Case Letter

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

One of the more common tick-borne infections seen in travelers returning from sub-Saharan Africa is caused by Rickettsia africae, which is the etiologic agent of African tick-bite fever (ATBF), the most common tick-borne bacterial zoonosis.¹ There are 2 known tick vectors of disease: Amblyomma variegatum, found in sub-Saharan Africa and the West Indies, and Amblyomma hebraeum, found specifically in southern Africa.^2,3

Unlike other disease-carrying ticks that passively wait on vegetation to be picked up by a host, A hebraeum uniquely attract other nearby ticks to the host. Studies have shown that male ticks feeding on a nonhuman host (usually cattle) can emit an aggression-attachment pheromone that attracts other ticks to the host. The presence of the pheromone allows unfed ticks to actively discriminate between hosts on which these parasites have fed successfully (ie, suitable hosts) and those on which they have not.⁴

The aggressive hunting nature of A hebraeum explains the clinical presentation of multiple eschars and why large groups of exposed travelers—such as soldiers, leisure safari tourists, game hunters, and foreign-aid workers—are affected.²

Another southern African spotted fever group, Rickettsia conorii is the causative agent of Mediterranean spotted fever (MSF). Ticks carrying R conorii exhibit a much less aggressive hunting stylethan A hebraeum; consequently, infected patients present with a single eschar site.⁵

Rickettsia africae is estimated to have very high prevalence (95.2%) in Amblyomma ticks and a fairly high prevalence (approximately 4.0% to 8.6%) in travelers coming from rural southern Africa,^6,7 with an incubation period of 5 to 10 days after inoculation by an infected tick.⁸ Signs include fever, a generalized maculopapular or papulovesicular rash, and regional lymphadenopathy; symptoms include fatigue, headache, and myalgia.

The inoculation eschar—single or multiple—commonly presents on the legs and is accompanied by tender lymphadenopathy of draining nodes^1,8 More severe findings, such as myocarditis and subacute neuropathy, have been reported in elderly patients.⁹

A 77-year-old man presented with a pruritic maculopapular and papulovesicular rash distributed over the upper and lower extremities of 3 weeks’ duration. The patient reported having been on a 12-day mission trip to Limpopo, South Africa, where he was constructing and installing safe toilets to replace dangerous toilet pits. He believed he had been bitten by 2 ticks, after which he noted a dark purple and black patch on the left lower leg by the third day of the trip. He developed a sudden persistent pruritic rash, first on the lower extremities and then spreading to the upper extremities. The patient was seen by an American physician in South Africa who gave him a 7-day course of oral doxycycline monohydrate 100 mg twice daily. He then returned to the United States.

Sixteen days after being bitten by the ticks, the patient was examined in our dermatology office. Physical examination revealed an erythematous plaque with a central eschar over the medial aspect of the left leg (Figure 1) and multiple 3- to 6-mm, erythematous, dome-shaped papules scattered over the dorsal aspects of the feet and ankles (Figure 2). The examination was otherwise normal. Blood was drawn the same day for laboratory analysis; no abnormalities of platelets, red blood cells, or white blood cells were found. Results of a chemistry panel and liver enzyme tests were within reference range.

Skin biopsies were taken to elucidate the underlying pathology. Although an arthropod assault was suspected, there also was concern for deep vessel vasculitis because of the presence of considerable petechiae and purpura (Figure 3). Histologically, leukocytoclasia was seen in deep dermal blood vessels. A mild eosinophilic spongiosis with a mixed dermal infiltrate was identified—strengthening our suspicion of an arthropod assault. Bacterial cultures for aerobes and anaerobes using material taken from the right shin showed no growth.

Ten days after the initial biopsies, serum specimens were drawn and swabs of eschar were collected and sent to the Centers for Disease Control and Prevention for further testing. Serum was tested by immunofluorescence assay (IFA) for spotted fever group IgG to detect Rocky Mountain spotted fever and ATBF antibodies; both tests were negative. Swab material from eschar was tested again by IFA for spotted fever group IgG (Rocky Mountain spotted fever) and antibodies to ATBF and with bacterial culture isolation and nucleic acid amplification; the culture and amplification came back positive for R africae.

Because the specialized tests confirmed infection with R africae, the patient was given triamcinolone cream 0.1% to apply twice daily to the pruritic lesions for as long as 4 weeks; an additional 14-day course of oral doxycycline monohydrate (100 mg twice daily) was given. At follow-up, the lesions had fully resolved without evident scarring.

Various diagnostic techniques can detect R africae. Bacterial culture and the polymerase chain reaction are specific and therefore diagnostic. In addition, the diagnosis of rickettsiosis can be made with serology testing, in which disease-specific antibodies are detected by indirect IFA using disease-specific antigens.

Antigens from R rickettsii (the agent of Rocky Mountain spotted fever), R conorii (Mediterranean spotted fever), and R africae (ATBF) are commercially available for making the diagnosis of rickettsiosis. However, antigens from R conorii exhibit cross-reactivity with R africae, which can confound the diagnosis.^1,10 Serologic IFA tests have been shown to be less sensitive, especially when performed after antibacterial treatment has started.

In a study, 17 of 65 (26%) ATBF-confirmed patients were seronegative (acute and convalescent-phase sera) against R africae; 14 had received doxycycline during the first week of clinical signs. The current hypothesis is that R africae is highly sensitive to doxycycline and that early exposure to the drug prevented development of detectable titers of reactive antibodies, thus producing a negative serology test.¹¹

Furthermore, it has been shown that seroconversion of IgG and IgM antibodies in R africae–infected sera is delayed compared to what is observed with R conorii–infected sera. Typically, seroconversion of R conorii–infected sera can be detected within 2 weeks; seroconversion in R africae–infected sera can take 4 weeks or longer.¹¹

Our patient had a confirmed case of ATBF secondary to R africae infection, which was evident from tissue culture isolation and polymerase chain reaction analysis of swab material obtained from eschar sites, both of which yielded a positive result for R africae. The traveler’s negative serologic status might be due to his early exposure to doxycycline or to the 4-week delay in R africae seroconversion; his serum was collected only 3 weeks after the tick bites.

Clinical signs also aid in making the diagnosis of ATBF and distinguishing R conorii from R africae infection. Because of the aggressive hunting nature of the tick carrying R africae, they are associated with multiple eschars and tend to affect groups of multiple people, especially in rural areas.^4,5 In contrast, ticks carrying R conorii yield a single eschar due to their passive style of infecting a host and because they favor a single host within urban areas.⁵ Both infections exhibit a maculopapular or papulovesicular rash and are accompanied by fatigue, headache, and myalgia, though ATBF tends to present with a milder rash than MSF.

Infection with either R conorii or R africae responds to tetracyclines, quinolones, and macrolides.^10,12

African tick-bite fever is becoming more common, which should encourage clinicians to become familiar with the disease. Less than 2 decades ago, ATBF virtually was unknown outside of Zimbabwe, Botswana, Tanzania, Zambia, and Kenya, where it is endemic. However, after the abolition of apartheid in the 1990s, international tourism in southern Africa increased 6-fold.¹³ African tick-bite fever is now one of the most common rickettsial infections in Africa.⁷ In addition to diagnosing ATBF and managing infected patients, clinicians can help prevent ATBF in individuals who travel to endemic areas by recommending commercial topical insect repellents containing at least 19.5% N,N-diethyl-meta-toluamide (DEET).¹⁴

To the Editor:

One of the more common tick-borne infections seen in travelers returning from sub-Saharan Africa is caused by Rickettsia africae, which is the etiologic agent of African tick-bite fever (ATBF), the most common tick-borne bacterial zoonosis.¹ There are 2 known tick vectors of disease: Amblyomma variegatum, found in sub-Saharan Africa and the West Indies, and Amblyomma hebraeum, found specifically in southern Africa.^2,3

Unlike other disease-carrying ticks that passively wait on vegetation to be picked up by a host, A hebraeum uniquely attract other nearby ticks to the host. Studies have shown that male ticks feeding on a nonhuman host (usually cattle) can emit an aggression-attachment pheromone that attracts other ticks to the host. The presence of the pheromone allows unfed ticks to actively discriminate between hosts on which these parasites have fed successfully (ie, suitable hosts) and those on which they have not.⁴

The aggressive hunting nature of A hebraeum explains the clinical presentation of multiple eschars and why large groups of exposed travelers—such as soldiers, leisure safari tourists, game hunters, and foreign-aid workers—are affected.²

Another southern African spotted fever group, Rickettsia conorii is the causative agent of Mediterranean spotted fever (MSF). Ticks carrying R conorii exhibit a much less aggressive hunting stylethan A hebraeum; consequently, infected patients present with a single eschar site.⁵

Rickettsia africae is estimated to have very high prevalence (95.2%) in Amblyomma ticks and a fairly high prevalence (approximately 4.0% to 8.6%) in travelers coming from rural southern Africa,^6,7 with an incubation period of 5 to 10 days after inoculation by an infected tick.⁸ Signs include fever, a generalized maculopapular or papulovesicular rash, and regional lymphadenopathy; symptoms include fatigue, headache, and myalgia.

