Brian J. Simmons, MD

To the Editor:

Paraneoplastic pemphigus (PNP), also known as paraneoplastic autoimmune multiorgan syndrome, is an autoimmune mucocutaneous blistering disease that typically occurs secondary to a lymphoproliferative disorder. Paraneoplastic pemphigus is characterized by severe erosive stomatitis, polymorphous skin lesions, and potential bronchiolitis obliterans that can mimic a wide array of conditions. The exact pathogenesis is unknown but is thought to be due to a combination of humoral and cell-mediated immunity. The condition usually confers a poor prognosis, with morbidity from 38% to upwards of 90%.¹

A 47-year-old man developed prominent pink to dusky, ill-defined, targetoid, coalescing papules over the back; violaceous macules over the palms and soles; and numerous crusted oral erosions while hospitalized for an infection. He had a history of stage IVB follicular lymphoma (double-hit type immunoglobulin heavy chain/BCL2 fusion and rearrangement of BCL6) complicated by extensive erosive skin lesions and multiple lines of infections. The clinical differential diagnosis included Stevens-Johnson syndrome vs erythema multiforme (EM) major secondary to administration of oxacillin vs PNP. Herpes simplex virus polymerase chain reaction and Mycoplasma titers were negative. Skin biopsies from the back and right abdomen revealed severe lichenoid interface dermatitis (IFD) with numerous dyskeratotic cells mimicking EM and eosinophils; however, direct immunofluorescence of the abdomen biopsy revealed an apparent suprabasal acantholysis with intercellular C3 in the lower half of the epidermis. Histologically, PNP was favored, but indirect immunofluorescence with monkey esophagus IgG was negative.

The skin lesions progressed, and an additional skin biopsy from the left arm performed 1 month later revealed similar histologic features with intercellular IgG and C3 in the lower half of the epidermis with weak basement membrane C3 (Figure 1). Serology also confirmed elevated serum antidesmoglein 1 and 3 antibodies. Thus, in the clinical setting of an erosive mucositis with EM-like and pemphigoidlike eruptions associated with B-cell lymphoma, the patient was diagnosed with PNP.

Although antidesmoglein 3 antibody was shown to be a pathologic driver in PNP, there is a weak correlation between antibody profiles and clinical presentation.⁸ In one case of PNP, antidesmoglein 3 antibody was negative, suggesting that lichenoid IFD may cause the phenotypic findings in PNP.⁹ Thus, the development of nail scarring in PNP may be explained by the presence of lichenoid IFD that is characteristic of PNP. However, the variation in antibody profile in PNP likely is a consequence of epitope spreading.

To the Editor:

Paraneoplastic pemphigus (PNP), also known as paraneoplastic autoimmune multiorgan syndrome, is an autoimmune mucocutaneous blistering disease that typically occurs secondary to a lymphoproliferative disorder. Paraneoplastic pemphigus is characterized by severe erosive stomatitis, polymorphous skin lesions, and potential bronchiolitis obliterans that can mimic a wide array of conditions. The exact pathogenesis is unknown but is thought to be due to a combination of humoral and cell-mediated immunity. The condition usually confers a poor prognosis, with morbidity from 38% to upwards of 90%.¹

A 47-year-old man developed prominent pink to dusky, ill-defined, targetoid, coalescing papules over the back; violaceous macules over the palms and soles; and numerous crusted oral erosions while hospitalized for an infection. He had a history of stage IVB follicular lymphoma (double-hit type immunoglobulin heavy chain/BCL2 fusion and rearrangement of BCL6) complicated by extensive erosive skin lesions and multiple lines of infections. The clinical differential diagnosis included Stevens-Johnson syndrome vs erythema multiforme (EM) major secondary to administration of oxacillin vs PNP. Herpes simplex virus polymerase chain reaction and Mycoplasma titers were negative. Skin biopsies from the back and right abdomen revealed severe lichenoid interface dermatitis (IFD) with numerous dyskeratotic cells mimicking EM and eosinophils; however, direct immunofluorescence of the abdomen biopsy revealed an apparent suprabasal acantholysis with intercellular C3 in the lower half of the epidermis. Histologically, PNP was favored, but indirect immunofluorescence with monkey esophagus IgG was negative.

