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Background: Clinical cases of leishmaniasis caused by Leishmania (Mundinia) parasites have been increasingly reported in Southeast Asia, particularly Thailand. Recent evidence has shown that Leishmania (Mundinia) parasites successfully developed into infective metacyclic promastigotes in Culicoides biting midges, strongly supporting their putative role in disease transmission. However, Culicoides diversity, host preference, and Leishmania prevalence in endemic areas remain largely unknown. Methods: We investigated the seasonal dynamics, infection prevalence, and blood meal identification of Culicoides collected from the emerging focus of visceral leishmaniasis in Lampang Province, Northern Thailand, during 2021–2023. Midge samples were molecularly screened for Leishmania using SSU rRNA-qPCR and ITS1-PCR, followed by Sanger plasmid sequencing, and parasite haplotype diversity was analyzed. Host blood meal origins were comparatively identified using host-specific Cytb-PCRs and a nanopore-based metabarcoding approach. Results: A total of 501 parous and gravid females and 46 blood-engorged ones belonging to at least 17 species of five subgenera (Remmia, Trithecoides, Avaritia, Hoffmania, and Meijerehelea) and two species groups (Shortti and Calvipalpis) were collected with temporal differences in abundance. Leishmania was detected by SSU rRNA-qPCR in 31 samples of at least 11 midge species, consisting of Culicoides oxystoma, C. guttifer, C. orientalis, C. mahasarakhamense, C (Trithecoides) spp., C. innoxius, C. shortti, C. arakawae, C. sumatrae, C. actoni, and C. fulvus, with the overall infection prevalence of 5.7%. The latter six species represent the new records as putative leishmaniasis vectors in Northern Thailand. The ITS1-PCR and plasmid sequencing revealed that Leishmania martiniquensis was predominantly identified in all qPCR-positive species, whereas L. orientalis was identified only in three C. oxystoma samples. The most dominant haplotype of L. martiniquensis in Thailand was genetically intermixed with those from other geographical regions, confirming its globalization. Neutrality test statistics were also significantly negative on regional and country-wide scales, suggesting rapid population expansion or selective sweeps. Nanopore-based blood meal analysis revealed that most Culicoides species are mammalophilic, with peridomestic and wild mammals (cow, pig, deer, and goat-like species) and humans as hosts, while C. guttifer and C. mahasarakhamense fed preferentially on chickens. Conclusions: This study revealed seasonal dynamics and sympatric circulation of L. martiniquensis and L. orientalis in different species of Culicoides. Evidence of human blood feeding was also demonstrated, implicating Culicoides as putative vectors of human leishmaniasis in endemic areas. Further research is therefore urgently needed to develop vector control strategies and assess the infection status of their reservoir hosts to effectively minimize disease transmission. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is an urgent public health concern in Brazil. We evaluated the spatiotemporal distribution of VL to better understand the effects of economic activities related to agriculture, livestock, and deforestation on its incidence in the Brazilian Legal Amazon (BLA). The data on newly confirmed cases of VL in Brazilian municipalities from 2007 to 2020 were extracted from the Brazilian Notifiable Diseases Information System (SINAN) and analyzed. The data on agricultural production (planted area in hectares) and livestock (total number of cattle) were obtained from the Brazilian Institute of Geography and Statistics (IBGE), whereas deforestation data (in hectares) were obtained from the Amazon Deforestation Estimation Project (PRODES). SatScan and the local indicators of spatial association (LISA) were used to identify the spatial and temporal patterns of VL and its relationships with economic and environmental variables. The cumulative incidence rate was found to be 4.5 cases per 100,000 inhabitants. Based on the LISA results, areas with a high incidence of VL and deforestation were identified in the states of Roraima, Pará, and Maranhão. Strengthening deforestation monitoring programs and environmental enforcement actions can help implement public policies to control illegal deforestation and mitigate the socio-environmental vulnerability in the BLA. Therefore, areas identified in this study should be prioritized for controlling VL. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis (VL) is among the world's most serious public health threats, causing immense human suffering and death. In Ethiopia, little is known about the barriers and facilitators of visceral leishmaniasis case management. This study aimed to explore such barriers and facilitators in the Amhara Regional State, Northwest Ethiopia. Methods: An exploratory qualitative study was conducted on 16 purposively selected patients and key informants from May 8 to June 2, 2023. The study participants were recruited using the maximum variation technique. The interviews were audio recorded, transcribed verbatim, and translated into English. Thematic analysis was employed using Atlas.ti 9 software with a blended approach of both deductive and inductive coding. Results: The study identified a variety of issues that hinder the success of visceral leishmaniasis case management. Treatment centers face frequent interruptions of medicinal supplies, a lack of funding, and a lack of trained healthcare providers. A lack of support from health authorities, including weak supervision and feedback systems, is also a source of concern. Most patients receive treatments after significant delays, which is primarily due to low awareness, poor surveillance, and misdiagnosis by healthcare workers. The case management is further constrained by malnutrition, VL-HIV co-infection, and other comorbidities. Despite these issues, we found that effective collaboration between hospital units and VL treatment centers, acceptance by hospitals, and the caring attitude of healthcare workers play a positive role in facilitating the program's effectiveness. Conclusions: Despite the existence of certain efforts that facilitate the program's effectiveness, VL remains largely neglected, with little government attention or intervention. Such inattention is the root cause of most of the issues. Despite limited resources, most issues could be resolved with cost-effective strategies if health authorities at all levels have the will and commitment to do so. [ABSTRACT FROM AUTHOR]

Introduction: Hemophagocytic lymphohistiocytosis characterized by hemophagocytosis leading to uncontrolled inflammation; the most common etiology in secondary cases of hemophagocytic lymphohistiocytosis is viral infections, especially Epstein–Barr virus. Visceral leishmaniasis is a vectorborne protozoal disease caused by Leishmania donovani complex. It is common in tropical and subtropical regions, with 50,000–90,000 new cases annually. Case presentation: A 15-month-old Arab female was admitted to our hospital with 15 days of fever and decreased weight. On clinical examination, she had a markedly enlarged liver and spleen that were palpable 4 cm and 6 cm below the costal margin, respectively. The peripheral blood smear showed hypochromic microcytic anemia, poikilocytosis, reactive lymphocytosis, and mild thrombocytopenia. Bone marrow aspiration did not show malignancy or any other pathological findings. The patient was put on antibiotic therapy without improvement. Repeated bone marrow aspiration showed erythrophagocytosis; intracellular small round organisms looked like the amastigote form of Leishmania (Donovan bodies) with no evidence of malignancies. Her lab values showed ferritin greater than 500 ug/L, pancytopenia, and hypertriglyceridemia. The patient was diagnosed with hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis. Conclusion: Hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis is an extensively rare phenomenon in the medical literature that causes challenges in diagnosis and management. Steroids should be used wisely to not cover the symptoms of infections or malignancy, and amphotericin B resistance should be kept in mind in unresponsive Leishmania cases. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Visceral leishmaniasis (VL) is a severe parasitic disease transmitted by phlebotomine sandflies. VL is endemic in West Pokot County, Kenya, where effective strategies to interrupt transmission are impeded by the limited understanding of VL risk factors. Therefore, this case–control study aimed to explore environmental, behavioural and household determinants of VL in West Pokot.From November 2022 to January 2023, a structured questionnaire was administered to 36 symptomatic primary VL cases attending Kacheliba Sub‐County Hospital in West Pokot and to 50 healthy controls from local villages. The VL status of all participants was confirmed using an rK39 rapid diagnostic test. Associations between questioned determinants and VL were investigated by means of age‐corrected univariate logistic regression analysis.Significant associations were found between VL and housing characteristics, such as window presence and floor type. VL cases more frequently reported the presence of cattle, dogs and sheep in their house yards. VL was also associated with cutting down trees in the house yard and house proximity to several Acacia tree species. Furthermore, outdoor activities, including travelling outside the residence for more than 2 weeks, activities near termite mounds, and forest activities during the rainy season, increased the risk of VL.This work reports a number of previously undescribed risk factors for VL in the understudied West Pokot focus. The results suggest VL transmission occurs both peri‐domestically at night and outdoors during the day, particularly when sandfly resting sites are disturbed. Our findings warrant further research into sandfly ecology and potential zoonotic parasite reservoirs in West Pokot. [ABSTRACT FROM AUTHOR]