The inoculation eschar—single or multiple—commonly presents on the legs and is accompanied by tender lymphadenopathy of draining nodes^1,8 More severe findings, such as myocarditis and subacute neuropathy, have been reported in elderly patients.⁹

A 77-year-old man presented with a pruritic maculopapular and papulovesicular rash distributed over the upper and lower extremities of 3 weeks’ duration. The patient reported having been on a 12-day mission trip to Limpopo, South Africa, where he was constructing and installing safe toilets to replace dangerous toilet pits. He believed he had been bitten by 2 ticks, after which he noted a dark purple and black patch on the left lower leg by the third day of the trip. He developed a sudden persistent pruritic rash, first on the lower extremities and then spreading to the upper extremities. The patient was seen by an American physician in South Africa who gave him a 7-day course of oral doxycycline monohydrate 100 mg twice daily. He then returned to the United States.

Sixteen days after being bitten by the ticks, the patient was examined in our dermatology office. Physical examination revealed an erythematous plaque with a central eschar over the medial aspect of the left leg (Figure 1) and multiple 3- to 6-mm, erythematous, dome-shaped papules scattered over the dorsal aspects of the feet and ankles (Figure 2). The examination was otherwise normal. Blood was drawn the same day for laboratory analysis; no abnormalities of platelets, red blood cells, or white blood cells were found. Results of a chemistry panel and liver enzyme tests were within reference range.

Skin biopsies were taken to elucidate the underlying pathology. Although an arthropod assault was suspected, there also was concern for deep vessel vasculitis because of the presence of considerable petechiae and purpura (Figure 3). Histologically, leukocytoclasia was seen in deep dermal blood vessels. A mild eosinophilic spongiosis with a mixed dermal infiltrate was identified—strengthening our suspicion of an arthropod assault. Bacterial cultures for aerobes and anaerobes using material taken from the right shin showed no growth.

Ten days after the initial biopsies, serum specimens were drawn and swabs of eschar were collected and sent to the Centers for Disease Control and Prevention for further testing. Serum was tested by immunofluorescence assay (IFA) for spotted fever group IgG to detect Rocky Mountain spotted fever and ATBF antibodies; both tests were negative. Swab material from eschar was tested again by IFA for spotted fever group IgG (Rocky Mountain spotted fever) and antibodies to ATBF and with bacterial culture isolation and nucleic acid amplification; the culture and amplification came back positive for R africae.

Because the specialized tests confirmed infection with R africae, the patient was given triamcinolone cream 0.1% to apply twice daily to the pruritic lesions for as long as 4 weeks; an additional 14-day course of oral doxycycline monohydrate (100 mg twice daily) was given. At follow-up, the lesions had fully resolved without evident scarring.

Various diagnostic techniques can detect R africae. Bacterial culture and the polymerase chain reaction are specific and therefore diagnostic. In addition, the diagnosis of rickettsiosis can be made with serology testing, in which disease-specific antibodies are detected by indirect IFA using disease-specific antigens.

Antigens from R rickettsii (the agent of Rocky Mountain spotted fever), R conorii (Mediterranean spotted fever), and R africae (ATBF) are commercially available for making the diagnosis of rickettsiosis. However, antigens from R conorii exhibit cross-reactivity with R africae, which can confound the diagnosis.^1,10 Serologic IFA tests have been shown to be less sensitive, especially when performed after antibacterial treatment has started.

In a study, 17 of 65 (26%) ATBF-confirmed patients were seronegative (acute and convalescent-phase sera) against R africae; 14 had received doxycycline during the first week of clinical signs. The current hypothesis is that R africae is highly sensitive to doxycycline and that early exposure to the drug prevented development of detectable titers of reactive antibodies, thus producing a negative serology test.¹¹

Furthermore, it has been shown that seroconversion of IgG and IgM antibodies in R africae–infected sera is delayed compared to what is observed with R conorii–infected sera. Typically, seroconversion of R conorii–infected sera can be detected within 2 weeks; seroconversion in R africae–infected sera can take 4 weeks or longer.¹¹

Our patient had a confirmed case of ATBF secondary to R africae infection, which was evident from tissue culture isolation and polymerase chain reaction analysis of swab material obtained from eschar sites, both of which yielded a positive result for R africae. The traveler’s negative serologic status might be due to his early exposure to doxycycline or to the 4-week delay in R africae seroconversion; his serum was collected only 3 weeks after the tick bites.

Clinical signs also aid in making the diagnosis of ATBF and distinguishing R conorii from R africae infection. Because of the aggressive hunting nature of the tick carrying R africae, they are associated with multiple eschars and tend to affect groups of multiple people, especially in rural areas.^4,5 In contrast, ticks carrying R conorii yield a single eschar due to their passive style of infecting a host and because they favor a single host within urban areas.⁵ Both infections exhibit a maculopapular or papulovesicular rash and are accompanied by fatigue, headache, and myalgia, though ATBF tends to present with a milder rash than MSF.

Infection with either R conorii or R africae responds to tetracyclines, quinolones, and macrolides.^10,12

African tick-bite fever is becoming more common, which should encourage clinicians to become familiar with the disease. Less than 2 decades ago, ATBF virtually was unknown outside of Zimbabwe, Botswana, Tanzania, Zambia, and Kenya, where it is endemic. However, after the abolition of apartheid in the 1990s, international tourism in southern Africa increased 6-fold.¹³ African tick-bite fever is now one of the most common rickettsial infections in Africa.⁷ In addition to diagnosing ATBF and managing infected patients, clinicians can help prevent ATBF in individuals who travel to endemic areas by recommending commercial topical insect repellents containing at least 19.5% N,N-diethyl-meta-toluamide (DEET).¹⁴

To the Editor:

One of the more common tick-borne infections seen in travelers returning from sub-Saharan Africa is caused by Rickettsia africae, which is the etiologic agent of African tick-bite fever (ATBF), the most common tick-borne bacterial zoonosis.¹ There are 2 known tick vectors of disease: Amblyomma variegatum, found in sub-Saharan Africa and the West Indies, and Amblyomma hebraeum, found specifically in southern Africa.^2,3

Unlike other disease-carrying ticks that passively wait on vegetation to be picked up by a host, A hebraeum uniquely attract other nearby ticks to the host. Studies have shown that male ticks feeding on a nonhuman host (usually cattle) can emit an aggression-attachment pheromone that attracts other ticks to the host. The presence of the pheromone allows unfed ticks to actively discriminate between hosts on which these parasites have fed successfully (ie, suitable hosts) and those on which they have not.⁴

The aggressive hunting nature of A hebraeum explains the clinical presentation of multiple eschars and why large groups of exposed travelers—such as soldiers, leisure safari tourists, game hunters, and foreign-aid workers—are affected.²

Another southern African spotted fever group, Rickettsia conorii is the causative agent of Mediterranean spotted fever (MSF). Ticks carrying R conorii exhibit a much less aggressive hunting stylethan A hebraeum; consequently, infected patients present with a single eschar site.⁵

Rickettsia africae is estimated to have very high prevalence (95.2%) in Amblyomma ticks and a fairly high prevalence (approximately 4.0% to 8.6%) in travelers coming from rural southern Africa,^6,7 with an incubation period of 5 to 10 days after inoculation by an infected tick.⁸ Signs include fever, a generalized maculopapular or papulovesicular rash, and regional lymphadenopathy; symptoms include fatigue, headache, and myalgia.

