MDedge Dermatology

To the Editor:

Amiodarone is an oral or intravenous (IV) drug commonly used to treat supraventricular and ventricular arrhythmia as well as atrial fibrillation.¹ Adverse drug reactions associated with the use of amiodarone include pulmonary, gastrointestinal, thyroid, ocular, neurologic, and cutaneous reactions.¹ Long-term use of amiodarone—typically more than 4 months—can lead to slate-gray skin discoloration and photosensitivity, both of which can be reversed with drug withdrawal.^2,3 Phlebitis also has been described in less than 3% of patients who receive peripheral IV administration of amiodarone.⁴

Amiodarone-induced skin necrosis due to extravasation is a rare complication of this antiarrhythmic medication, with only 3 reported cases in the literature according to a PubMed search of articles indexed for MEDLINE using the search terms amiodarone and skin and (necrosis or ischemia or extravasation or reaction).^5–7 Although hyaluronidase is a known therapy for extravasation of fluids, including parenteral nutrition and chemotherapy, its use for the treatment of extravasation from amiodarone is not well documented.⁶ We report a case of skin necrosis of the left dorsal forearm and the left dorsal and ventral hand following infusion of amiodarone through a peripheral IV line, which was treated with injections of hyaluronidase.

A 77-year-old man was admitted to the emergency department for sepsis secondary to cholangitis in the setting of an obstructive gallbladder stone. His medical history was notable for multivessel coronary artery disease and atrial flutter treated with ablation. One day after admission, endoscopic retrograde cholangiopancreatography was attempted and aborted due to atrial fibrillation with rapid ventricular response. A second endoscopic retrograde cholangiopancreatography attempt was made 4 days later, during which the patient underwent cardiac arrest. During this event, amiodarone was administered in a 200-mL solution (1.8 mg/mL) in 5% dextrose through a peripheral IV line in the left forearm. The patient was stabilized and transferred to the intensive care unit.

Twenty-four hours after amiodarone administration, erythema was noted on the left dorsal forearm. Within hours, the digits of the hand became a dark, dusky color, which spread to involve the forearm. Surgical debridement was not deemed necessary; the left arm was elevated, and warm compresses were applied regularly. Within the next week, the skin of the left hand and dorsal forearm had progressively worsened and took on a well-demarcated, dusky blue hue surrounded by an erythematous border involving the proximal forearm and upper arm (Figure 1A). The skin was fragile and had overlying bullae (Figure 1B).

Hyaluronidase (1000 U) was injected into the surrounding areas of erythema, which resolved from the left proximal forearm to the elbow within 2 days after injection (Figure 2). The dusky violaceous patches were persistent, and the necrotic bullae were unchanged. Hyaluronidase (1000 U) was injected into necrotic skin of the left dorsal forearm and dorsal and ventral hand. No improvement was noted on subsequent evaluations of this area. While still an inpatient, he received wound care and twice-daily Doppler ultrasounds in the areas of necrosis. The patient lost sensation in the left hand with increased soft tissue necrosis and developed an eschar on the left dorsal forearm. Due to the progressive loss of function and necrosis, a partial forearm amputation was performed that healed well, and the patient experienced improvement in range of motion of the left upper extremity.

Well-known adverse reactions of amiodarone treatment include pulmonary fibrosis, hepatic dysfunction, hypothyroidism and hyperthyroidism, peripheral neuropathy, and corneal deposits.¹ Cutaneous adverse reactions include photosensitivity (phototoxic and photoallergic reactions), hyperpigmentation, pseudoporphyria, and linear IgA bullous dermatosis. Less commonly, it also can cause urticaria, pruritus, erythema nodosum, purpura, and toxic epidermal necrolysis.³ Amiodarone-induced skin necrosis is rare, first described by Russell and Saltissi⁵ in 2006 in a 60-year-old man who developed dark discoloration and edema of the forearm 24 hours after initiation of an amiodarone peripheral IV. The patient was treated with hot or cold packs and steroid cream per the pharmaceutical company’s recommendations; however, patient outcomes were not discussed.⁵ A 77-year-old man who received subcutaneous amiodarone due to misplaced vascular access developed edema and bullae of the forearm followed by tissue necrosis, resulting in notably reduced mobility.⁶ Fox et al⁷ described a 60-year-old man who developed atrial fibrillation after emergent spinal fusion and laminectomy. He received intradermal hyaluronidase administration within 24 hours of developing severe pain from extravasation induced by amiodarone with no adverse outcomes and full recovery.⁷

There are numerous properties of amiodarone that may have resulted in the skin necrosis seen in these cases. The acidic pH (3.5–4.5) of amiodarone can contribute to coagulative necrosis, cellular desiccation, eschar formation, and edema.⁸ It also can contain additives such as polysorbate and benzyl alcohol, which may contribute to the drug’s vesicant properties.⁹

Current recommendations for IV administration of amiodarone include delivery through a central vein with high concentrations (>2 mg/mL) because peripheral infusion is slower and may cause phlebitis.⁴ In-line filters also may be a potential method of preventing phlebitis with peripheral IV administration of amiodarone.¹⁰ Extravasation of amiodarone can be treated nonpharmacologically with limb elevation and warm compresses, as these methods may promote vasodilation and enhance drug removal.^5-7 However, when extravasation leads to progressive erythema and skin necrosis or is refractory to these therapies, intradermal injection of hyaluronidase should be considered. Hyaluronidase mediates the degradation of hyaluronic acid in the extracellular matrix, allowing for increased permeability of injected fluids into tissues and diluting the concentration of toxins at the site of exposure.^9,11 It has been used to treat extravasation of fluids such as parenteral nutrition, electrolyte infusion, antibiotics, aminophylline, mannitol, and chemotherapy.¹¹ Although hyaluronidase has been recognized as therapeutic for extravasation, there is no established consistent dosing or proper technique. In the setting of infiltration of chemotherapy, doses of hyaluronidase ranging from 150 to 1500 U/mL can be subcutaneously or intradermally injected into the site within 1 hour of extravasation. Side effects of using hyaluronidase are rare, including local pruritus, allergic reactions, urticaria, and angioedema.¹²

The patient described by Fox et al⁷ who fully recovered from amiodarone extravasation after hyaluronidase injections likely benefited from quick intervention, as he received amiodarone within 24 hours of the care team identifying initial erythema. Although our patient did have improvement of the areas of erythema on the forearm, evidence of skin and subcutaneous tissue necrosis on the left hand and proximal forearm was already apparent and not reversible, most likely caused by late intervention of intradermal hyaluronidase almost a week after the extravasation event. It is important to identify amiodarone as the source of extravasation and administer intradermal hyaluronidase in a timely fashion for extravasation refractory to conventional measurements to prevent progression to severe tissue damage.

Our case draws attention to the risk for skin necrosis with peripheral IV administration of amiodarone. Interventions include limb elevation, warm compresses, and consideration of intradermal hyaluronidase within 24 hours of extravasation, as this may reduce the severity of subsequent tissue damage with minimal side effects.

To the Editor:

Amiodarone is an oral or intravenous (IV) drug commonly used to treat supraventricular and ventricular arrhythmia as well as atrial fibrillation.¹ Adverse drug reactions associated with the use of amiodarone include pulmonary, gastrointestinal, thyroid, ocular, neurologic, and cutaneous reactions.¹ Long-term use of amiodarone—typically more than 4 months—can lead to slate-gray skin discoloration and photosensitivity, both of which can be reversed with drug withdrawal.^2,3 Phlebitis also has been described in less than 3% of patients who receive peripheral IV administration of amiodarone.⁴

Amiodarone-induced skin necrosis due to extravasation is a rare complication of this antiarrhythmic medication, with only 3 reported cases in the literature according to a PubMed search of articles indexed for MEDLINE using the search terms amiodarone and skin and (necrosis or ischemia or extravasation or reaction).^5–7 Although hyaluronidase is a known therapy for extravasation of fluids, including parenteral nutrition and chemotherapy, its use for the treatment of extravasation from amiodarone is not well documented.⁶ We report a case of skin necrosis of the left dorsal forearm and the left dorsal and ventral hand following infusion of amiodarone through a peripheral IV line, which was treated with injections of hyaluronidase.

A 77-year-old man was admitted to the emergency department for sepsis secondary to cholangitis in the setting of an obstructive gallbladder stone. His medical history was notable for multivessel coronary artery disease and atrial flutter treated with ablation. One day after admission, endoscopic retrograde cholangiopancreatography was attempted and aborted due to atrial fibrillation with rapid ventricular response. A second endoscopic retrograde cholangiopancreatography attempt was made 4 days later, during which the patient underwent cardiac arrest. During this event, amiodarone was administered in a 200-mL solution (1.8 mg/mL) in 5% dextrose through a peripheral IV line in the left forearm. The patient was stabilized and transferred to the intensive care unit.

Twenty-four hours after amiodarone administration, erythema was noted on the left dorsal forearm. Within hours, the digits of the hand became a dark, dusky color, which spread to involve the forearm. Surgical debridement was not deemed necessary; the left arm was elevated, and warm compresses were applied regularly. Within the next week, the skin of the left hand and dorsal forearm had progressively worsened and took on a well-demarcated, dusky blue hue surrounded by an erythematous border involving the proximal forearm and upper arm (Figure 1A). The skin was fragile and had overlying bullae (Figure 1B).