Human visceral leishmaniasis (VL) is an endemic disease in eastern Sudan, particularly in Al Gadarif State, causing significant morbidity and fatality rates. This disease is induced by Leishmania donovani and Leishmania infantum. Several studies have suggested that dogs (Canis familiaris), which are known for being the primary reservoir hosts of L. infantum (causing canine leishmaniasis), may play a vital role in transmitting human VL caused by L. donovani. This study aimed to determine the prevalence of leishmaniasis in general and L. donovani, particularly in dogs, and to investigate the potential risk factors associated with the disease in Al Gadarif State. Blood samples were collected from 151 dogs from five localities and examined using Giemsa-stained blood smears and PCR. The overall prevalence was 44.4% based on microscopic examination. Significant variation in the prevalence of leishmaniasis was observed among the localities (p = 0.000), where the highest prevalence was reported in Algurreisha (85%) and the lowest was observed in Alhawata (4.2%). Dog type was another risk factor that was shown to be significantly associated with infection (p = 0.041). The highest prevalence was reported in household dogs (47.7%) compared to stray dogs (23.8%). The analysis revealed that factors such as the use of dogs, sex, and age were not statistically linked to the disease. However, among household dogs, the highest prevalence was reported in pet dogs (59.7%), males (49.1%) compared to females (32.6%), and young dogs (50%) compared to older dogs (40.9%). All blood samples tested negative for L. donovani by PCR, thus requiring further investigation to identify the causative species in dogs and their possible roles in the epidemiology of zoonotic leishmaniasis in Sudan. [ABSTRACT FROM AUTHOR]

In the American regions, Brazil accounts for 97% of visceral leishmaniasis (VL) cases, with a case fatality rate of approximately 10%. This study aimed to investigate the VL mortality distribution in Brazil and identify high-priority and high-risk areas for intervention strategies. This was an ecological study that analysed the spatial–temporal patterns of VL mortality in Brazilian municipalities. Age-standardised VL mortality rates from the Global Burden of Disease study from 2001 to 2018 were used. The distribution of mortality in the municipalities was assessed, and subsequently the Local Index of Spatial Autocorrelation (LISA) analysis was conducted to identify contiguous areas with high mortality rates. Scan analysis identified clusters of high spatial–temporal risks. The highest mortality rates and clusters were in municipalities located in the Northeast region and in the states of Tocantins and Roraima (North region), Mato Grosso do Sul (Central-West region), and Minas Gerais (Southeast region). According to LISA, there was an increase in the number of municipalities classified as high priority from the first 3-year period (n = 434) to the last 3-year period (n = 644). The spatio-temporal analysis identified 21 high-risk clusters for VL mortality. Areas with a high risk of VL mortality should prioritise preventing transmission, invest in early diagnosis and treatment, and promote the training of healthcare professionals. [ABSTRACT FROM AUTHOR]

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Visceral Leishmaniasis is a serious public health problem caused by Leishmania species parasites. Approximately 500 thousand people get Visceral Leishmaniasis (VL) every year. An effective and reliable vaccine against the disease has still not been formulated. Choosing the right adjuvant is important to increase immunogenicity in vaccines prepared with total antigens. In this study, we investigate the ideal adjuvant for use in vaccine formulations against VL. For this purpose, Leishmania antigens (FTLA) obtained from L. infantum parasites by the freeze-thaw method and three different adjuvants (alum-saponin and calcium phosphate) were used. The effectiveness of the formulations was investigated in vitro by cell viability analysis and determination of nitric oxide and cytokine production abilities in J774 macrophage cells. According to the study results, it was determined that formulations prepared with calcium phosphate produced 72% more NO and approximately 7.2 times more IL-12 cytokine. The results obtained showed that calcium phosphate salts can be used as ideal adjuvants in vaccine research against leishmaniasis. [ABSTRACT FROM AUTHOR]

Introduction: In Ethiopia, visceral leishmaniasis (VL) is a public health concern that has been spreading to new endemic foci in recent years. An estimated 3.2 million people are at risk of infection, with 3700–7400 new cases yearly. Thus, the study aimed to determine the prevalence of VL and associated risk factors among febrile patients attending Metema Hospital, North West Ethiopia. Methods: A hospital-based cross-sectional study was conducted on 404 febrile patients attending Metema Hospital from February 2021 to June 2021. The test for VL was done using an immune-chromatographic test (RK39) according to the manufacturer's instructions (InBios International Inc., USA). An interviewer-administered, pretested questionnaire was used to collect data on risk factors associated with VL. Logistic regression and Chi-square assessed the association between VL and the associated risk factors. Reults: The overall prevalence of visceral leishmaniasis was 18.8% (76/404), with a higher prevalence of VL in males, in the age category between 21 and 30, in study participants who completed elementary school, and in those who earned less than 500 birr monthly compared to their counterparts. Houses with thatched roofs (adjusted odd ratio (AOR) = 17.648, 95CI = 6.549,47.563), houses with mud walls (AOR = 2.538, 95% CI = 1.187–5.411), cattle ownership (AOR = 3.173, 95% CI = 1.286–7.826), dog ownership (AOR = 2,533, 95% CI = 1.256–5.111), presence of Acacia trees near houses (AOR = 1.975, 95% CI:1.004–3.886), presence of Balanites tree (AOR = 3.015, 95% CI = 1.610–5.992), and outdoor sleeping (AOR = 2.259, 95% CI: 1.107–14.607) were the predictors of VL in the present study. Conclusions: In the study area, VL is still very common. Thus, preventing and controlling infection in the area is largely dependent on raising community awareness of VL prevention and control measures and implementing the necessary interventions on the determinants that have been identified. [ABSTRACT FROM AUTHOR]

