Contact Dermatitis

MONTEREY, CALIF. – It’s only found in 2%-3% of allergy cases. So why was propylene glycol (PG) declared the Allergen of the Year for 2018 by the North American Contact Dermatitis Society? Because, a dermatologist told colleagues, it’s so common.

“If you’re allergic to it, it’s tough to stay away from it,” said Joseph F. Fowler Jr., MD, clinical professor of dermatology at the University of Louisville (Ky.) in a presentation about contact dermatitis at the annual Coastal Dermatology Symposium.

Indeed, the synthetic compound PG is found in skin care products and cosmetics, coated pills, topical medications such as corticosteroids, foods (including bread, food coloring, and such flavorings as vanilla extracts). “It’s in every topical acne product I know of,” and is even in brake fluid and so-called nontoxic antifreeze, he said. (Propylene glycol shouldn’t be confused with the poisonous toxin ethylene glycol, which also is found in antifreeze.)

Patients can be tested for allergy to PG, Dr. Fowler pointed out, but it’s important to understand that it can trigger an irritation reaction that can be mistaken for an allergic reaction.

Dr. Fowler offered the following tips related to contact dermatitis and allergens. Be aware that metals, topical antibiotics, fragrances, and preservatives are most likely to cause allergic contact dermatitis. According to 2016 figures on allergen prevalence from the North American Contact Dermatitis Group (NACDG), allergy to the metal nickel is the most common (16%); followed by neomycin (9%); fragrance mix I, a mixture of fragrances used in allergen testing (9%); bacitracin (8%); and myroxylon, also known as balsam of Peru, which is used for a variety of purposes in food, medicines, and fragrances (7%).

These are followed by the metal cobalt (6%); the preservatives quaternium 15 and formaldehyde (both 6%); para-phenylenediamine, also known as PPD, which is used in hair dye (5%); and the fragrance mix II (5%), another mix of fragrances used in allergen testing.

Dr. Fowler cautioned that nickel can trigger an intense body-wide allergic reaction in children with atopic dermatitis. “In this situation, it’s really good to be compulsive and tell parents to absolutely keep that person away from nickel as much as humanly possible,” he said.

Keep an eye out for allergens that aren’t on the NACDG list, which includes 70 items. According to Dr. Fowler, more than 20% of his patients were positive to allergens not on the NACDG list.

Contact dermatitis is as common in children as in adults and can even be more common in children. An Italian study published in 2012 found that 70% of children aged 1-15 years tested via patch test were allergic to at least one allergen, a number that’s similar in adults (Dermatitis. 2012 Nov-Dec;23[6]:275-80). There are wide disparities in reported levels of children who are allergic to nickel, cobalt, and myroxylon, Dr. Fowler said.

The T.R.U.E. Test patch test system has value, compared with standard patch tests, but beware of its limitations, he advised. T.R.U.E. is easy to use and requires no prep time, he said, but the number of allergens is limited. By contrast, his clinic mostly uses the Finn Chambers on Scanpor tape system, which can test for many more allergens and is cheaper if used at least 5-10 times a month.

He cautioned that T.R.U.E. could miss the cause of contact dermatitis as often as 39% of the time, as demonstrated in one study of children undergoing patch testing (Arch Dermatol. 2008 Oct;144[10]:1329-36). However, he said, the T.R.U.E test has value in detecting allergies to nickel, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), and neomycin (J Am Acad Dermatol. 2001 Dec;45[6]:836-9).

Consider patch testing in a child with eczema if the eczema is not in normal atopic areas, it spreads beyond normal areas, it doesn’t respond to usual treatments, or it begins later than 5 years of age.

And, Dr. Fowler added, it’s fine to perform patch testing on patients who are taking antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.

Dr. Fowler disclosed consulting for IntraDerm, serving on speakers bureaus for SmartPractice and Regeneron/Sanofi, and serving as an investigator for companies that include AbbVie, Allergan, Bayer, Dow, Galderma, Johnson & Johnson, Eli Lilly, Merck, Regeneron, SmartPractice, and Valeant (now Bausch).

The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

 

MONTEREY, CALIF. – It’s only found in 2%-3% of allergy cases. So why was propylene glycol (PG) declared the Allergen of the Year for 2018 by the North American Contact Dermatitis Society? Because, a dermatologist told colleagues, it’s so common.

“If you’re allergic to it, it’s tough to stay away from it,” said Joseph F. Fowler Jr., MD, clinical professor of dermatology at the University of Louisville (Ky.) in a presentation about contact dermatitis at the annual Coastal Dermatology Symposium.