The inoculation eschar—single or multiple—commonly presents on the legs and is accompanied by tender lymphadenopathy of draining nodes^1,8 More severe findings, such as myocarditis and subacute neuropathy, have been reported in elderly patients.⁹

A 77-year-old man presented with a pruritic maculopapular and papulovesicular rash distributed over the upper and lower extremities of 3 weeks’ duration. The patient reported having been on a 12-day mission trip to Limpopo, South Africa, where he was constructing and installing safe toilets to replace dangerous toilet pits. He believed he had been bitten by 2 ticks, after which he noted a dark purple and black patch on the left lower leg by the third day of the trip. He developed a sudden persistent pruritic rash, first on the lower extremities and then spreading to the upper extremities. The patient was seen by an American physician in South Africa who gave him a 7-day course of oral doxycycline monohydrate 100 mg twice daily. He then returned to the United States.

Sixteen days after being bitten by the ticks, the patient was examined in our dermatology office. Physical examination revealed an erythematous plaque with a central eschar over the medial aspect of the left leg (Figure 1) and multiple 3- to 6-mm, erythematous, dome-shaped papules scattered over the dorsal aspects of the feet and ankles (Figure 2). The examination was otherwise normal. Blood was drawn the same day for laboratory analysis; no abnormalities of platelets, red blood cells, or white blood cells were found. Results of a chemistry panel and liver enzyme tests were within reference range.

Skin biopsies were taken to elucidate the underlying pathology. Although an arthropod assault was suspected, there also was concern for deep vessel vasculitis because of the presence of considerable petechiae and purpura (Figure 3). Histologically, leukocytoclasia was seen in deep dermal blood vessels. A mild eosinophilic spongiosis with a mixed dermal infiltrate was identified—strengthening our suspicion of an arthropod assault. Bacterial cultures for aerobes and anaerobes using material taken from the right shin showed no growth.

Ten days after the initial biopsies, serum specimens were drawn and swabs of eschar were collected and sent to the Centers for Disease Control and Prevention for further testing. Serum was tested by immunofluorescence assay (IFA) for spotted fever group IgG to detect Rocky Mountain spotted fever and ATBF antibodies; both tests were negative. Swab material from eschar was tested again by IFA for spotted fever group IgG (Rocky Mountain spotted fever) and antibodies to ATBF and with bacterial culture isolation and nucleic acid amplification; the culture and amplification came back positive for R africae.

Because the specialized tests confirmed infection with R africae, the patient was given triamcinolone cream 0.1% to apply twice daily to the pruritic lesions for as long as 4 weeks; an additional 14-day course of oral doxycycline monohydrate (100 mg twice daily) was given. At follow-up, the lesions had fully resolved without evident scarring.

Various diagnostic techniques can detect R africae. Bacterial culture and the polymerase chain reaction are specific and therefore diagnostic. In addition, the diagnosis of rickettsiosis can be made with serology testing, in which disease-specific antibodies are detected by indirect IFA using disease-specific antigens.

Antigens from R rickettsii (the agent of Rocky Mountain spotted fever), R conorii (Mediterranean spotted fever), and R africae (ATBF) are commercially available for making the diagnosis of rickettsiosis. However, antigens from R conorii exhibit cross-reactivity with R africae, which can confound the diagnosis.^1,10 Serologic IFA tests have been shown to be less sensitive, especially when performed after antibacterial treatment has started.

In a study, 17 of 65 (26%) ATBF-confirmed patients were seronegative (acute and convalescent-phase sera) against R africae; 14 had received doxycycline during the first week of clinical signs. The current hypothesis is that R africae is highly sensitive to doxycycline and that early exposure to the drug prevented development of detectable titers of reactive antibodies, thus producing a negative serology test.¹¹

Furthermore, it has been shown that seroconversion of IgG and IgM antibodies in R africae–infected sera is delayed compared to what is observed with R conorii–infected sera. Typically, seroconversion of R conorii–infected sera can be detected within 2 weeks; seroconversion in R africae–infected sera can take 4 weeks or longer.¹¹

Our patient had a confirmed case of ATBF secondary to R africae infection, which was evident from tissue culture isolation and polymerase chain reaction analysis of swab material obtained from eschar sites, both of which yielded a positive result for R africae. The traveler’s negative serologic status might be due to his early exposure to doxycycline or to the 4-week delay in R africae seroconversion; his serum was collected only 3 weeks after the tick bites.

Clinical signs also aid in making the diagnosis of ATBF and distinguishing R conorii from R africae infection. Because of the aggressive hunting nature of the tick carrying R africae, they are associated with multiple eschars and tend to affect groups of multiple people, especially in rural areas.^4,5 In contrast, ticks carrying R conorii yield a single eschar due to their passive style of infecting a host and because they favor a single host within urban areas.⁵ Both infections exhibit a maculopapular or papulovesicular rash and are accompanied by fatigue, headache, and myalgia, though ATBF tends to present with a milder rash than MSF.

Infection with either R conorii or R africae responds to tetracyclines, quinolones, and macrolides.^10,12

African tick-bite fever is becoming more common, which should encourage clinicians to become familiar with the disease. Less than 2 decades ago, ATBF virtually was unknown outside of Zimbabwe, Botswana, Tanzania, Zambia, and Kenya, where it is endemic. However, after the abolition of apartheid in the 1990s, international tourism in southern Africa increased 6-fold.¹³ African tick-bite fever is now one of the most common rickettsial infections in Africa.⁷ In addition to diagnosing ATBF and managing infected patients, clinicians can help prevent ATBF in individuals who travel to endemic areas by recommending commercial topical insect repellents containing at least 19.5% N,N-diethyl-meta-toluamide (DEET).¹⁴

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

To the Editor:

A 44-year-old woman presented with a low-grade fever (temperature, 38.0 °C) and painful acral lesions of 1 week’s duration. She had a history of hepatitis C viral infection and intravenous (IV) drug use, as well as polymicrobial infective endocarditis that involved the tricuspid and aortic valves; pathogenic organisms were identified via blood culture as Enterococcus faecalis, Serratia species, Streptococcus viridans, and Candida albicans. The patient had received a mechanical aortic valve and bioprosthetic tricuspid valve replacement 5 months prior with warfarin therapy and had completed a postsurgical 6-week course of high-dose micafungin. She reported that she had developed painful, violaceous, thin papules on the plantar surface of the left foot 2 weeks prior to presentation. Her symptoms improved with a short systemic steroid taper; however, within a week she developed new tender, erythematous, thin papules on the plantar surface of the right foot and the palmar surface of the left hand with associated lower extremity swelling. She denied other symptoms, including fever, chills, neurologic symptoms, shortness of breath, chest pain, nausea, vomiting, hematuria, and hematochezia. Due to worsening cutaneous findings, the patient presented to the emergency department, prompting hospital admission for empiric antibacterial therapy with vancomycin and piperacillin-tazobactam for suspected infectious endocarditis. Dermatology was consulted after 1 day of antibacterial therapy without improvement to determine the etiology of the patient’s skin findings.