Purpose: Visceral leishmaniasis (VL) is caused by an intracellular parasite that is transmitted to humans by sandfly bites. It is prevalent throughout Asia, Africa, the Americas, and the Mediterranean area, where 147 million people are at risk of contracting the illness. The manifestation of heterotrophic illness relies on both Leishmania implicated and the host's immunological response, ranging from asymptomatic to severe leishmaniasis with potentially lethal effects. Method: We reviewed the literature (published till 31st December 2023) on the worldwide situation of leishmaniasis, standard and novel detection techniques, and traditional and modern treatment strategies and endeavors to eliminate VL. Moreover, epidemiological data was collected from the World Health Organization's publicly available databases. GraphPad Prism Version 8 was used to analyze and produce figures based on the epidemiological data. Results: Diagnosis of parasites in tissues or serology is commonly employed. Diagnosis by identifying parasite DNA using molecular techniques is becoming more popular. Despite recent findings of L. donovani resistance to pentavalent antimoniate medications, it continues to be the cornerstone in the medical management of VL. Amphotericin B and its lipid formulations, injectable paromomycin, and oral miltefosine are among the new therapy options being researched. The number of reported VL cases has reduced remarkably over the last decade due to human interventions made to eliminate VL. Particularly countries from the South East Asian region have experienced momentous progress in reducing VL cases and eliminating this disease from this region. Owing to the robust elimination programs, countries such as Bangladesh has eliminated VL as a public health concern. India and Nepal are on the verge of its elimination. Conclusion: Rapid diagnosis, effective and inexpensive treatment, simple access to newly discovered medications, appropriate vector control, and a well-designed vaccine are all required for the elimination of this disease burden in impoverished areas of the globe. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is characterized by an uncontrolled infection of internal organs such as the spleen, liver and bone marrow (BM) and can be lethal when left untreated. No effective vaccination is currently available for humans. The importance of B cells in infection and VL protective immunity has been controversial, with both detrimental and protective effects described. VL infection was found in this study to increase not only all analyzed B cell subsets in the spleen but also the B cell progenitors in the BM. The enhanced B lymphopoiesis aligns with the clinical manifestation of polyclonal hypergammaglobulinemia and the occurrence of autoantibodies. In line with earlier reports, flow cytometric and microscopic examination identified parasite attachment to B cells of the BM and spleen without internalization, and transformation of promastigotes into amastigote morphotypes. The interaction appears independent of IgM expression and is associated with an increased detection of activated lysosomes. Furthermore, the extracellularly attached amastigotes could be efficiently transferred to infect macrophages. The observed interaction underscores the potentially crucial role of B cells during VL infection. Additionally, using immunization against a fluorescent heterologous antigen, it was shown that the infection does not impair immune memory, which is reassuring for vaccination campaigns in VL endemic areas. [ABSTRACT FROM AUTHOR]

Introduction: Visceral leishmaniasis (VL) is an important tropical and neglected disease and represents a serious global health problem. The initial interaction between the phagocytes and the parasite is crucial to determine the pathogen's capacity to initiate infection and it shapes the subsequent immune response that will develop. While type-1 T-cells induce IL-6, IL-1β, TNF-α, and IL-12 production by monocytes/macrophages to fight the infection, type-2 T-cells are associated with a regulatory phenotype (IL-10 and TGF-β) and successful infection establishment. Recently, our group demonstrated the role of an important Th1/ Th17 T-cell population, the mucosal-associated invariant T (MAIT) cells, in VL. MAIT cells can respond to L. infantum by producing TNF-α and IFN-γ upon MR1- dependent activation. Objective and methods: Here, we describe the impact of the MR1-blockage on L. infantum internalization on the functional profile of circulating neutrophils and monocytes as well as the impact of the MR1-blockage on the soluble mediator signatures of in vitro whole blood cultures. Results: Overall, our data showed that VL patients presents higher percentage of activated neutrophils than asymptomatic and non-infected controls. In addition, MR1 blockade led to lower TNF-α and TGF-β production by non-activated neutrophils from asymptomatic individuals. Moreover, TNF-α and IL-10 production by monocytes was higher in VL patients. In the analysis of soluble mediators produced in vitro, MR1-blockade induced a decrease of IFN-γ and an increase of IL-10, IL-27 and IL-33 in the cell cultures of AS group, a cytokine pattern associated with type 2 deleterious response. Discussion and conclusion: These data corroborate the hypothesis that MR1- restricted responses are associated to a protective role during Leishmania infection. [ABSTRACT FROM AUTHOR]

Leishmaniases are a group of neglected vector-borne infectious diseases that are among the six priority endemic diseases worldwide. Visceral leishmaniasis (VL) is the most severe clinical manifestation, characterized by systemic and chronic visceral involvement and high mortality in immunosuppressed and untreated patients. VL can be complicated into post-kala-azar dermal leishmaniasis (PKDL), and when dermatologic disorders occur simultaneously with active VL, an intermediate clinical form called para-kala-azar dermal leishmaniasis (para-KDL) occurs. This clinical form is of great epidemiological relevance, as humans act as a source of infection for vectorial transmission. In the Americas, Brazil is among the seven countries responsible for more than 90% of VL cases, though reports of PKDL and para-KDL are rare. This paper presents three cases of VL-HIV co-infection with Leishmania-containing skin lesions resembling para-kala-azar dermal leishmaniasis. The cases were investigated by the team from the Infectious Diseases Department of University Hospital (HUMAP/UFMS) in Mato Grosso do Sul, Brazil. The three patients exhibited skin lesions where amastigote forms of L. (L.) infantum were identified. All cases exhibited similar clinical manifestations of para-KDL, including fever, hepatosplenomegaly, pancytopenia, and disseminated skin lesions. The study described the prevalence of comorbidities, the incidence of VL relapse, and the therapeutic regimen in relation to the outcomes. The study underscores the importance of follow-up and secondary prophylaxis in patients with VL, which are essential for the efficacy of the treatment. Furthermore, the study provides insight into the potential epidemiological profile of para-KDL cases in Brazil, which contributes to the development of more efficient clinical management strategies for patients. Author summary: Visceral leishmaniasis (VL) is a neglected vector-borne infectious disease with a systemic and chronic involvement that is lethal when untreated. Para-kala-azar dermal leishmaniasis (para-KDL) is a complication of VL, in which the patient presents with dermatological and visceral manifestations simultaneously. Para-KDL cases are of significant epidemiological importance, as humans act as a source of infection in parasite transmission. In the Americas, Brazil accounts for over 90% of VL cases. Nevertheless, reports of para-KDL remain scarce. This paper presents three cases of VL-HIV co-infection with Leishmania-containing skin lesions resembling para-kala-azar dermal leishmaniasis. The three cases exhibit similarities in terms of signs and symptoms, diagnostic criteria for AIDS, and the presence of active VL with skin lesions. The study contributes to the understanding of the epidemiological profile of para-PKDL cases in Brazil. It highlights the significance of multidisciplinary follow-up and secondary prophylaxis for patients with VL and emphasizes the need for more effective clinical management strategies for these patients. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is a neglected tropical disease caused by parasites from the Leishmania (L.) donovani complex. VL is characterised by uncontrolled parasite replication in spleen, liver and bone marrow, and by an impaired immune response and high systemic levels of inflammation. Monocytes have been poorly characterised in VL patients. The aim of this study was to evaluate the expression levels of markers involved in the regulation of T cell responses on different subsets of monocytes from the blood of VL patients and healthy non-endemic controls (HNEC). Monocytes can broadly be divided into three subsets: classical, intermediate and non-classical monocytes. Our results show that the percentages of all three subsets stay similar at the time of VL diagnosis (ToD) and at the end of anti-leishmanial treatment (EoT). We first looked at co-stimulatory receptors: the expression levels of CD40 were significantly increased on classical and intermediate, but not non-classical monocytes, at ToD as compared to EoT and HNEC. CD80 expression levels were also increased on intermediate monocytes at ToD as compared to EoT and HNEC, and on classical monocytes only as compared to HNEC. The levels of CD86 were similar at EoT and ToD and in HNEC on classical and intermediate monocytes, but significantly higher at EoT on non-classical monocytes. We also looked at an inhibitory molecule, PD-L1. Our results show that the expression levels of PD-L1 is significantly higher on all three monocyte subsets at ToD as compared to HNEC, and to EoT on classical and intermediate monocytes. These results show that monocytes from the blood of VL patients upregulate both co-stimulatory and inhibitory receptors and that their expression levels are restored at EoT. Author summary: Visceral leishmaniasis (VL) is a neglected tropical disease caused by Leishmania parasites. VL is characterised by uncontrolled parasite replication in internal organs and is often fatal if untreated. Monocytes are part of a group of cells called white blood cells. These cells can become activated and play an important role against infections. They have been poorly characterised in VL patients. The aim of this study was to evaluate the expression levels of markers of activation on different subsets of monocytes from the blood of VL patients and healthy non-endemic controls (HNEC). We assessed the expression levels of monocyte markers that are essential for activating and regulating the immune response. Our results how that these are increased on some monocyte subsets at the time of diagnosis as compared to the end of treatment and HNEC. We also looked at a marker that can inhibit the immune response and show that it is highly expressed at the time of diagnosis as compared to the end of treatment and HNEC. These results show that monocytes from the blood of VL patients upregulate both activating and inhibitory receptors and that their expression levels are restored at the end of treatment. [ABSTRACT FROM AUTHOR]