Hyaluronidase (1000 U) was injected into the surrounding areas of erythema, which resolved from the left proximal forearm to the elbow within 2 days after injection (Figure 2). The dusky violaceous patches were persistent, and the necrotic bullae were unchanged. Hyaluronidase (1000 U) was injected into necrotic skin of the left dorsal forearm and dorsal and ventral hand. No improvement was noted on subsequent evaluations of this area. While still an inpatient, he received wound care and twice-daily Doppler ultrasounds in the areas of necrosis. The patient lost sensation in the left hand with increased soft tissue necrosis and developed an eschar on the left dorsal forearm. Due to the progressive loss of function and necrosis, a partial forearm amputation was performed that healed well, and the patient experienced improvement in range of motion of the left upper extremity.

Well-known adverse reactions of amiodarone treatment include pulmonary fibrosis, hepatic dysfunction, hypothyroidism and hyperthyroidism, peripheral neuropathy, and corneal deposits.¹ Cutaneous adverse reactions include photosensitivity (phototoxic and photoallergic reactions), hyperpigmentation, pseudoporphyria, and linear IgA bullous dermatosis. Less commonly, it also can cause urticaria, pruritus, erythema nodosum, purpura, and toxic epidermal necrolysis.³ Amiodarone-induced skin necrosis is rare, first described by Russell and Saltissi⁵ in 2006 in a 60-year-old man who developed dark discoloration and edema of the forearm 24 hours after initiation of an amiodarone peripheral IV. The patient was treated with hot or cold packs and steroid cream per the pharmaceutical company’s recommendations; however, patient outcomes were not discussed.⁵ A 77-year-old man who received subcutaneous amiodarone due to misplaced vascular access developed edema and bullae of the forearm followed by tissue necrosis, resulting in notably reduced mobility.⁶ Fox et al⁷ described a 60-year-old man who developed atrial fibrillation after emergent spinal fusion and laminectomy. He received intradermal hyaluronidase administration within 24 hours of developing severe pain from extravasation induced by amiodarone with no adverse outcomes and full recovery.⁷

There are numerous properties of amiodarone that may have resulted in the skin necrosis seen in these cases. The acidic pH (3.5–4.5) of amiodarone can contribute to coagulative necrosis, cellular desiccation, eschar formation, and edema.⁸ It also can contain additives such as polysorbate and benzyl alcohol, which may contribute to the drug’s vesicant properties.⁹

Current recommendations for IV administration of amiodarone include delivery through a central vein with high concentrations (>2 mg/mL) because peripheral infusion is slower and may cause phlebitis.⁴ In-line filters also may be a potential method of preventing phlebitis with peripheral IV administration of amiodarone.¹⁰ Extravasation of amiodarone can be treated nonpharmacologically with limb elevation and warm compresses, as these methods may promote vasodilation and enhance drug removal.^5-7 However, when extravasation leads to progressive erythema and skin necrosis or is refractory to these therapies, intradermal injection of hyaluronidase should be considered. Hyaluronidase mediates the degradation of hyaluronic acid in the extracellular matrix, allowing for increased permeability of injected fluids into tissues and diluting the concentration of toxins at the site of exposure.^9,11 It has been used to treat extravasation of fluids such as parenteral nutrition, electrolyte infusion, antibiotics, aminophylline, mannitol, and chemotherapy.¹¹ Although hyaluronidase has been recognized as therapeutic for extravasation, there is no established consistent dosing or proper technique. In the setting of infiltration of chemotherapy, doses of hyaluronidase ranging from 150 to 1500 U/mL can be subcutaneously or intradermally injected into the site within 1 hour of extravasation. Side effects of using hyaluronidase are rare, including local pruritus, allergic reactions, urticaria, and angioedema.¹²

The patient described by Fox et al⁷ who fully recovered from amiodarone extravasation after hyaluronidase injections likely benefited from quick intervention, as he received amiodarone within 24 hours of the care team identifying initial erythema. Although our patient did have improvement of the areas of erythema on the forearm, evidence of skin and subcutaneous tissue necrosis on the left hand and proximal forearm was already apparent and not reversible, most likely caused by late intervention of intradermal hyaluronidase almost a week after the extravasation event. It is important to identify amiodarone as the source of extravasation and administer intradermal hyaluronidase in a timely fashion for extravasation refractory to conventional measurements to prevent progression to severe tissue damage.

Our case draws attention to the risk for skin necrosis with peripheral IV administration of amiodarone. Interventions include limb elevation, warm compresses, and consideration of intradermal hyaluronidase within 24 hours of extravasation, as this may reduce the severity of subsequent tissue damage with minimal side effects.

To the Editor:

Amiodarone is an oral or intravenous (IV) drug commonly used to treat supraventricular and ventricular arrhythmia as well as atrial fibrillation.¹ Adverse drug reactions associated with the use of amiodarone include pulmonary, gastrointestinal, thyroid, ocular, neurologic, and cutaneous reactions.¹ Long-term use of amiodarone—typically more than 4 months—can lead to slate-gray skin discoloration and photosensitivity, both of which can be reversed with drug withdrawal.^2,3 Phlebitis also has been described in less than 3% of patients who receive peripheral IV administration of amiodarone.⁴

Amiodarone-induced skin necrosis due to extravasation is a rare complication of this antiarrhythmic medication, with only 3 reported cases in the literature according to a PubMed search of articles indexed for MEDLINE using the search terms amiodarone and skin and (necrosis or ischemia or extravasation or reaction).^5–7 Although hyaluronidase is a known therapy for extravasation of fluids, including parenteral nutrition and chemotherapy, its use for the treatment of extravasation from amiodarone is not well documented.⁶ We report a case of skin necrosis of the left dorsal forearm and the left dorsal and ventral hand following infusion of amiodarone through a peripheral IV line, which was treated with injections of hyaluronidase.

A 77-year-old man was admitted to the emergency department for sepsis secondary to cholangitis in the setting of an obstructive gallbladder stone. His medical history was notable for multivessel coronary artery disease and atrial flutter treated with ablation. One day after admission, endoscopic retrograde cholangiopancreatography was attempted and aborted due to atrial fibrillation with rapid ventricular response. A second endoscopic retrograde cholangiopancreatography attempt was made 4 days later, during which the patient underwent cardiac arrest. During this event, amiodarone was administered in a 200-mL solution (1.8 mg/mL) in 5% dextrose through a peripheral IV line in the left forearm. The patient was stabilized and transferred to the intensive care unit.

Twenty-four hours after amiodarone administration, erythema was noted on the left dorsal forearm. Within hours, the digits of the hand became a dark, dusky color, which spread to involve the forearm. Surgical debridement was not deemed necessary; the left arm was elevated, and warm compresses were applied regularly. Within the next week, the skin of the left hand and dorsal forearm had progressively worsened and took on a well-demarcated, dusky blue hue surrounded by an erythematous border involving the proximal forearm and upper arm (Figure 1A). The skin was fragile and had overlying bullae (Figure 1B).

Hyaluronidase (1000 U) was injected into the surrounding areas of erythema, which resolved from the left proximal forearm to the elbow within 2 days after injection (Figure 2). The dusky violaceous patches were persistent, and the necrotic bullae were unchanged. Hyaluronidase (1000 U) was injected into necrotic skin of the left dorsal forearm and dorsal and ventral hand. No improvement was noted on subsequent evaluations of this area. While still an inpatient, he received wound care and twice-daily Doppler ultrasounds in the areas of necrosis. The patient lost sensation in the left hand with increased soft tissue necrosis and developed an eschar on the left dorsal forearm. Due to the progressive loss of function and necrosis, a partial forearm amputation was performed that healed well, and the patient experienced improvement in range of motion of the left upper extremity.

Well-known adverse reactions of amiodarone treatment include pulmonary fibrosis, hepatic dysfunction, hypothyroidism and hyperthyroidism, peripheral neuropathy, and corneal deposits.¹ Cutaneous adverse reactions include photosensitivity (phototoxic and photoallergic reactions), hyperpigmentation, pseudoporphyria, and linear IgA bullous dermatosis. Less commonly, it also can cause urticaria, pruritus, erythema nodosum, purpura, and toxic epidermal necrolysis.³ Amiodarone-induced skin necrosis is rare, first described by Russell and Saltissi⁵ in 2006 in a 60-year-old man who developed dark discoloration and edema of the forearm 24 hours after initiation of an amiodarone peripheral IV. The patient was treated with hot or cold packs and steroid cream per the pharmaceutical company’s recommendations; however, patient outcomes were not discussed.⁵ A 77-year-old man who received subcutaneous amiodarone due to misplaced vascular access developed edema and bullae of the forearm followed by tissue necrosis, resulting in notably reduced mobility.⁶ Fox et al⁷ described a 60-year-old man who developed atrial fibrillation after emergent spinal fusion and laminectomy. He received intradermal hyaluronidase administration within 24 hours of developing severe pain from extravasation induced by amiodarone with no adverse outcomes and full recovery.⁷

