OBSERVATION tropica–Induced Cutaneous and Presumptive Concomitant Viscerotropic With Prolonged Incubation

Francesca Weiss, BS; Nicholas Vogenthaler, MD, MPH; Carlos Franco-Paredes, MD; Sareeta R. S. Parker, MD

Background: Leishmaniasis includes a spectrum of dis- studies were highly suggestive of concomitant visceral eases caused by protozoan parasites belonging to the ge- involvement. The patient was treated with a 28-day course nus Leishmania. The disease is traditionally classified into of intravenous pentavalent antimonial compound so- visceral, cutaneous, or mucocutaneous leishmaniasis, de- dium stibogluconate with complete resolution of her sys- pending on clinical characteristics as well as the temic signs and symptoms and improvement of her pre- involved. is one of the causative agents tibial ulcerations. of , with a typical incubation pe- riod of weeks to months. Conclusions: This is an exceptional case in that our pa- tient presented with disease after an incubation period Observation: We describe a 17-year-old Afghani girl of years rather than the more typical weeks to months. who had lived in the United States for 4 years and who In addition, this patient had confirmed cutaneous in- presented with a 6-month history of pretibial ulcer- volvement, as well as strong evidence of viscerotropic dis- ations, 9.1-kg weight loss, abdominal pain, spleno- ease caused by L tropica, a species that characteristically megaly, and extreme fatigue. Histopathologic examina- displays dermotropism, not viscerotropism. tion and culture with isoenzyme electrophoresis speciation of her skin lesions confirmed the presence of L tropica. In addition, results of serum laboratory and serological Arch Dermatol. 2009;145(9):1023-1026

