BackgroundCutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance.Methodology/Principal FindingsThis study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sbv) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sbv. Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sbv group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p = 0.04). Miltefosine was more effective than Sbv in the age group of 13–65 years-old compared to 2–12 years-old group (78.9% versus 45% p = 0.02; 68.2% versus 70% p = 1.0, respectively). The incidence of adverse events was similar in the Sbv and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sbv group.ConclusionsThis study demonstrates that miltefosine therapy is more effective than standard Sbv and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil.Trial RegistrationClinicaltrials.gov Identifier NCT00600548

In Corte de Pedra (CP), northeastern Brazil, Leishmania braziliensis causes three distinct forms of American tegumentary leishmaniasis (ATL). To test the hypothesis that strain polymorphism may be involved in this disease spectrum and accurately characterize the parasite population structure in CP, we compared one L. major, two non-CP L. braziliensis, one CP L. amazonensis, and 45 CP L. braziliensis isolates, obtained over a 10-year period from localized cutaneous, mucosal, and disseminated leishmaniasis patients, with randomly amplified polymorphic DNA (RAPD). Electrophoretic profiles were mostly unique across species. All typing protocols revealed polymorphism among the 45 CP L. braziliensis isolates, which displayed eight different RAPD patterns and greater than 80% overall fingerprint identity, attesting to the adequacy of the tools to assess strain variability in CP's geographically limited population of parasites. The dendrogram based on the sum of RAPD profiles of each isolate unveiled nine discrete typing units clustered into five clades. Global positioning showed extensive overlap of these clades in CP, precluding geographic sequestration as the mechanism of the observed structuralization. Finally, all forms of ATL presented a statistically significant difference in their frequencies among the clades, suggesting that L. braziliensis genotypes may be accompanied by specific disease manifestation after infection.

The addition of pentoxifylline to Sb(v) in mucosal leishmaniasis reduces the healing time significantly and prevents the need for further courses of Sb(v).

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IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.

Leishmaniasis constitutes a spectrum of human diseases caused by protozoa belonging to the genus Leishmania, divided into two subgenera, Leishmania, which is present in both the Old World and the New World, and Viannia, which is restricted to the New World. Productive infections may either be asymptomatic or lead to different clinical syndromes involving internal organs, skin, and/or mucosal surfaces (3). Leishmania (Viannia) braziliensis is endemic in Latin America and causes at least three distinct clinical types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL) (3,4,6,9,29). The most striking feature that differentiates CL from either ML or DL is the degree of metastasis of lesions from the original inoculation site. CL lesions are restricted to the entry site of the parasites, whereas ML is defined by spreading to mucosal surfaces of the upper digestive and airways tracts. DL is characterized by wide dissemination to distant cutaneous sites. Some individuals with DL develop hundreds of lesions throughout their body surfaces.Many reports cite ML as the most common metastatic form of disease caused by L. (V.) braziliensis. It was previously more common, but ML currently develops in 4 to 5% of individuals with CL (2, 7, 17). Recently, in our study area, DL has emerged as the most prevalent metastatic form of L. (V.) braziliensis infection (26). The present study is based on the hypotheses that different strains of L. (V.) braziliensis are prone to cause the different forms of ATL, and it is the spread of a DL-predisposing strain that is responsible for the increasing incidence of this new cutaneous syndrome.Individuals living in the region of Corte de Pedra in the state of Bahia, Northeast Brazil, can be afflicted by any of the three forms of ATL due to L. (V.) braziliensis. However, DL has only recently been recognized in Corte de Pedra (6, 9). Careful longitudinal study of this form of leishmaniasis has revealed a recent increase in the absolute numbers of DL cases, an increase in the relative proportion of DL cases compared to the total number ATL cases, and a pattern of geographic spread of the disease across a wider region of Corte de Pedra over the past 2 decades (16,26,29). Indeed, the geographic distribution of DL cases differs from that of ML in Corte de Pedra, which led us to investigate the regional risks of these two forms of L. (V.) braziliensis disease (26).One of the first clues that different parasite strains may contribute to the different ATL forms was in vitro evidence showing that the total antigen from L. (V.) braziliensis isolated from a DL patient caused peripheral blood mononuclear cells to release larger amounts of the proinflammatory cytokines gamma interferon and tumor necrosis factor alpha than the total antigen of a parasite from a subject with CL (14). Parallel investigations revealed that parasites isolated from ATL patients could be distinguished according to randomly amplified poly...

Abstract. The Health Post of Corte de Pedra is located in a region endemic for American tegumentary leishmaniasis (ATL) in the Brazilian state of Bahia, and it treats 500-1,300 patients annually. To describe temporal changes in the epidemiology of ATL, we reviewed a random sample of 10% of patient charts (N = 1,209) from 1988 to 2008. There was a twofold increase in the number of cases over the 20-year period, with fluctuations in 10-year cycles. Patients were most frequently male, between the ages of 10 and 30 years, and engaged in agricultural labor; 4.3% of patients had mucosal disease, and 2.4% of patients had disseminated disease. Over the study period, the number of disseminated cases increased threefold, the proportion of cases in younger patients and agricultural workers decreased, and the proportion of patients residing in coastal areas increased. ATL is on the rise in Bahia, with a 10-year periodicity and evolving changes in epidemiology and manifestations of disease.

Leishmania braziliensis is a parasite that can induce at least two clinical forms of leishmaniasis in humans: cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). In humans, the specific mechanisms that determine which form will develop following infection are not well established. In this study, peripheral blood mononuclear cells from 17 CL and 9 ML patients were compared both ex vivo and after culture with soluble leishmania antigen (SLA). Patients with ML presented a higher frequency of activated T cells as measured by ex vivo frequen-þ than those with CL. Moreover, after stimulation with SLA, patients with ML presented a higher frequency of TNF-a-producing CD4 þ and CD14 þ cells than CL individuals. While CL patients displayed a positive correlation between the frequency of IL-10 and TNF-a-producing monocytes, the ML patients did not. This lack of a positive correlation between IL-10-producing and TNF-aproducing monocytes in ML patients could lead to a less controlled inflammatory response in vivo. These results corroborate with a model of an exacerbated, unregulated, immune response in ML patients and point to key immunomodulatory leucocyte populations and cytokine networks that may be involved in the development of immunopathology in ML patients.