There are numerous properties of amiodarone that may have resulted in the skin necrosis seen in these cases. The acidic pH (3.5–4.5) of amiodarone can contribute to coagulative necrosis, cellular desiccation, eschar formation, and edema.⁸ It also can contain additives such as polysorbate and benzyl alcohol, which may contribute to the drug’s vesicant properties.⁹

Current recommendations for IV administration of amiodarone include delivery through a central vein with high concentrations (>2 mg/mL) because peripheral infusion is slower and may cause phlebitis.⁴ In-line filters also may be a potential method of preventing phlebitis with peripheral IV administration of amiodarone.¹⁰ Extravasation of amiodarone can be treated nonpharmacologically with limb elevation and warm compresses, as these methods may promote vasodilation and enhance drug removal.^5-7 However, when extravasation leads to progressive erythema and skin necrosis or is refractory to these therapies, intradermal injection of hyaluronidase should be considered. Hyaluronidase mediates the degradation of hyaluronic acid in the extracellular matrix, allowing for increased permeability of injected fluids into tissues and diluting the concentration of toxins at the site of exposure.^9,11 It has been used to treat extravasation of fluids such as parenteral nutrition, electrolyte infusion, antibiotics, aminophylline, mannitol, and chemotherapy.¹¹ Although hyaluronidase has been recognized as therapeutic for extravasation, there is no established consistent dosing or proper technique. In the setting of infiltration of chemotherapy, doses of hyaluronidase ranging from 150 to 1500 U/mL can be subcutaneously or intradermally injected into the site within 1 hour of extravasation. Side effects of using hyaluronidase are rare, including local pruritus, allergic reactions, urticaria, and angioedema.¹²

The patient described by Fox et al⁷ who fully recovered from amiodarone extravasation after hyaluronidase injections likely benefited from quick intervention, as he received amiodarone within 24 hours of the care team identifying initial erythema. Although our patient did have improvement of the areas of erythema on the forearm, evidence of skin and subcutaneous tissue necrosis on the left hand and proximal forearm was already apparent and not reversible, most likely caused by late intervention of intradermal hyaluronidase almost a week after the extravasation event. It is important to identify amiodarone as the source of extravasation and administer intradermal hyaluronidase in a timely fashion for extravasation refractory to conventional measurements to prevent progression to severe tissue damage.

Our case draws attention to the risk for skin necrosis with peripheral IV administration of amiodarone. Interventions include limb elevation, warm compresses, and consideration of intradermal hyaluronidase within 24 hours of extravasation, as this may reduce the severity of subsequent tissue damage with minimal side effects.

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

Shedding of genital herpes simplex virus was frequent soon after first-time infection but declined significantly during the first year, based on data from 82 individuals.

Genital herpes simplex virus (HSV) infections remain common and incurable; consequently, the population with residual infection continues to rise, Christine Johnston, MD, of the University of Washington, Seattle, and colleagues wrote. However, data on the viral shedding trajectory of genital HSV-1 are limited, although HSV-1 accounts for an increasing number of infections.

In a study published in JAMA the researchers recruited 82 women with first-episode genital HSV-1 infections from sexual health and primary care clinics in Seattle, between 2013 and 2018. The participants supplied self-collected oral and genital swabs for daily HSV polymerase chain reaction testing for two 30-day periods at 2 months and 11 months after their initial symptoms. The study population was not pregnant and did not have HIV infection. The median age of the participants was 26 years, 54 were women, and 42 had primary HSV-1 infections. Primary HSV-1 infection was defined as the lack of HSV antibody at baseline or an evolving antibody profile, based on the University of Washington HSV Western Blot.

The primary outcome was the rates of genital and oral HSV shedding and lesions at 2 and 11 months and up to 2 years after an initial HSV-1 infection.

At 2 months, approximately two-thirds (64.6%) of the participants had HSV-1 in the genital tract and 29.3% had virus in the mouth. Genital shedding of HSV-1 was detected in 12.1% of 2,264 total testing days at 2 months, but this rate declined to 7.1% of 1,719 testing days at 11 months (relative risk, 0.52).

The researchers identified oral HSV-1 shedding on 3.9% of 2,247 testing days at 2 months, with a slight increase to 5.1% of 1,714 testing days at 11 months.

Both genital and oral lesions were rare, with reports of 2.6% and 0.4%, respectively, at 2 months and 3.8% and 0.5%, respectively, at 11 months.

The risk of genital shedding was significantly higher in individuals with primary HSV-1, compared with those with nonprimary infections (7.9% vs. 2.9%; RR, 2.75). The overall rate of genital shedding was 17.2% for those with primary HSV-1, of which 15.2% was asymptomatic. Oral shedding was similar for individuals with primary and nonprimary HSV in a multivariate analysis.

In addition, HSV-specific CD4+ and CD8+ T-cell responses were identified in all participants, and these remained stable during the study period. No association appeared between rates of genital and oral shedding and the proportion of cells that expressed two, three, or four cytokines.

The current study is the first known to comprehensively assess genital and oral HSV-1 viral shedding using polymerase chain reaction, the researchers wrote. “Characterizing shedding rates is clinically important because patients with genital herpes are often concerned about transmission to sexual partners, which usually occurs in the absence of lesions.”

The study findings were limited by several factors including the 22% loss of participants to follow-up by the end of the first year, and the use of data from a single location with a primarily White population, the researchers noted. Another limitation was reliance on self-reports and the potential underestimation of recurrences because of the possible use of antiviral medications between swabbing periods.

However, the results indicate the early frequency of HSV-1 shedding and suggest that suppressive therapy might benefit individuals with primary HSV-1 during their first year of infection, the researchers said.
 

Findings may improve HSV management

The current study helps fill a knowledge gap regarding the natural history of genital HSV-1 infections, Richard J. Whitley, MD, and Edward W. Hook III, MD, both of the University of Alabama at Birmingham, wrote in an accompanying editorial. Despite the small study population, the data represent the largest cohort to date of individuals with first-episode infection and up to 2 years’ follow-up.

Although HSV-2 shedding is greater and associated with more symptoms, seroprevalence of HSV-2 in the United States is declining, they noted. Therefore, the findings can inform patient counseling and recommendations for antiviral therapy that may extend to managing HSV-1 in pregnant women as well, although no pregnant women were included in the study.

“For clinicians, these data emphasize the importance of determining the HSV viral type in persons presenting with initial episodes of genital herpes to accurately counsel patients regarding risk of clinical recurrence, the likelihood of asymptomatic shedding of virus and hence transmission, and antiviral prophylaxis,” the editorialists emphasized. For investigators, the results should prompt additional studies of the host defense against HSV and improved serological testing.
 

Study supports need for attention to HSV-1

“Genital herpes is an extremely common sexually transmitted infection, and often only HSV-2 is measured,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. “This study shows that HSV-1 also accounts for a significant amount of genital disease, and should also be considered when determining prevalence of genital herpes.

“I was not surprised to see that viral shedding decreased significantly over the first year after diagnosis, and similarly not surprised that lesions were rare after the initial infection,” said Dr. Prager, who was not involved in the study. “I was somewhat surprised to see that genital HSV-1 shedding was more common than oral shedding.”

Dr. Prager said that she would advise clinicians against serum HSV testing unless someone has an active genital lesion. “Testing after a lesion will often reveal HSV-1, and patients should be counseled that shedding will decrease over the first year. Subsequent genital lesions are uncommon, but certainly possible, and oral lesions and shedding are both rare.” ]

More research is needed in a more diverse population, Dr. Prager emphasized. Following patients for more than a year and learning more about the use of antiviral medications also would be useful.

The study was supported in part by the National Institutes of Health/National Institute of Allergy and Infectious Diseases through grants to several authors, including lead author Dr. Johnston. Dr. Johnston also disclosed personal fees from AbbVie, grants from Gilead, royalties from UpToDate, and personal fees from GlaxoSmithKline unrelated to the current study. Dr. Whitley disclosed personal fees from Virios Therapeutics as a board member and shareholder during the conduct of the study, royalties from Aettis unrelated to the submitted work, and serving on an advisory board for Visby Diagnostics. Dr. Hook disclosed serving on an advisory board for Visby Diagnostics unrelated to the submitted work. Dr. Prager had no conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.
 

Shedding of genital herpes simplex virus was frequent soon after first-time infection but declined significantly during the first year, based on data from 82 individuals.

Genital herpes simplex virus (HSV) infections remain common and incurable; consequently, the population with residual infection continues to rise, Christine Johnston, MD, of the University of Washington, Seattle, and colleagues wrote. However, data on the viral shedding trajectory of genital HSV-1 are limited, although HSV-1 accounts for an increasing number of infections.

In a study published in JAMA the researchers recruited 82 women with first-episode genital HSV-1 infections from sexual health and primary care clinics in Seattle, between 2013 and 2018. The participants supplied self-collected oral and genital swabs for daily HSV polymerase chain reaction testing for two 30-day periods at 2 months and 11 months after their initial symptoms. The study population was not pregnant and did not have HIV infection. The median age of the participants was 26 years, 54 were women, and 42 had primary HSV-1 infections. Primary HSV-1 infection was defined as the lack of HSV antibody at baseline or an evolving antibody profile, based on the University of Washington HSV Western Blot.

The primary outcome was the rates of genital and oral HSV shedding and lesions at 2 and 11 months and up to 2 years after an initial HSV-1 infection.