Indeed, the synthetic compound PG is found in skin care products and cosmetics, coated pills, topical medications such as corticosteroids, foods (including bread, food coloring, and such flavorings as vanilla extracts). “It’s in every topical acne product I know of,” and is even in brake fluid and so-called nontoxic antifreeze, he said. (Propylene glycol shouldn’t be confused with the poisonous toxin ethylene glycol, which also is found in antifreeze.)

Patients can be tested for allergy to PG, Dr. Fowler pointed out, but it’s important to understand that it can trigger an irritation reaction that can be mistaken for an allergic reaction.

Dr. Fowler offered the following tips related to contact dermatitis and allergens. Be aware that metals, topical antibiotics, fragrances, and preservatives are most likely to cause allergic contact dermatitis. According to 2016 figures on allergen prevalence from the North American Contact Dermatitis Group (NACDG), allergy to the metal nickel is the most common (16%); followed by neomycin (9%); fragrance mix I, a mixture of fragrances used in allergen testing (9%); bacitracin (8%); and myroxylon, also known as balsam of Peru, which is used for a variety of purposes in food, medicines, and fragrances (7%).

These are followed by the metal cobalt (6%); the preservatives quaternium 15 and formaldehyde (both 6%); para-phenylenediamine, also known as PPD, which is used in hair dye (5%); and the fragrance mix II (5%), another mix of fragrances used in allergen testing.

Dr. Fowler cautioned that nickel can trigger an intense body-wide allergic reaction in children with atopic dermatitis. “In this situation, it’s really good to be compulsive and tell parents to absolutely keep that person away from nickel as much as humanly possible,” he said.

Keep an eye out for allergens that aren’t on the NACDG list, which includes 70 items. According to Dr. Fowler, more than 20% of his patients were positive to allergens not on the NACDG list.

Contact dermatitis is as common in children as in adults and can even be more common in children. An Italian study published in 2012 found that 70% of children aged 1-15 years tested via patch test were allergic to at least one allergen, a number that’s similar in adults (Dermatitis. 2012 Nov-Dec;23[6]:275-80). There are wide disparities in reported levels of children who are allergic to nickel, cobalt, and myroxylon, Dr. Fowler said.

The T.R.U.E. Test patch test system has value, compared with standard patch tests, but beware of its limitations, he advised. T.R.U.E. is easy to use and requires no prep time, he said, but the number of allergens is limited. By contrast, his clinic mostly uses the Finn Chambers on Scanpor tape system, which can test for many more allergens and is cheaper if used at least 5-10 times a month.

He cautioned that T.R.U.E. could miss the cause of contact dermatitis as often as 39% of the time, as demonstrated in one study of children undergoing patch testing (Arch Dermatol. 2008 Oct;144[10]:1329-36). However, he said, the T.R.U.E test has value in detecting allergies to nickel, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), and neomycin (J Am Acad Dermatol. 2001 Dec;45[6]:836-9).

Consider patch testing in a child with eczema if the eczema is not in normal atopic areas, it spreads beyond normal areas, it doesn’t respond to usual treatments, or it begins later than 5 years of age.

And, Dr. Fowler added, it’s fine to perform patch testing on patients who are taking antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.

Dr. Fowler disclosed consulting for IntraDerm, serving on speakers bureaus for SmartPractice and Regeneron/Sanofi, and serving as an investigator for companies that include AbbVie, Allergan, Bayer, Dow, Galderma, Johnson & Johnson, Eli Lilly, Merck, Regeneron, SmartPractice, and Valeant (now Bausch).

The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

 

MONTEREY, CALIF. – It’s only found in 2%-3% of allergy cases. So why was propylene glycol (PG) declared the Allergen of the Year for 2018 by the North American Contact Dermatitis Society? Because, a dermatologist told colleagues, it’s so common.

“If you’re allergic to it, it’s tough to stay away from it,” said Joseph F. Fowler Jr., MD, clinical professor of dermatology at the University of Louisville (Ky.) in a presentation about contact dermatitis at the annual Coastal Dermatology Symposium.

Indeed, the synthetic compound PG is found in skin care products and cosmetics, coated pills, topical medications such as corticosteroids, foods (including bread, food coloring, and such flavorings as vanilla extracts). “It’s in every topical acne product I know of,” and is even in brake fluid and so-called nontoxic antifreeze, he said. (Propylene glycol shouldn’t be confused with the poisonous toxin ethylene glycol, which also is found in antifreeze.)

Patients can be tested for allergy to PG, Dr. Fowler pointed out, but it’s important to understand that it can trigger an irritation reaction that can be mistaken for an allergic reaction.

