stratum corneum with epidermal necrosis, in addition to classic features of acute allergic contact dermatitis.³ Interestingly, because these lesions occur with the first exposure to poison ivy, a patient may not develop the typical itchy eczematous eruption characteristic of poison ivy dermatitis. Differential diagnosis includes superficial purpura; exogenous pigment such as marker, ink, or tattoo pigment; tinea nigra; purpuric allergic contact dermatitis to resins or dyes; arthropod assault; irritant contact dermatitis; and infectious and noninfectious vasculitis.¹¹

Similar to poison ivy, treatment of black-spot poison ivy involves oral and topical steroids combined with antihistamines if the patient continues to experience pruritus.^6,12 It was recommended to our patient to apply cool compresses with water or Burow solution to alleviate itching and promote drying of the lesions. Calamine lotion can provide similar outcomes.¹³ Once the oleoresin is oxidized and bound to skin, the black spots cannot be removed with soap, water, or alcohol. The black spots gradually desquamate 1 to 2 weeks after formation without scarring,¹¹ and patients do not require further monitoring.¹ Patients should clean or discard clothing and evaluate for possible sources of poison ivy exposure. Because this type of poison ivy dermatitis is rare, most health care workers likely have never seen black-spot poison ivy, and it is an important diagnosis to consider.¹³

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.