Entomological investigations were conducted for the first time in urban forest remnants of Porto Velho, state of Rondônia, Brazil, to explore the transmission dynamics of Leishmania. Sand fly collections were carried out at ten sites, encompassing both canopy and ground strata, from October to December 2021. A total of 1,671 sand flies were collected, representing 42 species within 12 genera. Nyssomyia Antunesi (n = 384) and Psychodopygus davisi (n = 111) were the most abundant species. Molecular analyses targeting the V7V8 region (18S gene) unveiled the presence of sequences 100% identical to Leishmania infantum in females of Bichromomyia flaviscutellata (1), Nyssomyia Antunesi complex (6), Nyssomyia umbratilis (1), Nyssomyia sp. (1), Psychodopygus ayrozai (1), Ps. davisi (3), Psychodopygus paraensis (1), and Sciopemyia sordellii (1). Sequences 100% similar to Trypanosoma minasense were found in two samples of the Nyssomyia Antunesi complex, and two samples of Sc. sordellii presented 100% identity to a Trypanosoma sp. strain, previously identified in this same sand fly in Rondônia. Sequencing of Cytb fragment suggested Homo sapiens, Dasypus novemcinctus and Tamandua tetradactyla as the blood source for distinct sand flies. The identification of sequences similar to L. infantum in sand flies collected in urban forest fragments is noteworthy, correlating with the recent local and regional occurrence of autochthonous cases of human visceral leishmaniasis. However, further studies are imperative to ascertain the presence of hosts/reservoirs and evaluate the risk of L. infantum transmission to humans. [ABSTRACT FROM AUTHOR]

Background: Vector control based on indoor residual spraying (IRS) is one of the main components of the visceral leishmaniasis (VL) elimination programme in India. Dichlorodiphenyltrichloroethane (DDT) was used for IRS until 2015 and was later replaced by the synthetic pyrethroid alpha-cypermethrin. Both classes of insecticides share the same target site, the voltage-gated sodium channel (Vgsc). As high levels of resistance to DDT have been documented in the local sand fly vector, Phlebotomus argentipes, it is possible that mutations in the Vgsc gene could provide resistance to alpha-cypermethrin, affecting current IRS pyrethroid-based vector control. Methods: This study aimed to compare frequencies of knockdown resistance (kdr) mutations in Vgsc between two sprayed and two unsprayed villages in Bihar state, India, which had the highest VL burden of the four endemic states. Across four villages, 350 female P. argentipes were collected as part of a 2019 molecular xenomonitoring study. DNA was extracted and used for sequence analysis of the IIS6 fragment of the Vgsc gene to assess the presence of kdr mutations. Results: Mutations were identified at various positions, most frequently at codon 1014, a common site known to be associated with insecticide resistance in mosquitoes and sand flies. Significant inter-village variation was observed, with sand flies from Dharampur, an unsprayed village, showing a significantly higher proportion of wild-type alleles (55.8%) compared with the three other villages (8.5–14.3%). The allele differences observed across the four villages may result from selection pressure caused by previous exposure to DDT. Conclusions: While DDT resistance has been reported in Bihar, P. argentipes is still susceptible to pyrethroids. However, the presence of kdr mutations in sand flies could present a threat to IRS used for VL control in endemic villages in India. Continuous surveillance of vector bionomics and insecticide resistance, using bioassays and target genotyping, is required to inform India's vector control strategies and to ensure the VL elimination target is reached and sustained. [ABSTRACT FROM AUTHOR]

Background: Dogs are considered the main domestic animals that may be a reservoir for Leishmania infantum, the agent of zoonotic visceral leishmaniasis (ZVL) in several countries of the world. The dog may host other Leishmania species, but its epidemiological role in the maintenance and spreading of these parasites is not completely elucidated. Zoonotic cutaneous leishmaniasis (ZCL), caused by Leishmania major, affects thousands of people every year and is particularly diffused in many countries of North Africa and Middle East Asia. In ZCL endemic countries, few reports of L. major-positive dogs have been reported, probably because most human cases occur in poor rural areas where the social role of the dog and its medical management is not well considered. The aim of the present study is to better understand the possible involvement of domestic dogs in the epidemiology of ZCL. Methods: Our research focused on a well-established endemic focus of ZCL, in the area of Echrarda, Kairouan Governorate, central Tunisia. A total of 51 dogs with no or mild clinical signs of vector borne diseases were selected in small villages where human cases of ZCL are yearly present. All dogs were sampled for the Leishmania spp. diagnosis, by using the following procedures: blood sample for serology and buffy coat quantitative polymerase chain reaction (qPCR), popliteal fine needle aspiration, and cutaneous biopsy punch for lymph node and skin qPCR. Results: The results demonstrated a high percentage (21.6%) of dogs positive at least at one or more test; the most sensitive technique was the lymph node qPCR that detected 8/11 positive dogs. Nine, out of the eleven positive dogs, resulted as infected by Leishmania infantum; ITS1-PCR-sequencing allowed Leishmania major identification in the remaining two cases, both from the popliteal lymph node samples, which can suggest a possible visceral spread of a cutaneous Leishmania species in the dog. Interestingly, one of the two L. major-positive dogs was living in the same house where 6-year-old children showed cutaneous lesions referred to as ZCL. Conclusions: To our knowledge, this is the first report of L. major-positive dogs in Tunisia, the epidemiological role of which remains under investigation. [ABSTRACT FROM AUTHOR]

Purpose: This case report examines the clinical presentation, diagnosis, treatment, and outcomes of mucocutaneous leishmaniasis with primary oral involvement in HIV-positive and HIV-negative patients diagnosed in Brazil. Methods: We discuss the clinical manifestations, diagnostic methods, and therapeutic strategies, highlighting the clinical and histopathologic diagnostic features and distinct progression patterns based on HIV status. Our findings are compared with patterns observed in other countries, emphasizing the differences between the Americas and Europe, Asia, and Africa. Results: In the Americas, particularly in Brazil, mucocutaneous leishmaniasis often presents with localized oral lesions, even in the presence of systemic immunosuppression, whereas in the Europe, Asia, and Africa, oral involvement is typically associated with visceral leishmaniasis in immunocompromised patients. These differences were due to variations in the parasite species involved. Conclusion: This comparison underscores the importance of regional and immunological factors in diagnosing and managing this neglected infectious disease. [ABSTRACT FROM AUTHOR]

Background: Leishmania infantum, one important intracellular parasite causes most potentially lethal diseases such as leishmaniasis i.e. Visceral leishmaniasis in dogs. Although certain chemical drugs such as pentostam, amphotericin B, miltefosine have been trailed against this disease, but all these drugs induced antibiotic resistance and toxicity in the host. Further, the trypanothione synthetase, a key enzyme of this parasite which catalyzes a reaction, maintaining thiol redox within the cell. Methods: The binding study was carried out with selected natural/synthetic phytocompounds/drugs against the modeled trypanothione synthetase though molecular docking. Result: The generated protein model with lowest discrete potential energy (DOPE) -19960.97 was found good in quality with z score of -5.19 and quality factor of 61.83% and it was found that the natural inhibitors glycyrrhetic acid (GRA) and Theaflavin (TFN) showed highest binding energies of -7.34 and -6.95 Kcal/mol. This study may be concluded that the natural inhibitors glycyrrhetic acid (GRA) and Theaflavin (TFN) would be potential regimen in treatment of canine leishmaniasis. [ABSTRACT FROM AUTHOR]

