A Veterinarian with Multiple Skin Ulcers after Travel to Costa Rica
A 32-year-old man returned from a 14-day vacation to Costa Rica with several ulcerative skin lesions on his left wrist, right and left flanks, and left leg. He also noted palpable nodules on his left arm proximal to the left wrist lesions. Besides the ulcers on his wrist (which began as papules), he also noted three ulcers on his flanks, as well as two on his lower legs. He did not recall any trauma to the areas, and initially thought the lesions were due to insect bites.
He had no prior medical history and had not traveled to destinations other than Costa Rica, and his work as a veterinarian mainly exposed him to dogs and cats. His itinerary included visits to the Arenal volcano region, as well as overnight stays in the Pacuare jungle lodges where he participated in outdoor activities including river rafting and ziplining. He had intermittently used insect repellant, and did not sleep under bed nets. He denied any systemic symptoms and was afebrile at the time of presentation to our travel medicine practice, 6 weeks after his initial skin lesions appeared. On physical examination, he had three coalesced ulcers on his wrist (Figure 13a.1), two lesions on his left flank (Figure 13a.2), one on the right flank, and two on the lower left leg. He also was noted to have a nodular subcutaneous lesion beneath the left bicep muscle, suggestive of lymphangitic spread from the wrist site.
Skin scrapings of the base of the lesion and biopsy revealed the presence of intracellular and extracellular Leishmania amastigotes with typical kinetoplast structures visible adjacent to the protozoan’s nucleus (Figure 13a.3). Cultures of the biopsy performed at the Centers for Disease Control subsequently were positive, and PCR testing confirmed that the species was L. v. panamensis. Prior to the confirmation of the culture results, the patient began therapy with oral miltefosine 50 mg orally, twice daily. The medication was obtained under a single-patient investigational new drug (IND) protocol under the supervision of the Food and Drug Administration, and imported from the manufacturer in Germany.
During the treatment regimen, the patient experienced mild nausea on two occasions when he did not take the medication with food, but otherwise was able to complete the 28 days of therapy without adverse events. Several weeks later, the patient’s lesions showed excellent healing and he experienced no further recurrences (Figures 13a.4 and 13a.5).
Case 13a Discussion: Leishmaniasis
Clinical Features and Diagnosis
Leishmaniasis is caused by the protozoan parasite Leishmania, and may present with a variety of clinical symptoms depending on the infecting species and the immune status of the host. The organism is transmitted to humans via the bite of a tiny insect vector known as the sandfly, and can cause disease in animal reservoirs such as dogs, foxes, and rodents in endemic areas. Leishmania is transmitted in a flagellated promastigote form, and is phagocytosed into tissue macrophages where it transforms into the amastigote form. The parasite is able to survive and replicate within immune cells, and lyses the cells as it multiplies. As the organism replicates in the tissue macrophages of the skin, the inflammatory response leads to a nodular lesion that erodes to become a painless ulcer. There is often a raised erythematous border surrounding the central ulceration, and proximal lymphadenopathy may be a sign of lymphangitic spread.1 This presentation of the illness has clinical overlap with other infections, such as sporotrichosis and Mycobacterium marinum infections.
Certain species of the Leishmania genus cause cutaneous disease alone, and approximately one-third of patients with this form of the infection have ulcers that heal over time without treatment. In parts of Central and South America, other species can spread to the mucosal tissues of the oropharynx and nose, and lead to a highly disfiguring form of the disease called mucocutaneous leishmaniasis. Visceral leishmaniasis is caused by species found in South America, Africa, Southern Europe, and India. This potentially fatal form manifests with fevers, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia. Its tendency to cause a darkening of the skin led to the designation, Kala-Azar, a Hindi term meaning “black sickness.”1
Leishmaniasis is widely distributed throughout the tropics, Middle East, South Asia, and Southern Europe. An estimated 12 million individuals suffer from the disease, and an estimated 2 million new cases of Leishmaniasis occur each year, with an annual estimated mortality of 70,000.1 Leishmaniasis has principally been a disease of impoverished nations in the tropics; however, reactivation illness in patients with AIDS has emerged as an important opportunistic infection in patients in southern Europe.1
The diagnosis of cutaneous leishmaniasis can be established by visualization of the intracellular or extracellular amastigotes on smears taken from superficial scrapings or punch biopsies of the ulcer. The kinetoplast is the intracytoplasmic body adjacent to the nucleus that distinguishes the amastigotes of Leishmania from the yeast cells of Histoplasma capsulatum. The organism can also be cultured from the scrapings or biopsied material when incubated on Novy-MacNeal-Nicolle (NNN) media. The use of polymerase chain reaction directly on tissue specimens has proven useful in many cases, and is performed in laboratories at the Centers for Disease Control and Prevention, and at the Walter Reed Army Institute of Research.2 Serologic assays may have some clinical utility in travelers, but are often falsely negative, especially in cutaneous disease. Given the protean manifestations of the Leishmania genus, confirmation of the species can be especially important in decisions regarding treatment.