The skin lesions progressed, and an additional skin biopsy from the left arm performed 1 month later revealed similar histologic features with intercellular IgG and C3 in the lower half of the epidermis with weak basement membrane C3 (Figure 1). Serology also confirmed elevated serum antidesmoglein 1 and 3 antibodies. Thus, in the clinical setting of an erosive mucositis with EM-like and pemphigoidlike eruptions associated with B-cell lymphoma, the patient was diagnosed with PNP.

Although antidesmoglein 3 antibody was shown to be a pathologic driver in PNP, there is a weak correlation between antibody profiles and clinical presentation.⁸ In one case of PNP, antidesmoglein 3 antibody was negative, suggesting that lichenoid IFD may cause the phenotypic findings in PNP.⁹ Thus, the development of nail scarring in PNP may be explained by the presence of lichenoid IFD that is characteristic of PNP. However, the variation in antibody profile in PNP likely is a consequence of epitope spreading.

To the Editor:

Paraneoplastic pemphigus (PNP), also known as paraneoplastic autoimmune multiorgan syndrome, is an autoimmune mucocutaneous blistering disease that typically occurs secondary to a lymphoproliferative disorder. Paraneoplastic pemphigus is characterized by severe erosive stomatitis, polymorphous skin lesions, and potential bronchiolitis obliterans that can mimic a wide array of conditions. The exact pathogenesis is unknown but is thought to be due to a combination of humoral and cell-mediated immunity. The condition usually confers a poor prognosis, with morbidity from 38% to upwards of 90%.¹

A 47-year-old man developed prominent pink to dusky, ill-defined, targetoid, coalescing papules over the back; violaceous macules over the palms and soles; and numerous crusted oral erosions while hospitalized for an infection. He had a history of stage IVB follicular lymphoma (double-hit type immunoglobulin heavy chain/BCL2 fusion and rearrangement of BCL6) complicated by extensive erosive skin lesions and multiple lines of infections. The clinical differential diagnosis included Stevens-Johnson syndrome vs erythema multiforme (EM) major secondary to administration of oxacillin vs PNP. Herpes simplex virus polymerase chain reaction and Mycoplasma titers were negative. Skin biopsies from the back and right abdomen revealed severe lichenoid interface dermatitis (IFD) with numerous dyskeratotic cells mimicking EM and eosinophils; however, direct immunofluorescence of the abdomen biopsy revealed an apparent suprabasal acantholysis with intercellular C3 in the lower half of the epidermis. Histologically, PNP was favored, but indirect immunofluorescence with monkey esophagus IgG was negative.

The skin lesions progressed, and an additional skin biopsy from the left arm performed 1 month later revealed similar histologic features with intercellular IgG and C3 in the lower half of the epidermis with weak basement membrane C3 (Figure 1). Serology also confirmed elevated serum antidesmoglein 1 and 3 antibodies. Thus, in the clinical setting of an erosive mucositis with EM-like and pemphigoidlike eruptions associated with B-cell lymphoma, the patient was diagnosed with PNP.

Although antidesmoglein 3 antibody was shown to be a pathologic driver in PNP, there is a weak correlation between antibody profiles and clinical presentation.⁸ In one case of PNP, antidesmoglein 3 antibody was negative, suggesting that lichenoid IFD may cause the phenotypic findings in PNP.⁹ Thus, the development of nail scarring in PNP may be explained by the presence of lichenoid IFD that is characteristic of PNP. However, the variation in antibody profile in PNP likely is a consequence of epitope spreading.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population. 

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population. 

Sun exposure and sunburns sustained during childhood are linked to an increased risk for development of skin cancers in adulthood. In infants, the skin is particularly vulnerable and is considered to be at increased risk for UV radiation damage,¹ even as early as the first 6 months of life.² Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ To effectively teach parents proper sun-safe practices, it is essential to understand their existing perceptions and behaviors. This study sought to examine differences in infant sun-safety practices during the first 6 months of life among black, Hispanic, and non-Hispanic white (NHW) parents in Miami, Florida.