At 2 months, approximately two-thirds (64.6%) of the participants had HSV-1 in the genital tract and 29.3% had virus in the mouth. Genital shedding of HSV-1 was detected in 12.1% of 2,264 total testing days at 2 months, but this rate declined to 7.1% of 1,719 testing days at 11 months (relative risk, 0.52).

The researchers identified oral HSV-1 shedding on 3.9% of 2,247 testing days at 2 months, with a slight increase to 5.1% of 1,714 testing days at 11 months.

Both genital and oral lesions were rare, with reports of 2.6% and 0.4%, respectively, at 2 months and 3.8% and 0.5%, respectively, at 11 months.

The risk of genital shedding was significantly higher in individuals with primary HSV-1, compared with those with nonprimary infections (7.9% vs. 2.9%; RR, 2.75). The overall rate of genital shedding was 17.2% for those with primary HSV-1, of which 15.2% was asymptomatic. Oral shedding was similar for individuals with primary and nonprimary HSV in a multivariate analysis.

In addition, HSV-specific CD4+ and CD8+ T-cell responses were identified in all participants, and these remained stable during the study period. No association appeared between rates of genital and oral shedding and the proportion of cells that expressed two, three, or four cytokines.

The current study is the first known to comprehensively assess genital and oral HSV-1 viral shedding using polymerase chain reaction, the researchers wrote. “Characterizing shedding rates is clinically important because patients with genital herpes are often concerned about transmission to sexual partners, which usually occurs in the absence of lesions.”

The study findings were limited by several factors including the 22% loss of participants to follow-up by the end of the first year, and the use of data from a single location with a primarily White population, the researchers noted. Another limitation was reliance on self-reports and the potential underestimation of recurrences because of the possible use of antiviral medications between swabbing periods.

However, the results indicate the early frequency of HSV-1 shedding and suggest that suppressive therapy might benefit individuals with primary HSV-1 during their first year of infection, the researchers said.
 

Findings may improve HSV management

The current study helps fill a knowledge gap regarding the natural history of genital HSV-1 infections, Richard J. Whitley, MD, and Edward W. Hook III, MD, both of the University of Alabama at Birmingham, wrote in an accompanying editorial. Despite the small study population, the data represent the largest cohort to date of individuals with first-episode infection and up to 2 years’ follow-up.

Although HSV-2 shedding is greater and associated with more symptoms, seroprevalence of HSV-2 in the United States is declining, they noted. Therefore, the findings can inform patient counseling and recommendations for antiviral therapy that may extend to managing HSV-1 in pregnant women as well, although no pregnant women were included in the study.

“For clinicians, these data emphasize the importance of determining the HSV viral type in persons presenting with initial episodes of genital herpes to accurately counsel patients regarding risk of clinical recurrence, the likelihood of asymptomatic shedding of virus and hence transmission, and antiviral prophylaxis,” the editorialists emphasized. For investigators, the results should prompt additional studies of the host defense against HSV and improved serological testing.
 

Study supports need for attention to HSV-1

“Genital herpes is an extremely common sexually transmitted infection, and often only HSV-2 is measured,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. “This study shows that HSV-1 also accounts for a significant amount of genital disease, and should also be considered when determining prevalence of genital herpes.

“I was not surprised to see that viral shedding decreased significantly over the first year after diagnosis, and similarly not surprised that lesions were rare after the initial infection,” said Dr. Prager, who was not involved in the study. “I was somewhat surprised to see that genital HSV-1 shedding was more common than oral shedding.”

Dr. Prager said that she would advise clinicians against serum HSV testing unless someone has an active genital lesion. “Testing after a lesion will often reveal HSV-1, and patients should be counseled that shedding will decrease over the first year. Subsequent genital lesions are uncommon, but certainly possible, and oral lesions and shedding are both rare.” ]

More research is needed in a more diverse population, Dr. Prager emphasized. Following patients for more than a year and learning more about the use of antiviral medications also would be useful.

The study was supported in part by the National Institutes of Health/National Institute of Allergy and Infectious Diseases through grants to several authors, including lead author Dr. Johnston. Dr. Johnston also disclosed personal fees from AbbVie, grants from Gilead, royalties from UpToDate, and personal fees from GlaxoSmithKline unrelated to the current study. Dr. Whitley disclosed personal fees from Virios Therapeutics as a board member and shareholder during the conduct of the study, royalties from Aettis unrelated to the submitted work, and serving on an advisory board for Visby Diagnostics. Dr. Hook disclosed serving on an advisory board for Visby Diagnostics unrelated to the submitted work. Dr. Prager had no conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.
 

Shedding of genital herpes simplex virus was frequent soon after first-time infection but declined significantly during the first year, based on data from 82 individuals.

Genital herpes simplex virus (HSV) infections remain common and incurable; consequently, the population with residual infection continues to rise, Christine Johnston, MD, of the University of Washington, Seattle, and colleagues wrote. However, data on the viral shedding trajectory of genital HSV-1 are limited, although HSV-1 accounts for an increasing number of infections.

In a study published in JAMA the researchers recruited 82 women with first-episode genital HSV-1 infections from sexual health and primary care clinics in Seattle, between 2013 and 2018. The participants supplied self-collected oral and genital swabs for daily HSV polymerase chain reaction testing for two 30-day periods at 2 months and 11 months after their initial symptoms. The study population was not pregnant and did not have HIV infection. The median age of the participants was 26 years, 54 were women, and 42 had primary HSV-1 infections. Primary HSV-1 infection was defined as the lack of HSV antibody at baseline or an evolving antibody profile, based on the University of Washington HSV Western Blot.

The primary outcome was the rates of genital and oral HSV shedding and lesions at 2 and 11 months and up to 2 years after an initial HSV-1 infection.

At 2 months, approximately two-thirds (64.6%) of the participants had HSV-1 in the genital tract and 29.3% had virus in the mouth. Genital shedding of HSV-1 was detected in 12.1% of 2,264 total testing days at 2 months, but this rate declined to 7.1% of 1,719 testing days at 11 months (relative risk, 0.52).

The researchers identified oral HSV-1 shedding on 3.9% of 2,247 testing days at 2 months, with a slight increase to 5.1% of 1,714 testing days at 11 months.

Both genital and oral lesions were rare, with reports of 2.6% and 0.4%, respectively, at 2 months and 3.8% and 0.5%, respectively, at 11 months.

The risk of genital shedding was significantly higher in individuals with primary HSV-1, compared with those with nonprimary infections (7.9% vs. 2.9%; RR, 2.75). The overall rate of genital shedding was 17.2% for those with primary HSV-1, of which 15.2% was asymptomatic. Oral shedding was similar for individuals with primary and nonprimary HSV in a multivariate analysis.

In addition, HSV-specific CD4+ and CD8+ T-cell responses were identified in all participants, and these remained stable during the study period. No association appeared between rates of genital and oral shedding and the proportion of cells that expressed two, three, or four cytokines.

The current study is the first known to comprehensively assess genital and oral HSV-1 viral shedding using polymerase chain reaction, the researchers wrote. “Characterizing shedding rates is clinically important because patients with genital herpes are often concerned about transmission to sexual partners, which usually occurs in the absence of lesions.”

The study findings were limited by several factors including the 22% loss of participants to follow-up by the end of the first year, and the use of data from a single location with a primarily White population, the researchers noted. Another limitation was reliance on self-reports and the potential underestimation of recurrences because of the possible use of antiviral medications between swabbing periods.

However, the results indicate the early frequency of HSV-1 shedding and suggest that suppressive therapy might benefit individuals with primary HSV-1 during their first year of infection, the researchers said.
 

Findings may improve HSV management

The current study helps fill a knowledge gap regarding the natural history of genital HSV-1 infections, Richard J. Whitley, MD, and Edward W. Hook III, MD, both of the University of Alabama at Birmingham, wrote in an accompanying editorial. Despite the small study population, the data represent the largest cohort to date of individuals with first-episode infection and up to 2 years’ follow-up.

Although HSV-2 shedding is greater and associated with more symptoms, seroprevalence of HSV-2 in the United States is declining, they noted. Therefore, the findings can inform patient counseling and recommendations for antiviral therapy that may extend to managing HSV-1 in pregnant women as well, although no pregnant women were included in the study.

“For clinicians, these data emphasize the importance of determining the HSV viral type in persons presenting with initial episodes of genital herpes to accurately counsel patients regarding risk of clinical recurrence, the likelihood of asymptomatic shedding of virus and hence transmission, and antiviral prophylaxis,” the editorialists emphasized. For investigators, the results should prompt additional studies of the host defense against HSV and improved serological testing.
 

Study supports need for attention to HSV-1

“Genital herpes is an extremely common sexually transmitted infection, and often only HSV-2 is measured,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. “This study shows that HSV-1 also accounts for a significant amount of genital disease, and should also be considered when determining prevalence of genital herpes.

“I was not surprised to see that viral shedding decreased significantly over the first year after diagnosis, and similarly not surprised that lesions were rare after the initial infection,” said Dr. Prager, who was not involved in the study. “I was somewhat surprised to see that genital HSV-1 shedding was more common than oral shedding.”

