Cutaneous and Presumed Visceral Leishmaniasis in a Soldier Deployed to Afghanistan

Abstract

Leishmaniasis has been frequently diagnosed in US military personnel returning from duty in Southwest Asia. The majority of cases have demonstrated cutaneous disease, although a few cases of visceral disease have been documented. We present the case of an immunocompetent, HIV-negative, US Army soldier who suffered both visceral and cutaneous manifestations of leishmaniasis after returning from deployment in Afghanistan. Overlap of cutaneous and visceral involvement is rare and has not been reported in our cohort. Latent Plasmodium vivax infection may have been an exacerbating cofactor. We discuss this case and present a review of the literature.

Introduction

Infection with the obligate intramacrophage parasite Leishmania is common in the Middle East, posing a serious health concern for immune-naive US troops deployed to the area.[1] Between August 2002 and February 2004, 522 cases of parasitologically confirmed cutaneous leishmaniasis (CL) have been reported in this particular population.[2] No official data have been published since 2004, but Walter Reed Army Medical Center (WRAMC) Infectious Diseases staff physicians indicate that the number of cases has continued to grow since 2004.

Leishmania is found in humans only as an incidental host, using small mammals as a reservoir in most urban cases. Using the sand fly as a vector,[3] Leishmania causes 3 distinct clinical syndromes in humans, encompassing cutaneous, visceral, and mucosal variants. The large majority of clinically apparent infections in US military personnel have been cutaneous. Of the cases evaluated from Operations Iraqi and Enduring Freedom, visceral involvement has been confirmed in only 4 patients.[4] Leishmania major has been identified as the responsible species in the overwhelming majority of cutaneous cases, while L donovani complex has been the only isotype recovered from patients with visceral disease. The current report is the first case of an American soldier with both cutaneous and visceral manifestations of leishmaniasis.

Case Report

A 35-year-old man presented to his local hospital, complaining of persistent fevers, testicular pain, night sweats, and weight loss. His symptoms began 1 week prior to presentation. He also noted a nonhealing lesion on his right forearm, which had been present for 3 months. An active-duty US Army soldier, he had recently returned from an 8-month deployment to Afghanistan near the Pakistani border. From the perspective of his health, he reported that his duty there had been uneventful except for numerous insect bites, which occurred despite the use of insect repellant, and 2 or 3 mild, self-limited bouts of diarrhea. While deployed he routinely ate food from the local economy and was exposed to local livestock. He reported complete adherence to his mefloquine malaria prophylaxis regimen, though he took only 3 doses of his primaquine for terminal prophylaxis. He stopped taking this medication due to perceived side effects. He began to feel ill 7 days after his return to the United States, and it was at this time that he sought medical attention.

On initial presentation to an outlying hospital, the patient had normal vital signs. His physical exam was notable for a 1×1-cm dry ulcer on the volar surface of his right forearm. His spleen was not palpable and he had no notable lymphadenopathy. His only recent medication was primaquine, which had been discontinued a few days earlier. Laboratory workup was significant for a mild normocytic anemia, a mild leukopenia, and a slight elevation of liver-associated enzymes (Hgb 12.4g/dL, MCV 87 fl, WBC 2800 cells/mm³, PLT 252×10³/mL, AST 186 U/L, ALT 372 U/L). A thick and thin smear for malarial parasites was negative. Radiographic data included a normal chest radiograph. A shave biopsy of his forearm lesion was subsequently performed and amastigotes were directly visualized, confirming a diagnosis of cutaneous leishmaniasis. PCR analysis of the tissue biopsy identified L donovani complex as the causative organism. At this time the patient was transferred to Walter Reed Army Medical Center (WRAMC) for further evaluation.

Upon arrival to WRAMC, the patient continued to complain of fevers, weight loss, night sweats, and testicular pain. He had developed diarrhea, consisting of 3 to 4 loose watery bowel movements per day. His temperature was 102 degrees F with otherwise normal vital signs. Initial laboratory studies revealed a persistence of his leukopenia, anemia, and elevated liver-associated enzymes, but a normal platelet count. Blood and urine cultures, as well as 3 additional thick and thin blood smears for malaria, were negative. Serum HIV enzyme-linked immunoadsorbent assay (ELISA) was negative. An elevated lactate dehydrogenase (LDH) and an undetectable haptoglobin were consistent with hemolysis. He had a negative stool culture, negative ova and parasite screen, negative occult blood, and negative fecal leukocytes. A computed tomography scan of his abdomen and pelvis revealed splenomegaly and thickening of the sigmoid colon.