Physical examination revealed the patient was afebrile with partially blanching violaceous to purpuric, tender, edematous papules on the left fourth and fifth finger pads, as well as scattered, painful, purpuric patches with stellate borders on the right plantar foot (Figure 1). Laboratory test results revealed mild anemia (hemoglobin, 11.9 g/dL [reference range, 12.0–15.0 g/dL], mild neutrophilia (neutrophils, 8.4×10⁹/L [reference range, 1.9–7.9×10⁹/L], elevated acute-phase reactants (erythrocyte sedimentation rate, 71 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 5.7 mg/dL [reference range, 0.0–0.5 mg/dL]), and positive hepatitis C virus antibody with an undetectable viral load. At the time of dermatologic evaluation, admission blood cultures and transthoracic echocardiogram were negative. Additionally, a transesophageal echocardiogram, limited by artifact from the mechanical aortic valve, was equivocal for valvular pathology. Subsequent ophthalmologic evaluation was negative for lesions associated with endocarditis, such as retinal hemorrhages.

Punch biopsies of the left fourth finger pad were submitted for histopathologic analysis and tissue cultures. Histopathology demonstrated deep dermal perivascular neutrophilic inflammation with multiple intravascular thrombi, perivascular fibrin, and karyorrhectic debris (Figure 2). Periodic acid–Schiff and Grocott-Gomori methenamine-silver stains revealed fungal spores with rare pseudohyphae within the thrombosed vascular spaces and the perivascular dermis, consistent with fungal septic emboli (Figure 3).

Empiric systemic antifungal coverage composed of IV liposomal amphotericin B and oral flucytosine was initiated, and the patient’s tender acral papules rapidly improved. Within 48 hours of biopsy, skin tissue culture confirmed the presence of C albicans. Four days after the preliminary dermatopathology report, confirmatory blood cultures resulted with pansensitive C albicans. Final tissue and blood cultures were negative for bacteria including mycobacteria. In addition to a 6-week course of IV amphotericin B and flucytosine, repeat surgical intervention was considered, and lifelong suppressive antifungal oral therapy was recommended. Unfortunately, the patient did not present for follow-up. Three months later, she presented to the emergency department with peritonitis; in the operating room, she was found to have ischemia of the entirety of the small and large intestines and died shortly thereafter.

Fungal endocarditis is rare, tending to develop in patient populations with particular risk factors such as immune compromise, structural heart defects or prosthetic valves, and IV drug use. Candida infective endocarditis (CIE) represents less than 2% of infective endocarditis cases and carries a high mortality rate (30%–80%).^1-3 Diagnosis may be challenging, as the clinical presentation varies widely. Although some patients may present with classic features of infective endocarditis, including fever, cardiac murmurs, and positive blood cultures, many cases of infective endocarditis present with nonspecific symptoms, raising a broad clinical differential diagnosis. Delay in diagnosis, which is seen in 82% of patients with fungal endocarditis, may be attributed to the slow progression of symptoms, inconclusive cardiac imaging, or negative blood cultures seen in almost one-third of cases.^2,3 The feared complication of systemic embolization via infective endocarditis may occur in up to one-half of cases, with the highest rates associated with staphylococcal or fungal pathogens.² The risk for embolization in fungal endocarditis is independent of the size of the cardiac valve vegetations; accordingly, sequelae of embolic complications may arise despite negative cardiac imaging.⁴ Embolic complications, which typically are seen within the first 2 to 4 weeks of treatment, may serve as the presenting feature of endocarditis and may even occur after completion of antimicrobial therapy.

Detection of cutaneous manifestations of infective endocarditis, including Janeway lesions, Osler nodes, and splinter hemorrhages, may allow for earlier diagnosis. Despite eponymous recognition, Janeway lesions and Osler nodes are relatively uncommon manifestations of infective endocarditis and may be found in only 5% to 15% of cases.⁵ Biopsies of suspected Janeway lesions and Osler nodes may allow for recognition of relevant vascular pathology, identification of the causative pathogen, and strong support for the diagnosis of infective endocarditis.^4-7

The initial photomicrograph of corresponding Janeway lesion histopathology was published by Kerr in 1955 and revealed dermal microabscesses posited to be secondary to bacterial emboli.^8,9 Additional cases through the years have reported overlapping histopathologic features of Janeway lesions and Osler nodes, with the latter often defined by the presence of vasculitis.⁴ Although there appears to be ongoing debate and overlap between the 2 integumentary findings, a general consensus on differentiation takes into account both the clinical signs and symptoms as well as the histopathologic findings.^10,11

Osler nodes present as tender, violaceous, subcutaneous nodules on the acral surfaces, usually on the pads of the fingers and toes.⁵ The pathogenesis involves the deposition of immune complexes as a sequela of vascular occlusion by microthrombi classically seen in the late phase of subacute endocarditis. Janeway lesions present as nontender erythematous macules on the acral surfaces and are thought to represent microthrombi with dermal microabscesses, more common in acute endocarditis. Our patient demonstrated features of both Osler nodes and Janeway lesions. Despite the presence of fungal thrombi—a pathophysiology closer to that of Janeway lesions—the clinical presentation of painful acral nodules affecting finger pads and histologic features of vasculitis may be better characterized as Osler nodes. Regardless of pathogenesis, these cutaneous findings serve as a minor clinical criterion in the Duke criteria for the diagnosis of infective endocarditis when present.¹²

Candida infective endocarditis should be suspected in a patient with a history of valvular disease or prior infective endocarditis with fungemia, unexplained neurologic signs, or manifestations of peripheral embolization despite negative blood cultures.³ Particularly in the setting of negative cardiac imaging, recognition of CIE requires heightened diagnostic acumen and clinicopathologic correlation. Although culture and pathologic examination of valvular vegetations represents the gold standard for diagnosis of CIE, aspiration and culture of easily accessible septic emboli may provide rapid identification of the etiologic pathogen. In 1976, Alpert et al¹³ identified C albicans from an aspirated Osler node. Postmortem examination revealed extensive involvement of the homograft valve and aortic root with C albicans.¹³ Many other examples exist in the literature demonstrating matching pathogenic isolates from microbiologic cultures of skin and blood.^4,9,14,15 Thadepalli and Francis⁷ investigated 26 cases of endocarditis in heroin users in which the admitting diagnosis was endocarditis in only 4 cases. The etiologic pathogen was aspirated from secondary sites of localized infections secondary to emboli, including cutaneous lesions in 10 of the cases. Gram stain and culture revealed the causative organism leading to the ultimate diagnosis and management in 17 of 26 patients with endocarditis.⁷

The incidence of fungal endocarditis is increasing, with a reported 67% of cases caused by nosocomial infection.¹ Given the rising incidence of fungal endocarditis and its accompanying diagnostic difficulties, including frequently negative blood cultures and cardiac imaging, clinicians must perform careful skin examinations, employ judicious use of skin biopsy, and carefully correlate clinical and pathologic findings to improve recognition of this disease and guide patient care.

To the Editor:

A 44-year-old woman presented with a low-grade fever (temperature, 38.0 °C) and painful acral lesions of 1 week’s duration. She had a history of hepatitis C viral infection and intravenous (IV) drug use, as well as polymicrobial infective endocarditis that involved the tricuspid and aortic valves; pathogenic organisms were identified via blood culture as Enterococcus faecalis, Serratia species, Streptococcus viridans, and Candida albicans. The patient had received a mechanical aortic valve and bioprosthetic tricuspid valve replacement 5 months prior with warfarin therapy and had completed a postsurgical 6-week course of high-dose micafungin. She reported that she had developed painful, violaceous, thin papules on the plantar surface of the left foot 2 weeks prior to presentation. Her symptoms improved with a short systemic steroid taper; however, within a week she developed new tender, erythematous, thin papules on the plantar surface of the right foot and the palmar surface of the left hand with associated lower extremity swelling. She denied other symptoms, including fever, chills, neurologic symptoms, shortness of breath, chest pain, nausea, vomiting, hematuria, and hematochezia. Due to worsening cutaneous findings, the patient presented to the emergency department, prompting hospital admission for empiric antibacterial therapy with vancomycin and piperacillin-tazobactam for suspected infectious endocarditis. Dermatology was consulted after 1 day of antibacterial therapy without improvement to determine the etiology of the patient’s skin findings.