Dr. Prager said that she would advise clinicians against serum HSV testing unless someone has an active genital lesion. “Testing after a lesion will often reveal HSV-1, and patients should be counseled that shedding will decrease over the first year. Subsequent genital lesions are uncommon, but certainly possible, and oral lesions and shedding are both rare.” ]

More research is needed in a more diverse population, Dr. Prager emphasized. Following patients for more than a year and learning more about the use of antiviral medications also would be useful.

The study was supported in part by the National Institutes of Health/National Institute of Allergy and Infectious Diseases through grants to several authors, including lead author Dr. Johnston. Dr. Johnston also disclosed personal fees from AbbVie, grants from Gilead, royalties from UpToDate, and personal fees from GlaxoSmithKline unrelated to the current study. Dr. Whitley disclosed personal fees from Virios Therapeutics as a board member and shareholder during the conduct of the study, royalties from Aettis unrelated to the submitted work, and serving on an advisory board for Visby Diagnostics. Dr. Hook disclosed serving on an advisory board for Visby Diagnostics unrelated to the submitted work. Dr. Prager had no conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.
 

MONTREAL – Children and young people with severe atopic dermatitis had a more rapid treatment response with ciclosporin, but more sustained disease control with methotrexate in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.

The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.

“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.

In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.

Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.

Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.

On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).

However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.

The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.

Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.

Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).

“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.

What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”

Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”

Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.

A version of this article first appeared on Medscape.com.

MONTREAL – Children and young people with severe atopic dermatitis had a more rapid treatment response with ciclosporin, but more sustained disease control with methotrexate in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.

The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.

“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.

In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.

Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.

Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.

On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).

However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.

The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.

Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.

Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).

“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.

What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”

Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”

Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.

A version of this article first appeared on Medscape.com.

MONTREAL – Children and young people with severe atopic dermatitis had a more rapid treatment response with ciclosporin, but more sustained disease control with methotrexate in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.

The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.

“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.

In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.

Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.

Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.

On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).

However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.

The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.

Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.

Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).

“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.

What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”

Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”

Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.

A version of this article first appeared on Medscape.com.

MONTREAL – An online behavioral intervention called Eczema Care Online, aimed at supporting self-management of atopic dermatitis (AD), resulted in a “small but sustained” improvement in eczema severity for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.

The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).

The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.

Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.

In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.

In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.

At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.

In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”

An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”

While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”

Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.

“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”

In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.

Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MONTREAL – An online behavioral intervention called Eczema Care Online, aimed at supporting self-management of atopic dermatitis (AD), resulted in a “small but sustained” improvement in eczema severity for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.

The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).

The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.

Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.

In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.

In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.

At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.

In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”

An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”

While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”

Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.

“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”

In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.

Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MONTREAL – An online behavioral intervention called Eczema Care Online, aimed at supporting self-management of atopic dermatitis (AD), resulted in a “small but sustained” improvement in eczema severity for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.

The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).

The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.

Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.

In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.

In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.

At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.

In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”

An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”

While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”

Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.

“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”

In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.

Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with the systemic sclerosis subtype of pulmonary arterial hypertension showed a distinctive bioactive metabolic profile associated with more severe disease than other subgroups, based on data from approximately 1,500 individuals.

The overall prognosis and therapeutic response for patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) tends to be worse than for patients with other types of PAH, such as idiopathic pulmonary arterial hypertension (IPAH), but the impact of different metabolite profiles among subtypes of disease has not been explored, wrote Mona Alotaibi, MD, of the University of California, San Diego, and colleagues.

“Recently, metabolic dysregulation has been proposed as a key mechanism by which IPAH and SSc-PAH differ and could control such disparities,” they noted. Clarifying the molecular mechanisms of SSc-PAH could inform management and treatment, they added.

In a study published in the journal Chest, the researchers sought to identify a bioactive lipid signature unique to SSc-PAH. They identified 400 patients with SSc-PAH and 1,082 with IPAH. An additional 100 patients with scleroderma but no PH and 44 patients with scleroderma who had PH were included for external validation. The mean ages of the patients with IPAH and SSc-PAH in the discovery and validation cohorts ranged from approximately 51 to 65 years; more than 75% of patients across the groups were women.

The researchers tested more than 700 bioactive lipid metabolites using liquid chromatography/mass spectrometry. They found five metabolites that distinguished SSc-PAH and IPAH that were significantly associated with markers of disease severity: 17-beta estradiol, novel Eic, nervonic acid, fatty acid esters of hydroxy fatty acids, and prostaglandin F2 alpha (PGF 2 alpha).

The biomarkers were increased in SSc-PAH patients compared to patients with SSC alone, which suggests that the biomarkers are related to PAH and not to scleroderma alone, the researchers noted.

In particular, nervonic acid was associated with worse functional capacity, in SSc-PAH patients, as were higher levels of 17-beta estradiol and prostaglandin F2 alpha. Also, 17-beta estradiol was associated with lower cardiac impairment (CI) and stroke volume index (SVI) in SSc-PAH patients, but higher SVI in IPAH patients. PGF 2 alpha was associated with lower CI and SVI and higher pulmonary vascular resistance in SSc-PAH and IPAH combined.

The study findings were limited by several factors including the inability to adjust for all potential confounders between IPAH and SSc-PAH, and the fact that a clear causal relationship could not be determined, the researchers noted. Inadequate statistical power to analyze SSc-PAH data was another limitation, and studies with detailed scleroderma phenotypes are needed to validate the results, they said.

However, the current study provides insight on the metabolic differences in SSc-PAH and the potential impact on disease pathology that may inform diagnosis, prognosis, and treatment strategies for SSc-PAH patients, they concluded.

The study was supported by the National Institutes of Health. Several individual investigators received support from organizations including the American Heart Association and the Chest Foundation, and from companies including Livanova, Equillium, Corvus, Bayer, and Actelion, but the authors had no relevant financial conflicts to disclose.

Patients with the systemic sclerosis subtype of pulmonary arterial hypertension showed a distinctive bioactive metabolic profile associated with more severe disease than other subgroups, based on data from approximately 1,500 individuals.

The overall prognosis and therapeutic response for patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) tends to be worse than for patients with other types of PAH, such as idiopathic pulmonary arterial hypertension (IPAH), but the impact of different metabolite profiles among subtypes of disease has not been explored, wrote Mona Alotaibi, MD, of the University of California, San Diego, and colleagues.

“Recently, metabolic dysregulation has been proposed as a key mechanism by which IPAH and SSc-PAH differ and could control such disparities,” they noted. Clarifying the molecular mechanisms of SSc-PAH could inform management and treatment, they added.

In a study published in the journal Chest, the researchers sought to identify a bioactive lipid signature unique to SSc-PAH. They identified 400 patients with SSc-PAH and 1,082 with IPAH. An additional 100 patients with scleroderma but no PH and 44 patients with scleroderma who had PH were included for external validation. The mean ages of the patients with IPAH and SSc-PAH in the discovery and validation cohorts ranged from approximately 51 to 65 years; more than 75% of patients across the groups were women.

The researchers tested more than 700 bioactive lipid metabolites using liquid chromatography/mass spectrometry. They found five metabolites that distinguished SSc-PAH and IPAH that were significantly associated with markers of disease severity: 17-beta estradiol, novel Eic, nervonic acid, fatty acid esters of hydroxy fatty acids, and prostaglandin F2 alpha (PGF 2 alpha).

The biomarkers were increased in SSc-PAH patients compared to patients with SSC alone, which suggests that the biomarkers are related to PAH and not to scleroderma alone, the researchers noted.

In particular, nervonic acid was associated with worse functional capacity, in SSc-PAH patients, as were higher levels of 17-beta estradiol and prostaglandin F2 alpha. Also, 17-beta estradiol was associated with lower cardiac impairment (CI) and stroke volume index (SVI) in SSc-PAH patients, but higher SVI in IPAH patients. PGF 2 alpha was associated with lower CI and SVI and higher pulmonary vascular resistance in SSc-PAH and IPAH combined.

The study findings were limited by several factors including the inability to adjust for all potential confounders between IPAH and SSc-PAH, and the fact that a clear causal relationship could not be determined, the researchers noted. Inadequate statistical power to analyze SSc-PAH data was another limitation, and studies with detailed scleroderma phenotypes are needed to validate the results, they said.

However, the current study provides insight on the metabolic differences in SSc-PAH and the potential impact on disease pathology that may inform diagnosis, prognosis, and treatment strategies for SSc-PAH patients, they concluded.

The study was supported by the National Institutes of Health. Several individual investigators received support from organizations including the American Heart Association and the Chest Foundation, and from companies including Livanova, Equillium, Corvus, Bayer, and Actelion, but the authors had no relevant financial conflicts to disclose.

Patients with the systemic sclerosis subtype of pulmonary arterial hypertension showed a distinctive bioactive metabolic profile associated with more severe disease than other subgroups, based on data from approximately 1,500 individuals.

The overall prognosis and therapeutic response for patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) tends to be worse than for patients with other types of PAH, such as idiopathic pulmonary arterial hypertension (IPAH), but the impact of different metabolite profiles among subtypes of disease has not been explored, wrote Mona Alotaibi, MD, of the University of California, San Diego, and colleagues.

“Recently, metabolic dysregulation has been proposed as a key mechanism by which IPAH and SSc-PAH differ and could control such disparities,” they noted. Clarifying the molecular mechanisms of SSc-PAH could inform management and treatment, they added.

