Forecasting visceral leishmaniasis in Sudan using hybrid wavelet based deep learning models on climate driven multivariate time series.

Field investigations on the sandfly Phlebotomus orientalis (Diptera: Psychodidae), the vector of Leishmania donovani causing visceral leishmaniasis (VL) in Sudan, were undertaken in two villages (Bellow and Elgamel) and Dinder National Park, to determine the protective value of bednets (polyester, 100 denier) impregnated with lambda-cyhalothrin 10 mg a.i./m2 pyrethroid insecticide. After exposure to treated netting for 30 s, P. orientalis females all died within 1 h. When field-tested in Acacia woodland, treated bednets provided complete protection from bites of the vector. Numbers of P. orientalis females landing on human collectors without bednets or using untreated bednets averaged 32.0 +/- 8.3 or 6.9 +/- 2.7 per man-night, respectively, whereas collectors using treated bednets experienced no sandfly bites during the same period (18.00-06.00 hours, 12 nights in June 1995). Socio-behavioural observations on the bed-time of people living in both study villages indicated that the use of impregnated bednets against P. orientalis would give more potential protection for women and children than for male adults. Overall the proportions of people and their durations of exposure to the risk of sandfly bites (i.e. after sunset until they went to bed) were 40% unprotected for< 1h, 50% for 1-2h and >10% for > or = 2h. Because visceral leishmaniasis in Sudan occurs mainly in children, the use of impregnated bednets (outdoors as well as indoors), and going to bed early could provide a high degree of personal protection against this zoonotic infection.

Visceral leishmaniasis in eastern Sudan: parasite identification in humans and dogs; host-parasite relationships

Visceral leishmaniasis (VL) is a neglected parasitic disease that is fatal if left untreated and is endemic in eastern Sudan. We estimated the direct and indirect costs of treatment of VL from the perspective of the provider and the household at three public hospitals in Gedaref State. The median total cost for one VL episode was estimated to be US$450. Despite the free provision of VL drugs at public hospitals, households bore 53% of the total cost of VL with one episode of VL representing 40% of the annual household income. More than 75% of households incurred catastrophic out-of-pocket expenditures. The length of treatment of 30 days led to important costs for both health providers and households. Alternative treatment regimens that reduce the duration of treatment are urgently needed.

BackgroundSince 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.MethodsBetween the 5th of May and the 17th 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).ResultsIn 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.Discussion and ConclusionVL 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 vector-borne disease highly influenced by environmental factors. A model was developed for mapping the distribution and incidence of VL in Gedaref State, eastern Sudan, in relation to different environmental factors. Geographical information systems (GIS) were used to extract and map regression results for environmental variables of 190 villages in Gedaref State, including rainfall, vegetation status, soil type, altitude, distance from river, topography, wetness indexes, and average rainfall estimates. VL incidence in each village was calculated from hospital records. By use of logistic and linear multivariate regression analyses, models were developed to determine which environmental factors explain variability in VL presence and incidence. We found that average rainfall and the altitude were the best predictors of VL incidence. The resulting models were mapped by GIS software predicting both VL presence or absence and incidence at any locality in Gedaref State. The results are discussed in relation to VL control.

Phlebotominae fauna (Diptera: Psychodidae) in an urban district of Belo Horizonte, Brazil, endemic for visceral leishmaniasis: Characterization of favored locations as determined by spatial analysis

We conducted a longitudinal study in an endemic area for visceral leishmaniasis (VL) in eastern Sudan to compare the epidemiology and clinical spectrum of Leishmania donovani infection in two populations differing in ethnic background and duration of residence in the area. The study took place in two villages from April 1994 to April 1996. In Um-Salala village, which is inhabited by members of the Masaleet tribe, half of the villagers had previous exposure to cutaneous leishmaniasis (Leishmaria major) before moving there. The population of the second village, Mushrau Koka, belong to the Hausa tribe and most were born there. The incidence of VL was 20.4/1000 person-years in 1994/1995 and increased sharply to 38.3/1000 person-years in 1995/1996 in Um-Salala. A rise in the incidence of VL was also observed in Mushrau Koka but with a lower incidence, 3.3/1000 person-years to 4.6/1000 person-years. The incidence rate of confirmed VL reflects only a limited part of the total infection rate which includes various forms of subclinical infection. The ratio of clinical to subclinical infection in Um-Salala was 1.2 : 1 in 1994/1995 compared with 2.6 : 1 in 1995/1996. This ratio was 1 : 11 in 1994/1995 and 1 : 2.5 in 1995/1996 in Mushrau Koka. In both villages the mean age of subclinical cases was higher, but in Mushrau Koka the mean age of subclinical cases also was higher than that of subclinical cases in Um-Salala. The leishmanin skin test (LST) was positive in 56% of individuals in Um-Salala and in 33% in Mushrau Koka. VL only occurred in leishmanin-negative individuals. Post kala-azar dermal leishmaniasis (PKDL) followed in 58% of confirmed VL patients in Um-Salala; the low incidence of VL for Mushrau Koka did not permit to estimate a PKDL rate. The clinical manifestations resulting from exposure to L. donovani range from subclinical infection to VL and PKDL. No firm conclusion as to the difference in incidence of VL between the two villages could be reached but differences in exposure to VL and cutaneous leishmaniasis (CL) as well as other factors such as ethnic background and differences in nutritional status may play a role.