Physical examination revealed the patient was afebrile with partially blanching violaceous to purpuric, tender, edematous papules on the left fourth and fifth finger pads, as well as scattered, painful, purpuric patches with stellate borders on the right plantar foot (Figure 1). Laboratory test results revealed mild anemia (hemoglobin, 11.9 g/dL [reference range, 12.0–15.0 g/dL], mild neutrophilia (neutrophils, 8.4×10⁹/L [reference range, 1.9–7.9×10⁹/L], elevated acute-phase reactants (erythrocyte sedimentation rate, 71 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 5.7 mg/dL [reference range, 0.0–0.5 mg/dL]), and positive hepatitis C virus antibody with an undetectable viral load. At the time of dermatologic evaluation, admission blood cultures and transthoracic echocardiogram were negative. Additionally, a transesophageal echocardiogram, limited by artifact from the mechanical aortic valve, was equivocal for valvular pathology. Subsequent ophthalmologic evaluation was negative for lesions associated with endocarditis, such as retinal hemorrhages.

Punch biopsies of the left fourth finger pad were submitted for histopathologic analysis and tissue cultures. Histopathology demonstrated deep dermal perivascular neutrophilic inflammation with multiple intravascular thrombi, perivascular fibrin, and karyorrhectic debris (Figure 2). Periodic acid–Schiff and Grocott-Gomori methenamine-silver stains revealed fungal spores with rare pseudohyphae within the thrombosed vascular spaces and the perivascular dermis, consistent with fungal septic emboli (Figure 3).

Empiric systemic antifungal coverage composed of IV liposomal amphotericin B and oral flucytosine was initiated, and the patient’s tender acral papules rapidly improved. Within 48 hours of biopsy, skin tissue culture confirmed the presence of C albicans. Four days after the preliminary dermatopathology report, confirmatory blood cultures resulted with pansensitive C albicans. Final tissue and blood cultures were negative for bacteria including mycobacteria. In addition to a 6-week course of IV amphotericin B and flucytosine, repeat surgical intervention was considered, and lifelong suppressive antifungal oral therapy was recommended. Unfortunately, the patient did not present for follow-up. Three months later, she presented to the emergency department with peritonitis; in the operating room, she was found to have ischemia of the entirety of the small and large intestines and died shortly thereafter.

Fungal endocarditis is rare, tending to develop in patient populations with particular risk factors such as immune compromise, structural heart defects or prosthetic valves, and IV drug use. Candida infective endocarditis (CIE) represents less than 2% of infective endocarditis cases and carries a high mortality rate (30%–80%).^1-3 Diagnosis may be challenging, as the clinical presentation varies widely. Although some patients may present with classic features of infective endocarditis, including fever, cardiac murmurs, and positive blood cultures, many cases of infective endocarditis present with nonspecific symptoms, raising a broad clinical differential diagnosis. Delay in diagnosis, which is seen in 82% of patients with fungal endocarditis, may be attributed to the slow progression of symptoms, inconclusive cardiac imaging, or negative blood cultures seen in almost one-third of cases.^2,3 The feared complication of systemic embolization via infective endocarditis may occur in up to one-half of cases, with the highest rates associated with staphylococcal or fungal pathogens.² The risk for embolization in fungal endocarditis is independent of the size of the cardiac valve vegetations; accordingly, sequelae of embolic complications may arise despite negative cardiac imaging.⁴ Embolic complications, which typically are seen within the first 2 to 4 weeks of treatment, may serve as the presenting feature of endocarditis and may even occur after completion of antimicrobial therapy.

Detection of cutaneous manifestations of infective endocarditis, including Janeway lesions, Osler nodes, and splinter hemorrhages, may allow for earlier diagnosis. Despite eponymous recognition, Janeway lesions and Osler nodes are relatively uncommon manifestations of infective endocarditis and may be found in only 5% to 15% of cases.⁵ Biopsies of suspected Janeway lesions and Osler nodes may allow for recognition of relevant vascular pathology, identification of the causative pathogen, and strong support for the diagnosis of infective endocarditis.^4-7

The initial photomicrograph of corresponding Janeway lesion histopathology was published by Kerr in 1955 and revealed dermal microabscesses posited to be secondary to bacterial emboli.^8,9 Additional cases through the years have reported overlapping histopathologic features of Janeway lesions and Osler nodes, with the latter often defined by the presence of vasculitis.⁴ Although there appears to be ongoing debate and overlap between the 2 integumentary findings, a general consensus on differentiation takes into account both the clinical signs and symptoms as well as the histopathologic findings.^10,11

Osler nodes present as tender, violaceous, subcutaneous nodules on the acral surfaces, usually on the pads of the fingers and toes.⁵ The pathogenesis involves the deposition of immune complexes as a sequela of vascular occlusion by microthrombi classically seen in the late phase of subacute endocarditis. Janeway lesions present as nontender erythematous macules on the acral surfaces and are thought to represent microthrombi with dermal microabscesses, more common in acute endocarditis. Our patient demonstrated features of both Osler nodes and Janeway lesions. Despite the presence of fungal thrombi—a pathophysiology closer to that of Janeway lesions—the clinical presentation of painful acral nodules affecting finger pads and histologic features of vasculitis may be better characterized as Osler nodes. Regardless of pathogenesis, these cutaneous findings serve as a minor clinical criterion in the Duke criteria for the diagnosis of infective endocarditis when present.¹²

Candida infective endocarditis should be suspected in a patient with a history of valvular disease or prior infective endocarditis with fungemia, unexplained neurologic signs, or manifestations of peripheral embolization despite negative blood cultures.³ Particularly in the setting of negative cardiac imaging, recognition of CIE requires heightened diagnostic acumen and clinicopathologic correlation. Although culture and pathologic examination of valvular vegetations represents the gold standard for diagnosis of CIE, aspiration and culture of easily accessible septic emboli may provide rapid identification of the etiologic pathogen. In 1976, Alpert et al¹³ identified C albicans from an aspirated Osler node. Postmortem examination revealed extensive involvement of the homograft valve and aortic root with C albicans.¹³ Many other examples exist in the literature demonstrating matching pathogenic isolates from microbiologic cultures of skin and blood.^4,9,14,15 Thadepalli and Francis⁷ investigated 26 cases of endocarditis in heroin users in which the admitting diagnosis was endocarditis in only 4 cases. The etiologic pathogen was aspirated from secondary sites of localized infections secondary to emboli, including cutaneous lesions in 10 of the cases. Gram stain and culture revealed the causative organism leading to the ultimate diagnosis and management in 17 of 26 patients with endocarditis.⁷

The incidence of fungal endocarditis is increasing, with a reported 67% of cases caused by nosocomial infection.¹ Given the rising incidence of fungal endocarditis and its accompanying diagnostic difficulties, including frequently negative blood cultures and cardiac imaging, clinicians must perform careful skin examinations, employ judicious use of skin biopsy, and carefully correlate clinical and pathologic findings to improve recognition of this disease and guide patient care.

To the Editor:

A 44-year-old woman presented with a low-grade fever (temperature, 38.0 °C) and painful acral lesions of 1 week’s duration. She had a history of hepatitis C viral infection and intravenous (IV) drug use, as well as polymicrobial infective endocarditis that involved the tricuspid and aortic valves; pathogenic organisms were identified via blood culture as Enterococcus faecalis, Serratia species, Streptococcus viridans, and Candida albicans. The patient had received a mechanical aortic valve and bioprosthetic tricuspid valve replacement 5 months prior with warfarin therapy and had completed a postsurgical 6-week course of high-dose micafungin. She reported that she had developed painful, violaceous, thin papules on the plantar surface of the left foot 2 weeks prior to presentation. Her symptoms improved with a short systemic steroid taper; however, within a week she developed new tender, erythematous, thin papules on the plantar surface of the right foot and the palmar surface of the left hand with associated lower extremity swelling. She denied other symptoms, including fever, chills, neurologic symptoms, shortness of breath, chest pain, nausea, vomiting, hematuria, and hematochezia. Due to worsening cutaneous findings, the patient presented to the emergency department, prompting hospital admission for empiric antibacterial therapy with vancomycin and piperacillin-tazobactam for suspected infectious endocarditis. Dermatology was consulted after 1 day of antibacterial therapy without improvement to determine the etiology of the patient’s skin findings.