Standard systemic therapy for leishmaniasis in most parts of the world includes the intravenous infusion of the heavy metal, pentavalent antimony. The duration of treatment with this intravenous medication varies from 20–28 days, and the toxicities include muscle and joint aches, electrolyte abnormalities, and potential cardiotoxicity. In the United States, it is available only through the Centers for Disease Control and Prevention’s antiparasitic medication branch. Amphotericin deoxycholate and lipid preparations of amphotericin have demonstrated efficacy in treating both mucocutaneous and visceral forms of leishmaniasis.3 Single-dose liposomal amphotericin therapy has been effective in treating visceral leishmaniasis in the Bihar state of India, where resistance to antimonial medications remains an important problem.4 The use of lipid preparations of amphotericin for cutaneous leishmaniasis have been extrapolated from studies in visceral leishmaniasis, and 5–6 doses of 5mg/kg of liposomal amphotericin B have yielded satisfactory results.1
New World cutaneous leishmaniasis has been an emerging infection among travelers, as travel to endemic regions has increased. Systemic treatment for cutaneous leishmaniasis is currently recommended for patients whose infections may be caused by species with the potential to cause mucocutaneous disease in the future. Because of the potential toxicities of the currently available parenteral therapies, oral agents such as miltefosine have generated increased interest. Miltefosine was originally developed as a chemotherapeutic agent, but it was discovered to have antiprotozoal activity by inhibiting phospholipid and sterol biosynthesis.5 Its low toxicity profile and oral formulation make it an excellent agent to treat many forms of leishmaniasis. Studies of miltefosine for New World cutaneous leishmaniasis use indicate that it is more effective against the L. v. panamensis complex than against the L. v. braziliensis and L. m. mexicana subspecies.5,6 Miltefosine is currently not routinely available in the United States except when imported via an investigational new drug protocol under the supervision of the Food and Drug Administration.
Prevention of leishmaniasis in travelers is mainly achieved through the use of insect precautions with N,N-Diethyl-meta-toluamide (DEET)-based skin repellents and premethrin-based clothing treatments. The usefulness of many bed nets is limited by the small size of the sandfly, although insecticide-treated nets can offer some protection against leishmaniasis in areas where the sandflies are predominantly nocturnal feeders. As leishmaniasis is also a zoonotic illness that can affect dogs and other small mammals, control of the disease in animal reservoirs is another potential intervention to reduce human disease. Dog collars treated with deltamethrin have been demonstrated to reduce the rate of canine disease, as well as human disease in children in areas in which the collars were used. Efforts to develop an effective vaccine against Leishmania have been hampered by the organism’s species diversity, and mechanisms for intracellular survival and immune evasion.1 Killed Leishmania vaccine combined with Bacillus Calmette-Guérin has had some limited efficacy in South American studies, but investigation is also ongoing in the development of live attenuated vaccines as well as novel antigenic targets.1
1. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet. 2005;366(9496):1561–1577.Find this resource:
2. Wortmann G, Hochberg L, Houng HH, et al. Rapid identification of Leishmania complexes by a real-time PCR assay. Am J Trop Med Hyg. 2005 Dec;73(6):999–1004.Find this resource:
3. Tuon FF, Amato VS, Graf ME, Siqueira AM, Nicodemo AC, Amato Neto V. Treatment of New World cutaneous leishmaniasis–a systematic review with a meta-analysis. Int J Dermatol. 2008 Feb;47(2):109–124.Find this resource:
4. Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med. 2010 Feb 11;362(6):504–512.Find this resource:
5. Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis. 2001 Oct 1;33(7):E57–E61.Find this resource:
6. Soto J, Toledo J, Valda L, et al. Treatment of Bolivian mucosal leishmaniasis with miltefosine. Clin Infect Dis. 2007 Feb 1;44(3):350–356.Find this resource: