• Humans
• Leishmaniasis, Visceral/epidemiology
• Kenya/epidemiology
• Male
• Female
• Adult
• Recurrence
• Adolescent
• Follow-Up Studies
• Child
• Treatment Outcome
• Young Adult
• Child, Preschool
• Leishmaniasis, Cutaneous/epidemiology
• Middle Aged
• Antiprotozoal Agents/therapeutic use
• Prevalence

• Northeastern University

• Humans
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Cutaneous/drug therapy
• Antiprotozoal Agents/therapeutic use
• Observational Studies as Topic
• Clinical Trials as Topic
• Feasibility Studies
• Treatment Outcome
• India/epidemiology
• Bangladesh/epidemiology

• Bill and Melinda Gates Foundation

• parasitic infection
• preclinical research
• parasitology

• Animals
• Leishmania donovani
• CD8-Positive T-Lymphocytes
• Antigens, Protozoan
• Leishmaniasis, Cutaneous/prevention & control
• Skin Tests

• Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)

• Leishmania donovani
• Leishmania infantum
• clinical presentation
• innate immunity
• kala-azar
• pathogenesis
• systemic inflammation
• visceral leishmaniasis

• 307606/221-0 Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq

The leishmanin skin test (LST) has been used for decades to detect exposure and immunity to the parasite Leishmania, the causative agent of the neglected tropical disease leishmaniasis. In the LST, Leishmania antigen (leishmanin) is intradermally injected into the forearm. In an individual who has been previously infected, a delayed-type hypersensitivity (DTH) reaction results in a measurable induration at the site of the injection, indicating that previous exposure to Leishmania has resulted in the development of cell-mediated immunity. LST positivity is associated with long-lasting protective immunity against reinfection, most notably as reported for visceral leishmaniasis (VL). Despite efforts over the past few decades, leishmanin antigen is no longer produced under good manufacturing practice (GMP) conditions anywhere in the world. Consequently, the use of the LST in epidemiological studies has declined in favor of serological and molecular tests. In this review, we provide a historical overview of the LST and justification for the reintroduction of leishmanin. A GMP-grade leishmanin can be used to detect immunity in vivo by the LST and can be investigated for use in an interferon-γ release assay (IGRA), which may serve as an in vitro version of the LST. The LST will be a valuable tool for surveillance and epidemiological studies in support of the VL elimination programs and as a surrogate marker of immunity in vaccine clinical trials.

Leishmaniasis includes a spectrum of diseases ranging from debilitating cutaneous to fatal visceral infections. This disease is caused by the parasitic protozoa of the genus Leishmania that is transmitted by infected sandflies. Over 1 billion people are at risk of leishmaniasis with an annual incidence of over 2 million cases throughout tropical and subtropical regions in close to 100 countries. Leishmaniasis is the only human parasitic disease where vaccination has been successful through a procedure known as leishmanization that has been widely used for decades in the Middle East. Leishmanization involved intradermal inoculation of live Leishmania major parasites resulting in a skin lesion that following natural healing provided protective immunity to re-infection. Leishmanization is however no longer practiced due to safety and ethical concerns that the lesions at the site of inoculation that can last for months in some people. New genome editing technologies involving CRISPR has now made it possible to engineer safer attenuated strains of Leishmania, which induce protective immunity making way for a second generation leishmanization that can enter into human trials. A major consideration will be how the test the efficacy of a vaccine in the midst of the visceral leishmaniasis elimination program. One solution will be to use the leishmanin skin test (LST) that was also used for decades to determine exposure and immunity to Leishmania. The LST involves injection of antigen from Leishmania in the skin dermis resulting in a delayed type hypersensitivity (DTH) immune reaction associated with a Th1 immune response and protection against visceral leishmaniasis. Reintroduction of novel approaches for leishmanization and the leishmanin skin test can play a major role in eliminating leishmaniasis.

• immunity
• leishmaniasis
• leishmanin
• leishmanization
• vaccine

Tropical diseases are public health problems affecting hundreds of millions of people globally. However, the development of adequate, affordable, and accessible treatments is mostly neglected, resulting in significant morbidity and mortality that could otherwise be averted. Leishmaniasis is one of the neglected tropical diseases caused by the obligate intracellular protozoan Leishmania parasite and transmitted by the bite of infected phlebotomine sandflies. No systematic review and meta-analysis has been done to identify the prevalence and risk factors of leishmaniasis to the authors’ knowledge. Therefore, the objective was to determine the prevalence and risk factors of human leishmaniasis in Ethiopia.

Eleven studies conducted in all regions of Ethiopia, which were fully accessible, written in any language, and original articles done on prevalence and risk factors of leishmaniasis, were included. STATA™ version 11.1 was used for statistical analysis. Chi-square, I², and p values were assessed to check heterogeneity. A random effects model with heterogeneity taken from an inverse-variance model was employed to estimate the pooled effect. Subgroup meta-analysis was computed to reduce random variations among each article’s point prevalence, and Egger and funnel plots were used to check for publication bias.

The highest proportion of human leishmaniasis was reported from a study done in Amhara region (39.1%), and the lowest was reported from a survey done in Tigray (2.3%). The overall pooled prevalence of leishmaniasis was 9.13% (95% CI 5–13.27). Subgroup analysis by region revealed moderate heterogeneity (I² = 51.8%) in studies conducted in the Southern Nations Nationalities and Peoples Region (SNNPR). The presence of hyraxes and being male were associated with an increased risk of human leishmaniasis.

The prevalence of leishmaniasis in Ethiopia remains high (9.13%), with significant risk factors being male and the presence of hyraxes within a 300-m radius of the sleeping area.

• Ethiopia
• Infectious disease
• Leishmaniasis
• Neglected tropical diseases
• Prevalence

Visceral Leishmaniasis (VL) due to Leishmania donovani is a neglected protozoan parasitic disease in humans, which is usually fatal if untreated. Phlebotomus orientalis, the predominant VL vector in East Africa, is a highly exophilic/exophagic species that poses a major challenge to current Integrated Vector Management (IVM). Here we report results of pilot studies conducted in rural villages in Gedarif state, Sudan, to evaluate outdoor residual spraying of 20mg active ingredient (a.i.) /m² deltamethrin insecticide applied to the characteristic household compound boundary reed fence and to the outside of household buildings (Outdoor Residual Insecticide Spraying, ODRS), and as an alternative, spraying restricted to the boundary fence only (Restricted Outdoor Residual Insecticide Spraying, RODRS). Four to six clusters of 20 households were assigned to insecticide treatments or control in three experiments. Changes in sand fly numbers were monitored over 2,033 trap-nights over 43–76 days follow-up in four sentinel houses per cluster relative to unsprayed control clusters. Sand fly numbers were monitored by sticky traps placed on the ground on the inside (“outdoor”) and the outside (“peridomestic”) of the boundary fence, and by CDC light traps suspended outdoors in the household compound. The effects of ODRS on sand fly numbers inside sleeping huts were monitored by insecticide knockdown. After a single application, ODRS reduced P. orientalis abundance by 83%-99% in outdoor and peridomestic trap locations. ODRS also reduced numbers of P. orientalis found resting inside sleeping huts. RODRS reduced outdoor and peridomestic P. orientalis by 60%-88%. By direct comparison, RODRS was 58%-100% as effective as ODRS depending on the trapping method. These impacts were immediate on intervention and persisted during follow-up, representing a large fraction of the P. orientalis activity season. Relative costs of ODRS and RODRS delivery were $5.76 and $3.48 per household, respectively. The study demonstrates the feasibility and high entomological efficacy of ODRS and RODRS, and the expected low costs relative to current IVM practises. These methods represent novel sand fly vector control tools against predominantly exophilic/exophagic sand fly vectors, aimed to lower VL burdens in Sudan, with potential application in other endemic regions in East Africa.

Phlebotomus orientalis is the predominant vector of visceral leishmaniasis (VL, kala azar) in Sudan and other countries of East Africa, where the disease causes high morbidity and mortality. This sylvatic sand fly species is abundant in wild habitats characterized by presence of black cotton soil and vegetation dominated by Balanites aegyptiaca and/or Acacia seyal trees. In villages, the vector bites people in the household yard and in nearby peri-domestic locations, exhibiting limited indoor resting behaviour. The marked exophagic and exophilic behaviours of P. orientalis represent a profound challenge for VL control by excluding indoor residual spraying of insecticides (IRS) and compromising the efficacy of insecticide-impregnated bednets (ITNs). In this study, we evaluated the entomological efficacy of residual pyrethroid applied outdoors to household boundary fences and the exterior walls of household huts (outdoor residual insecticide spraying, ODRS), to reduce the abundance of P. orientalis inside and outside houses. We also evaluated the entomological impact of a restricted outdoor residual insecticide spraying (RODRS), whereby insecticide was applied only to the boundary fence. The study was carried out in June 2016-June 2017 in Jebel-Algana and Umsalala villages, Gedarif state, eastern Sudan, which are highly endemic for VL. The results showed that a single ODRS application of 20mg a.i. /m² 2.8% deltamethrin provided average reductions of 83%-99% in outdoor and peridomestic P. orientalis sand fly numbers relative to unsprayed control clusters. RODRS reduced outdoor and peridomestic P. orientalis by 60%-88%. The average cost of ODRS and RODRS per household were $5.76 and $3.48, respectively. The costs of these community-based control measures were substantially lower than the costs of LLINs, which is the only evidence-based tool used to protect against VL in the area. Future studies should evaluate the impact of ODRS/RODRS transmission of VL incidence in endemic villages and in seasonal agricultural farms.

• Africa, Eastern/epidemiology
• Animals
• Female
• Humans
• Insect Control/economics
• Insect Control/methods
• Insect Vectors/drug effects
• Insect Vectors/parasitology
• Insect Vectors/physiology
• Insecticides/economics
• Insecticides/pharmacology
• Leishmania donovani/physiology
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/parasitology
• Leishmaniasis, Visceral/transmission
• Male
• Phlebotomus/drug effects
• Phlebotomus/parasitology
• Phlebotomus/physiology
• Seasons

• BB/R005362/1 Biotechnology and Biological Sciences Research Council
• Department for International Development

In Ethiopia, visceral leishmaniasis (VL) is caused by Leishmania donovani. The estimated country-wide incidence of VL in Ethiopia is 3700–7400 cases/year. The balance between anthroponotic and zoonotic transmission is still unknown even though most authors believe that visceral leishmaniasis in East Africa is anthroponotic. Asymptomatic leishmania infections occur more frequently than clinically apparent visceral leishmaniasis cases. The aim of this study was to determine the prevalence of asymptomatic VL infection and assess the degree of exposure among residents in Raya Azebo Woreda villages where cases of VL were recently reported.

A community based cross-sectional survey was conducted in 2013 between 1^st of May and 25^th of July. A total of 1099 individuals living in 314 households were included in the study. Socio-demographic and clinical data were collected from each of the participants and venous blood was also collected for the detection of antibodies to visceral leishmaniasis using Direct Agglutination Test. Leishmanin skin test was performed to detect the exposure to the parasite. Data was entered into excel and exported to SPSS version 17 for statistical analysis. Chi-square and the corresponding p-values were used to determine the statistical significance of the proportions/ratios obtained from the cross tabulated data. A p-value < 0.05 was considered statistically significant.

A total of 1099 study subjects comprising 401 males and 698 females were included in the study. The overall positive leishmanian skin test and sero-prevalence rates respectively were 9.08% and 0.87%. The difference in LST positivity by age group and sero-prevalence by sex were statistically significant (P <0.01 and P<0.05 respectively). Out of the 9 sero-positive individuals, 7 had no history of travel to visceral leishmaniasis endemic areas out of Raya Azebo.

In general our results suggest occurrence of VL in the study area is, very low. Our survey also indicates that due to the low incidence of the disease, and lack of awareness, some patients remain under diagnosed.

• Adolescent
• Adult
• Agglutination Tests
• Child
• Cross-Sectional Studies
• Ethiopia/epidemiology
• Female
• Health Surveys
• Humans
• Incidence
• Leishmaniasis, Visceral/epidemiology
• Male
• Prevalence
• Seroepidemiologic Studies
• Young Adult

Leishmaniasis in Yemen is still not fully investigated nor well studied. Recently, outbreaks of cutaneous leishmaniasis (CL) in western highland were declared. However, there are no reports concerning the disease and the circulating species in the region. The aim of this study was to determine the prevalence of cutaneous leishmaniasis in Utmah district located in Western Highlands in Yemen. A cross-sectional survey was carried out at those highlands. For the survey, 1165 participants were subjected to Leishmanin Skin Test (LST) accompanied with direct interviews and physical examination. The overall prevalence of cutaneous leishmaniasis in the district was 18.5% and the cutaneous leishmaniasis (CL) was more frequent in the escarpments with a prevalence of 37%, including 5.5% for active lesion and 31.5% for scar of healed lesions. Children under the age of 16 years old comprised most of the CL cases (76.3%). The escarpments of western highlands in Yemen were hyperendemic areas for CL and the infection was more prevalent in children.

• Age Distribution
• Asia, Western/epidemiology
• Female
• Humans
• Incidence
• Leishmania donovani/immunology
• Leishmania donovani/isolation & purification
• Leishmaniasis, Visceral/diagnosis
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/parasitology
• Leishmaniasis, Visceral/transmission
• Longitudinal Studies
• Male
• Models, Statistical
• Prevalence
• Seroepidemiologic Studies

• Bill and Melinda Gates Foundation

Visceral leishmaniasis [VL] is a debilitating parasitic disease which invariably kills untreated patients. The disease is caused by Leishmania (L.) donovani or L. infantum, and transmitted by the bite of female phlebotomine sandflies. VL often remains subclinical but can become symptomatic with an acute/subacute or chronic course. Globally, the Eastern Africa region is one of the main VL endemic areas. The disease is prevalent in numerous foci within Eritrea, Ethiopia, Kenya, Somalia, Sudan South Sudan, and Uganda. In Ethiopia, the Lower Omo plain is one of the many VL endemic regions.

The objective of this study was to determine the prevalence of asymptomatic visceral leishmaniasisin Hamar and Banna-Tsamai districts of the South Omo plains where VL is becoming an emerging health problem of neglected communities.

A community based cross-sectional survey was conducted in 2013 between 25th of July and 14^th of August. A total of 1682 individuals living in 404 households were included in the study. Socio-demographic and clinical data were collected from each of the participants and venous blood was also collected for the detection of antibodies to visceral leishmaniasis using Direct Agglutination Test. Leishmanin Skin Test was performed to detect the exposure to the parasite.

The surveys included 14 villages located in areas where VL had been reported. In a study population of 1682 individuals, the overall positive leishmanian skin test and sero-prevalence rates respectively were 8.6% and 1.8%. A statistically significant variation in the rate of positive LST response was observed in different study sites and age groups. Positive LST response showed an increasing trend with age. The sero-prevalence rate also showed a statistically significant variation among different study sites. Higher rates of sero-prevalence were observed in children and adolescents. The LST and sero-prevalence rates in Hamar District exceeded significantly that of Banna-Tsamai District (10.7% versus 5.8% for LST; and 2.6% versus 0.7% for sero-prevalence).

The prevalence of asymptomatic VL infection in Hamar and Banna-Tsamai districts during the study period in 2013 was low compared to rates previously reported in other endemic areas of Ethiopia. This could be due to the fact that the disease is emerging in Hamar and Banna-Tsamai districts. Based on records of a nearby Hospital, increasing numbers of active VL cases have been reported in these districts through the years 2006–2012, especially in Hamar District. Both districts are important destinations of tourism, and thus the importance of surveillance should be emphasized. Detailed epidemiological and entomological studies are recommended.