Dr. Fowler offered the following tips related to contact dermatitis and allergens. Be aware that metals, topical antibiotics, fragrances, and preservatives are most likely to cause allergic contact dermatitis. According to 2016 figures on allergen prevalence from the North American Contact Dermatitis Group (NACDG), allergy to the metal nickel is the most common (16%); followed by neomycin (9%); fragrance mix I, a mixture of fragrances used in allergen testing (9%); bacitracin (8%); and myroxylon, also known as balsam of Peru, which is used for a variety of purposes in food, medicines, and fragrances (7%).

These are followed by the metal cobalt (6%); the preservatives quaternium 15 and formaldehyde (both 6%); para-phenylenediamine, also known as PPD, which is used in hair dye (5%); and the fragrance mix II (5%), another mix of fragrances used in allergen testing.

Dr. Fowler cautioned that nickel can trigger an intense body-wide allergic reaction in children with atopic dermatitis. “In this situation, it’s really good to be compulsive and tell parents to absolutely keep that person away from nickel as much as humanly possible,” he said.

Keep an eye out for allergens that aren’t on the NACDG list, which includes 70 items. According to Dr. Fowler, more than 20% of his patients were positive to allergens not on the NACDG list.

Contact dermatitis is as common in children as in adults and can even be more common in children. An Italian study published in 2012 found that 70% of children aged 1-15 years tested via patch test were allergic to at least one allergen, a number that’s similar in adults (Dermatitis. 2012 Nov-Dec;23[6]:275-80). There are wide disparities in reported levels of children who are allergic to nickel, cobalt, and myroxylon, Dr. Fowler said.

The T.R.U.E. Test patch test system has value, compared with standard patch tests, but beware of its limitations, he advised. T.R.U.E. is easy to use and requires no prep time, he said, but the number of allergens is limited. By contrast, his clinic mostly uses the Finn Chambers on Scanpor tape system, which can test for many more allergens and is cheaper if used at least 5-10 times a month.

He cautioned that T.R.U.E. could miss the cause of contact dermatitis as often as 39% of the time, as demonstrated in one study of children undergoing patch testing (Arch Dermatol. 2008 Oct;144[10]:1329-36). However, he said, the T.R.U.E test has value in detecting allergies to nickel, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), and neomycin (J Am Acad Dermatol. 2001 Dec;45[6]:836-9).

Consider patch testing in a child with eczema if the eczema is not in normal atopic areas, it spreads beyond normal areas, it doesn’t respond to usual treatments, or it begins later than 5 years of age.

And, Dr. Fowler added, it’s fine to perform patch testing on patients who are taking antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.

Dr. Fowler disclosed consulting for IntraDerm, serving on speakers bureaus for SmartPractice and Regeneron/Sanofi, and serving as an investigator for companies that include AbbVie, Allergan, Bayer, Dow, Galderma, Johnson & Johnson, Eli Lilly, Merck, Regeneron, SmartPractice, and Valeant (now Bausch).

The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

 

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

Allergic contact dermatitis (ACD) can affect individuals regardless of age, race, or sex, but ACD accounts for 20% of all contact dermatitis reactions. ACD results in an inflammatory reaction in those who have been previously sensitized to an allergen. This type of delayed hypersensitivity reaction is known as cell-mediated hypersensitivity. Generally, no reaction is elicited upon the first exposure to the allergen. In fact, it may take years of exposure to allergens for someone to develop an allergic contact dermatitis.

Courtesy Dr. Donna Bilu-Martin

Once sensitized, epidermal antigen-presenting cells (APCs) called Langerhans cells process the allergen and present it in a complex on the surface of the cell to a CD4+ T cell. Subsequently, inflammatory cytokines and mediators are released, resulting in an allergic cutaneous (eczematous) reaction. Lesions may appear to be vesicular or bullous. Occasionally, a generalized eruption may occur. With repeated exposure, reactions may be acute or chronic.

Common causes of allergic contact dermatitis include toxicodendron plants (poison ivy, oak, and sumac; cashew nut tree; and mango), metals (nickel and gold), topical antibiotics (neomycin and bacitracin), fragrance and Balsam of Peru, deodorant, preservatives (formaldehyde), and rubber (elastic and gloves).

Patch testing is the standard means of detecting which allergen is causing the sensitization in an individual. The Thin-Layer Rapid Use Epicutaneous (TRUE) test or individually prepared aluminum (Finn) chambers containing the most common allergens are applied to the patient’s upper back. The patches are removed after 48 hours and read, and then reevaluated at day 4 or 5. Positive reactions appear as eczematous or vesicular papules or plaques.

Treatment includes avoidance of the allergens. Topical corticosteroid creams are helpful. For severe or generalized reactions, oral prednisone may be used. It is important to note that patient may be allergic to topical steroids. Patch testing can be performed to elucidate such allergens.