An in‐depth understanding of the mechanism concerning the parasitic disease called visceral leishmaniasis (VL) remains challenging. Thus, we modeled the dynamics of this illness using two fractional‐order operators, including Caputo–Fabrizio and Atangana–Baleanu. In the proposed dynamical model, the endemic and disease‐free equilibrium points were considered the symmetrical components. The fractional Euler method was applied to simulate the developed model, thus determining the equilibrium points' stability. The numerical simulation results were compared with the measured data to validate the model. The results obtained from the optimum fractional operator disclosed the minimum absolute and relative errors. The primary outcome of our study is the successful application of fractional‐order operators, specifically the Atangana–Baleanu operators with α$$ \alpha $$ = 0.98, in modeling the dynamics of VL. Notably, the numerical simulation results, validated against real data from Sudan, demonstrated that the Atangana–Baleanu operators with α$$ \alpha $$ = 0.98 yielded the best performance, with minimum absolute and relative errors. This underscores the precision of our fractional calculus‐based dynamical model in predicting VL dynamics compared to the classical framework, particularly for fractional‐order values of α$$ \alpha $$ = 0.99 and α$$ \alpha $$ = 0.98. [ABSTRACT FROM AUTHOR]

Purpose: Leishmaniasis, caused by the parasite of the genus Leishmania, is a neglected tropical disease which is endemic in more than 60 countries. In South-East Asia, Brazil, and East Africa, it mainly occurs as kala-azar (visceral leishmaniasis, VL), and subsequently as post kala-azar dermal leishmaniasis (PKDL) in a smaller portion of cases. As stated per WHO roadmap, accessibility to accurate diagnostic methods is an essential step to achieve elimination. This study aimed to test the accuracy of a portable minoo device, a small battery-driven, multi-use fluorimeter operating with isothermal technology for molecular diagnosis of VL and PKDL. Methods: Fluorescence data measured by the device within 20 min are reported back to the mobile application (or app) via Bluetooth and onward via the internet to a backend. This allows anonymous analysis and storage of the test data. The test result is immediately returned to the app displaying it to the user. Results: The limit of detection was 11.2 genome copies (95% CI) as determined by screening a tenfold dilution range of whole Leishmania donovani genomes using isothermal recombinase polymerase amplification (RPA). Pathogens considered for differential diagnosis were tested and no cross-reactivity was observed. For its diagnostic performance, DNA extracted from 170 VL and PKDL cases, comprising peripheral blood samples (VL, n = 96) and skin biopsies (PKDL, n = 74) from India (n = 108) and Bangladesh (n = 62), was screened. Clinical sensitivity and specificity were 88% and 91%, respectively. Conclusion: Minoo devices can offer a convenient, cheaper alternative to other molecular diagnostics. Its easy handling makes it ideal for use in low-resource settings to identify parasite burden. [ABSTRACT FROM AUTHOR]

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Leishmania infantum is considered the predominant Leishmania species responsible for visceral leishmaniasis (VL) in Greece but limited molecular-typing-based studies have been performed so far. We retrospectively analyzed data and serum samples collected from 3661 individuals suspected for VL in a sixteen-year period, from 2005 to 2020, to study the seasonality and demographic characteristics of VL cases and to define the L. infantum genotypes circulating in the country. Serum samples were tested with immunofluorescence assay and/or molecular assay. qPCR Leishmania-positive samples were subjected to genotypic analysis based on polymorphisms in 12 microsatellite regions of the internal transcribed spacers (ITSs) 1 and 2. We diagnosed 219 definite (6%, sample with a positive molecular assay and/or antibody titer ≥ 1:400) and 230 probable (6.3%, sample with antibody titer between 1:100 and 1:200) VL cases. Data analysis revealed that amongst VL-definite cases, the age group (≥65) constitutes the most affected factor, since 36.9% of the VL cases belonged to this age group. Amongst the VL definite cases, the most frequently reported symptoms were fever (83%), splenomegaly (49%), and hepatomegaly (40%), but this was not the case for immunocompromised patients that developed non-typical symptoms of leishmaniasis. Although no statistically significant differences in the overall seasonality of VL cases were observed, February and June showed a significantly higher proportion of VL cases compared to August and December. Genotyping of ITS1 and ITS2 regions revealed that all VL cases belong to ITS type A of L. infantum. Our study provides epidemiological information on VL and demonstrates for the first time, providing genotypic data, the circulation of ITS type A L. infantum in Greece. [ABSTRACT FROM AUTHOR]

Blood transfusion remains an important aspect of patient management in visceral leishmaniasis (VL). However, transfusion triggers considered are poorly understood. This review summarises the transfusion practices adopted in VL efficacy studies using the Infectious Diseases Data Observatory VL clinical trials library. Of the 160 studies (1980–2021) indexed in the IDDO VL library, description of blood transfusion was presented in 16 (10.0%) (n=3459 patients) studies. Transfusion was initiated solely based on haemoglobin (Hb) measurement in nine studies, combining Hb measurement with an additional condition (epistaxis/poor health/clinical instability) in three studies and the criteria was not mentioned in four studies. The Hb threshold range for triggering transfusion was 3–8 g/dL. The number of patients receiving transfusion was explicitly reported in 10 studies (2421 patients enrolled, 217 underwent transfusion). The median proportion of patients who received transfusion in a study was 8.0% (Interquartile range: 4.7% to 47.2%; range: 0–100%; n=10 studies). Of the 217 patients requiring transfusion, 58 occurred before VL treatment initiation, 46 during the treatment/follow-up phase and the time was not mentioned in 113. This review describes the variation in clinical practice and is an important initial step in policy/guideline development, where both the patient's Hb concentration and clinical status must be considered. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions Leishmaniasis stands out as a public health problem in the state of Minas Gerais, Brazil, especially in the Midwest region. However, the entomological aspects in several municipalities remain unknown. Therefore, this study aimed to investigate the sand fly fauna in Bambuí, encompassing ecological dynamics and molecular detection of Leishmania.Monthly collections were conducted using CDC light traps from September 2018 to August 2020 across 16 selected points with urban and rural characteristics, chosen based on the coverage area of the Municipal Health Department and the occurrence of canine and human visceral leishmaniasis (VL) cases. Ecological indices of the sand fly population (Chao1, Shannon, Simpson and Pielou) were assessed, and sand fly abundance was correlated to climatic variables (humidity, temperature and rainfall).A total of 8838 specimens representing 17 species within nine genera were collected (estimated species richness by Chao 1 estimator = 17; SE ± 1.8). Predominantly, Lutzomyia longipalpis, Nyssomyia whitmani and Evandromyia cortelezzii constituted approximately 98% of all captured sand flies. While species richness and diversity displayed variations throughout the study, a positive correlation emerged between temperature (p < 0.0001; r = 0.7767), monthly rainfall (p < 0.0001; r = 0.7810) and sand fly abundance. Molecular analysis revealed Leishmania DNA in 2.05% of female sand flies, with the presence of Leishmania infantum in Lu. longipalpis and both Le. infantum and Leishmania braziliensis in Ev. cortelezzii.The entomological data, coupled with the occurrence of autochthonous cases of canine visceral leishmaniasis, offer valuable insights for evidence‐based strategies to prevent leishmaniasis in Bambuí. [ABSTRACT FROM AUTHOR]