Physical examination revealed the patient was afebrile with partially blanching violaceous to purpuric, tender, edematous papules on the left fourth and fifth finger pads, as well as scattered, painful, purpuric patches with stellate borders on the right plantar foot (Figure 1). Laboratory test results revealed mild anemia (hemoglobin, 11.9 g/dL [reference range, 12.0–15.0 g/dL], mild neutrophilia (neutrophils, 8.4×10⁹/L [reference range, 1.9–7.9×10⁹/L], elevated acute-phase reactants (erythrocyte sedimentation rate, 71 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 5.7 mg/dL [reference range, 0.0–0.5 mg/dL]), and positive hepatitis C virus antibody with an undetectable viral load. At the time of dermatologic evaluation, admission blood cultures and transthoracic echocardiogram were negative. Additionally, a transesophageal echocardiogram, limited by artifact from the mechanical aortic valve, was equivocal for valvular pathology. Subsequent ophthalmologic evaluation was negative for lesions associated with endocarditis, such as retinal hemorrhages.

Punch biopsies of the left fourth finger pad were submitted for histopathologic analysis and tissue cultures. Histopathology demonstrated deep dermal perivascular neutrophilic inflammation with multiple intravascular thrombi, perivascular fibrin, and karyorrhectic debris (Figure 2). Periodic acid–Schiff and Grocott-Gomori methenamine-silver stains revealed fungal spores with rare pseudohyphae within the thrombosed vascular spaces and the perivascular dermis, consistent with fungal septic emboli (Figure 3).

Empiric systemic antifungal coverage composed of IV liposomal amphotericin B and oral flucytosine was initiated, and the patient’s tender acral papules rapidly improved. Within 48 hours of biopsy, skin tissue culture confirmed the presence of C albicans. Four days after the preliminary dermatopathology report, confirmatory blood cultures resulted with pansensitive C albicans. Final tissue and blood cultures were negative for bacteria including mycobacteria. In addition to a 6-week course of IV amphotericin B and flucytosine, repeat surgical intervention was considered, and lifelong suppressive antifungal oral therapy was recommended. Unfortunately, the patient did not present for follow-up. Three months later, she presented to the emergency department with peritonitis; in the operating room, she was found to have ischemia of the entirety of the small and large intestines and died shortly thereafter.

Fungal endocarditis is rare, tending to develop in patient populations with particular risk factors such as immune compromise, structural heart defects or prosthetic valves, and IV drug use. Candida infective endocarditis (CIE) represents less than 2% of infective endocarditis cases and carries a high mortality rate (30%–80%).^1-3 Diagnosis may be challenging, as the clinical presentation varies widely. Although some patients may present with classic features of infective endocarditis, including fever, cardiac murmurs, and positive blood cultures, many cases of infective endocarditis present with nonspecific symptoms, raising a broad clinical differential diagnosis. Delay in diagnosis, which is seen in 82% of patients with fungal endocarditis, may be attributed to the slow progression of symptoms, inconclusive cardiac imaging, or negative blood cultures seen in almost one-third of cases.^2,3 The feared complication of systemic embolization via infective endocarditis may occur in up to one-half of cases, with the highest rates associated with staphylococcal or fungal pathogens.² The risk for embolization in fungal endocarditis is independent of the size of the cardiac valve vegetations; accordingly, sequelae of embolic complications may arise despite negative cardiac imaging.⁴ Embolic complications, which typically are seen within the first 2 to 4 weeks of treatment, may serve as the presenting feature of endocarditis and may even occur after completion of antimicrobial therapy.

Detection of cutaneous manifestations of infective endocarditis, including Janeway lesions, Osler nodes, and splinter hemorrhages, may allow for earlier diagnosis. Despite eponymous recognition, Janeway lesions and Osler nodes are relatively uncommon manifestations of infective endocarditis and may be found in only 5% to 15% of cases.⁵ Biopsies of suspected Janeway lesions and Osler nodes may allow for recognition of relevant vascular pathology, identification of the causative pathogen, and strong support for the diagnosis of infective endocarditis.^4-7

The initial photomicrograph of corresponding Janeway lesion histopathology was published by Kerr in 1955 and revealed dermal microabscesses posited to be secondary to bacterial emboli.^8,9 Additional cases through the years have reported overlapping histopathologic features of Janeway lesions and Osler nodes, with the latter often defined by the presence of vasculitis.⁴ Although there appears to be ongoing debate and overlap between the 2 integumentary findings, a general consensus on differentiation takes into account both the clinical signs and symptoms as well as the histopathologic findings.^10,11

Osler nodes present as tender, violaceous, subcutaneous nodules on the acral surfaces, usually on the pads of the fingers and toes.⁵ The pathogenesis involves the deposition of immune complexes as a sequela of vascular occlusion by microthrombi classically seen in the late phase of subacute endocarditis. Janeway lesions present as nontender erythematous macules on the acral surfaces and are thought to represent microthrombi with dermal microabscesses, more common in acute endocarditis. Our patient demonstrated features of both Osler nodes and Janeway lesions. Despite the presence of fungal thrombi—a pathophysiology closer to that of Janeway lesions—the clinical presentation of painful acral nodules affecting finger pads and histologic features of vasculitis may be better characterized as Osler nodes. Regardless of pathogenesis, these cutaneous findings serve as a minor clinical criterion in the Duke criteria for the diagnosis of infective endocarditis when present.¹²

Candida infective endocarditis should be suspected in a patient with a history of valvular disease or prior infective endocarditis with fungemia, unexplained neurologic signs, or manifestations of peripheral embolization despite negative blood cultures.³ Particularly in the setting of negative cardiac imaging, recognition of CIE requires heightened diagnostic acumen and clinicopathologic correlation. Although culture and pathologic examination of valvular vegetations represents the gold standard for diagnosis of CIE, aspiration and culture of easily accessible septic emboli may provide rapid identification of the etiologic pathogen. In 1976, Alpert et al¹³ identified C albicans from an aspirated Osler node. Postmortem examination revealed extensive involvement of the homograft valve and aortic root with C albicans.¹³ Many other examples exist in the literature demonstrating matching pathogenic isolates from microbiologic cultures of skin and blood.^4,9,14,15 Thadepalli and Francis⁷ investigated 26 cases of endocarditis in heroin users in which the admitting diagnosis was endocarditis in only 4 cases. The etiologic pathogen was aspirated from secondary sites of localized infections secondary to emboli, including cutaneous lesions in 10 of the cases. Gram stain and culture revealed the causative organism leading to the ultimate diagnosis and management in 17 of 26 patients with endocarditis.⁷

The incidence of fungal endocarditis is increasing, with a reported 67% of cases caused by nosocomial infection.¹ Given the rising incidence of fungal endocarditis and its accompanying diagnostic difficulties, including frequently negative blood cultures and cardiac imaging, clinicians must perform careful skin examinations, employ judicious use of skin biopsy, and carefully correlate clinical and pathologic findings to improve recognition of this disease and guide patient care.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Today’s geriatric population is the fastest growing in history. The National Institutes of Health predicts there will be over 1.5 billion individuals aged 65 years and older by the year 2050: 17% of the world’s population.¹ Pruritus—either acute or chronic (>6 weeks)—is defined as a sensory perception that leads to an intense desire to scratch.² Chronic pruritus is an increasing health concern that impacts quality of life within the geriatric population. Elderly patients have various risk factors for developing chronic itch, including aging skin, polypharmacy, and increased systemic comorbidities.^3-7

Although the therapeutic armamentarium for chronic itch continues to grow, health care providers often are hesitant to prescribe medications for geriatric patients because of comorbidities and potential drug-drug interactions. Novel biologic therapies now provide alternatives for this complex population. Dupilumab is a fully humanized, monoclonal antibody approved for treatment-resistant atopic dermatitis. This biologic prevents helper T-cell (T_H2) signaling, IL-4 and IL-13 release, and subsequent effector cell (eg, mast cell, eosinophil) activity.^8-10 The combined efficacy and safety of this medication has changed the treatment landscape of resistant atopic dermatitis. We present the use of dupilumab in a geriatric patient with severe and recalcitrant itch resistant to numerous topical and oral medications.