Courtesy Dr. Donna Bilu-Martin

In contrast, 80% of contact dermatitis reactions are irritant, not allergic. Irritant contact dermatitis results is a local inflammatory reaction in people who have come into contact with a substance. Previous sensitization is not required. The reaction usually occurs immediately after exposure. Common causes include alkalis (detergents, soaps), acids (often found as an industrial work exposure), metals, solvents (occupational dermatitis), hydrocarbons, and chlorinated compounds.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Allergic contact dermatitis (ACD) can affect individuals regardless of age, race, or sex, but ACD accounts for 20% of all contact dermatitis reactions. ACD results in an inflammatory reaction in those who have been previously sensitized to an allergen. This type of delayed hypersensitivity reaction is known as cell-mediated hypersensitivity. Generally, no reaction is elicited upon the first exposure to the allergen. In fact, it may take years of exposure to allergens for someone to develop an allergic contact dermatitis.

Courtesy Dr. Donna Bilu-Martin

Once sensitized, epidermal antigen-presenting cells (APCs) called Langerhans cells process the allergen and present it in a complex on the surface of the cell to a CD4+ T cell. Subsequently, inflammatory cytokines and mediators are released, resulting in an allergic cutaneous (eczematous) reaction. Lesions may appear to be vesicular or bullous. Occasionally, a generalized eruption may occur. With repeated exposure, reactions may be acute or chronic.

Common causes of allergic contact dermatitis include toxicodendron plants (poison ivy, oak, and sumac; cashew nut tree; and mango), metals (nickel and gold), topical antibiotics (neomycin and bacitracin), fragrance and Balsam of Peru, deodorant, preservatives (formaldehyde), and rubber (elastic and gloves).

Patch testing is the standard means of detecting which allergen is causing the sensitization in an individual. The Thin-Layer Rapid Use Epicutaneous (TRUE) test or individually prepared aluminum (Finn) chambers containing the most common allergens are applied to the patient’s upper back. The patches are removed after 48 hours and read, and then reevaluated at day 4 or 5. Positive reactions appear as eczematous or vesicular papules or plaques.

Treatment includes avoidance of the allergens. Topical corticosteroid creams are helpful. For severe or generalized reactions, oral prednisone may be used. It is important to note that patient may be allergic to topical steroids. Patch testing can be performed to elucidate such allergens.

Courtesy Dr. Donna Bilu-Martin

In contrast, 80% of contact dermatitis reactions are irritant, not allergic. Irritant contact dermatitis results is a local inflammatory reaction in people who have come into contact with a substance. Previous sensitization is not required. The reaction usually occurs immediately after exposure. Common causes include alkalis (detergents, soaps), acids (often found as an industrial work exposure), metals, solvents (occupational dermatitis), hydrocarbons, and chlorinated compounds.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Allergic contact dermatitis (ACD) can affect individuals regardless of age, race, or sex, but ACD accounts for 20% of all contact dermatitis reactions. ACD results in an inflammatory reaction in those who have been previously sensitized to an allergen. This type of delayed hypersensitivity reaction is known as cell-mediated hypersensitivity. Generally, no reaction is elicited upon the first exposure to the allergen. In fact, it may take years of exposure to allergens for someone to develop an allergic contact dermatitis.

Courtesy Dr. Donna Bilu-Martin

Once sensitized, epidermal antigen-presenting cells (APCs) called Langerhans cells process the allergen and present it in a complex on the surface of the cell to a CD4+ T cell. Subsequently, inflammatory cytokines and mediators are released, resulting in an allergic cutaneous (eczematous) reaction. Lesions may appear to be vesicular or bullous. Occasionally, a generalized eruption may occur. With repeated exposure, reactions may be acute or chronic.

Common causes of allergic contact dermatitis include toxicodendron plants (poison ivy, oak, and sumac; cashew nut tree; and mango), metals (nickel and gold), topical antibiotics (neomycin and bacitracin), fragrance and Balsam of Peru, deodorant, preservatives (formaldehyde), and rubber (elastic and gloves).

Patch testing is the standard means of detecting which allergen is causing the sensitization in an individual. The Thin-Layer Rapid Use Epicutaneous (TRUE) test or individually prepared aluminum (Finn) chambers containing the most common allergens are applied to the patient’s upper back. The patches are removed after 48 hours and read, and then reevaluated at day 4 or 5. Positive reactions appear as eczematous or vesicular papules or plaques.

Treatment includes avoidance of the allergens. Topical corticosteroid creams are helpful. For severe or generalized reactions, oral prednisone may be used. It is important to note that patient may be allergic to topical steroids. Patch testing can be performed to elucidate such allergens.

