cells and associated interferon-γ-induced macrophage activation. That response sets the stage for control, but probably not uniform eradication, of the parasite. Macrophage defenses required to kill Leishmania have been extensively studied, as have the pathogen’s antiphagocytic defenses (Cunningham 2002; Teixeira et al. 2006).

Of the twelve people who had viscerotropic leishmaniasis caused by L. tropica in the Gulf War, one was asymptomatic, and the remainder had a mixed picture involving many of the classic features of VL (Hyams et al. 1995; Magill et al. 1994). Those presentations were distinguished from typical VL in that anemia was typically the sole hematologic sign, and most patients had modest increases in liver enzymes. Three of the patients had an underlying disease of relevance: HIV, acute infection with Epstein-Barr virus, and renal-cell cancer (Hyams et al. 1995).

Diagnosis of Leishmaniasis

Several methods have been used to diagnose the various forms of leishmaniasis. Most CL is diagnosed on the basis of its classic clinical appearance, although if the lesion is atypical, prolonged, or not responsive to therapy, biopsy may be performed at the margin of the lesion. PCR is increasingly used in this setting, especially because misdiagnosis may occur (many lesions clinically diagnosed as CL are bacterial in origin). PCR was the mainstay of diagnosis in a recent description of 237 cases of CL acquired in OIF (Willard et al. 2005). Skin testing based on antigens of L. major demonstrates prior infection with Leishmania spp. and is usually positive in active CL caused by L. major.

VL is often diagnosed on the basis of histopathologic detection of amastigotes in biopsy or aspirate of bone marrow, spleen, or lymph nodes. Indirect immunofluorescent monoclonal antibody can also be applied to those tissues. Biopsy samples can be directly cultured, and isoenzyme analysis used for further speciation. Serum antibody testing, often used in assessment of persons with suspected VL, is most commonly performed with the direct agglutination test. However, the performance of this test is highly variable; in fact, serology was negative in a number of the viscerotropic cases identified in Gulf War soldiers. Available serologic tests are based on L. major antigens, so the relevance to viscerotropic leishmaniasis (caused by L. tropica) is unclear. Finally, some investigators have reported that urine-based assays that detect either Leishmania antigen (Sundar et al. 2005) or Leishmania-specific IgG (Islam et al. 2002) were valuable in diagnosing VL.

Treatments for Leishmaniasis and Related Long-Term Toxicity

Most cases of CL will resolve without specific medical therapy. Oral azoles (fluconazole and ketoconazole), cryotherapy, or paromomycin ointment may hasten resolution. Under study is a device called ThermoMed that delivers radiofrequency-generated heat directly to a lesion through a set of prongs placed on the lesion; the device has Food and Drug Administration 510K clearance as of this writing.

Systemic treatment is always indicated for VL. The mainstay of therapy has been pentavalent antimonials, including sodium stibogluconate and meglumine antimonite (Aronson et al. 1998; Murray 2000; Murray 2004). Liposomal amphotericin B was traditionally reserved for antimony-treatment failures, but it is increasingly used as first-line therapy and has been the regimen of choice for soldiers who acquired VL in OEF. Antimonials are not well tolerated in the acute treatment period. Gastrointestinal intolerance, bone marrow suppression, and



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