In a study published in the journal Chest, the researchers sought to identify a bioactive lipid signature unique to SSc-PAH. They identified 400 patients with SSc-PAH and 1,082 with IPAH. An additional 100 patients with scleroderma but no PH and 44 patients with scleroderma who had PH were included for external validation. The mean ages of the patients with IPAH and SSc-PAH in the discovery and validation cohorts ranged from approximately 51 to 65 years; more than 75% of patients across the groups were women.

The researchers tested more than 700 bioactive lipid metabolites using liquid chromatography/mass spectrometry. They found five metabolites that distinguished SSc-PAH and IPAH that were significantly associated with markers of disease severity: 17-beta estradiol, novel Eic, nervonic acid, fatty acid esters of hydroxy fatty acids, and prostaglandin F2 alpha (PGF 2 alpha).

The biomarkers were increased in SSc-PAH patients compared to patients with SSC alone, which suggests that the biomarkers are related to PAH and not to scleroderma alone, the researchers noted.

In particular, nervonic acid was associated with worse functional capacity, in SSc-PAH patients, as were higher levels of 17-beta estradiol and prostaglandin F2 alpha. Also, 17-beta estradiol was associated with lower cardiac impairment (CI) and stroke volume index (SVI) in SSc-PAH patients, but higher SVI in IPAH patients. PGF 2 alpha was associated with lower CI and SVI and higher pulmonary vascular resistance in SSc-PAH and IPAH combined.

The study findings were limited by several factors including the inability to adjust for all potential confounders between IPAH and SSc-PAH, and the fact that a clear causal relationship could not be determined, the researchers noted. Inadequate statistical power to analyze SSc-PAH data was another limitation, and studies with detailed scleroderma phenotypes are needed to validate the results, they said.

However, the current study provides insight on the metabolic differences in SSc-PAH and the potential impact on disease pathology that may inform diagnosis, prognosis, and treatment strategies for SSc-PAH patients, they concluded.

The study was supported by the National Institutes of Health. Several individual investigators received support from organizations including the American Heart Association and the Chest Foundation, and from companies including Livanova, Equillium, Corvus, Bayer, and Actelion, but the authors had no relevant financial conflicts to disclose.

The Diagnosis: Maculopapular Cutaneous Mastocytosis (Urticaria Pigmentosa)

A stroke test revealed urtication at the exact traumatized site (Figure). A skin biopsy performed 2 years prior by another physician in the same hospital had revealed mast cell infiltration of virtually the entire dermis. The diagnosis was then firmly established as maculopapular cutaneous mastocytosis (CM)(also known as urticaria pigmentosa) with both the pathology results and a confirmative stroke test, and no additional biopsy was attempted. Serum IgE and tryptase levels were within the reference range. General recommendations about the avoidance of trigger factors were given to the family, and a new-generation H₁ blocker antihistaminic syrup was prescribed for flushing, itching, and urtication.

Mastocytosis is a canopy term for a heterogeneous group of disorders caused by clonal proliferation and accumulation of abnormal mast cells within the skin and visceral organs (ie, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract). Cutaneous mastocytosis, the skin-restricted variant, is by far the most common form of childhood mastocytosis (90% of mastocytosis cases in children)¹ and generally appears within the first 2 years of life.^1-7 Pediatric CM usually is a benign and transient disease with an excellent prognosis and a negligible risk for systemic involvement.^2,3,5

The pathogenesis of CM in children is obscure¹; however, somatic or germline gain-of-function mutations of the c-KIT proto-oncogene, which encodes KIT (ie, a tyrosine kinase membrane receptor for stem cell factor), may account for most pediatric CM phenotypes.^1,3,6 Activating c-KIT mutations leads to constitutive activation of the KIT receptor (expressed on the surface membrane of mast cells) and instigates autonomous (stem cell factor– independent) clonal proliferation, enhanced survival, and accumulation of mast cells.²

Maculopapular CM is the most common clinical form of CM.^2,4,5 In children, maculopapular CM usually presents with polymorphous red-brown lesions of varying sizes and types—macule, papule, plaque, or nodule—on the torso and extremities.^1-5 The distribution may be widespread and rarely is almost universal, as in our patient.² Darier sign typically is positive, with a wheal and flare developing upon stroking or rubbing 1 or several lesions.1-6 The lesions gradually involute and often spontaneously regress at the time of puberty.^1-3,5-7

The clinical signs and symptoms of mastocytosis are not only related to mast cell infiltration but also to mast cell activation within the tissues. The release of intracellular mediators from activated mast cells may have local and/or systemic consequences.^4,7 Erythema, edema, flushing, pruritus, urticaria, blistering, and dermatographism are among the local cutaneous symptoms of mast cell activation.^2-4,7 Systemic symptoms are rare in childhood CM and consist of wheezing, shortness of breath, nausea, vomiting, reflux, abdominal cramping, diarrhea, tachycardia, hypotension, syncope, anaphylaxis, and cyanotic spells.^1-7 An elevated serum tryptase level is an indicator of both mast cell burden and risk for mast cell activation in the skin.^4,7

Treatment of pediatric CM is conservative and symptomatic.³ Prevention of mediator release may be accomplished through avoidance of trigger factors.¹ Alleviation of mediator-related symptoms might be attained using H1 and H2 histamine receptor blockers, oral cromolyn sodium, leukotriene antagonists, and epinephrine autoinjectors.^1-3,5 Short-term topical or oral corticosteroids; calcineurin inhibitors (eg, pimecrolimus, tacrolimus); phototherapy; psoralen plus UVA; omalizumab; and innovative agents such as topical miltefosine, nemolizumab (an IL-31 antagonist), kinase inhibitors such as midostaurin, and tyrosine kinase inhibitors such as imatinib and masitinib may be tried in refractory or extensive pediatric CM.^1,2,5,6

Although several disorders in childhood may present with red-brown macules and papules, Darier sign is unique to cutaneous mastocytosis. A biopsy also will be helpful in establishing the definitive diagnosis.

Histiocytosis X (also referred to as Langerhans cell histiocytosis) is the most common proliferative histiocytic disorder. Cutaneous lesions are polymorphic and consist of seborrheic involvement of the scalp with yellow, scaly or crusted papules; eroded patches; pustules; vesicles; petechiae; purpura; or red to purplish papules on the groin, abdomen, back, or chest.8

LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines) is an acronym denoting lentigines (multiple), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retarded growth, and deafness (sensorineural). The disorder is caused by a genetic mutation involving the PTPN11 gene and currently is categorized under the canopy of RASopathies. Cutaneous findings consist of lentiginous and café-au-lait macules and patches.⁹

Neurofibromatosis is a genetic disorder with a plethora of cutaneous and systemic manifestations. The type 1 variant that constitutes more than 95% of cases is caused by mutations in the neurofibromin gene. The main cutaneous findings include café-au-lait macules, freckling in axillary and inguinal locations (Crowe sign), and neurofibromas. These lesions may present as macules, patches, papules, or nodules.¹⁰

Xanthoma disseminatum is a rare sporadic proliferative histiocyte disorder involving the skin and mucosa. The disorder may be a harbinger of diabetes insipidus. Cutaneous lesions consist of asymptomatic, symmetrical, discrete, erythematous to yellow-brown papules and nodules.¹¹

The Diagnosis: Maculopapular Cutaneous Mastocytosis (Urticaria Pigmentosa)

A stroke test revealed urtication at the exact traumatized site (Figure). A skin biopsy performed 2 years prior by another physician in the same hospital had revealed mast cell infiltration of virtually the entire dermis. The diagnosis was then firmly established as maculopapular cutaneous mastocytosis (CM)(also known as urticaria pigmentosa) with both the pathology results and a confirmative stroke test, and no additional biopsy was attempted. Serum IgE and tryptase levels were within the reference range. General recommendations about the avoidance of trigger factors were given to the family, and a new-generation H₁ blocker antihistaminic syrup was prescribed for flushing, itching, and urtication.