Courtesy Dr. Donna Bilu-Martin

In contrast, 80% of contact dermatitis reactions are irritant, not allergic. Irritant contact dermatitis results is a local inflammatory reaction in people who have come into contact with a substance. Previous sensitization is not required. The reaction usually occurs immediately after exposure. Common causes include alkalis (detergents, soaps), acids (often found as an industrial work exposure), metals, solvents (occupational dermatitis), hydrocarbons, and chlorinated compounds.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

An allergic reaction is an exaggerated immune response that is known as a type I or immediate hypersensitivity reaction when provoked by reexposure to an allergen or antigen. Upon initial exposure to the antigen, dendritic cells bind it for presentation to helper T (T_H2) lymphocytes. The T_H2 cells then interact with B cells, stimulating them to become plasma cells and produce IgE antibodies to the antigen. When exposed to the same allergen a second time, IgE antibodies bind the allergen and cross-link on mast cells and basophils in the blood. Cross-linking stimulates degranulation of the cells, releasing histamine, leukotrienes, prostaglandins, and other cytokines. The major effects of the release of these mediators include vasodilation, increased vascular permeability, and bronchoconstriction. Leukotrienes also are responsible for chemotaxis of white blood cells, further propagating the immune response.¹

Effects of a type I hypersensitivity reaction can be either local or systemic, resulting in symptoms ranging from mild irritation to anaphylactic shock and death. Latex allergy is a common example of a type I hypersensitivity reaction. Latex is found in many medical products, including gloves, rubber, elastics, blood pressure cuffs, bandages, dressings, and syringes. Reactions can include runny nose, tearing eyes, itching, hives, wheals, wheezing, and in rare cases anaphylaxis.² Diagnosis can be suspected based on history and physical examination. Screening is performed with radioallergosorbent testing, which identifies specific IgE antibodies to latex; however, the reported sensitivity and specificity for the latex-specific IgE antibody varies widely in the literature, and the test cannot reliably rule in or rule out a true latex allergy.³

Allergic responses to latex in psoriasis patients receiving frequent injections with biologic agents are not commonly reported in the literature. We report the case of a patient with a long history of psoriasis who developed an allergic response after exposure to injection devices that contained latex components while undergoing treatment with biologic agents.

Case Report

A 72-year-old man presented with an extensive history of severe psoriasis with frequent flares. Treatment with topical agents and etanercept 6 months prior at an outside facility failed. At the time of presentation, the patient had more than 10% body surface area (BSA) involvement, which included the scalp, legs, chest, and back. He subsequently was started on ustekinumab injections. He initially responded well to therapy, but after 8 months of treatment, he began to have recurrent episodes of acute eruptive rashes over the trunk with associated severe pruritus that reproducibly recurred within 24 hours after each ustekinumab injection. It was decided to discontinue ustekinumab due to concern for intolerance, and the patient was switched to secukinumab. 

After starting secukinumab, the patient's BSA involvement was reduced to 2% after 1 month; however, he began to develop an eruptive rash with severe pruritus again that reproducibly recurred after each secukinumab injection. On physical examination the patient had ill-defined, confluent, erythematous patches over much of the trunk and extremities. Punch biopsies of the eruptive dermatitis showed spongiform psoriasis and eosinophils with dermal hypersensitivity, consistent with a drug eruption. Upon further questioning, the patient noted that he had a long history of a strong latex allergy and he would develop a blistering dermatitis when coming into contact with latex, which caused a high suspicion for a latex allergy as the cause of the patient's acute dermatitis flares from his prior ustekinumab and secukinumab injections. Although it was confirmed with the manufacturers that both the ustekinumab syringe and secukinumab pen did not contain latex, the caps of these medications (and many other biologic injections) do have latex (Table). Other differential diagnoses included an atypical paradoxical   psoriasis flare and a drug eruption to secukinumab, which previously has been reported.⁴

Based on the suspected cause of the eruption, the patient was instructed not to touch the cap of the secukinumab pen. Despite this recommendation, the rash was still present at the next appointment 1 month later. Repeat punch biopsy showed similar findings to the one prior with likely dermal hypersensitivity. The rash improved with steroid injections and continued to improve after holding the secukinumab for 1 month.

After resolution of the hypersensitivity reaction, the patient was started on ixekizumab, which does not contain latex in any component according to the manufacturer. After 2 months of treatment, the patient had 2% BSA involvement of psoriasis and has had no further reports of itching, rash, or other symptoms of a hypersensitivity reaction. On follow-up, the patient's psoriasis symptoms continue to be controlled without further reactions after injections of ixekizumab. Radioallergosorbent testing was not performed due to the lack of specificity and sensitivity of the test3 as well as the patient's known history of latex allergy and characteristic dermatitis that developed after exposure to latex and resolution with removal of the agent. These clinical manifestations are highly indicative of a type I hypersensitivity to injection devices that contain latex components during biologic therapy.

