Leishmania tropica–Induced Cutaneous and Presumptive Concomitant Viscerotropic Leishmaniasis With Prolonged Incubation FREE

Leishmaniasis includes a spectrum of disease caused by a group of protozoan parasites belonging to the genus Leishmania. Approximately 12 million people worldwide have some form of this disease, and more than 350 million people live in at-risk areas.¹ Indeed, Leishmania species infections, which are primarily transmitted by the bite of infected sand flies, produce a substantial burden of disease in more than 88 countries worldwide.¹ Leishmaniasis presents with 3 major clinical syndromes: visceral (VL), cutaneous (CL), and mucocutaneous leishmaniasis (ML).¹ These clinical manifestations depend on complex host-parasite interactions leading to primary replication of the parasite within macrophages in the reticuloendothelial system in the case of VL, in the dermis in CL, or in the nasopharynx or oropharynx in ML.¹

There are over 21 Leishmania species, with each species having the potential to cause more than 1 clinical syndrome.^{2 - 3} Cutaneous leishmaniasis may be divided geographically into New World and Old World disease. Old World disease is caused by Leishmania major, Leishmania tropica, Leishmania aethiopica, and, rarely, by Leishmania infantum, which are endemic in the Middle East, India, and Africa. New World disease is caused by Leishmania braziliensis, Leishmania mexicana, or Leishmania panamensis/Leishmania guyanesis complexes and is endemic in some areas of Latin America.¹ Clinical manifestations of CL vary from crusted verrucoid papules and plaques to disfiguring ulcerations. Lesions are typically located on exposed body surfaces such as the lower legs and arms. Mucocutaneous leishmaniasis is an immunopathogenic variant and is considered an oligoparasitic syndrome caused mainly by persistent L braziliensis disease.

Visceral leishmaniasis is predominantly caused by Leishmania donovani or L infantum/Leishmania chagasi, and most cases are concentrated in India (Bihar State), Bangladesh, Sudan, and Brazil. Clinical manifestations of VL include fever, weakness, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia.^{1 - 3} Viscerotropic leishmaniasis, in contrast to visceral leishmaniasis, is a recently described clinical variant of visceral disease primarily caused by L tropica (which traditionally causes cutaneous manifestations) that produces visceral infection but does not necessarily present with the classical manifestations of VL. This is an oligoparasitic syndrome with nonspecific clinical manifestations caused by the spread of L tropica to the reticuloendothelial system. This syndrome was initially described among 12 US servicemen returning from the Persian Gulf War in 1991 with nonspecific symptoms including fever, anemia, weight loss, and anorexia.^{4 - 5} It is notable that none of these originally described cases had concurrent evidence of cutaneous involvement, and subsequent reports have also failed to demonstrate this association.^{6 - 7} Thus, we were interested in reporting a case of concomitant cutaneous and presumptive viscerotropic leishmaniasis caused by L tropica in an Afghani refugee who resettled in the United States.

A 17-year-old Afghani girl who had lived in the United States for 4 years presented with a 6-month history of bilateral pretibial ulcerations. The patient was born in Kabul, Afghanistan, but soon after was displaced to refugee camps in Northeastern Pakistan. Subsequent to her relocation to the United States, she had no history of travel. The patient denied a history of preceding trauma to the lower extremities but reported a 9.1-kg weight loss over the previous 8-month period. In addition, she reported epigastric and hypogastric pain and extreme fatigue affecting her daily activities and school performance. Examination revealed a thin girl with nontender splenomegaly. A skin examination revealed 2 ulcerations, one 4 × 2 cm, the other 2 × 2 cm, on the pretibial aspects of her lower extremities (Figure 1). Skin biopsy specimens were obtained for routine histologic tests and tissue culture. Findings from a chest radiograph and tests for antinuclear antibody, human immunodeficiency virus, stool guiaic, and urine Histoplasma antigen were reported as within the reference range or negative. Serum aspartate aminotransferase and alanine aminotransferase levels were found to be slightly elevated (36 U/L and 39 U/L, respectively, upper limit of normal range, 32 U/L [to convert to microkatals per liter, multiply by 0.0167]). She had evidence of mild anemia with a hemoglobin level of 10.9 g/dL (reference range, 11.5-14.5 g/dL [to convert to grams per liter, multiply by 10.0]), but other blood cell counts were within the reference range. Tests with tissue fungal and mycobacterial stains and cultures were negative. However, skin histologic findings revealed the presence of predominantly intracellular and few extracellular microorganisms suspicious for amastigotes (Figure 2). Given the high clinical suspicion for leishmaniasis, additional tissue specimens were obtained and sent with serum to the Laboratory of Parasitic Diseases of the Centers for Disease Control and Prevention, Atlanta, Georgia. Findings from a tissue smear demonstrated the presence of amastigotes on light-microscopic examination; tissue culture using Novy, McNeal, and Nicolle media with 10% defibrinated rabbit blood with 15% fetal calf serum was positive, and isoenzyme electrophoresis results yielded L tropica. Serum indirect immunofluorescent antibody (using whole promastigotes of L donovani) titer for L tropica was elevated at 1:64 (diagnostic titer >1:16), which, given her systemic signs and symptoms, was highly suggestive evidence of visceral dissemination of L tropica in this patient.