In Mediterranean countries visceral leishmaniasis (VL) is a zoonosis caused by the protozoon Leishmania infantum. In the early 1990s, the incidence of VL increased in southern European countries, probably because of the increased number of cases that occurred in patients with HIV infection [1]. Recently, highly active antiretroviral therapy (HAART), using a combination of protease inhibitors and reverse transcriptase inhibitors [2], has been demonstrated not only to have a powerful activity on HIV, as shown by the reduction in plasma HIV RNA and the increase in peripheral CD4 cells, but also to cause a drop in the incidence of opportunistic infections and deaths [3,4]. However, no data are presently available on the effect, if any, of HAART on the incidence of VL in HIV-infected individuals. Therefore, the aim of this study was to assess the incidence of VL, before and after the introduction of HAART, as standard therapy in HIV-infected patients in a large cohort of Italian HIV-infected subjects. In particular, we performed a 9 year (1991–1999) retrospective cohort study considering all cases of VL admitted to the Department of Infectious Diseases of a large university hospital in Rome, Italy. Over the study period, we observed 36 cases of leishmaniosis, 20 cases (55%) in HIV-infected patients and 16 (35%) in immunocompetent individuals. For a better evaluation of the differences in VL incidence in HIV-infected patients attributed to HAART, two periods of time were compared: January 1991–December 1995 (period A), and January 1997–December 1999 (period B). HAART became the standard of care in the majority of our patients after September 1996, when protease inhibitors became available in Italy, and for this reason we have not considered, in the statistical analysis, cases of VL occurring in 1996. In particular, we observed 18 episodes of VL in period A and 13 in period B. HIV infection was present in 78% (14/18) of the total VL cases observed in period A and in 15% (2/13) in period B (P < 0.01; odds ratio 19.25; 95% confidence interval 2.37–220.18). Comparing the incidence of VL in HIV-infected patients in periods A and B, a statistically significant reduction in the incidence of VL, from 0.7 episodes per 100 person/years to 0.13 episodes per 100 person/years, was observed (P < 0.01; odds ratio 5.25; 95% confidence interval 1.20–47.65). The majority of HIV-infected patients with VL were men (72%) and in the C3 category of HIV infection (75%) without any significant statistical differences between period A and period B. The mean number of peripheral CD4 cells was 54/mm3 (range 1–207/mm3). The mean level of plasma HIV RNA, available in patients observed in period B only, was 105 000 copies/ml. The analysis of risk factors for VL, including the geographical area of origin of the patients, did not differ significantly between the two study periods. In conclusion, our study confirms that HIV is a relevant predisposing condition for VL, in Italy as well as in other Mediterranean countries [5,6], and indicates, as a novel observation, a significant decrease in the incidence of VL in HIV-infected patients after the introduction of HAART. The reduction in the incidence of VL is probably the consequence of the well-known immune restoration induced by HAART [2], as witnessed by the increase in median peripheral CD4 cell counts and the decrease in HIV viraemia (data not shown). Such a reduced incidence of VL in HIV-infected patients could have a substantial impact on future morbidity and health costs in Mediterranean countries as well as in other geographical areas where VL is endemic. Mario Tumbarello Evelina Tacconelli Silvia Bertagnolio Roberto Cauda