• Adolescent
• Agglutination Tests
• Antigens, Protozoan/metabolism
• Child
• Child, Preschool
• Ethiopia/epidemiology
• Female
• Geography
• Humans
• Leishmaniasis, Visceral/blood
• Leishmaniasis, Visceral/epidemiology
• Male
• Middle Aged
• Prevalence
• Residence Characteristics
• Seroepidemiologic Studies
• Skin Tests/methods
• Surveys and Questionnaires

• Jimma University (ET) and LDRL-AAU

• Adolecence
• Antigenic variation
• Central Sudan
• Childhood
• Demography
• L. donovani

• Adolescent
• Adult
• Agglutination Tests
• Child
• Female
• Humans
• Leishmania donovani/immunology
• Leishmania donovani/isolation & purification
• Leishmaniasis, Visceral/epidemiology
• Male
• Sudan/epidemiology

• cell-mediated immunity
• immunoregulation
• immunotherapy
• leishmaniasis
• pathology

• U19 AI074321 NIAID NIH HHS

Quantitation of the nonlinear heterogeneities in Leishmania parasites, sand fly vectors, and mammalian host relationships provides insights to better understand leishmanial transmission epidemiology towards improving its control. The parasite manipulates the sand fly via production of promastigote secretory gel (PSG), leading to the “blocked sand fly” phenotype, persistent feeding attempts, and feeding on multiple hosts. PSG is injected into the mammalian host with the parasite and promotes the establishment of infection. Animal models demonstrate that sand flies with the highest parasite loads and percent metacyclic promastigotes transmit more parasites with greater frequency, resulting in higher load infections that are more likely to be both symptomatic and efficient reservoirs. The existence of mammalian and sand fly “super-spreaders” provides a biological basis for the spatial and temporal clustering of clinical leishmanial disease. Sand fly blood-feeding behavior will determine the efficacies of indoor residual spraying, topical insecticides, and bed nets. Interventions need to have sufficient coverage to include transmission hot spots, especially in the absence of field tools to assess infectiousness. Interventions that reduce sand fly densities in the absence of elimination could have negative consequences, for example, by interfering with partial immunity conferred by exposure to sand fly saliva. A deeper understanding of both sand fly and host biology and behavior is essential to ensuring effectiveness of vector interventions.

We review recent research that sheds light on the quantitative biology of leishmanial transmission between sand flies and mammalian hosts and use these insights to better understand transmission, the observed epidemiology of the disease, and their implications in choice of control strategy. Using animal models, we show how the parasite-induced processes manipulate sand fly blood-feeding behavior and the infectious metacyclic dose to promote host infection and to differentially regulate the onward transmission potential of individual vectors and hosts. The existence of subpopulations of mammalian and sand fly “super-spreaders” provides a biological basis for the spatial and temporal clustering of clinical leishmanial disease. While tools are unavailable to distinguish these individuals in mixed populations, blanket interventions will be necessary to ensure inclusion of transmission hot spots. Interventions that reduce sand fly densities without elimination could interfere with vector—host dynamics and conferred partial immunity to host populations.

• Animals
• Host-Pathogen Interactions/immunology
• Humans
• Insect Vectors/parasitology
• Leishmania/parasitology
• Leishmaniasis/epidemiology
• Leishmaniasis/parasitology
• Leishmaniasis/transmission
• Parasites/parasitology
• Parasites/pathogenicity
• Psychodidae/parasitology

• Wellcome Trust
• BB/H022406/1 Biotechnology and Biological Sciences Research Council

• Administration, Intravenous
• Adolescent
• Adult
• Africa, Eastern
• Antimony Sodium Gluconate/administration & dosage
• Antiprotozoal Agents/administration & dosage
• Child
• Child, Preschool
• Coinfection
• Drug Therapy, Combination
• Female
• HIV Infections/drug therapy
• Humans
• Leishmaniasis, Visceral/drug therapy
• Male
• Middle Aged
• Paromomycin/administration & dosage
• Pharmacovigilance
• Prospective Studies
• Recurrence
• Treatment Outcome
• Young Adult