Cullin-1-RING ubiquitin ligases (CRL1) or SCF1 (SKP1-CUL1-RBX1) E3 ubiquitin ligases are the largest and most extensively investigated class of E3 ligases in mammals that regulate fundamental processes, such as the cell cycle and proliferation. These enzymes are multiprotein complexes comprising SKP1, CUL1, RBX1, and an F-box protein that acts as a specificity factor by interacting with SKP1 through its F-box domain and recruiting substrates via other domains. E3 ligases are important players in the ubiquitination process, recognizing and transferring ubiquitin to substrates destined for degradation by proteasomes or processing by deubiquitinating enzymes. The ubiquitin-proteasome system (UPS) is the main regulator of intracellular proteolysis in eukaryotes and is required for parasites to alternate hosts in their life cycles, resulting in successful parasitism. Leishmania UPS is poorly investigated, and CRL1 in L. infantum, the causative agent of visceral leishmaniasis in Latin America, is yet to be described. Here, we show that the L. infantum genes LINF_110018100 (SKP1-like protein), LINF_240029100 (cullin-like protein-like protein), and LINF_210005300 (ring-box protein 1 –putative) form a LinfCRL1 complex structurally similar to the H. sapiens CRL1. Mass spectrometry analysis of the LinfSkp1 and LinfCul1 interactomes revealed proteins involved in several intracellular processes, including six F-box proteins known as F-box-like proteins (Flp) (data are available via ProteomeXchange with identifier PXD051961). The interaction of LinfFlp 1–6 with LinfSkp1 was confirmed, and using in vitro ubiquitination assays, we demonstrated the function of the LinfCRL1(Flp1) complex to transfer ubiquitin. We also found that LinfSKP1 and LinfRBX1 knockouts resulted in nonviable L. infantum lineages, whereas LinfCUL1 was involved in parasite growth and rosette formation. Finally, our results suggest that LinfCul1 regulates the S phase progression and possibly the transition between the late S to G2 phase in L. infantum. Thus, a new class of E3 ubiquitin ligases has been described in L. infantum with functions related to various parasitic processes that may serve as prospective targets for leishmaniasis treatment. Author summary: In eukaryotes, intracellular proteolysis is mostly performed by the ubiquitin-proteasome system (UPS), which regulates numerous cellular functions by ubiquitinating regulatory proteins that may be degraded by the proteasome. Substrate recruitment and ubiquitination are mediated by E3 ubiquitin ligases. CRL1 (Cullin-1-RING ligases) are the largest and most researched family of E3 proteins in eukaryotes, comprising SKP1, Cullin1, RBX1, and F-box proteins. The life cycle and infection of Leishmania depends on the UPS, and the role of CRL1 in these parasites has not been studied. Here, we identified CRL1 proteins in L. infantum and demonstrated the assembly of LinfCRL1, which shares a three-dimensional structure with the H. sapiens complex, suggesting a functional relationship. A set of LinfSkp1 and LinfCul1 protein partners were found to be associated with several cellular processes, indicating their pleiotropic effects. Six F-box proteins were found interacting with LinfSkp1 and were designated F-box-like proteins (Flp). Flp1 assembly in an active LinfCRL1(Flp1) complex capable of ubiquitin transfer. Our study demonstrated the critical role of LinfSKP1 and LinfRBX1 in the parasite, whereas knockout of LinfCUL1 resulted in impaired proliferation and duplication, along with the stimulation of rosette formation. In addition, LinfCul1 regulates L. infantum cell cycle progression. Overall, we characterized a novel E3 ubiquitin ligase class that could potentially be targeted by antileishmanial drugs. [ABSTRACT FROM AUTHOR]

Background: Understanding and mapping the distribution of sandflies and sandfly-associated pathogens (SAPs) is crucial for guiding the surveillance and control effort. However, their distribution and the related risk burden in China remain poorly understood. Methods: We mapped the distribution of sandflies and SAPs using literature data from 1940 to 2022. We also mapped the human visceral leishmaniasis (VL) cases using surveillance data from 2014 to 2018. The ecological drivers of 12 main sandfly species and VL were identified by applying machine learning, and their distribution and risk were predicted in three time periods (2021–2040, 2041–2060, and 2061–2080) under three scenarios of climate and socioeconomic changes. Results: In the mainland of China, a total of 47 sandfly species have been reported, with the main 12 species classified into three clusters according to their ecological niches. Additionally, 6 SAPs have been identified, which include two protozoa, two bacteria, and two viruses. The incidence risk of different VL subtypes was closely associated with the distribution risk of specific vectors. The model predictions also revealed a substantial underestimation of the current sandfly distribution and VL risk. The predicted areas affected by the 12 major species of sandflies and the high-risk areas for VL were found to be 37.9–1121.0% and 136.6% larger, respectively, than the observed range in the areas. The future global changes were projected to decrease the risk of mountain-type zoonotic VL (MT-ZVL), but anthroponotic VL (AVL) and desert-type zoonotic VL (DT-ZVL) could remain stable or slightly increase. Conclusions: Current field observations underestimate the spatial distributions of main sandfly species and VL in China. More active surveillance and field investigations are needed where high risks are predicted, especially in areas where the future risk of VL is projected to remain high or increase. Author summary: Our research provides a comprehensive understanding of the distribution of sandflies and SAPs in China. We have identified 47 sandfly species and 6 SAPs, with 12 main sandfly species forming three distinct ecological clusters. Our machine learning models predict the distribution and risk of sandfly species and VL under various climate and socioeconomic scenarios. The model predictions reveal a significant underestimation of the current sandfly distribution and VL risk. Future global changes are projected to decrease the risk of MT-ZVL, but AVL and DT-ZVL could remain stable or slightly increase. These findings underscore the need for more active surveillance and field investigations of vectors, especially where the future risk of VL is projected to remain high or increase. This study provides important theoretical support for guiding the surveillance and control of sandflies and SAPs. [ABSTRACT FROM AUTHOR]

Background People with human immunodeficiency virus (PWH) with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness. Methods This study is nested within the Predicting Visceral Leishmaniasis in HIV-InfectedPatients (PreLeisH) prospective cohort study, following 490 PWH free of VL at enrollment for up to 24–37 months in northwest Ethiopia. Blood Leishmania polymerase chain reaction (PCR) was done systematically. This case series reports on 10 PWH with chronic VL (≥3 VL episodes during follow-up) for up to 37 months, and 3 individuals with asymptomatic Leishmania infection for up to 24 months. Results All 10 chronic VL cases were male, on antiretroviral treatment, with 0–11 relapses before enrollment. Median baseline CD4 count was 82 cells/µL. They displayed 3–6 VL treatment episodes over a period up to 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up (median cycle threshold value, 26 [interquartile range, 23–30]), including during periods between VL treatment. Additionally, we describe 3 PWH with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of up to 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL. Conclusions These are the first data on chronic parasitemia in PWH from Leishmania donovani –endemic areas. PWH with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness. [ABSTRACT FROM AUTHOR]

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials. [ABSTRACT FROM AUTHOR]

Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection. [ABSTRACT FROM AUTHOR]