An 81-year-old man presented to the clinic with a long history of generalized pruritic rash. His medical history was significant for insulin-dependent type 2 diabetes mellitus (T2DM), hypertension, and renal cancer following a right nephrectomy. Laboratory results approximately 14 months prior to the visit revealed a blood urea nitrogen level of 31 mg/dL (reference range, 7–20 mg/dL), creatinine level of 2.20 mg/dL (reference range, 0.7–1.3 mg/dL), and glomerular filtration rate of 29 mL/min (reference range, 90–120 mL/min). Physical examination revealed numerous pink excoriated papules on the face, neck, trunk, and extremities. Lichenified plaques were present on both arms and legs. The patient received the diagnosis of severe atopic dermatitis with greater than 10% body surface area involvement. The investigator global assessment score was 4/4, indicating severe disease burden, and biopsy results reported spongiotic dermatitis. He proceeded to trial various topical corticosteroids, including hydrocortisone ointment 2.5%, betamethasone valerate ointment 0.01%, fluocinonide ointment 0.05%, and mupirocin ointment without benefit. Three subsequent courses of oral steroids failed to provide durable relief. At this point, the peak pruritus numerical rating scale (NRS) score was 7/10, indicating severe pruritus, with a negative impact on the patient’s quality of life and sleep.

Therapy was switched to tacrolimus acetonide ointment 0.1%, betamethasone dipropionate ointment 0.05%, and triamcinolone acetonide ointment 0.1%. Eleven days later, the patient denied experiencing any response to the topical regimen and sought alternative therapy for the itch and associated poor sleep; the NRS score was 10/10, indicating very severe pruritus. Prednisone 20 mg and doxepin 10 mg were initiated for symptom management until the intended transition to dupilumab. The patient began dupilumab with a loading dose of 600 mg, then 300 mg every other week thereafter. At 2- and 4-month follow-up, the patient reported notable relief in symptoms. The rash had improved, and the NRS score decreased from 10/10 to 3/10. He endorsed improved sleep and quality of life.

Pruritus may arise from a series of age-related mechanisms such as structural and chemical changes within the epidermis, underlying neuropathy, medication side effects, infection, malignancy, thyroid dysregulation, liver disease, and chronic kidney disease (CKD).^5,6,11 Identifying the underlying etiology often is difficult and involves a complete history and physical examination as well as an appropriate contextualized laboratory workup.

Our patient’s comorbid T2DM and renal disease may have contributed to the pruritus. Type 2 diabetes mellitus can cause diabetic neuropathy, a sequela known to lead to various complications, including pruritus. One study identified a 4-fold increase in pruritus in those with diabetic polyneuropathy compared with age-matched nondiabetics.^12,13 An additional study found that pruritus was present in 70% of patients with small fiber neuropathy.¹⁴ We needed to consider the role of our patient’s insulin-dependent T2DM and potential underlying neuropathy when addressing the pruritic symptoms.

Furthermore, our patient’s stage IV CKD and elevated urea level also may factor into the pruritus. The pathophysiology of CKD-associated pruritus (also referred to as uremic pruritus) remains poorly understood. Suggested mechanisms include immune-mediated neural inflammation and erroneous nociceptive-receptor activity.^15,16 Although uremic pruritus is appreciated primarily in late dialysis-dependent disease, research shows that a notable portion of those with lesser disease, similar to our patient, also experience a significant itch burden.¹⁷ Diminishing pruritus is difficult and often aided by management of the underlying renal disease.¹⁸

In addition to disease management, symptomatic treatment incorporates the use of emollients, corticosteroids, and antihistamines. Unfortunately, the clinical response in the elderly population to such regimens often is poor.¹⁹ Dupilumab is an optimistic therapeutic option for chronic pruritus. By inhibiting the IL-4α receptor found on helper T cells, this biologic inhibits T_H2 differentiation and subsequent inflammatory activity. One report identified an optimistic response to dupilumab in the management of uremic pruritus.²⁰ The remarkable improvement and absence of adverse effects in our patient confirmed the utility and safety of dupilumab in complex cases such as elderly patients with multiple comorbidities. Such relief may result from inhibition of proinflammatory cytokine activity as well as decreased afferent spinal cord itch stimuli.¹⁰ The positive results from this case cast a favorable outlook on the treatment of chronic itch in the complex geriatric population.

To the Editor:

Today’s geriatric population is the fastest growing in history. The National Institutes of Health predicts there will be over 1.5 billion individuals aged 65 years and older by the year 2050: 17% of the world’s population.¹ Pruritus—either acute or chronic (>6 weeks)—is defined as a sensory perception that leads to an intense desire to scratch.² Chronic pruritus is an increasing health concern that impacts quality of life within the geriatric population. Elderly patients have various risk factors for developing chronic itch, including aging skin, polypharmacy, and increased systemic comorbidities.^3-7

Although the therapeutic armamentarium for chronic itch continues to grow, health care providers often are hesitant to prescribe medications for geriatric patients because of comorbidities and potential drug-drug interactions. Novel biologic therapies now provide alternatives for this complex population. Dupilumab is a fully humanized, monoclonal antibody approved for treatment-resistant atopic dermatitis. This biologic prevents helper T-cell (T_H2) signaling, IL-4 and IL-13 release, and subsequent effector cell (eg, mast cell, eosinophil) activity.^8-10 The combined efficacy and safety of this medication has changed the treatment landscape of resistant atopic dermatitis. We present the use of dupilumab in a geriatric patient with severe and recalcitrant itch resistant to numerous topical and oral medications.

An 81-year-old man presented to the clinic with a long history of generalized pruritic rash. His medical history was significant for insulin-dependent type 2 diabetes mellitus (T2DM), hypertension, and renal cancer following a right nephrectomy. Laboratory results approximately 14 months prior to the visit revealed a blood urea nitrogen level of 31 mg/dL (reference range, 7–20 mg/dL), creatinine level of 2.20 mg/dL (reference range, 0.7–1.3 mg/dL), and glomerular filtration rate of 29 mL/min (reference range, 90–120 mL/min). Physical examination revealed numerous pink excoriated papules on the face, neck, trunk, and extremities. Lichenified plaques were present on both arms and legs. The patient received the diagnosis of severe atopic dermatitis with greater than 10% body surface area involvement. The investigator global assessment score was 4/4, indicating severe disease burden, and biopsy results reported spongiotic dermatitis. He proceeded to trial various topical corticosteroids, including hydrocortisone ointment 2.5%, betamethasone valerate ointment 0.01%, fluocinonide ointment 0.05%, and mupirocin ointment without benefit. Three subsequent courses of oral steroids failed to provide durable relief. At this point, the peak pruritus numerical rating scale (NRS) score was 7/10, indicating severe pruritus, with a negative impact on the patient’s quality of life and sleep.

Therapy was switched to tacrolimus acetonide ointment 0.1%, betamethasone dipropionate ointment 0.05%, and triamcinolone acetonide ointment 0.1%. Eleven days later, the patient denied experiencing any response to the topical regimen and sought alternative therapy for the itch and associated poor sleep; the NRS score was 10/10, indicating very severe pruritus. Prednisone 20 mg and doxepin 10 mg were initiated for symptom management until the intended transition to dupilumab. The patient began dupilumab with a loading dose of 600 mg, then 300 mg every other week thereafter. At 2- and 4-month follow-up, the patient reported notable relief in symptoms. The rash had improved, and the NRS score decreased from 10/10 to 3/10. He endorsed improved sleep and quality of life.