Asymptomatic leishmaniasis may drive the epidemic and an important challenge to reach the goal of joint Visceral Leishmaniasis (VL) elimination initiative taken by three Asian countries. The role of these asymptomatic carriers in disease transmission, prognosis at individual level and rate of transformation to symptomatic VL/Post Kala-azar Dermal Leishmaniasis (PKDL) needs to be evaluated. Asymptomatic cases were diagnosed by active mass survey in eight tribal villages by detecting antileishmanial antibody using rK39 based rapid diagnostic kits and followed up for three years to observe the pattern of sero-conversion and disease transformation. Out of 2890 total population, 2603 were screened. Antileishmanial antibody was detected in 185 individuals of them 96 had a history of VL/PKDL and 89 without such history. Seventy nine such individuals were classified as asymptomatic leishmaniasis and ten as active VL with a ratio of 7.9:1. Out of 79 asymptomatic cases 2 were lost to follow up as they moved to other places. Amongst asymptomatically infected persons, disease transformation in 8/77 (10.39%) and sero-conversion in 62/77 (80.52%) cases were noted. Seven (9.09%) remained sero-positive even after three years. Progression to clinical disease among asymptomatic individuals was taking place at any time up to three years after the baseline survey. If there are no VL /PKDL cases for two or more years, it does not mean that the area is free from leishmaniasis as symptomatic VL or PKDL may appear even after three years, if there are such asymptomatic cases. So, asymptomatic infected individuals need much attention for VL elimination programme that has been initiated by three adjoining endemic countries.

A total of 79 asymptomatic VL cases were detected from two kala-azar endemic blocks of Malda districts of West Bengal by active mass screening. Follow study of the asymptomatic cases revealed that 10.39% cases transformed into disease and 9.09% cases remained as sero-positive even after three years. So progression to clinical disease among asymptomatic individuals was taking place at any time up to three years after the baseline survey. Therefore, in a given period if there are no cases of VL/PKDL for two or more years, it does not mean that the area is free from leishmaniasis as symptomatic VL or PKDL may appear even after three years, if there are such asymptomatic cases. So, asymptomatic infected individuals need much attention for VL elimination programme that has been initiated by three adjoining endemic countries.

• Adolescent
• Adult
• Antimony Sodium Gluconate/administration & dosage
• Antiprotozoal Agents/administration & dosage
• Asymptomatic Diseases
• Child
• Child, Preschool
• Female
• Follow-Up Studies
• Humans
• India/epidemiology
• Infant
• Leishmaniasis, Visceral/diagnosis
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/epidemiology
• Male
• Young Adult

• Indian Council of Medical Research

Visceral leishmaniasis (VL, Kala-azar) is one of the growing public health challenges in Ethiopia with over 3.2 million people at risk and estimated up to 4000 new cases per year. Historically, VL was known as the diseases of the lowlanders; in the lower and upper Kola agro-ecological zones of Ethiopia. The 2005–07 out breaks in highlands of Libo Kemkem and Fogera, in the Woina Degas, that affected thousands and claimed the life of hundreds misdiagnosed as drug resistance malaria marked that VL is no more the problem of the lowlanders. The Kola (lower and upper) and the Woina Dega are the most productive agroecological zones, supporting both the ongoing and planned expansions of large or small scale agriculture and/or agriculture based industries. Thus, the (re)emergence of VL is not only a public health and social problem but also have a direct implication on the country’s economy and further development. Thus is high time for its control and/or elimination. Yet, the available data seem incomplete to plan for a cost-effective and efficient VL control strategy: there is a need to update data on vector behaviour in specific ecosystems and the roles of domestic animals need to be ascertained. The effectiveness and social acceptability of available vector control tools need be evaluated. There is a need for identifying animal reservoir(s), or establish the absence of zoonosis in Ethiopia. The planning of prevention of (re)emergence and spread of VL to areas adjacent to endemic foci need be supported with information from spatio-temporal mapping. In affected communities, available data showed that their knowledge about VL is generally very low. Thus, well designed studies to identify risk factors, as well as better tools for social mobilization with the understanding of their knowledge, aptitude and practice towards VL are necessary.