EISHMANIASIS INCLUDES A graphically into New World and Old World spectrum of disease caused disease. Old World disease is caused by by a group of protozoan , Leishmania tropica, Leish- parasites belonging to the ge- mania aethiopica, and, rarely, by Leish- nus Leishmania. Approxi- mania infantum, which are endemic in the matelyL 12 million people worldwide Middle East, India, and Africa. New World have some form of this disease, and more disease is caused by Leishmania brazilien- than 350 million people live in at-risk sis, , or Leishmania areas.1 Indeed, Leishmania species infec- panamensis/Leishmania guyanesis com- tions, which are primarily transmitted by plexes and is endemic in some areas of the bite of infected sand flies, produce a Latin America.1 Clinical manifestations substantial burden of disease in more of CL vary from crusted verrucoid pap- than 88 countries worldwide.1 Leish- ules and plaques to disfiguring ulcer- maniasis presents with 3 major clinical ations. Lesions are typically located on ex- syndromes: visceral (VL), cutaneous posed body surfaces such as the lower legs (CL), and mucocutaneous leishmaniasis and arms. Mucocutaneous leishmaniasis is (ML).1 These clinical manifestations de- an immunopathogenic variant and is con- pend on complex host-parasite interac- sidered an oligoparasitic syndrome caused tions leading to primary replication of mainly by persistent L braziliensis disease. Author Affiliations: the parasite within macrophages in the is predomi- Departments of Dermatology reticuloendothelial system in the case of nantly caused by or (Ms Weiss and Dr Parker) VL, in the dermis in CL, or in the naso- L infantum/Leishmania chagasi, and most and Infectious Disease 1 (Drs Vogenthaler and pharynx or oropharynx in ML. cases are concentrated in India (Bihar Franco-Paredes), Emory There are over 21 Leishmania species, State), Bangladesh, Sudan, and Brazil. University School of Medicine with each species having the potential to Clinical manifestations of VL include fe- and Grady Memorial Hospital cause more than 1 clinical syndrome.2,3 Cu- ver, weakness, weight loss, hepatospleno- Atlanta, Georgia. taneous leishmaniasis may be divided geo- megaly, pancytopenia, and hypergamma-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 rus, stool guiaic, and urine Histoplasma antigen were re- ported as within the reference range or negative. Serum aspartate aminotransferase and alanine aminotransfer- ase 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 con- vert 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 extra- cellular microorganisms suspicious for amastigotes (Figure 2). Given the high clinical suspicion for leish- maniasis, additional tissue specimens were obtained and sent with serum to the Laboratory of Parasitic Dis- eases of the Centers for Disease Control and Preven- tion, Atlanta, Georgia. Findings from a tissue smear Figure 1. Leishmania tropica–induced bilateral pretibial ulcerations. demonstrated the presence of amastigotes on light- microscopic examination; tissue culture using Novy, McNeal, and Nicolle media with 10% defibrinated rab- globulinemia.1-3 Viscerotropic leishmaniasis, in contrast bit blood with 15% fetal calf serum was positive, and iso- to visceral leishmaniasis, is a recently described clinical enzyme electrophoresis results yielded L tropica. Serum variant of visceral disease primarily caused by L tropica indirect immunofluorescent antibody (using whole (which traditionally causes cutaneous manifestations) that promastigotes of L donovani) titer for L tropica was el- produces visceral infection but does not necessarily pre- evated at 1:64 (diagnostic titer Ͼ1:16), which, given her sent with the classical manifestations of VL. This is an systemic signs and symptoms, was highly suggestive oligoparasitic syndrome with nonspecific clinical mani- evidence of visceral dissemination of L tropica in this festations caused by the spread of L tropica to the reticu- patient. loendothelial system. This syndrome was initially de- Based on these clinical and laboratory findings, the pa- scribed among 12 US servicemen returning from the tient was diagnosed as having simultaneous cutaneous Persian Gulf War in 1991 with nonspecific symptoms in- and viscerotropic leishmaniasis caused by L tropica. cluding fever, anemia, weight loss, and anorexia.4,5 It is Therapy with a 28-day course of intravenous pentava- notable that none of these originally described cases had lent antimonial compound sodium stibogluconate was concurrent evidence of cutaneous involvement, and sub- provided by the Centers for Disease Control and Preven- sequent reports have also failed to demonstrate this as- tion, Atlanta, Georgia, under an investigational new drug sociation.6,7 Thus, we were interested in reporting a case protocol. A protocol for monitoring potential adverse ef- of concomitant cutaneous and presumptive viscero- fects was performed in our patient, which included a tropic leishmaniasis caused by L tropica in an Afghani weekly electrocardiogram, complete white blood cell refugee who resettled in the United States. count, comprehensive metabolic panel, and pancreatic enzyme measurements. The patient completed treat- REPORT OF A CASE ment successfully. She developed mild hypomagnese- mia, but this promptly corrected with oral supplemen- A 17-year-old Afghani girl who had lived in the United tation. By the end of therapy, the patient had notable States for 4 years presented with a 6-month history of improvement in systemic symptoms, including resolu- bilateral pretibial ulcerations. The patient was born in tion of fatigue, increased appetite, and a weight gain of Kabul, Afghanistan, but soon after was displaced to refu- 1.6 kg. Her splenomegaly and anemia resolved, and her gee camps in Northeastern Pakistan. Subsequent to her liver transaminase levels returned to reference range. At relocation to the United States, she had no history of travel. follow-up 8 months after treatment, the patient’s pre- The patient denied a history of preceding trauma to the tibial ulcerations were reepithelialized, although scar- lower extremities but reported a 9.1-kg weight loss over ring was evident, and she has experienced no signs or the previous 8-month period. In addition, she reported symptoms of relapse. epigastric and hypogastric pain and extreme fatigue af- fecting her daily activities and school performance. Ex- amination revealed a thin girl with nontender spleno- COMMENT megaly. A skin examination revealed 2 ulcerations, one 4ϫ2 cm, the other 2 ϫ 2 cm, on the pretibial aspects of Specific Leishmania organisms are often associated with her lower extremities (Figure 1). Skin biopsy speci- particular clinical presentations such as CL, VL, or ML. mens were obtained for routine histologic tests and tis- However, the relationship between selected species and sue culture. Findings from a chest radiograph and tests clinical syndromes is not always straightforward. In this for antinuclear antibody, immunodeficiency vi- regard, recent reports have demonstrated the biological