Mastocytosis is a canopy term for a heterogeneous group of disorders caused by clonal proliferation and accumulation of abnormal mast cells within the skin and visceral organs (ie, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract). Cutaneous mastocytosis, the skin-restricted variant, is by far the most common form of childhood mastocytosis (90% of mastocytosis cases in children)¹ and generally appears within the first 2 years of life.^1-7 Pediatric CM usually is a benign and transient disease with an excellent prognosis and a negligible risk for systemic involvement.^2,3,5

The pathogenesis of CM in children is obscure¹; however, somatic or germline gain-of-function mutations of the c-KIT proto-oncogene, which encodes KIT (ie, a tyrosine kinase membrane receptor for stem cell factor), may account for most pediatric CM phenotypes.^1,3,6 Activating c-KIT mutations leads to constitutive activation of the KIT receptor (expressed on the surface membrane of mast cells) and instigates autonomous (stem cell factor– independent) clonal proliferation, enhanced survival, and accumulation of mast cells.²

Maculopapular CM is the most common clinical form of CM.^2,4,5 In children, maculopapular CM usually presents with polymorphous red-brown lesions of varying sizes and types—macule, papule, plaque, or nodule—on the torso and extremities.^1-5 The distribution may be widespread and rarely is almost universal, as in our patient.² Darier sign typically is positive, with a wheal and flare developing upon stroking or rubbing 1 or several lesions.1-6 The lesions gradually involute and often spontaneously regress at the time of puberty.^1-3,5-7

The clinical signs and symptoms of mastocytosis are not only related to mast cell infiltration but also to mast cell activation within the tissues. The release of intracellular mediators from activated mast cells may have local and/or systemic consequences.^4,7 Erythema, edema, flushing, pruritus, urticaria, blistering, and dermatographism are among the local cutaneous symptoms of mast cell activation.^2-4,7 Systemic symptoms are rare in childhood CM and consist of wheezing, shortness of breath, nausea, vomiting, reflux, abdominal cramping, diarrhea, tachycardia, hypotension, syncope, anaphylaxis, and cyanotic spells.^1-7 An elevated serum tryptase level is an indicator of both mast cell burden and risk for mast cell activation in the skin.^4,7

Treatment of pediatric CM is conservative and symptomatic.³ Prevention of mediator release may be accomplished through avoidance of trigger factors.¹ Alleviation of mediator-related symptoms might be attained using H1 and H2 histamine receptor blockers, oral cromolyn sodium, leukotriene antagonists, and epinephrine autoinjectors.^1-3,5 Short-term topical or oral corticosteroids; calcineurin inhibitors (eg, pimecrolimus, tacrolimus); phototherapy; psoralen plus UVA; omalizumab; and innovative agents such as topical miltefosine, nemolizumab (an IL-31 antagonist), kinase inhibitors such as midostaurin, and tyrosine kinase inhibitors such as imatinib and masitinib may be tried in refractory or extensive pediatric CM.^1,2,5,6

Although several disorders in childhood may present with red-brown macules and papules, Darier sign is unique to cutaneous mastocytosis. A biopsy also will be helpful in establishing the definitive diagnosis.

Histiocytosis X (also referred to as Langerhans cell histiocytosis) is the most common proliferative histiocytic disorder. Cutaneous lesions are polymorphic and consist of seborrheic involvement of the scalp with yellow, scaly or crusted papules; eroded patches; pustules; vesicles; petechiae; purpura; or red to purplish papules on the groin, abdomen, back, or chest.8

LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines) is an acronym denoting lentigines (multiple), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retarded growth, and deafness (sensorineural). The disorder is caused by a genetic mutation involving the PTPN11 gene and currently is categorized under the canopy of RASopathies. Cutaneous findings consist of lentiginous and café-au-lait macules and patches.⁹

Neurofibromatosis is a genetic disorder with a plethora of cutaneous and systemic manifestations. The type 1 variant that constitutes more than 95% of cases is caused by mutations in the neurofibromin gene. The main cutaneous findings include café-au-lait macules, freckling in axillary and inguinal locations (Crowe sign), and neurofibromas. These lesions may present as macules, patches, papules, or nodules.¹⁰

Xanthoma disseminatum is a rare sporadic proliferative histiocyte disorder involving the skin and mucosa. The disorder may be a harbinger of diabetes insipidus. Cutaneous lesions consist of asymptomatic, symmetrical, discrete, erythematous to yellow-brown papules and nodules.¹¹

The Diagnosis: Maculopapular Cutaneous Mastocytosis (Urticaria Pigmentosa)

A stroke test revealed urtication at the exact traumatized site (Figure). A skin biopsy performed 2 years prior by another physician in the same hospital had revealed mast cell infiltration of virtually the entire dermis. The diagnosis was then firmly established as maculopapular cutaneous mastocytosis (CM)(also known as urticaria pigmentosa) with both the pathology results and a confirmative stroke test, and no additional biopsy was attempted. Serum IgE and tryptase levels were within the reference range. General recommendations about the avoidance of trigger factors were given to the family, and a new-generation H₁ blocker antihistaminic syrup was prescribed for flushing, itching, and urtication.

Mastocytosis is a canopy term for a heterogeneous group of disorders caused by clonal proliferation and accumulation of abnormal mast cells within the skin and visceral organs (ie, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract). Cutaneous mastocytosis, the skin-restricted variant, is by far the most common form of childhood mastocytosis (90% of mastocytosis cases in children)¹ and generally appears within the first 2 years of life.^1-7 Pediatric CM usually is a benign and transient disease with an excellent prognosis and a negligible risk for systemic involvement.^2,3,5

The pathogenesis of CM in children is obscure¹; however, somatic or germline gain-of-function mutations of the c-KIT proto-oncogene, which encodes KIT (ie, a tyrosine kinase membrane receptor for stem cell factor), may account for most pediatric CM phenotypes.^1,3,6 Activating c-KIT mutations leads to constitutive activation of the KIT receptor (expressed on the surface membrane of mast cells) and instigates autonomous (stem cell factor– independent) clonal proliferation, enhanced survival, and accumulation of mast cells.²

Maculopapular CM is the most common clinical form of CM.^2,4,5 In children, maculopapular CM usually presents with polymorphous red-brown lesions of varying sizes and types—macule, papule, plaque, or nodule—on the torso and extremities.^1-5 The distribution may be widespread and rarely is almost universal, as in our patient.² Darier sign typically is positive, with a wheal and flare developing upon stroking or rubbing 1 or several lesions.1-6 The lesions gradually involute and often spontaneously regress at the time of puberty.^1-3,5-7

The clinical signs and symptoms of mastocytosis are not only related to mast cell infiltration but also to mast cell activation within the tissues. The release of intracellular mediators from activated mast cells may have local and/or systemic consequences.^4,7 Erythema, edema, flushing, pruritus, urticaria, blistering, and dermatographism are among the local cutaneous symptoms of mast cell activation.^2-4,7 Systemic symptoms are rare in childhood CM and consist of wheezing, shortness of breath, nausea, vomiting, reflux, abdominal cramping, diarrhea, tachycardia, hypotension, syncope, anaphylaxis, and cyanotic spells.^1-7 An elevated serum tryptase level is an indicator of both mast cell burden and risk for mast cell activation in the skin.^4,7

Treatment of pediatric CM is conservative and symptomatic.³ Prevention of mediator release may be accomplished through avoidance of trigger factors.¹ Alleviation of mediator-related symptoms might be attained using H1 and H2 histamine receptor blockers, oral cromolyn sodium, leukotriene antagonists, and epinephrine autoinjectors.^1-3,5 Short-term topical or oral corticosteroids; calcineurin inhibitors (eg, pimecrolimus, tacrolimus); phototherapy; psoralen plus UVA; omalizumab; and innovative agents such as topical miltefosine, nemolizumab (an IL-31 antagonist), kinase inhibitors such as midostaurin, and tyrosine kinase inhibitors such as imatinib and masitinib may be tried in refractory or extensive pediatric CM.^1,2,5,6

Although several disorders in childhood may present with red-brown macules and papules, Darier sign is unique to cutaneous mastocytosis. A biopsy also will be helpful in establishing the definitive diagnosis.

Histiocytosis X (also referred to as Langerhans cell histiocytosis) is the most common proliferative histiocytic disorder. Cutaneous lesions are polymorphic and consist of seborrheic involvement of the scalp with yellow, scaly or crusted papules; eroded patches; pustules; vesicles; petechiae; purpura; or red to purplish papules on the groin, abdomen, back, or chest.8

LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines) is an acronym denoting lentigines (multiple), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retarded growth, and deafness (sensorineural). The disorder is caused by a genetic mutation involving the PTPN11 gene and currently is categorized under the canopy of RASopathies. Cutaneous findings consist of lentiginous and café-au-lait macules and patches.⁹

Neurofibromatosis is a genetic disorder with a plethora of cutaneous and systemic manifestations. The type 1 variant that constitutes more than 95% of cases is caused by mutations in the neurofibromin gene. The main cutaneous findings include café-au-lait macules, freckling in axillary and inguinal locations (Crowe sign), and neurofibromas. These lesions may present as macules, patches, papules, or nodules.¹⁰

Xanthoma disseminatum is a rare sporadic proliferative histiocyte disorder involving the skin and mucosa. The disorder may be a harbinger of diabetes insipidus. Cutaneous lesions consist of asymptomatic, symmetrical, discrete, erythematous to yellow-brown papules and nodules.¹¹

DENVER – The top three social media platforms used by patients who seek aesthetic medical treatments in the United States are Facebook, Instagram, and YouTube. However, in a recent survey, when asked if an aesthetic medical provider’s social media presence positively affects their desire to see that provider, 48% of patients were neutral or had no opinion, while 41% indicated yes.

Gerd Altmann/pixabay

Those are key findings from the survey, which aimed to evaluate the social media preferences and perceptions of patients who undergo aesthetic procedures.

“Aesthetic providers have firmly established a presence on social media,” Morgan Murphrey, MD, said at the annual meeting of the American Society for Dermatologic Surgery, where she presented the results. “According to the dermatology literature, somewhere between 25% and 50% of patients are looking up aesthetic providers on social media before they even see them in the clinic. This raises the question: How do patients perceive aesthetic providers that are on social media, and what do they want to see on their professional accounts?”

To find out, Dr. Murphrey, chief dermatology resident at the University of California, Davis, and Sabrina Fabi, MD, a San Diego–based cosmetic dermatologist, used Survey Monkey to randomly survey 2,063 individuals in the United States. They used descriptive statistics to analyze characteristics and responses of the study participants.