The differential diagnosis at that point included visceral leishmaniasis vs other endemic and troop-common illnesses including lymphoma, brucellosis, tuberculosis, typhoid fever, and Q fever. A serum Kalazar Detect Assay (InBios, Seattle, Washington) was positive, consistent with a diagnosis of visceral leishmaniasis (VL). A bone marrow biopsy and aspirate was performed and revealed a normal marrow histopathology, and cultures for mycobacteria, fungi, Leishmania, Brucella, and routine pathogens were negative. A PCR assay of the bone marrow tissue for Leishmania was also negative. Given his exposure history, clinical syndrome, multiple negative malaria smears, and a positive rK39 assay, a presumed diagnosis of VL was made and treatment was initiated.

The patient received liposomal amphotericin B (Ambisome, Astellas Pharma US, Inc., Deerfield, Illinois) at an intravenous dose of 3 mg/kg per day. He was dosed on Days 1 through 5, then again on Days 14 and 21 without any significant drug toxicity. The patient became afebrile, and laboratory studies demonstrated normalization of his liver-associated enzymes and improvement in his leukopenia and anemia. The patient was discharged from the hospital and returned home. However, after several weeks of clinical normalcy he became acutely ill and was diagnosed with malaria (P vivax), which was successfully treated with chloroquine and primaquine.

Discussion

Both cutaneous and visceral leishmaniasis have been reported in troops returning from Operations Iraqi and Enduring Freedom,[1,2] but the current case represents the first case of leishmaniasis with concurrent manifestations of CL and presumed VL in our cohort. The simultaneous presentation of CL and VL is rare in the presence of an intact immune system. Manson-Bahr[5] reported in 1955 that some immunocompetant patients with CL may eventually develop VL through lymphatic spread; however, this theory has not been proven over time.[6] A more recent report of VL occurring 4 months following CL has been described in a child.[6] The parasites in this case were not typed, so it is possible that the patient was infected by different zymodemes. Another report from Israel described L donovani complex being isolated from both skin and bone marrow biopsies of a 41-year-old with simultaneous CL/VL manifestations.[7] In a Brazilian study of 18 patients with VL, 7 patients yielded skin cultures positive for L chagasi.[8] In that study, only 2 patients had cutaneous lesions, while 16 cases were from biopsies of clinically normal skin. Simultaneous cutaneous and visceral disease is a known phenomenon in the HIV patient population,[9–11] and it often is an opportunist of concomitant cutaneous morbidity such as Kaposi's sarcoma. It is reported that cutaneous/visceral overlap syndromes are seen in 2%-12% of HIV-positive cases.[12]

VL is not generally associated with cutaneous ulcers, and those affected do not usually recall any insect bite or lesion at the site of inoculation. However, the interplay of cutaneous and visceral disease is further clouded by the recognition of post kala-azar dermal leishmaniasis (PKDL). PKDL is an entity associated both with L donovani and infantum, and is manifest by diffuse skin lesions that typically develop after therapy for VL.

L donovani complex, which includes L infantum, L chagasi, and L donovani, is responsible for most cases of VL.[13] Though the majority of cases are asymptomatic, a fulminant, often fatal progression of disease may develop. Known in endemic populations as kala-azar (Hindi for “the black sickness”), this can present with severe fever, fatigue, and cachexia following an incubation period ranging from weeks to months.[14] Organisms are spread via the reticuloendothelial system and may be found in the spleen, liver, and bone marrow. Clinical features include hepatosplenomegaly, pancytopenia, and elevated liver-associated enzymes. Gastrointestinal involvement, including diarrhea, is a known manifestation of VL regardless of HIV status.[12] However, gastrointestinal symptoms are more common among children and HIV-positive individuals.[12,15,16]

Classically, VL is diagnosed by demonstrating the presence of Leishmania organisms in visceral tissue. The bone marrow, liver, and spleen offer the highest-yield biopsy sites.[17] Proving Leishmania infection is accomplished by direct visualization under light microscopy, tissue culture, animal inoculation, detection of DNA via PCR, or detection of parasite-specific antigens.[18] Invasive procedures confirm the diagnosis, but carry the risk of complications. Technical expertise presumably decreases the risk of complications, and 1 center has reported only 2 cases of fatal hemorrhage in a total of 9612 splenic biopsies performed over 10 years.[18]