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway. Author summary: The antifungal drug, amphotericin B, is also used in the treatment of visceral leishmaniasis, a potentially lethal parasitic disease infecting the specialised immune cells (macrophages) in the liver, spleen, and bone marrow. Treatment failures due to emerging drug resistance are a significant concern. Using a combination of genetic and biochemical approaches, we have confirmed the mechanisms by which these parasites become less sensitive to treatment with amphotericin B. In addition, we have identified a novel mechanism involving loss of a key enzyme (cytochrome P450 reductase 1) in the biosynthetic pathway to ergosterol, an important lipid component of the parasite's plasma membrane. These studies increase our fundamental understanding of this important metabolic pathway and provide information that may be exploited to develop novel therapeutic strategies to combat this killer disease. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis (VL) patients are at high risk of acquiring hepatitis B virus (HBV) and hepatitis C virus (HCV) infections during multiple injections and the anti-leishmanial treatment possesses a potential hepatotoxic effect. This systematic review and meta-analysis determined the pooled prevalence of HBV and HCV infections in VL patients. Methods: This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned number CRD42024516889, and conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed using PubMed, Medline, EMBASE, Google Scholar, Web of Science, and Science Direct databases. Data were extracted using Microsoft Excel and analyzed using STATA version 11.0 software. A random-effects model was used to estimate the pooled effect size of outcome variables across studies with a 95% confidence interval and was displayed in a forest plot. The I2 statistic was used to check for heterogeneity. The presence of publication bias was determined using a funnel plot and Egger's test with a p value <0.05 evidence of statistically significant bias. Results: Among 216 retrieved records, seven studies were eligible for systematic review and meta-analysis. A total of 937 VL patients were examined, revealing that 105 and 93 were infected with HBV and HCV, respectively. The pooled prevalence of HBV was 16.15% (95% CI: -4.10 to 36.39), with a significant heterogeneity (I² = 91.4%, p < 0.001). The combined prevalence of HCV was 13.74% (95% CI: 1.32-26.16, I² = 71.6%, p = 0.003). The funnel plot (symmetry), and Egger's test in both HBV (p value = 0.650) and HCV (p value = 0.841) revealed no publication bias. In subgroup analysis, high HBV and HCV prevalence was detected in Sudan; 20.64% (95% CI: -13.60 to 54.88) and India; 18.26% (95% CI: -0.40 to 36.92%), respectively. Conclusion: This study revealed a high prevalence of both HBV and HCV infections in VL patients. In subgroup analysis, the prevalence of HBV and HCV was high in Sudan and India, respectively. Therefore, screening of VL patients for HBV and HCV, vaccination of VL patients in endemic regions, and collaboration between kala-azar and hepatitis elimination programs are required. [ABSTRACT FROM AUTHOR]

Background: Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. Methods: In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. Results: Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis. Conclusions: Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL. [ABSTRACT FROM AUTHOR]

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold. [ABSTRACT FROM AUTHOR]

Introduction Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. Methods Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20 mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. Results Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 µg/g (IQR: 21.94–60.65 µg/g) in skin and 33.29 µg/mL (IQR: 25.9–42.58 µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79–1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6 mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. Conclusion This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL. [ABSTRACT FROM AUTHOR]

Phlebotomus argentipes is the predominant sandfly vector of leishmaniasis in the Indian subcontinent. India and Sri Lanka primarily report visceral and cutaneous leishmaniasis caused by Leishmania donovani. We compared Ph. argentipes from two locations, focusing on its morphological, molecular, and salivary protein characteristics. Sandflies were captured using CDC light traps and cattle-baited net traps. Species identification and morphological comparisons were carried out using standard taxonomic keys. DNA extracted from 12 Sri Lankan sandfly samples was PCR-amplified and sequenced for the variable region of Cytochrome oxidase subunit I. Existing DNA sequences of India from GenBank were utilized for a phylogenetic analysis between Sri Lanka and India. Salivary protein profiles were studied using SDS-PAGE, Western blot, and electrospray ionization/LC/MS/MS. The morphological similarities observed between female Ph. argentipes from India and Sri Lanka suggest the presence of Ph. argentipes var. glaucus. A phylogenetic analysis showed genetic divergence between Ph. argentipes populations, but both shared a similar salivary protein profile. A common, strong 30 kDa immunogenic band comprised PagSP05, PagSP06, and PagSP17 proteins of Ph. argentipes. The similarity between the immunogenic salivary proteins suggests their potential use as common markers for vector exposure or immune response stimulants across regions. The use of multiple samples for each category of serum would improve the comprehensiveness of the immunogenic profiles obtained. [ABSTRACT FROM AUTHOR]

Background Visceral leishmaniasis results from complex interactions among humans, dogs and environment. Brazil accounts for 97% of cases in the Americas. Methods Twenty years (2001–2020) of the endemic disease in the state of Rio de Janeiro were studied. Incidence, lethality, sociodemographic and clinical characteristics were investigated, complemented with spatial methodologies (kernel and clusters). Results Ninety-seven human cases and 625 dogs were reported. Of the 92 cities, 22 were human endemic areas. The state had a low incidence level (0.6 per 100 000). Lethality was higher compared with the Brazilian average. More than 90% of infections occurred in urban areas. Most cases (66%) occurred in men. The predominant age groups were 0–4 y (28.7%) and 20–39 y (32.9%). Fever (89.5%), splenomegaly (83.2%) and hepatomegaly (76.8%) were the main clinical manifestations. Spatial analysis showed a displacement of the human endemic: in the first decade (2001–2010), cases were concentrated in the Metropolitan region, and in the second decade (2011–2020) in the Médio Paraíba region of the state. Most of the endemic area (56.4%) had canine infections without reported human cases. Conclusions Disorderly urbanisation and precarious living conditions favour the transmission of the disease. Changes in the environment and migratory processes contribute to its expansion. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL), also known as kala-azar. It is characterized by prolonged intermittent fever, anemia, splenomegaly, hepatomegaly, and skin darkening. VL is primarily endemic in regions, such as Brazil, East Africa, and India. However, Northern Xinjiang, which is located in northwestern China, is considered a low-incidence area for VL, contributing to its status as a neglected infectious disease. In this report, we present a case of VL caused by Leishmania donovani that was diagnosed using metagenomic next-generation sequencing (mNGS). This case underscores the diagnostic value of mNGS, particularly in regions with low incidence of VL. [ABSTRACT FROM AUTHOR]

Abstract Introduction Hemophagocytic lymphohistiocytosis characterized by hemophagocytosis leading to uncontrolled inflammation; the most common etiology in secondary cases of hemophagocytic lymphohistiocytosis is viral infections, especially Epstein–Barr virus. Visceral leishmaniasis is a vectorborne protozoal disease caused by Leishmania donovani complex. It is common in tropical and subtropical regions, with 50,000–90,000 new cases annually. Case presentation A 15-month-old Arab female was admitted to our hospital with 15 days of fever and decreased weight. On clinical examination, she had a markedly enlarged liver and spleen that were palpable 4 cm and 6 cm below the costal margin, respectively. The peripheral blood smear showed hypochromic microcytic anemia, poikilocytosis, reactive lymphocytosis, and mild thrombocytopenia. Bone marrow aspiration did not show malignancy or any other pathological findings. The patient was put on antibiotic therapy without improvement. Repeated bone marrow aspiration showed erythrophagocytosis; intracellular small round organisms looked like the amastigote form of Leishmania (Donovan bodies) with no evidence of malignancies. Her lab values showed ferritin greater than 500 ug/L, pancytopenia, and hypertriglyceridemia. The patient was diagnosed with hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis. Conclusion Hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis is an extensively rare phenomenon in the medical literature that causes challenges in diagnosis and management. Steroids should be used wisely to not cover the symptoms of infections or malignancy, and amphotericin B resistance should be kept in mind in unresponsive Leishmania cases.