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Figure 2. Skin from the edge of an ulcer. A, Histopathologic characteristics revealed a mixed inflammatory cell infiltrate with necrosis (hematoxylin-eosin, original magnification ϫ20). B, Intracellular amastigotes later confirmed to be Leishmania tropica (hematoxylin-eosin, original magnification ϫ100; oil immersion).

plausibility of some species that are typically associated cerotropic disease has been considered an oligoparasitic with VL to also produce CL, such as in the case of L in- syndrome, and this issue may explain the nonspecific pre- fantum infection. Conversely, traditionally dermotropic sentation compared with the full-blown syndrome of VL species can disseminate viscerally, leading to visceral dis- characterized by excessive numbers of parasites in in- ease such as we believe occurred in our patient.5,7,8 In- fected macrophages of the reticuloendothelial system. At deed, similar to what has been reported previously in this point, we can speculate that either strain variants of American troops returning from the Middle East, our pa- L tropica or specific host immune response to this para- tient had evidence of viscerotropic disease, as demon- site may explain the dual tropism (dermal and visceral) strated by her clinical findings (anorexia, weight loss, and in our patient. In support of the latter, a recent study12 splenomegaly), laboratory abnormalities (anemia and of a mouse model of dermal infection has begun to char- mild transaminitis), and positive serological evidence of acterize the role of interleukin 10 and transforming growth L tropica infection. We did not have confirmatory evi- factor ␤ in chronic infection with L tropica. dence of visceral involvement (demonstration of organ- Another unusual characteristic of our patient was that isms in visceral tissue samples), which is typically nec- she had lived in the United States for 4 years prior to show- essary for a conclusive diagnosis of VL. However, given ing signs of disease, indicating a prolonged incubation our patient’s clinical scenario, her laboratory results, and period or chronic subclinical infection similar to what the complete resolution of her systemic abnormalities sub- occurs in leishmaniasis recidivans caused by L tropica. sequent to leishmaniasis-specific therapy, the diagnosis The incubation period for cutaneous leishmaniasis typi- of concomitant viscerotropic disease was highly sup- cally varies from weeks to months.1 Visceral disease typi- ported. Notwithstanding this variant of viscerotropic dis- cally manifests after a 3- to 8-month incubation period.1 ease, it becomes relevant to mention that the typical VL Thus, in our patient, who had lived in an L tropica en- syndrome caused by L tropica, although rare, has also been demic region (Pakistan) 4 years prior to presentation, the described.9 The first 2 cases of VL caused by L tropica in incubation period was much longer than is typical. In sup- Africa were reported in 1989.10 Later, in a study of 66 port of a possible longer subclinical period for L tropica patients in southern Iran diagnosed clinically with VL, is a case report7 of an Operation Desert Storm veteran 1 of the 66 cases was found to be caused by L tropica when presenting with visceral L tropica disease 2 years after leav- splenic and bone marrow aspirates were analyzed.11 ing Saudi Arabia. A mid-20th century report13 on cuta- Compared with patients with classic VL and in the pre- neous leishmaniasis also described a possible incuba- viously reported cases of viscerotropic disease in Gulf War tion period of many years. In contrast, the individuals veterans, our patient is unique in that she had clear evi- initially reported with viscerotropic disease returning from dence of L tropica cutaneous infection. This was based the Persian Gulf developed symptoms a median of 7 on her cutaneous findings and confirmed by positive skin months (range, 8 weeks to 1 year) after arrival in the Per- histopathologic examination and culture with isoen- sian Gulf and within 5 months after they left the area.4,5 zyme electrophoresis speciation. Indeed, L tropica is as- In summary, this is a rare report of L tropica–induced sociated with Old World cutaneous disease in urban areas cutaneous leishmaniasis with presumptive coexisting vis- of the Middle East and cities in the Mediterranean area, cerotropic disease and an unusually prolonged incuba- India, and Pakistan. Whether visceral involvement of tion period. The patient’s excellent response to therapy L tropica is rare or only rarely recognized is unknown. supports a strategy of aggressive evaluation for viscero- Little is known about what specific host or parasitic fac- tropic disease in patients with cutaneous leishmaniasis tors facilitate this classically dermotropic organism to turn who also have systemic symptoms that are potentially viscerally. Speculation exists that lack of prior expo- compatible with visceral involvement. We suggest that sure, type of immune response, and strain variation each in the face of growing international travel and migra- may play some role in dissemination. In addition, vis- tion, a diagnosis of leishmaniasis must be considered in