• Africa, Eastern/epidemiology
• CD4 Lymphocyte Count
• Coinfection/epidemiology
• HIV Infections/complications
• Humans
• Leishmaniasis, Visceral/diagnosis
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/prevention & control
• Leishmaniasis, Visceral/therapy
• Polymerase Chain Reaction
• Prospective Studies

Human OX40 is necessary for robust CD4⁺ T cell memory and confers selective protective immunity against HHV-8 infection in endothelial cells.

Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)–induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4⁺ T cells in the peripheral blood, consistent with impaired CD4⁺ T cell responses to recall antigens in vitro. The proportion of effector memory CD8⁺ T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4⁺ T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

• Adolescent
• Adult
• Amphotericin B/administration & dosage
• Amphotericin B/adverse effects
• Antiprotozoal Agents/administration & dosage
• Antiprotozoal Agents/adverse effects
• Child
• Child, Preschool
• Female
• Humans
• Infusions, Intravenous
• Leishmaniasis/blood
• Leishmaniasis/drug therapy
• Leishmaniasis/epidemiology
• Leishmaniasis, Cutaneous/blood
• Leishmaniasis, Cutaneous/drug therapy
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Visceral/blood
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/epidemiology
• Male
• Skin/drug effects
• Skin Tests
• Sudan/epidemiology
• Treatment Outcome

• Brazil
• Electrophoresis, Agar Gel
• Gene Frequency
• Genetic Predisposition to Disease/genetics
• Genome-Wide Association Study
• Genotype
• HLA-DQ alpha-Chains/genetics
• HLA-DRB1 Chains/genetics
• Haplotypes/genetics
• Humans
• India
• Leishmaniasis, Visceral/genetics
• Linear Models
• Odds Ratio
• Oligonucleotide Array Sequence Analysis
• Polymorphism, Single Nucleotide/genetics

• 087436/Z/10/Z Wellcome Trust
• P50 AI-30639 NIAID NIH HHS
• P50 AI074321 NIAID NIH HHS
• 095552 Wellcome Trust
• R01 AI048822 NIAID NIH HHS
• 085475/B/08/Z Wellcome Trust
• 085475 Wellcome Trust
• 089698 Wellcome Trust
• 075491/Z/04/B Wellcome Trust
• 074196 Wellcome Trust
• 090532 Wellcome Trust
• Wellcome Trust
• 087436 Wellcome Trust
• P50 AI030639 NIAID NIH HHS
• 097364/Z/11/Z Wellcome Trust
• U19 AI074321 NIAID NIH HHS
• 083948 Wellcome Trust
• 084694 Wellcome Trust
• 074196/Z/04/Z Wellcome Trust
• MC_G1000735 Medical Research Council
• P50AI074321 NIAID NIH HHS
• R01 AI076233 NIAID NIH HHS
• 090532/Z/09/Z Wellcome Trust
• 4584 Cancer Research UK
• 085475/Z/08/Z Wellcome Trust

Since December 2009, Médecins Sans Frontières has diagnosed and treated patients with visceral leishmaniasis (VL) in Tabarak Allah Hospital, eastern Gedaref State, one of the main endemic foci of VL in Sudan. A survey was conducted to estimate the VL incidence in villages around Tabarak Allah.

Between the 5^th of May and the 17^th of June 2011, we conducted an exhaustive door-to-door survey in 45 villages of Al-Gureisha locality. Deaths were investigated by verbal autopsies. All individuals with (i) fever of at least two weeks, (ii) VL diagnosed and treated in the previous year, and (iii) clinical suspicion of post-kala-azar dermal leishmaniasis (PKDL) were referred to medical teams for case ascertainment. A new case of VL was a clinical suspect with a positive rk39 rapid test or direct agglutination test (DAT).

In the 45 villages screened, 17,702 households were interviewed, for a population of 94,369 inhabitants. The crude mortality rate over the mean recall period of 409 days was 0.13/10'000 people per day. VL was a possible or probable cause for 19% of all deaths. The VL-specific mortality rate was estimated at 0.9/1000 per year.

