Case Report: Cutaneous Leishmaniasis due to Leishmania (Viannia) panamensis in Two Travelers Successfully Treated with Miltefosine

DISCUSSION

Leishmaniasis refers collectively to a spectrum of clinical syndromes (cutaneous, mucocutaneous, and visceral) caused by infection with intracellular protozoa of the subgenera Leishmania (Leishmania), Leishmania (Viannia), or Leishmania (Mundinia) acquired by the bite of sand flies.¹ Cutaneous leishmaniasis (CL) is the most frequently reported form of the disease, and it is associated with more than 20 Leishmania (L.) species with different degrees of pathogenicity.² In addition to producing CL, some species may also produce nasopharyngeal and laryngeal mucosal involvement, causing additional morbidity and disfigurement. Mucosal leishmaniasis (ML) may occur concomitantly with the cutaneous lesion, or it may manifest a few months, or even years, after the cutaneous lesions have healed.^3–5 In the New World (Americas), species of the subgenus L. Viannia (V) are associated with the mucosal forms of the disease, particularly Leishmania (V) braziliensis, Leishmania (V) guyanensis, and L. (V) panamensis.⁶ New evidence suggests that some of these Leishmania species are coinfected with Leishmania RNA virus and that the immune response to this virus elicits an hyperinflammatory response through toll-like receptors, leading to mucosal damage.⁷ In addition, some Leishmania species, which are traditional causes of CL, may produce a mixed syndrome of cutaneous and visceral disease denominated viscerotropic disease caused predominantly by Leishmania tropica in the Old World and Leishmania amazonensis in the New World.⁸

Cutaneous leishmaniasis typically occurs at the site of the sand fly bite, starting as small papules which enlarge slowly over months eventually ulcerating with heaped up borders.⁴ The spectrum of cutaneous manifestations associated with CL in the New World includes ulcerative, diffuse, disseminated, and atypical forms (psoriasiform, verrucous, zosteriform, or nodular).^6,9

The Pan American Health Organization recommends assessing the annual CL transmission index to identify the locations within the Americas with the highest risk of transmission. Used to prioritize and control interventions, this index is constituted by the annual incidence of CL and the density of transmission which is defined as the total annual number of CL cases in a defined geographic area by municipalities, regions, and subregions of countries with existing leishmaniasis transmission. Travel medicine practitioners can use this index to counsel travelers about high transmission areas and prevent phlebotomine sand fly bites.⁶

Cutaneous leishmaniasis occurring in an immune-competent individual with no evidence of mucosal involvement does not usually require treatment because it spontaneously resolves. However, local or systemic treatment is recommended for individuals with complex CL defined as the presence of subcutaneous nodules; area greater than 5 cm; regional adenopathy; lesions on the face, fingers, toes, or genitalia; location or size not amenable to localized treatment; immunocompromised host; previous clinical failure; infection due to a Leishmania species potentially associated with mucosal disease; or diffuse CL.^9,10 In these clinical scenarios, treatment accelerates the healing process and reduces the chances of relapse and dissemination (mucosal or visceral).

Treatment options for CL acquired in the New World include either systemic or local therapy. Systemic therapies include parenteral or oral options. In the armamentarium of parenteral infusions, the most frequently used is pentavalent antimonial compounds (SbV), followed by amphotericin B (deoxycholate or liposomal formulations), and pentamidine. Oral options include azoles and the more recently approved antiparasitic drug miltefosine. Local treatment includes topical paromomycin, intralesional injections of antimonials, thermotherapy, and photo or laser treatment for clinically simple lesions not associated with ML.

There is no ideal treatment regimen for leishmaniasis. Experts recommend individualizing therapy based on a patient’s immune status, comorbid conditions, childbearing plans, risk of mucocutaneous disease, extent of involvement, and published agent response rates of the therapy in the relevant geographic region.¹¹ A retrospective study of CL involving 43 European travelers demonstrated that the use of amphotericin B formulations was mostly effective against some of the Old World leishmaniasis: Leishmania infantum and Leishmania tropica.¹² However, for species of the subgenus L. Viannia, the use of amphotericin B was associated with high rates of treatment failure.¹²

Because our patients had confirmed L. (V) panamensis, we decided to institute systemic therapy. We chose miltefosine over pentavalent antimonials based on existing efficacy against L. (V) panamensis^13,14 and for logistic reasons to avoid the need for parenteral administration. We also recommended wound care and applying emollients, such as petroleum jelly, to the wound.

Miltefosine, approved by the FDA in 2014 for CL caused by L. panamensis, L. braziliensis, and L. guyanensis, is a phosphocholine analogue that interferes with cell-signaling pathways and membrane synthesis.¹⁴ The major benefits of this treatment regimen are oral administration and a minimal side effect profile. Adverse effects include nausea and diarrhea, which can be ameliorated by ingesting the medication with food. Patients should also receive safe sex counseling, as the medication has teratogenic potential. Other rare side effects include hepatotoxicity and renal insufficiency. Additional disadvantages are the cost of the medication and the potential risk of relapse.

Although there are a limited number of clinical trials evaluating miltefosine, most of the studies have revealed that miltefosine is efficacious. A randomized open-label trial of 90 patients with L. braziliensis revealed a statistically significant cure rate of 75% in the miltefosine group compared with 53.3% in the pentavalent antimony group.¹⁵ Furthermore, a trial of miltefosine in pediatric children in Colombia with L. panamensis and L. guyanensis revealed that miltefosine was not inferior to meglumine antimoniate and had a lower toxicity profile.¹⁶ The use of miltefosine in CL from Columbia revealed cure rates > 80% for patients infected with L. panamensis.^13,14 Other trials demonstrated a cure rate of < 70% that was attributed to higher proportions of L. braziliensis cases.¹⁷ This may be secondary to L. braziliensis’ reduced capacity to internalize milefosine.¹⁸

For treatment, a course of 28 days of miltefosine is preferred, but one may recommend extended courses for lymphangitic spread such as in our patient. Because leishmaniasis may recur, there is a need for intermittently monitoring patients after completing therapy. If treatment is successful, the lesion size should decrease by greater than 50%, with no evidence of new lesions. In addition, ulcerative lesions should re-epithelialize and heal by 3 months.¹⁰ The wife had resolution of ulcerations with no new lesions (Figure 4), and the husband had re-epithelialization of his ulcer at of our first 3-month follow-up (Figure 5). We also identified the potential benefit of collagenase ointment in patients with CL to improve residual scar accumulation at the prior ulcer border.

In summary, our cases contribute to the growing threat of CL in travelers.¹⁹ Travel health practitioners should advice travelers to avoid phlebotomine sand fly bites in regions with high leishmaniasis cutaneous indexes. Cutaneous leishmaniasis should always be on the differential diagnosis for a returning traveler with cutaneous lesions. Because of the risk of mucosal involvement with particular Leishmania species in returning travelers from the New World, it is highly recommended to identify the species involved to guide the preferred treatment regimen. Miltefosine is a convenient and well-tolerated oral alternative for the treatment of CL caused by L. (V) panamensis.