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 civilian overseas travelers, soldiers coming home from nett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principals and Practice of abroad, and foreign-born travelers to the United States Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:3145- 3156. presenting with vague systemic complaints and/or iso- 2. Herwaldt BL. Leishmaniasis. Lancet. 1999;354(9185):1191-1199. lated cutaneous disease even a few months or years after 3. Jacobson RL. Leishmania tropica (: Trypanosomatidae): a per- leaving Leishmania-endemic areas. plexing parasite. Folia Parasitol (Praha). 2003;50(4):241-250. 4. Centers for Disease Control (CDC). Viscerotropic leishmaniasis in persons re- Accepted for Publication: January 12, 2009. turning from Operation Desert Storm: 1990-1991. MMWR Morb Mortal Wkly Rep. 1992;41(8):131-134. Correspondence: Sareeta R. S. Parker, MD, Department 5. Magill AJ, Grogl M, Gasser RA Jr, Sun W, Oster CN. Visceral infection caused by of Dermatology, Grady Memorial Hospital, Emory Uni- Leishmania tropica in veterans of operation desert storm. N Engl J Med. 1993; versity, 1365 Clifton Rd NE, Ste 1100, Bldg A, Atlanta, 328(19):1383-1387. GA 30322 ([email protected]). 6. Kreutzer RD, Grogl M, Neva FA, Fryauff DJ, Magill AJ, Aleman-Munoz MM. Identification and genetic comparison of leishmania parasites causing viscero- Author Contributions: All of the authors had full ac- tropic and cutaneous disease in soldiers returning from Operation Desert Storm. cess to all the data in the study and take responsibility Am J Trop Med Hyg. 1993;49(3):357-363. for the integrity of the data and the accuracy of the data 7. Magill AJ, Grogl M, Johnson SC, Gasser RA Jr. Visceral infection due to Leish- analysis. Study concept and design: Weiss, Vogenthaler, mania tropica in a veteran of Operation Desert Storm who presented 2 years af- and Parker. Acquisition of data: Weiss and Parker. Analy- ter leaving Saudi Arabia. Clin Infect Dis. 1994;19(4):805-806. 8. Ponce C, Ponce E, Morrison A, et al. Leishmania donovani chagasi: new clinical sis and interpretation of data: Vogenthaler and Parker. variant of cutaneous leishmaniasis in Honduras. Lancet. 1991;337(8733):67- Drafting of the manuscript: Weiss, Vogenthaler, Franco- 70. Paredes, and Parker. Critical revision of the manuscript for 9. Sacks DL, Kenney RT, Kreutzer RD, et al. Indian kala-azar caused by Leishmania important intellectual content: Weiss, Vogenthaler, Franco- tropica. Lancet. 1995;345(8955):959-961. Paredes, and Parker. Administrative, technical, and mate- 10. Mebrahtu Y, Lawyer P, Githure J, et al. Visceral leishmaniasis unresponsive to pentostam caused by Leishmania tropica in Kenya. Am J Trop Med Hyg. 1989; rial support: Weiss. Study supervision: Franco-Paredes. 41(3):289-294. Financial Disclosure: None. 11. Alborzi A, Rasouli M, Shamsizadeh A. Leishmania tropica-isolated patient with visceral leishmaniasis in southern Iran. Am J Trop Med Hyg. 2006;74(2):306- 307. REFERENCES 12. Anderson CF, Mendez S, Sacks DL. Nonhealing infection despite Th1 polariza- tion produced by a strain of Leishmania major in C57BL/6 mice. J Immunol. 2005; 1. Jeronimo SMB, De Queiroz Sousa A, Pearson RD. Leishmania species: visceral 174(5):2934-2941. (Kala-Azar), cutaneous, and mucocutaneous leishmaniasis. In: Mandell GL, Ben- 13. Smith PAJ. Long incubation period in leishmaniasis. Br Med J. 1955;2:1143.

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