Contact Dermatitis

The Diagnosis: Acute Contact Dermatitis

Dermoscopy demonstrated caterpillar hairs (Figure) and established the diagnosis of acute contact dermatitis due to a caterpillar. Upon further questioning, the patient recalled that something dustlike fell on the left cheek as she walked under some trees. The clinical and dermoscopic findings suggested a diagnosis of caterpillar dermatitis (family Limacodidae or Lymantriinae, order Lepidoptera). During the life cycle from young larvae to mature larvae, the quantities of the toxic thorns and hairs increase from 60,000 to 80,000 to 2,000,000 to 3,000,000. The toxic hairs measure 0.5 to 2.0 mm in length. They drop from the mature larvae's skin during desquamation as well as from the cocoon curing maturation to a moth. The hairs appear tubular and arrowlike with terminal spines.¹ The larvae are called "the fiery hot" in Chinese, which vividly describes the swelling and sensation of burning with immediate contact.

Eruption severity and distribution depend on exposure modality and intensity. Exposed body parts, including the face, neck, forearms, interdigital spaces, and dorsal aspects of the hands, most commonly are involved. The eruption can be immediate or delayed, occurring hours or even days after the first contact.2 Itching is intense and continuous, with intermittent worsening. Clinically, the eruption manifests with rose to bright red, round macules and papules. Although rare, skin manifestations can be accompanied by systemic symptoms, such as malaise, fever, and anaphylaxis syndrome.³ The cutaneous lesions may last for 3 to 4 days and subside, leaving a brownish macule.^1,4

The differential diagnosis includes acute herpes simplex, which presents as grouped vesicles on an erythematous base with itching or burning, and recurrences in the same location are common. Acute Sweet syndrome may appear as erythematous or edematous painful plaques with fever and neutrophilia. Acute urticaria appears as wheals with severe pruritus, and individual lesions can resolve within several hours. Insect bites often appear as itching or painful erythema or papules.

We sterilized the lesion with alcohol, removed the thorns as much as possible with ophthalmic forceps under the guidance of dermoscopy, and prescribed chloramphenicol ointment 1% twice daily. Our patient was completely cured within 24 hours with no systemic symptoms or pigmentation.

This case directly showed a novel usage of dermoscopy in diagnosis and therapy, especially in acute contact dermatitis. Small irritants such as caterpillar thorns and hairs easily can be observed and removed by dermoscopy devices with higher magnification.

The Diagnosis: Acute Contact Dermatitis

Dermoscopy demonstrated caterpillar hairs (Figure) and established the diagnosis of acute contact dermatitis due to a caterpillar. Upon further questioning, the patient recalled that something dustlike fell on the left cheek as she walked under some trees. The clinical and dermoscopic findings suggested a diagnosis of caterpillar dermatitis (family Limacodidae or Lymantriinae, order Lepidoptera). During the life cycle from young larvae to mature larvae, the quantities of the toxic thorns and hairs increase from 60,000 to 80,000 to 2,000,000 to 3,000,000. The toxic hairs measure 0.5 to 2.0 mm in length. They drop from the mature larvae's skin during desquamation as well as from the cocoon curing maturation to a moth. The hairs appear tubular and arrowlike with terminal spines.¹ The larvae are called "the fiery hot" in Chinese, which vividly describes the swelling and sensation of burning with immediate contact.

Eruption severity and distribution depend on exposure modality and intensity. Exposed body parts, including the face, neck, forearms, interdigital spaces, and dorsal aspects of the hands, most commonly are involved. The eruption can be immediate or delayed, occurring hours or even days after the first contact.2 Itching is intense and continuous, with intermittent worsening. Clinically, the eruption manifests with rose to bright red, round macules and papules. Although rare, skin manifestations can be accompanied by systemic symptoms, such as malaise, fever, and anaphylaxis syndrome.³ The cutaneous lesions may last for 3 to 4 days and subside, leaving a brownish macule.^1,4

The differential diagnosis includes acute herpes simplex, which presents as grouped vesicles on an erythematous base with itching or burning, and recurrences in the same location are common. Acute Sweet syndrome may appear as erythematous or edematous painful plaques with fever and neutrophilia. Acute urticaria appears as wheals with severe pruritus, and individual lesions can resolve within several hours. Insect bites often appear as itching or painful erythema or papules.