Comment

Allergic responses to latex are most commonly seen in those exposed to gloves or rubber, but little has been reported on reactions to injections with pens or syringes that contain latex components. Some case reports have demonstrated allergic responses in diabetic patients receiving insulin injections.^5,6 MacCracken et al⁵ reported the case of a young boy who had an allergic response to an insulin injection with a syringe containing latex. The patient had a history of bladder exstrophy with a recent diagnosis of diabetes mellitus. It is well known that patients with spina bifida and other conditions who undergo frequent urological procedures more commonly develop latex allergies. This patient reported a history of swollen lips after a dentist visit, presumably due to contact with latex gloves. Because of the suspected allergy, his first insulin injection was given using a glass syringe and insulin was withdrawn with the top removed due to the top containing latex. He did not experience any complications. After being injected later with insulin drawn through the top using a syringe that contained latex, he developed a flare-up of a 0.5-cm erythematous wheal within minutes with associated pruritus.⁵

Towse et al⁶ described another patient with diabetes who developed a local allergic reaction at the site of insulin injections. Workup by the physician ruled out insulin allergy but showed elevated latex-specific IgE antibodies. Future insulin draws through a latex-containing top produced a wheal at the injection site. After switching to latex-free syringes, the allergic reaction resolved.⁶

Latex allergies are common in medical practice, as latex is found in a wide variety of medical supplies, including syringes used for injections and their caps. Physicians need to be aware of latex allergies in their patients and exercise extreme caution in the use of latex-containing products. In the treatment of psoriasis, care must be given when injecting biologic agents. Although many injection devices contain latex limited to the cap, it may be enough to invoke an allergic response. If such a response is elicited, therapy with injection devices that do not contain latex in either the cap or syringe should be considered.

An allergic reaction is an exaggerated immune response that is known as a type I or immediate hypersensitivity reaction when provoked by reexposure to an allergen or antigen. Upon initial exposure to the antigen, dendritic cells bind it for presentation to helper T (T_H2) lymphocytes. The T_H2 cells then interact with B cells, stimulating them to become plasma cells and produce IgE antibodies to the antigen. When exposed to the same allergen a second time, IgE antibodies bind the allergen and cross-link on mast cells and basophils in the blood. Cross-linking stimulates degranulation of the cells, releasing histamine, leukotrienes, prostaglandins, and other cytokines. The major effects of the release of these mediators include vasodilation, increased vascular permeability, and bronchoconstriction. Leukotrienes also are responsible for chemotaxis of white blood cells, further propagating the immune response.¹

Effects of a type I hypersensitivity reaction can be either local or systemic, resulting in symptoms ranging from mild irritation to anaphylactic shock and death. Latex allergy is a common example of a type I hypersensitivity reaction. Latex is found in many medical products, including gloves, rubber, elastics, blood pressure cuffs, bandages, dressings, and syringes. Reactions can include runny nose, tearing eyes, itching, hives, wheals, wheezing, and in rare cases anaphylaxis.² Diagnosis can be suspected based on history and physical examination. Screening is performed with radioallergosorbent testing, which identifies specific IgE antibodies to latex; however, the reported sensitivity and specificity for the latex-specific IgE antibody varies widely in the literature, and the test cannot reliably rule in or rule out a true latex allergy.³

Allergic responses to latex in psoriasis patients receiving frequent injections with biologic agents are not commonly reported in the literature. We report the case of a patient with a long history of psoriasis who developed an allergic response after exposure to injection devices that contained latex components while undergoing treatment with biologic agents.

Case Report

A 72-year-old man presented with an extensive history of severe psoriasis with frequent flares. Treatment with topical agents and etanercept 6 months prior at an outside facility failed. At the time of presentation, the patient had more than 10% body surface area (BSA) involvement, which included the scalp, legs, chest, and back. He subsequently was started on ustekinumab injections. He initially responded well to therapy, but after 8 months of treatment, he began to have recurrent episodes of acute eruptive rashes over the trunk with associated severe pruritus that reproducibly recurred within 24 hours after each ustekinumab injection. It was decided to discontinue ustekinumab due to concern for intolerance, and the patient was switched to secukinumab. 