Recently, a noninvasive immunochromatographic test strip for VL has been marketed in the United States. The test uses a recombinant k39 antigen cloned from L chagasi, which is immobilized on a nitrocellulose membrane, and will produce a colored band when exposed to sera with target antibodies.[18] This test is inexpensive, accurate, and can be performed in the field by inexperienced personnel. A specificity ranging from 93% to 99% and a sensitivity ranging from 89% to 97% have been confirmed in both retrospective[19] and prospective studies[20–23] using splenic and bone marrow biopsies as a gold standard. Furthermore, the test has been shown to not be falsely positive in patients with CL, although this finding was based on a study of patients with CL caused by L braziliensis and may not be applicable to patients infected with L donovani complex.[24] It is also important to mention that these studies used Leishmania-endemic populations, and so the test characteristics may not apply when used on US military personnel.

In the case described in the current report, the initial diagnosis of VL was made using the rK39 dipstick. The Leishmania parasite was not isolated by subsequent bone marrow or colorectal biopsy. The sensitivity of bone marrow biopsy in detecting VL has been reported at 60% to 85% in 1 study[17] and 55% to 97% in another.[15] Given a positive rK39 assay in the setting of strong clinical suspicion and negative results on other diagnostic assays, the patient was treated empirically for VL. The patient's rapid clinical and laboratory responses to Ambisome were reassuring and supportive of the diagnosis.

There are 3 alternative explanations for this patient's unusual presentation. First, it is possible that our patient was infected with 2 different zymodemes of L donovani complex species, which would explain his seemingly contradictory clinical manifestations (cutaneous and visceral).[25,26] An analysis of L infantum zymodemes isolated from patients with cutaneous disease suggested a correlation between isotype and clinical pattern of disease (visceral vs cutaneous).[25] Another study reported treatment failure in a patient with a mixed infection with the parasite L infantum.[26] The authors suggested that the mixed infections with different strains may explain the differences in clinical course experienced by patients.[26] Our patient's geographic exposure would be supportive of this supposition. L donovani is a more common cause of VL in East Africa and the Indian subcontinent, while L infantum is more commonly found in Southern Europe, North Africa, and the Mediterranean Basin.[27,28] Our patient was deployed along the Afghan/Pakistani border, which would potentially put him at risk for infection with either, or both, organisms.

Second, it is possible that the patient's clinical manifestations were a result of infection with Plasmodium vivax. Multiple blood smears for malaria parasites were examined during the hospital course, all of which were negative. In addition, the patient's normal platelet count during hospitalization argues against active malaria (the patient was thrombocytopenic when he later presented with documented malaria infection). Finally, the patient's clinical response to Ambisome (resolution of fever and laboratory abnormalities) suggests that his initial febrile episode was due to VL. Plasmodicidal properties of amphotericin have been reported,[29,30] though this has not been investigated in vivo. Therefore, we believe it is more likely that the presence of latent infection with P vivax was a confounding variable in this case. Both leishmaniasis and P vivax malaria are endemic to Afghanistan. Co-infection has been reported, as have suggestions of enhanced virulence by Leishmania in the setting of malaria.[31–35]

A final alternative explanation for this patient's clinical course would be an underlying, undiagnosed, immunosuppressive medical condition. Simultaneous presentation of cutaneous and visceral manifestations, as mentioned previously, is not uncommon in immunosuppressed patient populations (specifically patients with late-stage HIV infection). Our patient had negative HIV serologic tests performed during the initial evaluation and 6 months later. He was not taking any immunosuppressive medications, and there was no clinical/laboratory/radiologic suggestion of malignancy, connective tissue disease, or primary immunodeficiency. The patient had no prior history of unusual or recurrent infections, and remains well after treatment for presumed VL and malaria.

Conclusion

We report on a case involving a US soldier returning from Afghanistan with concomitant manifestations of cutaneous and visceral leishmaniasis, as well as latent infection with P vivax. Such presentation is rare, and highlights the importance of considering VL in the presence of CL, as well as the possibility of co-infection with other endemic diseases in the evaluation of ill travelers.

Note: The opinions or assertions contained herein are those of the authors and should not be construed as reflecting the views of the Department of the Army or the Department of Defense.