We sterilized the lesion with alcohol, removed the thorns as much as possible with ophthalmic forceps under the guidance of dermoscopy, and prescribed chloramphenicol ointment 1% twice daily. Our patient was completely cured within 24 hours with no systemic symptoms or pigmentation.

This case directly showed a novel usage of dermoscopy in diagnosis and therapy, especially in acute contact dermatitis. Small irritants such as caterpillar thorns and hairs easily can be observed and removed by dermoscopy devices with higher magnification.

The Diagnosis: Acute Contact Dermatitis

Dermoscopy demonstrated caterpillar hairs (Figure) and established the diagnosis of acute contact dermatitis due to a caterpillar. Upon further questioning, the patient recalled that something dustlike fell on the left cheek as she walked under some trees. The clinical and dermoscopic findings suggested a diagnosis of caterpillar dermatitis (family Limacodidae or Lymantriinae, order Lepidoptera). During the life cycle from young larvae to mature larvae, the quantities of the toxic thorns and hairs increase from 60,000 to 80,000 to 2,000,000 to 3,000,000. The toxic hairs measure 0.5 to 2.0 mm in length. They drop from the mature larvae's skin during desquamation as well as from the cocoon curing maturation to a moth. The hairs appear tubular and arrowlike with terminal spines.¹ The larvae are called "the fiery hot" in Chinese, which vividly describes the swelling and sensation of burning with immediate contact.

Eruption severity and distribution depend on exposure modality and intensity. Exposed body parts, including the face, neck, forearms, interdigital spaces, and dorsal aspects of the hands, most commonly are involved. The eruption can be immediate or delayed, occurring hours or even days after the first contact.2 Itching is intense and continuous, with intermittent worsening. Clinically, the eruption manifests with rose to bright red, round macules and papules. Although rare, skin manifestations can be accompanied by systemic symptoms, such as malaise, fever, and anaphylaxis syndrome.³ The cutaneous lesions may last for 3 to 4 days and subside, leaving a brownish macule.^1,4

The differential diagnosis includes acute herpes simplex, which presents as grouped vesicles on an erythematous base with itching or burning, and recurrences in the same location are common. Acute Sweet syndrome may appear as erythematous or edematous painful plaques with fever and neutrophilia. Acute urticaria appears as wheals with severe pruritus, and individual lesions can resolve within several hours. Insect bites often appear as itching or painful erythema or papules.

We sterilized the lesion with alcohol, removed the thorns as much as possible with ophthalmic forceps under the guidance of dermoscopy, and prescribed chloramphenicol ointment 1% twice daily. Our patient was completely cured within 24 hours with no systemic symptoms or pigmentation.

This case directly showed a novel usage of dermoscopy in diagnosis and therapy, especially in acute contact dermatitis. Small irritants such as caterpillar thorns and hairs easily can be observed and removed by dermoscopy devices with higher magnification.

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷ Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷ Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷ Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

SAN DIEGO – Patch testing may be in order for some patients with atopic dermatitis, according to Jonathan Silverberg, MD, PhD, of the department of dermatology, Northwestern University, Chicago.

Allergic contact dermatitis is a common comorbid condition in people with AD “and sometimes, can flare up the severity of the disease,” he said in a video interview at the American Academy of Dermatology annual meeting.

Patch testing can ferret out a trigger in atopic dermatitis patients with atypical disease distribution or refractory disease, and help avoid the need for systemic therapy, Dr. Silverman pointed out.

In the interview, he discussed these and other clinical scenarios, as well as how patch testing differs in these patients and what screening series to consider using.

Dr. Silverberg had no relevant financial disclosures.

[email protected]

SOURCE: Silverberg, J. et al, Session 061.

SAN DIEGO – Patch testing may be in order for some patients with atopic dermatitis, according to Jonathan Silverberg, MD, PhD, of the department of dermatology, Northwestern University, Chicago.

Allergic contact dermatitis is a common comorbid condition in people with AD “and sometimes, can flare up the severity of the disease,” he said in a video interview at the American Academy of Dermatology annual meeting.

Patch testing can ferret out a trigger in atopic dermatitis patients with atypical disease distribution or refractory disease, and help avoid the need for systemic therapy, Dr. Silverman pointed out.

In the interview, he discussed these and other clinical scenarios, as well as how patch testing differs in these patients and what screening series to consider using.

Dr. Silverberg had no relevant financial disclosures.

[email protected]

SOURCE: Silverberg, J. et al, Session 061.

SAN DIEGO – Patch testing may be in order for some patients with atopic dermatitis, according to Jonathan Silverberg, MD, PhD, of the department of dermatology, Northwestern University, Chicago.

Allergic contact dermatitis is a common comorbid condition in people with AD “and sometimes, can flare up the severity of the disease,” he said in a video interview at the American Academy of Dermatology annual meeting.

Patch testing can ferret out a trigger in atopic dermatitis patients with atypical disease distribution or refractory disease, and help avoid the need for systemic therapy, Dr. Silverman pointed out.

In the interview, he discussed these and other clinical scenarios, as well as how patch testing differs in these patients and what screening series to consider using.

Dr. Silverberg had no relevant financial disclosures.

[email protected]

SOURCE: Silverberg, J. et al, Session 061.

SAN DIEGO – With propylene glycol already declared 2018 Allergen of the Year in a published journal article, the news at the Allergen of the Year session of the American Contact Dermatitis Society was announcement of the 2019 pick, parabens.

From a skin perspective, parabens are “perhaps the safest” preservative, but despite that they have a bad public reputation Donald V. Belsito, MD, said in his Allergen of the Year talk during the Society’s annual meeting held the day before the annual meeting of the American Academy of Dermatology.

There is an unfounded public perception that parabens cause endocrine disruption. Naming parabens the “nonallergen” of the year for 2019 is an effort to dispel this myth, Dr. Belsito said in a video interview.

The public prejudice against parabens, exacerbated by many products that tout being paraben free, has helped cause a crisis because preservative systems in general have been under attack and facing restrictions. Dr. Belsito cited European limitations on the preservative methylisothiazolinone (Allergen of the Year in 2013) and withdrawal of formaldehyde (2015 Allergen of the Year) from many products.

Dr. Belsito also highlighted why propylene glycol received the nod as 2018’s Allergen of the Year (Dermatitis. 2018 Jan/Feb;29[1]:3-5). Propylene glycol is a very ubiquitous emulsifier found in cosmetics, foods, and both topical and oral medications. Caution is needed when running a patch test on the agent to distinguish an irritation reaction from an allergic reaction. Interpreting the test result correctly is very important, said Dr. Belsito, professor of dermatology at Columbia University in New York.

Parabens is the 20th Allergen of the Year named by the Society, an annual event since 2000.

Dr. Belsito has participated in the program since its start.

[email protected]

SAN DIEGO – With propylene glycol already declared 2018 Allergen of the Year in a published journal article, the news at the Allergen of the Year session of the American Contact Dermatitis Society was announcement of the 2019 pick, parabens.

From a skin perspective, parabens are “perhaps the safest” preservative, but despite that they have a bad public reputation Donald V. Belsito, MD, said in his Allergen of the Year talk during the Society’s annual meeting held the day before the annual meeting of the American Academy of Dermatology.

There is an unfounded public perception that parabens cause endocrine disruption. Naming parabens the “nonallergen” of the year for 2019 is an effort to dispel this myth, Dr. Belsito said in a video interview.

The public prejudice against parabens, exacerbated by many products that tout being paraben free, has helped cause a crisis because preservative systems in general have been under attack and facing restrictions. Dr. Belsito cited European limitations on the preservative methylisothiazolinone (Allergen of the Year in 2013) and withdrawal of formaldehyde (2015 Allergen of the Year) from many products.

Dr. Belsito also highlighted why propylene glycol received the nod as 2018’s Allergen of the Year (Dermatitis. 2018 Jan/Feb;29[1]:3-5). Propylene glycol is a very ubiquitous emulsifier found in cosmetics, foods, and both topical and oral medications. Caution is needed when running a patch test on the agent to distinguish an irritation reaction from an allergic reaction. Interpreting the test result correctly is very important, said Dr. Belsito, professor of dermatology at Columbia University in New York.

Parabens is the 20th Allergen of the Year named by the Society, an annual event since 2000.

Dr. Belsito has participated in the program since its start.

[email protected]

SAN DIEGO – With propylene glycol already declared 2018 Allergen of the Year in a published journal article, the news at the Allergen of the Year session of the American Contact Dermatitis Society was announcement of the 2019 pick, parabens.

From a skin perspective, parabens are “perhaps the safest” preservative, but despite that they have a bad public reputation Donald V. Belsito, MD, said in his Allergen of the Year talk during the Society’s annual meeting held the day before the annual meeting of the American Academy of Dermatology.

There is an unfounded public perception that parabens cause endocrine disruption. Naming parabens the “nonallergen” of the year for 2019 is an effort to dispel this myth, Dr. Belsito said in a video interview.

The public prejudice against parabens, exacerbated by many products that tout being paraben free, has helped cause a crisis because preservative systems in general have been under attack and facing restrictions. Dr. Belsito cited European limitations on the preservative methylisothiazolinone (Allergen of the Year in 2013) and withdrawal of formaldehyde (2015 Allergen of the Year) from many products.

Dr. Belsito also highlighted why propylene glycol received the nod as 2018’s Allergen of the Year (Dermatitis. 2018 Jan/Feb;29[1]:3-5). Propylene glycol is a very ubiquitous emulsifier found in cosmetics, foods, and both topical and oral medications. Caution is needed when running a patch test on the agent to distinguish an irritation reaction from an allergic reaction. Interpreting the test result correctly is very important, said Dr. Belsito, professor of dermatology at Columbia University in New York.

Parabens is the 20th Allergen of the Year named by the Society, an annual event since 2000.

Dr. Belsito has participated in the program since its start.

[email protected]

KAUAI, HAWAII – When someone reacts to a tixocortol pivalate skin patch, it doesn’t necessarily mean that topical steroids are no longer a treatment option.

That’s sometimes the assumption, but it’s incorrect, according to Mark Davis, MD, chair of the department of dermatology at the Mayo Clinic, Rochester, Minn. Tixocortol is the marker for topical steroid allergy in many series of patch tests, but there is research showing that it is a marker for one class of topical steroids, and “there’s substantial literature saying that if you’re only reacting to tixocortol pivalate, it should be safe to use other classes of topical steroids,” he said.

It’s also important to remember that skin patch tests need to be checked on day 5, not just day 3; it’s the only way to differentiate a true skin allergy from mere skin irritation, and it does matter.

Dr. Davis explained those issues and more – including what to do with minor reactions and how to use the T.R.U.E. TEST kit – in an interview filled with pearls at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Meanwhile, during a presentation at the meeting, he noted two newer options to help allergic patients find skin care products they won’t react to: the Mayo Clinic’s SkinSAFE database and the Contact Allergen Management Program from the American Contact Dermatitis Society.

Dr. Davis had no disclosures.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – When someone reacts to a tixocortol pivalate skin patch, it doesn’t necessarily mean that topical steroids are no longer a treatment option.

That’s sometimes the assumption, but it’s incorrect, according to Mark Davis, MD, chair of the department of dermatology at the Mayo Clinic, Rochester, Minn. Tixocortol is the marker for topical steroid allergy in many series of patch tests, but there is research showing that it is a marker for one class of topical steroids, and “there’s substantial literature saying that if you’re only reacting to tixocortol pivalate, it should be safe to use other classes of topical steroids,” he said.

It’s also important to remember that skin patch tests need to be checked on day 5, not just day 3; it’s the only way to differentiate a true skin allergy from mere skin irritation, and it does matter.

Dr. Davis explained those issues and more – including what to do with minor reactions and how to use the T.R.U.E. TEST kit – in an interview filled with pearls at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Meanwhile, during a presentation at the meeting, he noted two newer options to help allergic patients find skin care products they won’t react to: the Mayo Clinic’s SkinSAFE database and the Contact Allergen Management Program from the American Contact Dermatitis Society.

Dr. Davis had no disclosures.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – When someone reacts to a tixocortol pivalate skin patch, it doesn’t necessarily mean that topical steroids are no longer a treatment option.