Pruritus may arise from a series of age-related mechanisms such as structural and chemical changes within the epidermis, underlying neuropathy, medication side effects, infection, malignancy, thyroid dysregulation, liver disease, and chronic kidney disease (CKD).^5,6,11 Identifying the underlying etiology often is difficult and involves a complete history and physical examination as well as an appropriate contextualized laboratory workup.

Our patient’s comorbid T2DM and renal disease may have contributed to the pruritus. Type 2 diabetes mellitus can cause diabetic neuropathy, a sequela known to lead to various complications, including pruritus. One study identified a 4-fold increase in pruritus in those with diabetic polyneuropathy compared with age-matched nondiabetics.^12,13 An additional study found that pruritus was present in 70% of patients with small fiber neuropathy.¹⁴ We needed to consider the role of our patient’s insulin-dependent T2DM and potential underlying neuropathy when addressing the pruritic symptoms.

Furthermore, our patient’s stage IV CKD and elevated urea level also may factor into the pruritus. The pathophysiology of CKD-associated pruritus (also referred to as uremic pruritus) remains poorly understood. Suggested mechanisms include immune-mediated neural inflammation and erroneous nociceptive-receptor activity.^15,16 Although uremic pruritus is appreciated primarily in late dialysis-dependent disease, research shows that a notable portion of those with lesser disease, similar to our patient, also experience a significant itch burden.¹⁷ Diminishing pruritus is difficult and often aided by management of the underlying renal disease.¹⁸

In addition to disease management, symptomatic treatment incorporates the use of emollients, corticosteroids, and antihistamines. Unfortunately, the clinical response in the elderly population to such regimens often is poor.¹⁹ Dupilumab is an optimistic therapeutic option for chronic pruritus. By inhibiting the IL-4α receptor found on helper T cells, this biologic inhibits T_H2 differentiation and subsequent inflammatory activity. One report identified an optimistic response to dupilumab in the management of uremic pruritus.²⁰ The remarkable improvement and absence of adverse effects in our patient confirmed the utility and safety of dupilumab in complex cases such as elderly patients with multiple comorbidities. Such relief may result from inhibition of proinflammatory cytokine activity as well as decreased afferent spinal cord itch stimuli.¹⁰ The positive results from this case cast a favorable outlook on the treatment of chronic itch in the complex geriatric population.

To the Editor:

Today’s geriatric population is the fastest growing in history. The National Institutes of Health predicts there will be over 1.5 billion individuals aged 65 years and older by the year 2050: 17% of the world’s population.¹ Pruritus—either acute or chronic (>6 weeks)—is defined as a sensory perception that leads to an intense desire to scratch.² Chronic pruritus is an increasing health concern that impacts quality of life within the geriatric population. Elderly patients have various risk factors for developing chronic itch, including aging skin, polypharmacy, and increased systemic comorbidities.^3-7

Although the therapeutic armamentarium for chronic itch continues to grow, health care providers often are hesitant to prescribe medications for geriatric patients because of comorbidities and potential drug-drug interactions. Novel biologic therapies now provide alternatives for this complex population. Dupilumab is a fully humanized, monoclonal antibody approved for treatment-resistant atopic dermatitis. This biologic prevents helper T-cell (T_H2) signaling, IL-4 and IL-13 release, and subsequent effector cell (eg, mast cell, eosinophil) activity.^8-10 The combined efficacy and safety of this medication has changed the treatment landscape of resistant atopic dermatitis. We present the use of dupilumab in a geriatric patient with severe and recalcitrant itch resistant to numerous topical and oral medications.

An 81-year-old man presented to the clinic with a long history of generalized pruritic rash. His medical history was significant for insulin-dependent type 2 diabetes mellitus (T2DM), hypertension, and renal cancer following a right nephrectomy. Laboratory results approximately 14 months prior to the visit revealed a blood urea nitrogen level of 31 mg/dL (reference range, 7–20 mg/dL), creatinine level of 2.20 mg/dL (reference range, 0.7–1.3 mg/dL), and glomerular filtration rate of 29 mL/min (reference range, 90–120 mL/min). Physical examination revealed numerous pink excoriated papules on the face, neck, trunk, and extremities. Lichenified plaques were present on both arms and legs. The patient received the diagnosis of severe atopic dermatitis with greater than 10% body surface area involvement. The investigator global assessment score was 4/4, indicating severe disease burden, and biopsy results reported spongiotic dermatitis. He proceeded to trial various topical corticosteroids, including hydrocortisone ointment 2.5%, betamethasone valerate ointment 0.01%, fluocinonide ointment 0.05%, and mupirocin ointment without benefit. Three subsequent courses of oral steroids failed to provide durable relief. At this point, the peak pruritus numerical rating scale (NRS) score was 7/10, indicating severe pruritus, with a negative impact on the patient’s quality of life and sleep.

Therapy was switched to tacrolimus acetonide ointment 0.1%, betamethasone dipropionate ointment 0.05%, and triamcinolone acetonide ointment 0.1%. Eleven days later, the patient denied experiencing any response to the topical regimen and sought alternative therapy for the itch and associated poor sleep; the NRS score was 10/10, indicating very severe pruritus. Prednisone 20 mg and doxepin 10 mg were initiated for symptom management until the intended transition to dupilumab. The patient began dupilumab with a loading dose of 600 mg, then 300 mg every other week thereafter. At 2- and 4-month follow-up, the patient reported notable relief in symptoms. The rash had improved, and the NRS score decreased from 10/10 to 3/10. He endorsed improved sleep and quality of life.

Pruritus may arise from a series of age-related mechanisms such as structural and chemical changes within the epidermis, underlying neuropathy, medication side effects, infection, malignancy, thyroid dysregulation, liver disease, and chronic kidney disease (CKD).^5,6,11 Identifying the underlying etiology often is difficult and involves a complete history and physical examination as well as an appropriate contextualized laboratory workup.

Our patient’s comorbid T2DM and renal disease may have contributed to the pruritus. Type 2 diabetes mellitus can cause diabetic neuropathy, a sequela known to lead to various complications, including pruritus. One study identified a 4-fold increase in pruritus in those with diabetic polyneuropathy compared with age-matched nondiabetics.^12,13 An additional study found that pruritus was present in 70% of patients with small fiber neuropathy.¹⁴ We needed to consider the role of our patient’s insulin-dependent T2DM and potential underlying neuropathy when addressing the pruritic symptoms.

Furthermore, our patient’s stage IV CKD and elevated urea level also may factor into the pruritus. The pathophysiology of CKD-associated pruritus (also referred to as uremic pruritus) remains poorly understood. Suggested mechanisms include immune-mediated neural inflammation and erroneous nociceptive-receptor activity.^15,16 Although uremic pruritus is appreciated primarily in late dialysis-dependent disease, research shows that a notable portion of those with lesser disease, similar to our patient, also experience a significant itch burden.¹⁷ Diminishing pruritus is difficult and often aided by management of the underlying renal disease.¹⁸

In addition to disease management, symptomatic treatment incorporates the use of emollients, corticosteroids, and antihistamines. Unfortunately, the clinical response in the elderly population to such regimens often is poor.¹⁹ Dupilumab is an optimistic therapeutic option for chronic pruritus. By inhibiting the IL-4α receptor found on helper T cells, this biologic inhibits T_H2 differentiation and subsequent inflammatory activity. One report identified an optimistic response to dupilumab in the management of uremic pruritus.²⁰ The remarkable improvement and absence of adverse effects in our patient confirmed the utility and safety of dupilumab in complex cases such as elderly patients with multiple comorbidities. Such relief may result from inhibition of proinflammatory cytokine activity as well as decreased afferent spinal cord itch stimuli.¹⁰ The positive results from this case cast a favorable outlook on the treatment of chronic itch in the complex geriatric population.