After starting secukinumab, the patient's BSA involvement was reduced to 2% after 1 month; however, he began to develop an eruptive rash with severe pruritus again that reproducibly recurred after each secukinumab injection. On physical examination the patient had ill-defined, confluent, erythematous patches over much of the trunk and extremities. Punch biopsies of the eruptive dermatitis showed spongiform psoriasis and eosinophils with dermal hypersensitivity, consistent with a drug eruption. Upon further questioning, the patient noted that he had a long history of a strong latex allergy and he would develop a blistering dermatitis when coming into contact with latex, which caused a high suspicion for a latex allergy as the cause of the patient's acute dermatitis flares from his prior ustekinumab and secukinumab injections. Although it was confirmed with the manufacturers that both the ustekinumab syringe and secukinumab pen did not contain latex, the caps of these medications (and many other biologic injections) do have latex (Table). Other differential diagnoses included an atypical paradoxical   psoriasis flare and a drug eruption to secukinumab, which previously has been reported.⁴

Based on the suspected cause of the eruption, the patient was instructed not to touch the cap of the secukinumab pen. Despite this recommendation, the rash was still present at the next appointment 1 month later. Repeat punch biopsy showed similar findings to the one prior with likely dermal hypersensitivity. The rash improved with steroid injections and continued to improve after holding the secukinumab for 1 month.

After resolution of the hypersensitivity reaction, the patient was started on ixekizumab, which does not contain latex in any component according to the manufacturer. After 2 months of treatment, the patient had 2% BSA involvement of psoriasis and has had no further reports of itching, rash, or other symptoms of a hypersensitivity reaction. On follow-up, the patient's psoriasis symptoms continue to be controlled without further reactions after injections of ixekizumab. Radioallergosorbent testing was not performed due to the lack of specificity and sensitivity of the test3 as well as the patient's known history of latex allergy and characteristic dermatitis that developed after exposure to latex and resolution with removal of the agent. These clinical manifestations are highly indicative of a type I hypersensitivity to injection devices that contain latex components during biologic therapy.

Comment

Allergic responses to latex are most commonly seen in those exposed to gloves or rubber, but little has been reported on reactions to injections with pens or syringes that contain latex components. Some case reports have demonstrated allergic responses in diabetic patients receiving insulin injections.^5,6 MacCracken et al⁵ reported the case of a young boy who had an allergic response to an insulin injection with a syringe containing latex. The patient had a history of bladder exstrophy with a recent diagnosis of diabetes mellitus. It is well known that patients with spina bifida and other conditions who undergo frequent urological procedures more commonly develop latex allergies. This patient reported a history of swollen lips after a dentist visit, presumably due to contact with latex gloves. Because of the suspected allergy, his first insulin injection was given using a glass syringe and insulin was withdrawn with the top removed due to the top containing latex. He did not experience any complications. After being injected later with insulin drawn through the top using a syringe that contained latex, he developed a flare-up of a 0.5-cm erythematous wheal within minutes with associated pruritus.⁵

Towse et al⁶ described another patient with diabetes who developed a local allergic reaction at the site of insulin injections. Workup by the physician ruled out insulin allergy but showed elevated latex-specific IgE antibodies. Future insulin draws through a latex-containing top produced a wheal at the injection site. After switching to latex-free syringes, the allergic reaction resolved.⁶

Latex allergies are common in medical practice, as latex is found in a wide variety of medical supplies, including syringes used for injections and their caps. Physicians need to be aware of latex allergies in their patients and exercise extreme caution in the use of latex-containing products. In the treatment of psoriasis, care must be given when injecting biologic agents. Although many injection devices contain latex limited to the cap, it may be enough to invoke an allergic response. If such a response is elicited, therapy with injection devices that do not contain latex in either the cap or syringe should be considered.

An allergic reaction is an exaggerated immune response that is known as a type I or immediate hypersensitivity reaction when provoked by reexposure to an allergen or antigen. Upon initial exposure to the antigen, dendritic cells bind it for presentation to helper T (T_H2) lymphocytes. The T_H2 cells then interact with B cells, stimulating them to become plasma cells and produce IgE antibodies to the antigen. When exposed to the same allergen a second time, IgE antibodies bind the allergen and cross-link on mast cells and basophils in the blood. Cross-linking stimulates degranulation of the cells, releasing histamine, leukotrienes, prostaglandins, and other cytokines. The major effects of the release of these mediators include vasodilation, increased vascular permeability, and bronchoconstriction. Leukotrienes also are responsible for chemotaxis of white blood cells, further propagating the immune response.¹

Effects of a type I hypersensitivity reaction can be either local or systemic, resulting in symptoms ranging from mild irritation to anaphylactic shock and death. Latex allergy is a common example of a type I hypersensitivity reaction. Latex is found in many medical products, including gloves, rubber, elastics, blood pressure cuffs, bandages, dressings, and syringes. Reactions can include runny nose, tearing eyes, itching, hives, wheals, wheezing, and in rare cases anaphylaxis.² Diagnosis can be suspected based on history and physical examination. Screening is performed with radioallergosorbent testing, which identifies specific IgE antibodies to latex; however, the reported sensitivity and specificity for the latex-specific IgE antibody varies widely in the literature, and the test cannot reliably rule in or rule out a true latex allergy.³

Allergic responses to latex in psoriasis patients receiving frequent injections with biologic agents are not commonly reported in the literature. We report the case of a patient with a long history of psoriasis who developed an allergic response after exposure to injection devices that contained latex components while undergoing treatment with biologic agents.