That’s sometimes the assumption, but it’s incorrect, according to Mark Davis, MD, chair of the department of dermatology at the Mayo Clinic, Rochester, Minn. Tixocortol is the marker for topical steroid allergy in many series of patch tests, but there is research showing that it is a marker for one class of topical steroids, and “there’s substantial literature saying that if you’re only reacting to tixocortol pivalate, it should be safe to use other classes of topical steroids,” he said.

It’s also important to remember that skin patch tests need to be checked on day 5, not just day 3; it’s the only way to differentiate a true skin allergy from mere skin irritation, and it does matter.

Dr. Davis explained those issues and more – including what to do with minor reactions and how to use the T.R.U.E. TEST kit – in an interview filled with pearls at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Meanwhile, during a presentation at the meeting, he noted two newer options to help allergic patients find skin care products they won’t react to: the Mayo Clinic’s SkinSAFE database and the Contact Allergen Management Program from the American Contact Dermatitis Society.

Dr. Davis had no disclosures.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

Researchers at the University of Leuven (Belgium) conducted patch tests on six patients between 2004 and 2016 who presented with psoriasis that did not improve with use of topical calcipotriol.

Reports of contact allergy to calcipotriol are rare in the literature, considering its widespread use. However, the patch testing and successful alternative treatment confirmed the diagnosis of allergic contact dermatitis in all six cases.

“The lesions improved following replacement of calcipotriol therapy with topical corticosteroids and/or oral medication,” wrote An Goossens, MD, of the contact allergy unit in the department of dermatology at the university.

Five of the patients were adults ranging in age from 26 to 59 years (two men and three women), and the sixth was a 10-year-old girl. They all had lesions on their feet, scalp, or hands.

The successful patch test consisted of a 2 mcg/mL solution of calcipotriol in citrate-buffered isopropanol.

Patients who are diagnosed with this specific allergy may be able to tolerate treatment with a different topical vitamin D analog such as tacalcitol (Contact Derm. 2017 Nov. doi: 10.1111/cod.12910).

[email protected]

Researchers at the University of Leuven (Belgium) conducted patch tests on six patients between 2004 and 2016 who presented with psoriasis that did not improve with use of topical calcipotriol.

Reports of contact allergy to calcipotriol are rare in the literature, considering its widespread use. However, the patch testing and successful alternative treatment confirmed the diagnosis of allergic contact dermatitis in all six cases.

“The lesions improved following replacement of calcipotriol therapy with topical corticosteroids and/or oral medication,” wrote An Goossens, MD, of the contact allergy unit in the department of dermatology at the university.

Five of the patients were adults ranging in age from 26 to 59 years (two men and three women), and the sixth was a 10-year-old girl. They all had lesions on their feet, scalp, or hands.

The successful patch test consisted of a 2 mcg/mL solution of calcipotriol in citrate-buffered isopropanol.

Patients who are diagnosed with this specific allergy may be able to tolerate treatment with a different topical vitamin D analog such as tacalcitol (Contact Derm. 2017 Nov. doi: 10.1111/cod.12910).

[email protected]

Researchers at the University of Leuven (Belgium) conducted patch tests on six patients between 2004 and 2016 who presented with psoriasis that did not improve with use of topical calcipotriol.

Reports of contact allergy to calcipotriol are rare in the literature, considering its widespread use. However, the patch testing and successful alternative treatment confirmed the diagnosis of allergic contact dermatitis in all six cases.

“The lesions improved following replacement of calcipotriol therapy with topical corticosteroids and/or oral medication,” wrote An Goossens, MD, of the contact allergy unit in the department of dermatology at the university.

Five of the patients were adults ranging in age from 26 to 59 years (two men and three women), and the sixth was a 10-year-old girl. They all had lesions on their feet, scalp, or hands.

The successful patch test consisted of a 2 mcg/mL solution of calcipotriol in citrate-buffered isopropanol.

Patients who are diagnosed with this specific allergy may be able to tolerate treatment with a different topical vitamin D analog such as tacalcitol (Contact Derm. 2017 Nov. doi: 10.1111/cod.12910).

[email protected]