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Leishmaniasis is a poverty-related disease with two main clinical forms: visceral leishmaniasis and cutaneous leishmaniasis. An estimated 0·7–1 million new cases of leishmaniasis per year are reported from nearly 100 endemic countries. The number of reported visceral leishmaniasis cases has decreased substantially in the past decade as a result of better access to diagnosis and treatment and more intense vector control within an elimination initiative in Asia, although natural cycles in transmission intensity might play a role. In east Africa however, the case numbers of this fatal disease continue to be sustained. Increased conflict in endemic areas of cutaneous leishmaniasis and forced displacement has resulted in a surge in these endemic areas as well as clinics across the world. WHO lists leishmaniasis as one of the neglected tropical diseases for which the development of new treatments is a priority. Major evidence gaps remain, and new tools are needed before leishmaniasis can be definitively controlled.

Some sand fly species are the vectors responsible for the transmission of Leishmania spp. (Kinetoplastida: Trypanosomatidae), the etiological agent of leishmaniasis, and in the state of Sergipe, the two main forms of the disease (visceral and cutaneous) are recorded. Few works show information about the species that form the Phlebotominae fauna in Sergipe. This study aimed to update and determine how they are distributed throughout the state. The study used data from surveys about phlebotomines in Sergipe, from the Program of Surveillance and Control of Visceral Leishmaniasis, carried out by the Central Public Health Laboratory of Sergipe, from 2008 to 2018, along with review and original data from 2022. The commentary on this information was developed with focus on the species that can be vectors for the disease. Sergipe has, up to now, 27 registered species of phlebotomines from 12 genera, 15 of them are of sanitary relevance. Twenty two of these species are in the mesoregion East, 19 in the Agreste, and 11 in the Sertao of Sergipe. The species with the greatest distribution was Evandromyia Ienti (Mangabeira, 1938), present in 74.6% of the municipalities of Sergipe, followed by Lutzomyia longipalpis (Lutz & Neiva, 1912), the main vector of the etiological agent of visceral leishmaniasis in Brazil, present in 68% of the municipalities studied. This study expands the number and distribution of species recorded in the state. This information can contribute to disease containment plans and support health education actions aimed at the control of leishmaniasis in Sergipe.

Northern Morocco is endemic for cutaneous and visceral leishmaniasis. Our entomological investigations aim to evaluate the risk of Leishmania transmission by determining the species composition, the density, and seasonal fluctuation of sand fly populations in endemic and nonendemic areas of leishmaniasis in Tetouan province (North-Western Morocco). Using Sticky-paper traps, 8,370 specimens were collected between May and November 2015 in two localities: peri-urban area of Tetouan city, where leishmaniasis is endemic and that of the Oued Laou village where no cases of leishmaniasis have been recorded. Six sand fly species were identified. The genus Phebotomus was represented by five species: Phlebotomus ariasi, Phlebotomus. longicuspis, Phlebotomus perniciosus, Phlebotomus kazeruni, and Phlebotomus sergenti, while the genus Sergentomyia was represented by only one species Sergentomyia minuta. Phlebotomus perniciosus was dominant in the nonendemic area (47%) while Phlebotomus sergenti was dominant in the endemic area (51%). The spatio-temporal distribution of sand fly populations is discussed according to biotic and abiotic variables. Seasonal fluctuation in sand fly density showed a bimodal pattern for the subgenus Larroussius and a unimodal pattern for the subgenus Paraphlebotomus in Tetouan city. But, in Oued Laou village, a unimodal density distribution for species of the Larroussius subgenus and a bimodal seasonal distribution for species of the subgenus Paraphlebotomus were identified. We affirm the coexistence, in the study area, of vectors of both cutaneous and visceral leishmaniasis, namely P. ariasi, P. longicuspis and P. perniciosus vectors of Leishmania infantum and P. sergenti vector of L. tropica. However, the geographic distribution, the specific abundance, and the activity reveal significant differences between endemic and nonendemic areas in the region.

Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of \"resistance\" related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.

Co-infection of leishmaniasis and HIV is increasingly reported. The clinical presentation of leishmaniasis is determined by the host immune response to the parasite; as a consequence, this presentation will be influenced by HIV-induced immunosuppression. As leishmaniasis commonly affects the skin, increasing immunosuppression changes the clinical presentation, such as in post-kala-azar dermal leishmaniasis (PKDL) and cutaneous leishmaniasis (CL); dermal lesions are also commonly reported in visceral leishmaniasis (VL) and HIV co-infection. We reviewed the literature with regard to dermal manifestations in leishmaniasis and HIV co-infection, in three clinical syndromes, according to the primary presentation: PKDL, VL, or CL. A wide variety of descriptions of dermal leishmaniasis in HIV co-infection has been reported. Lesions are commonly described as florid, symmetrical, non-ulcerating, nodular lesions with atypical distribution and numerous parasites. Pre-existing, unrelated dermal lesions may become parasitized. Parasites lose their tropism and no longer exclusively cause VL or CL. PKDL in HIV co-infected patients is more common and more severe and is not restricted to Leishmania donovani. In VL, dermal lesions occur in up to 18% of patients and may present as (severe) localized cutaneous leishmaniasis, disseminated cutaneous leishmaniasis (DL) or diffuse cutaneous leishmaniasis (DCL); there may be an overlap with para-kala-azar dermal leishmaniasis. In CL, dissemination in the skin may occur resembling DL or DCL; subsequent spread to the viscera may follow. Mucosal lesions are commonly found in VL or CL and HIV co-infection. Classical mucocutaneous leishmaniasis is more severe. Immune reconstitution disease (IRD) is uncommon in HIV co-infected patients with leishmaniasis on antiretroviral treatment (ART). With increasing immunosuppression, the clinical syndromes of CL, VL, and PKDL become more severe and may overlap. These syndromes may be best described as VL with disseminated cutaneous lesions (before, during, or after VL) and disseminated cutaneous leishmaniasis with or without visceralization.

Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

The leishmaniases are diseases caused by pathogenic protozoan parasites of the genus Leishmania. Infections are initiated when a sand fly vector inoculates Leishmania parasites into the skin of a mammalian host. Leishmania causes a spectrum of inflammatory cutaneous disease manifestations. The type of cutaneous pathology is determined in part by the infecting Leishmania species, but also by a combination of inflammatory and anti-inflammatory host immune response factors resulting in different clinical outcomes. This review discusses the distinct cutaneous syndromes described in humans, and current knowledge of the inflammatory responses associated with divergent cutaneous pathologic responses to different Leishmania species. The contribution of key hematopoietic cells in experimental cutaneous leishmaniasis in mouse models are also reviewed and compared with those observed during human infection. We hypothesize that local skin events influence the ensuing adaptive immune response to Leishmania spp. infections, and that the balance between inflammatory and regulatory factors induced by infection are critical for determining cutaneous pathology and outcome of infection.