Abstract Background Visceral leishmaniasis (VL) is among the world’s most serious public health threats, causing immense human suffering and death. In Ethiopia, little is known about the barriers and facilitators of visceral leishmaniasis case management. This study aimed to explore such barriers and facilitators in the Amhara Regional State, Northwest Ethiopia. Methods An exploratory qualitative study was conducted on 16 purposively selected patients and key informants from May 8 to June 2, 2023. The study participants were recruited using the maximum variation technique. The interviews were audio recorded, transcribed verbatim, and translated into English. Thematic analysis was employed using Atlas.ti 9 software with a blended approach of both deductive and inductive coding. Results The study identified a variety of issues that hinder the success of visceral leishmaniasis case management. Treatment centers face frequent interruptions of medicinal supplies, a lack of funding, and a lack of trained healthcare providers. A lack of support from health authorities, including weak supervision and feedback systems, is also a source of concern. Most patients receive treatments after significant delays, which is primarily due to low awareness, poor surveillance, and misdiagnosis by healthcare workers. The case management is further constrained by malnutrition, VL-HIV co-infection, and other comorbidities. Despite these issues, we found that effective collaboration between hospital units and VL treatment centers, acceptance by hospitals, and the caring attitude of healthcare workers play a positive role in facilitating the program’s effectiveness. Conclusions Despite the existence of certain efforts that facilitate the program’s effectiveness, VL remains largely neglected, with little government attention or intervention. Such inattention is the root cause of most of the issues. Despite limited resources, most issues could be resolved with cost-effective strategies if health authorities at all levels have the will and commitment to do so.

Abstract Background Visceral leishmaniasis (VL) is a neglected disease endemic to many tropical and subtropical countries. In Brazil, VL is caused by the protozoan parasite Leishmania infantum and is transmitted by the sand fly Lutzomyia longipalpis. The geographical variation in the incidence of the disease in certain urban areas of Brazil suggests a possible association with features of the urban landscape. The objective of this study was to verify the association of urban tree families with the presence of the vector Lu. longipalpis . Methods The study area of the municipality of Teresina, capital of the State of Piauí. The sand flies were captured using CDC light traps—one placed close to the houses, on a tree in the backyard, less than 5 m from the house, and another in the living room. The traps remained three consecutive nights, or, at the most, alternating days, working 12 h a night (from 6 p.m. to 6 a.m.), during 2016 and 2017. Results Tree species were identified in an area of 100 m radius around CDC-type traps for capturing Lu. longipalpis installed in household backyards. Association between tree families and the occurrence of Lu. longipalpis was evaluated using the Fisher exact test and multiple correspondence analysis. Both Anacardiaceae (represented by mango and cashew trees) and Meliaceae (neem) families were more commonly found around sand fly traps capturing fewer Lu. longipalpis. Conversely, Fabaceae (several species of legumes) and Myrtaceae (guava) trees were associated with traps capturing higher number of VL vectors. In multiple correspondence analysis, the presence of trees from the Myrtaceae, Combretaceae (Almond), Fabaceae and Arecaceae (different species of palm trees) families were grouped with traps capturing high number of insects. Conclusions The findings suggest that trees from the Fabaceae, Myrtaceae, Combretaceae, and Arecaceae families might potentially attract sand flies, and Anacardiaceae and Meliaceae families may have a repellent effect. Finer analyses to distinguish the specific effects from the different species of the Anacardiaceae (mango and cashew), Arecaceae and Fabaceae families are still needed. The manipulation of urban landscaping might be a useful and clean alternative to help in the control of urban VL.

Jian Li,1,&ast; Li Liu,2,&ast; Zhiyun Gao,1 Xia Chuai,3 Xiaokun Liu,4 Xiaobo Zhang,2 Xinyu Zhang,2 Xiaoqing Su,2 Qian Xu,2 Zhuojun Deng2 1Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Emergency, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, Hubei, People’s Republic of China; 4Department of Ophthalmology, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhuojun Deng, Department of Emergency, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email dengzhuojun@126.com; 37700469@hebmu.edu.cnPurpose: The incidence of visceral leishmaniasis (VL), a global infectious disease, has been on the rise in China’s Hebei province. When patients achieve clinical cure, they often do not reach an etiological cure, which may lead to recurrence of the disease. Here, we report a case of visceral leishmaniasis with a negative blood smear and bone marrow cytology.Patients and Methods: A 65-year-old man and bronchoalveolar lavage fluid mNGS.Results: A 65-year-old man developed a chronic fever, anorexia, splenomegaly, and pancytopenia. The blood metagenomic second-generation sequencing (mNGS) revealed Leishmania sequence readings, which led to the diagnosis of VL. After sodium antimony gluconate treatment, the blood smear and bone marrow cytology revealed no Leishmania bodies. However, pancytopenia and respiratory failure did not fully subside, and cardiotoxic damage emerged. The bronchoalveolar lavage fluid (BALF) mNGS was performed to detect the pathogen. Through BALF mNGS, Leishmania sequence was still detectable. Therefore, after the ECG returned to normal, antimony sodium gluconate was administered as a next course of treatment.Conclusion: BALF mNGS may assist in evaluating the therapeutic efficacy of VL with respiratory failure, especially in patients with negative blood and bone marrow cytology.Plain Language Summary: Accurate detection of visceral leishmaniasis is essential for clinical diagnosis.It is uncommon to use alveolar lavage fluid mNGS in etiological diagnosis.Patient with negative bone marrow cytology may refer to alveolar lavage fluid mNGS. Keywords: visceral leishmaniasis, metagenomic second-generation sequencing, bronchoalveolar lavage fluid, parasite diseases, case report

Abstract Background Vector control based on indoor residual spraying (IRS) is one of the main components of the visceral leishmaniasis (VL) elimination programme in India. Dichlorodiphenyltrichloroethane (DDT) was used for IRS until 2015 and was later replaced by the synthetic pyrethroid alpha-cypermethrin. Both classes of insecticides share the same target site, the voltage-gated sodium channel (Vgsc). As high levels of resistance to DDT have been documented in the local sand fly vector, Phlebotomus argentipes, it is possible that mutations in the Vgsc gene could provide resistance to alpha-cypermethrin, affecting current IRS pyrethroid-based vector control. Methods This study aimed to compare frequencies of knockdown resistance (kdr) mutations in Vgsc between two sprayed and two unsprayed villages in Bihar state, India, which had the highest VL burden of the four endemic states. Across four villages, 350 female P. argentipes were collected as part of a 2019 molecular xenomonitoring study. DNA was extracted and used for sequence analysis of the IIS6 fragment of the Vgsc gene to assess the presence of kdr mutations. Results Mutations were identified at various positions, most frequently at codon 1014, a common site known to be associated with insecticide resistance in mosquitoes and sand flies. Significant inter-village variation was observed, with sand flies from Dharampur, an unsprayed village, showing a significantly higher proportion of wild-type alleles (55.8%) compared with the three other villages (8.5–14.3%). The allele differences observed across the four villages may result from selection pressure caused by previous exposure to DDT. Conclusions While DDT resistance has been reported in Bihar, P. argentipes is still susceptible to pyrethroids. However, the presence of kdr mutations in sand flies could present a threat to IRS used for VL control in endemic villages in India. Continuous surveillance of vector bionomics and insecticide resistance, using bioassays and target genotyping, is required to inform India’s vector control strategies and to ensure the VL elimination target is reached and sustained. Graphical Abstract

Visceral leishmaniasis (VL) is widespread in tropical and temperate region. It is caused by the protozoan parasite leishmania species and is transmitted through the bite of infected female sandflies. It manifests as pancytopenia, hepatosplenomegaly and fever. Here, we present a case of 20-year-old male presented with difficulty in swallowing for 2 months, abdominal distention for 30 days and shortness of breath for 20 days along with progressive renal impairment. Clinical examination revealed hepatosplenomegaly and laboratory investigations confirmed pancytopenia, nephrotic range proteinuria, hematuria and hypocomplementemia. Bone marrow aspiration and biopsy was performed which showed leishmania donovani (LD) bodies. It’suncommon presentation makes it challenging for physicians as well as pathologist to make a timely diagnosis.

Abstract Background Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. Methods In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. Results Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis. Conclusions Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL. Graphical Abstract