Of the 2,063 respondents, 651 (32%) indicated that they undergo medical aesthetic treatments including Botox injections, fillers, or laser procedures. More than half (56%) were women, 25% were 18-30 years old, 64% were 31-60 years old, and 11% were 61 years or older.

The three most common social media platforms they used were Facebook (70%), Instagram (65%), and YouTube (63%), followed by TikTok (45%) and Snapchat (29%). When the researchers stratified respondents by income level, individuals making $200,000 or more per year were statistically more likely to be on Instagram while those making less than $200,000 were more likely to be on Facebook and YouTube.

When asked if their aesthetic medical provider’s social media presence positively impacts their desire to see them as a patient, 48% of respondent were neutral or had no opinion, while 41% answered yes. “Only 2% felt strongly about this if the provider was on a specific social media platform, while 9% of respondents preferred that their provider not be on social media,” Dr. Murphrey added.

When asked if the number of social media followers influences their perception of an aesthetic provider as an expert, 43% of respondents answered no while 57% answered yes. “Once you get to about 20,000 followers, there seems to be somewhat of a law of diminishing returns in the number of followers,” she said. However, 55% indicated that they prefer to see a provider with a social media account that is verified with a blue check mark.

As for content published, 70% of respondents found it very important (36%) or important (34%) that a provider show before-and-after photos on their social media pages, while 67% said that they favor viewing personal content such as posts about the provider’s family and hobbies.

“This study summarizes to us that there is really low risk to creating a social media account; it’s something to think about,” Dr. Murphrey said. “Only 9% of respondents really didn’t want aesthetic providers to be on social media, but when we stratified our results, those individuals were less likely to be on social media themselves.”

Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and was asked to comment on the results, characterized the findings as important, “as the role of social media (especially visually based platforms like Instagram) will only continue to grow in our dermatologic and aesthetic practices.” Several studies have displayed a trend of plastic surgeons and other subspecialities outnumbering dermatologists within the aesthetic realm of social media, she noted. “As our patients increasingly seek out health care information and advice through these platforms, studies like Dr. Murphrey’s and Dr. Fabi’s are helpful in allowing us to better understand patient preferences and perspectives, in that we, as dermatologists, may be able to better aid their medical decisions in the future,” she added.

Neither the researchers nor Dr. Richey reported having relevant financial disclosures.

DENVER – The top three social media platforms used by patients who seek aesthetic medical treatments in the United States are Facebook, Instagram, and YouTube. However, in a recent survey, when asked if an aesthetic medical provider’s social media presence positively affects their desire to see that provider, 48% of patients were neutral or had no opinion, while 41% indicated yes.

Gerd Altmann/pixabay

Those are key findings from the survey, which aimed to evaluate the social media preferences and perceptions of patients who undergo aesthetic procedures.

“Aesthetic providers have firmly established a presence on social media,” Morgan Murphrey, MD, said at the annual meeting of the American Society for Dermatologic Surgery, where she presented the results. “According to the dermatology literature, somewhere between 25% and 50% of patients are looking up aesthetic providers on social media before they even see them in the clinic. This raises the question: How do patients perceive aesthetic providers that are on social media, and what do they want to see on their professional accounts?”

To find out, Dr. Murphrey, chief dermatology resident at the University of California, Davis, and Sabrina Fabi, MD, a San Diego–based cosmetic dermatologist, used Survey Monkey to randomly survey 2,063 individuals in the United States. They used descriptive statistics to analyze characteristics and responses of the study participants.

Of the 2,063 respondents, 651 (32%) indicated that they undergo medical aesthetic treatments including Botox injections, fillers, or laser procedures. More than half (56%) were women, 25% were 18-30 years old, 64% were 31-60 years old, and 11% were 61 years or older.

The three most common social media platforms they used were Facebook (70%), Instagram (65%), and YouTube (63%), followed by TikTok (45%) and Snapchat (29%). When the researchers stratified respondents by income level, individuals making $200,000 or more per year were statistically more likely to be on Instagram while those making less than $200,000 were more likely to be on Facebook and YouTube.

When asked if their aesthetic medical provider’s social media presence positively impacts their desire to see them as a patient, 48% of respondent were neutral or had no opinion, while 41% answered yes. “Only 2% felt strongly about this if the provider was on a specific social media platform, while 9% of respondents preferred that their provider not be on social media,” Dr. Murphrey added.

When asked if the number of social media followers influences their perception of an aesthetic provider as an expert, 43% of respondents answered no while 57% answered yes. “Once you get to about 20,000 followers, there seems to be somewhat of a law of diminishing returns in the number of followers,” she said. However, 55% indicated that they prefer to see a provider with a social media account that is verified with a blue check mark.

As for content published, 70% of respondents found it very important (36%) or important (34%) that a provider show before-and-after photos on their social media pages, while 67% said that they favor viewing personal content such as posts about the provider’s family and hobbies.

“This study summarizes to us that there is really low risk to creating a social media account; it’s something to think about,” Dr. Murphrey said. “Only 9% of respondents really didn’t want aesthetic providers to be on social media, but when we stratified our results, those individuals were less likely to be on social media themselves.”

Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and was asked to comment on the results, characterized the findings as important, “as the role of social media (especially visually based platforms like Instagram) will only continue to grow in our dermatologic and aesthetic practices.” Several studies have displayed a trend of plastic surgeons and other subspecialities outnumbering dermatologists within the aesthetic realm of social media, she noted. “As our patients increasingly seek out health care information and advice through these platforms, studies like Dr. Murphrey’s and Dr. Fabi’s are helpful in allowing us to better understand patient preferences and perspectives, in that we, as dermatologists, may be able to better aid their medical decisions in the future,” she added.

Neither the researchers nor Dr. Richey reported having relevant financial disclosures.

DENVER – The top three social media platforms used by patients who seek aesthetic medical treatments in the United States are Facebook, Instagram, and YouTube. However, in a recent survey, when asked if an aesthetic medical provider’s social media presence positively affects their desire to see that provider, 48% of patients were neutral or had no opinion, while 41% indicated yes.

Gerd Altmann/pixabay

Those are key findings from the survey, which aimed to evaluate the social media preferences and perceptions of patients who undergo aesthetic procedures.

“Aesthetic providers have firmly established a presence on social media,” Morgan Murphrey, MD, said at the annual meeting of the American Society for Dermatologic Surgery, where she presented the results. “According to the dermatology literature, somewhere between 25% and 50% of patients are looking up aesthetic providers on social media before they even see them in the clinic. This raises the question: How do patients perceive aesthetic providers that are on social media, and what do they want to see on their professional accounts?”

To find out, Dr. Murphrey, chief dermatology resident at the University of California, Davis, and Sabrina Fabi, MD, a San Diego–based cosmetic dermatologist, used Survey Monkey to randomly survey 2,063 individuals in the United States. They used descriptive statistics to analyze characteristics and responses of the study participants.

Of the 2,063 respondents, 651 (32%) indicated that they undergo medical aesthetic treatments including Botox injections, fillers, or laser procedures. More than half (56%) were women, 25% were 18-30 years old, 64% were 31-60 years old, and 11% were 61 years or older.

The three most common social media platforms they used were Facebook (70%), Instagram (65%), and YouTube (63%), followed by TikTok (45%) and Snapchat (29%). When the researchers stratified respondents by income level, individuals making $200,000 or more per year were statistically more likely to be on Instagram while those making less than $200,000 were more likely to be on Facebook and YouTube.

When asked if their aesthetic medical provider’s social media presence positively impacts their desire to see them as a patient, 48% of respondent were neutral or had no opinion, while 41% answered yes. “Only 2% felt strongly about this if the provider was on a specific social media platform, while 9% of respondents preferred that their provider not be on social media,” Dr. Murphrey added.

When asked if the number of social media followers influences their perception of an aesthetic provider as an expert, 43% of respondents answered no while 57% answered yes. “Once you get to about 20,000 followers, there seems to be somewhat of a law of diminishing returns in the number of followers,” she said. However, 55% indicated that they prefer to see a provider with a social media account that is verified with a blue check mark.

As for content published, 70% of respondents found it very important (36%) or important (34%) that a provider show before-and-after photos on their social media pages, while 67% said that they favor viewing personal content such as posts about the provider’s family and hobbies.

“This study summarizes to us that there is really low risk to creating a social media account; it’s something to think about,” Dr. Murphrey said. “Only 9% of respondents really didn’t want aesthetic providers to be on social media, but when we stratified our results, those individuals were less likely to be on social media themselves.”

Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and was asked to comment on the results, characterized the findings as important, “as the role of social media (especially visually based platforms like Instagram) will only continue to grow in our dermatologic and aesthetic practices.” Several studies have displayed a trend of plastic surgeons and other subspecialities outnumbering dermatologists within the aesthetic realm of social media, she noted. “As our patients increasingly seek out health care information and advice through these platforms, studies like Dr. Murphrey’s and Dr. Fabi’s are helpful in allowing us to better understand patient preferences and perspectives, in that we, as dermatologists, may be able to better aid their medical decisions in the future,” she added.

Neither the researchers nor Dr. Richey reported having relevant financial disclosures.