Methods

Parents presenting to the University of Miami general pediatrics clinic from February 2015 through April 2015 with a child younger than 5 years were administered a 15-item questionnaire that included items on demographics, sun-safety strategies, sunburns and tanning, beliefs and limitations regarding sunscreen, and primary information source regarding sun safety (eg, physician, Internet, media, instincts). Parents were approached by the investigators consecutively for participation in scheduled blocks, with the exception of those who were otherwise engaged in appointment-related tasks (eg, paperwork). The study was approved by the University of Miami Miller School of Medicine institutional review board. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use.

All data were analyzed using SAS software version 9.3. Wilcoxon signed rank test, Kruskal-Wallis test, Fisher exact test, and proportional-odds cumulative logit model were used to compare nonparametric data. Parents reporting on the full first 6 months of life (ie, the child was older than 6 months at the time of study completion) were included for analysis of sun-safety strategies. All survey respondents were included for analysis of secondary objectives. Responses from parents of infants of mixed racial and ethnic backgrounds were excluded from applicable subgroup analyses.

Results

Ninety-eight parents were approached for participation in the study; 97 consented to participate and 95 completed the survey. Seventy parents had children who were at least 6 months of age and were included for analysis of the primary objectives (ie, sun-protection strategies in the first 6 months of life). The cohort included 49 Hispanic parents, 26 black parents, and 9 NHW parents; 5 parents indicated their child was of mixed racial and ethnic background. Six respondents indicated another minority group (eg, Native American, Pacific Islander). Eighty-three respondents were mothers, 72 were educated beyond high school, and 14 were Spanish-speaking only. Four reported a known family history of skin cancer.

There were notable differences in application of sunscreen, belief in the efficacy of sunscreen, and primary source of information between parents (Tables 1 and 2). Hispanic parents reported applying sunscreen more consistently than black parents (odds ratio, 4.656; 95% confidence interval, 1.154-18.782; P<.01). Hispanic parents also were more likely than black parents to believe sunscreen is effective in the prevention of skin cancers (odds ratio, 7.499; 95% confidence interval, 1.535-36.620; P<.01). Hispanic parents were more likely to report receiving information regarding sun-safety practices for infants from their pediatrician, whereas NHW parents were more likely to follow their instincts regarding how and if infants should be exposed to the sun (P<.05). No significant differences were found in the reported primary source of information in black versus Hispanic parents or in black versus NHW parents. Three percent (3/95) of respondents reported a sunburn in the infant's first 6 months of life, and 12% (11/95) reported tanning of infants' skin from sun exposure. Tanning was associated with inconsistent shade (P<.01), inconsistent clothing coverage (P<.01), and consistently allowing infants to "develop tolerance to the sun's rays by slowly increasing sun exposure each day" (P<.05).

Comment

The survey results indicated suboptimal sun-protection practices among parents of black and Hispanic infants in Miami. Although the majority of respondents (83% [58/70]) reported keeping their infants in the shade, less than half of parents consistently covered their infants adequately with clothing and hats (40% [28/70] and 43% [30/70], respectively). More alarmingly, one-third of parents reported intentionally increasing their infant's level of sun exposure to develop his/her tolerance to the sun. A minority of parents reported sunburns (3%) and tanning (12%) within the first 6 months of life. Twenty-nine percent of parents (20/70) reported consistently applying sunscreen to their infants who were younger than 6 months despite limited safety data available for this age group.

Although our study included a limited sample size and represents a narrow geographic distribution, these results suggest that shortcomings in current practices in sun protection for black and Hispanic infants younger than 6 months may be a widespread problem. Black and Hispanic patients have a lower incidence of skin cancer, but the diagnosis often is delayed and the mortality is higher when skin cancer does occur.⁴ The common perception among laypeople as well as many health care providers that black and Hispanic individuals are not at risk for skin cancer may limit sun-safety counseling as well as the overall knowledge base of this patient demographic. As demonstrated by the results of this study, there is a need for counseling on sun-safe behaviors from a young age among this population.

Conclusion

This study highlights potential shortcomings in current sun-protection practices for black and Hispanic infants younger than 6 months. Sun-safe behaviors instituted from a young age may help reduce the risk for future skin cancers.³ Additional studies are needed to further define sun-safety behaviors in black and Hispanic children across the United States. Further, additional studies should focus on developing interventions that positively influence sun-safety behaviors in this patient population.