Based on these clinical and laboratory findings, the patient was diagnosed as having simultaneous cutaneous and viscerotropic leishmaniasis caused by L tropica. Therapy with a 28-day course of intravenous pentavalent antimonial compound sodium stibogluconate was provided by the Centers for Disease Control and Prevention, Atlanta, Georgia, under an investigational new drug protocol. A protocol for monitoring potential adverse effects was performed in our patient, which included a weekly electrocardiogram, complete white blood cell count, comprehensive metabolic panel, and pancreatic enzyme measurements. The patient completed treatment successfully. She developed mild hypomagnesemia, but this promptly corrected with oral supplementation. By the end of therapy, the patient had notable improvement in systemic symptoms, including resolution of fatigue, increased appetite, and a weight gain of 1.6 kg. Her splenomegaly and anemia resolved, and her liver transaminase levels returned to reference range. At follow-up 8 months after treatment, the patient's pretibial ulcerations were reepithelialized, although scarring was evident, and she has experienced no signs or symptoms of relapse.

Specific Leishmania organisms are often associated with particular clinical presentations such as CL, VL, or ML. However, the relationship between selected species and clinical syndromes is not always straightforward. In this regard, recent reports have demonstrated the biological plausibility of some species that are typically associated with VL to also produce CL, such as in the case of L infantum infection. Conversely, traditionally dermotropic species can disseminate viscerally, leading to visceral disease such as we believe occurred in our patient.^{5 ,7 - 8} Indeed, similar to what has been reported previously in American troops returning from the Middle East, our patient had evidence of viscerotropic disease, as demonstrated by her clinical findings (anorexia, weight loss, and splenomegaly), laboratory abnormalities (anemia and mild transaminitis), and positive serological evidence of L tropica infection. We did not have confirmatory evidence of visceral involvement (demonstration of organisms in visceral tissue samples), which is typically necessary for a conclusive diagnosis of VL. However, given our patient's clinical scenario, her laboratory results, and the complete resolution of her systemic abnormalities subsequent to leishmaniasis-specific therapy, the diagnosis of concomitant viscerotropic disease was highly supported. Notwithstanding this variant of viscerotropic disease, it becomes relevant to mention that the typical VL syndrome caused by L tropica, although rare, has also been described.⁹ The first 2 cases of VL caused by L tropica in Africa were reported in 1989.¹⁰ Later, in a study of 66 patients in southern Iran diagnosed clinically with VL, 1 of the 66 cases was found to be caused by L tropica when splenic and bone marrow aspirates were analyzed.¹¹

Compared with patients with classic VL and in the previously reported cases of viscerotropic disease in Gulf War veterans, our patient is unique in that she had clear evidence of L tropica cutaneous infection. This was based on her cutaneous findings and confirmed by positive skin histopathologic examination and culture with isoenzyme electrophoresis speciation. Indeed, L tropica is associated with Old World cutaneous disease in urban areas of the Middle East and cities in the Mediterranean area, India, and Pakistan. Whether visceral involvement of L tropica is rare or only rarely recognized is unknown. Little is known about what specific host or parasitic factors facilitate this classically dermotropic organism to turn viscerally. Speculation exists that lack of prior exposure, type of immune response, and strain variation each may play some role in dissemination. In addition, viscerotropic disease has been considered an oligoparasitic syndrome, and this issue may explain the nonspecific presentation compared with the full-blown syndrome of VL characterized by excessive numbers of parasites in infected macrophages of the reticuloendothelial system. At this point, we can speculate that either strain variants of L tropica or specific host immune response to this parasite may explain the dual tropism (dermal and visceral) in our patient. In support of the latter, a recent study¹² of a mouse model of dermal infection has begun to characterize the role of interleukin 10 and transforming growth factor β in chronic infection with L tropica.

Another unusual characteristic of our patient was that she had lived in the United States for 4 years prior to showing signs of disease, indicating a prolonged incubation period or chronic subclinical infection similar to what occurs in leishmaniasis recidivans caused by L tropica. The incubation period for cutaneous leishmaniasis typically varies from weeks to months.¹ Visceral disease typically manifests after a 3- to 8-month incubation period.¹ Thus, in our patient, who had lived in an L tropica endemic region (Pakistan) 4 years prior to presentation, the incubation period was much longer than is typical. In support of a possible longer subclinical period for L tropica is a case report⁷ of an Operation Desert Storm veteran presenting with visceral L tropica disease 2 years after leaving Saudi Arabia. A mid-20th century report¹³ on cutaneous leishmaniasis also described a possible incubation period of many years. In contrast, the individuals initially reported with viscerotropic disease returning from the Persian Gulf developed symptoms a median of 7 months (range, 8 weeks to 1 year) after arrival in the Persian Gulf and within 5 months after they left the area.^{4 - 5}

In summary, this is a rare report of L tropica–induced cutaneous leishmaniasis with presumptive coexisting viscerotropic disease and an unusually prolonged incubation period. The patient's excellent response to therapy supports a strategy of aggressive evaluation for viscerotropic disease in patients with cutaneous leishmaniasis who also have systemic symptoms that are potentially compatible with visceral involvement. We suggest that in the face of growing international travel and migration, a diagnosis of leishmaniasis must be considered in civilian overseas travelers, soldiers coming home from abroad, and foreign-born travelers to the United States presenting with vague systemic complaints and/or isolated cutaneous disease even a few months or years after leaving Leishmania-endemic areas.

Correspondence: Sareeta R. S. Parker, MD, Department of Dermatology, Grady Memorial Hospital, Emory University, 1365 Clifton Rd NE, Ste 1100, Bldg A, Atlanta, GA 30322 (srsingh@emory.edu).

Accepted for Publication: January 12, 2009.

Author Contributions: All of the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Weiss, Vogenthaler, and Parker. Acquisition of data: Weiss and Parker. Analysis and interpretation of data: Vogenthaler and Parker. Drafting of the manuscript: Weiss, Vogenthaler, Franco-Paredes, and Parker. Critical revision of the manuscript for important intellectual content: Weiss, Vogenthaler, Franco-Paredes, and Parker. Administrative, technical, and material support: Weiss. Study supervision: Franco-Paredes.

Financial Disclosure: None.