Case Report

A 72-year-old man presented with an extensive history of severe psoriasis with frequent flares. Treatment with topical agents and etanercept 6 months prior at an outside facility failed. At the time of presentation, the patient had more than 10% body surface area (BSA) involvement, which included the scalp, legs, chest, and back. He subsequently was started on ustekinumab injections. He initially responded well to therapy, but after 8 months of treatment, he began to have recurrent episodes of acute eruptive rashes over the trunk with associated severe pruritus that reproducibly recurred within 24 hours after each ustekinumab injection. It was decided to discontinue ustekinumab due to concern for intolerance, and the patient was switched to secukinumab. 

After starting secukinumab, the patient's BSA involvement was reduced to 2% after 1 month; however, he began to develop an eruptive rash with severe pruritus again that reproducibly recurred after each secukinumab injection. On physical examination the patient had ill-defined, confluent, erythematous patches over much of the trunk and extremities. Punch biopsies of the eruptive dermatitis showed spongiform psoriasis and eosinophils with dermal hypersensitivity, consistent with a drug eruption. Upon further questioning, the patient noted that he had a long history of a strong latex allergy and he would develop a blistering dermatitis when coming into contact with latex, which caused a high suspicion for a latex allergy as the cause of the patient's acute dermatitis flares from his prior ustekinumab and secukinumab injections. Although it was confirmed with the manufacturers that both the ustekinumab syringe and secukinumab pen did not contain latex, the caps of these medications (and many other biologic injections) do have latex (Table). Other differential diagnoses included an atypical paradoxical   psoriasis flare and a drug eruption to secukinumab, which previously has been reported.⁴

Based on the suspected cause of the eruption, the patient was instructed not to touch the cap of the secukinumab pen. Despite this recommendation, the rash was still present at the next appointment 1 month later. Repeat punch biopsy showed similar findings to the one prior with likely dermal hypersensitivity. The rash improved with steroid injections and continued to improve after holding the secukinumab for 1 month.

After resolution of the hypersensitivity reaction, the patient was started on ixekizumab, which does not contain latex in any component according to the manufacturer. After 2 months of treatment, the patient had 2% BSA involvement of psoriasis and has had no further reports of itching, rash, or other symptoms of a hypersensitivity reaction. On follow-up, the patient's psoriasis symptoms continue to be controlled without further reactions after injections of ixekizumab. Radioallergosorbent testing was not performed due to the lack of specificity and sensitivity of the test3 as well as the patient's known history of latex allergy and characteristic dermatitis that developed after exposure to latex and resolution with removal of the agent. These clinical manifestations are highly indicative of a type I hypersensitivity to injection devices that contain latex components during biologic therapy.

Comment

Allergic responses to latex are most commonly seen in those exposed to gloves or rubber, but little has been reported on reactions to injections with pens or syringes that contain latex components. Some case reports have demonstrated allergic responses in diabetic patients receiving insulin injections.^5,6 MacCracken et al⁵ reported the case of a young boy who had an allergic response to an insulin injection with a syringe containing latex. The patient had a history of bladder exstrophy with a recent diagnosis of diabetes mellitus. It is well known that patients with spina bifida and other conditions who undergo frequent urological procedures more commonly develop latex allergies. This patient reported a history of swollen lips after a dentist visit, presumably due to contact with latex gloves. Because of the suspected allergy, his first insulin injection was given using a glass syringe and insulin was withdrawn with the top removed due to the top containing latex. He did not experience any complications. After being injected later with insulin drawn through the top using a syringe that contained latex, he developed a flare-up of a 0.5-cm erythematous wheal within minutes with associated pruritus.⁵

Towse et al⁶ described another patient with diabetes who developed a local allergic reaction at the site of insulin injections. Workup by the physician ruled out insulin allergy but showed elevated latex-specific IgE antibodies. Future insulin draws through a latex-containing top produced a wheal at the injection site. After switching to latex-free syringes, the allergic reaction resolved.⁶

Latex allergies are common in medical practice, as latex is found in a wide variety of medical supplies, including syringes used for injections and their caps. Physicians need to be aware of latex allergies in their patients and exercise extreme caution in the use of latex-containing products. In the treatment of psoriasis, care must be given when injecting biologic agents. Although many injection devices contain latex limited to the cap, it may be enough to invoke an allergic response. If such a response is elicited, therapy with injection devices that do not contain latex in either the cap or syringe should be considered.

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.⁷Without 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.⁷Without 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.⁷Without 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.