The medical teams examined 551 individuals referred for a history of fever of at least two weeks. Out of these, 16 were diagnosed with primary VL. The overall incidence of VL over the past year was 7.0/1000 persons per year, or 7.9/1000 per year when deaths possibly or probably due to VL were included. Overall, 12.5% (11,943/95,609) of the population reported a past VL treatment episode.

VL represents a significant health burden in eastern Gedaref State. Active VL case detection had a very low yield in this specific setting with adequate access to care and may not be the priority intervention to enhance control in similar contexts.

Visceral leishmaniasis (VL) is a life-threatening parasitic disease, transmitted by a sandfly. A survey was conducted to estimate the VL incidence in 45 villages located in the eastern part of Gedaref State, the main endemic focus of VL in Sudan. Between the 5^th of May and the 17^th of June 2011, we interviewed 17,702 households for a population of 94,369.

Sixteen individuals were diagnosed with primary VL through active case-detection, and 725 reported VL treatment over the past year. The overall incidence rate of VL over the past year was 7.0/1000 persons per year. The crude mortality rate over the mean recall period of 409 days was 0.13/10'000 persons per day. VL was a possible or probable cause for 19% of all deaths. Taking also into account the VL-specific mortality of 0.9/1000 per year, the incidence was estimated at 7.9/1000 per year. Overall, 12.5% of the population reported having been treated for VL in the past.

VL is a major public health issue in Gedaref. Active VL case detection had a very low yield in a context of adequate access to care. Such strategy seems redundant if patients already have access to care.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Child
• Child, Preschool
• Cross-Sectional Studies
• Female
• Humans
• Incidence
• Infant
• Infant, Newborn
• Leishmaniasis, Visceral/epidemiology
• Male
• Middle Aged
• Rural Population
• Sudan/epidemiology
• Survival Analysis
• Young Adult

• EpiMatrix
• T cell epitopes
• vaccine
• visceral leishmaniasis

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Agglutination Tests/methods
• Antibodies, Protozoan/blood
• Asymptomatic Diseases
• Child
• Child, Preschool
• Cohort Studies
• Endemic Diseases
• Female
• Follow-Up Studies
• Humans
• Incidence
• India/epidemiology
• Infant
• Infant, Newborn
• Leishmania donovani/isolation & purification
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/parasitology
• Leishmaniasis, Visceral/pathology
• Male
• Middle Aged
• Nepal/epidemiology
• Prospective Studies
• Young Adult

Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.

We undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.

GWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.

• Adolescent
• Adult
• Aged
• Child
• Child, Preschool
• Chromosome Mapping
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• India
• Infant
• Leishmaniasis, Visceral/genetics
• Lod Score
• Male
• Microsatellite Repeats
• Middle Aged
• Pedigree
• Regression Analysis

• P50 AI074321 NIAID NIH HHS
• U19 AI074321 NIAID NIH HHS
• 1P50AI074321-01 NIAID NIH HHS
• R01 AI076233 NIAID NIH HHS
• Wellcome Trust

• genetic association
• interleukin 10
• leishmaniasis
• post kala-azar dermal leishmaniasis

• Humans
• Interleukin-10/genetics
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/genetics
• Leishmaniasis, Cutaneous/pathology
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/genetics
• Leishmaniasis, Visceral/pathology
• Polymorphism, Genetic
• Sudan/epidemiology

• Wellcome Trust

• Adolescent
• Adult
• Amphotericin B/therapeutic use
• Animals
• Antimony Sodium Gluconate/therapeutic use
• Cells, Cultured
• Coculture Techniques
• Disease Susceptibility/immunology
• Female
• Humans
• India/epidemiology
• Interleukin-10/physiology
• Leishmania donovani/drug effects
• Leishmania donovani/immunology
• Leishmaniasis, Cutaneous/drug therapy
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/immunology
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/immunology
• Male
• Recurrence
• Transforming Growth Factor beta/physiology