Spending by aid agencies on emergencies has quadrupled over the last decade, to over US$6 billion. To date, cost-effectiveness has seldom been considered in the prioritization and evaluation of emergency interventions. The sheer volume of resources spent on humanitarian aid and the chronicity of many humanitarian interventions call for more attention to be paid to the issue of 'value for money'. In this paper we present data from a major humanitarian crisis, an epidemic of visceral leishmaniasis (VL) in war-torn Sudan. The special circumstances provided us, in retrospect, with unusually accurate data on excess mortality, costs of the intervention and its effects, thus allowing us to express cost-effectiveness as the cost per Disability Adjusted Life Year (DALY) averted. The cost-effectiveness ratio, of US$18.40 per DALY (uncertainty range between US$13.53 and US$27.63), places the treatment of VL in Sudan among health interventions considered 'very good value for money' (interventions of less than US$25 per DALY). We discuss the usefulness of this analysis to the internal management of the VL programme, the procurement of funds for the programme, and more generally, to priority setting in humanitarian relief interventions. We feel that in evaluations of emergency interventions attempts could be made more often to perform cost-effectiveness analyses, including the use of DALYs, provided that the outcomes of these analyses are seen in the broad context of the emergency situation and its consequences on the affected population. This paper provides a first contribution to what is hoped to become an international database of cost-effectiveness studies of health interventions during relief operations, which use a comparable measure of health outcome such as the DALY.

BackgroundA recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.MethodsThis randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.Findings42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).ConclusionData suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.Trial RegistrationClinicalTrials.gov NCT00255567

Given the detrimental interaction between both pathogens, visceral leishmaniasis (VL)–HIV co-infection has been identified as one of the emerging challenges for VL control [1]. The epidemiological impact of HIV on VL was most strikingly illustrated by the effect of the HIV epidemic in VL-endemic countries in southern Europe, with HIV contributing to the re-emergence of VL. By early 2000, almost 2,000 cases of VL–HIV co-infection (predominantly in intravenous drug users) had been identified, with up to 50%–60% of all VL cases being HIV co-infected [2]. Fortunately, with the wide-scale introduction of highly active antiretroviral therapy (ART), a gradual decline in VL incidence has been observed in Europe over the last decade [1], [3]. Currently, the burden of VL–HIV co-infection is most apparent in some regions in East Africa, like Northwest Ethiopia, where between 20%–40% of VL cases are co-infected with HIV [1]. The problem also seems to be emerging in India and Brazil [1]. There is abundant evidence that HIV strongly affects VL treatment response, including in the East African setting. Initial parasitological failure rates are typically below 2%–3% in immunocompetent individuals, but can be as high as 50% in co-infected patients [4]. Case fatality rates in East Africa are 3–9-fold higher in HIV co-infected patients, reaching up to 15%–33% [1], [5]. Whereas relapses are uncommon (<5%) in immunocompetent individuals, this can reach 50%–60% by one year in some high-risk HIV co-infected individuals [1], [6]. ART is apparently only partially protective against relapse [6]. Importantly, repeated relapses tend to become increasingly unresponsive to treatment, and secondary prophylaxis is often required until sufficient CD4 cell count recovery has taken place (at least in areas with zoonotic transmission) [1]. At an early stage, several meetings on VL–HIV co-infection were organized by the World Health Organization (WHO) trypanosomiasis and leishmaniasis unit (Division of Tropical Diseases), and an international surveillance system was put in place. Based on the evidence available, VL was proposed—in 1995—as an Acquired Immunodeficiency Syndrome (AIDS)–defining condition requiring ART initiation irrespective of CD4 counts [7], and this has remained so since then (see Table 1) [8]. VL is now included as an AIDS-defining condition in virtually all VL-treatment guidelines for use in countries where VL–HIV is prevalent. Table 1 Overview of integration of visceral leishmaniasis as an AIDS-defining condition in WHO guidelines. Early on in the HIV epidemic—in 1990—WHO developed an HIV clinical staging system adopted for use in low- and middle-income countries [9]. This WHO clinical staging system is widely used by the HIV medical community and forms the backbone of several important recommendations like cotrimoxazole prophylaxis and eligibility for ART. It has undergone several adaptations over the years, with the latest revision of the WHO staging system reported in 2007 [10]. This clinical staging system has also systematically been endorsed across all revised WHO ART guidelines over the last 10 years, up to the most recent version in 2013 [11]–[14]. Surprisingly, and in contrast with the latest recommendations coming out of the WHO Department of Neglected Tropical Disease and the WHO Expert Committee on the Control of Leishmaniases, VL is not systematically included as an AIDS-defining condition. Although VL appeared in the interim revised clinical staging recommendations (as a WHO stage 4 condition), the finalized version (2007) only stated “atypical disseminated leishmaniasis” as a stage 4 condition, and this was included in the 2006, 2010, and 2013 ART guidelines. This term (atypical disseminated leishmaniasis) is not clearly defined, with no presumptive clinical diagnosis proposed and as definitive diagnosis: “… histology (amastigotes visualized) or culture from any appropriate clinical specimen.” Disseminated cutaneous leishmaniasis is an established clinical entity, but “atypical disseminated leishmaniasis” is not. Strictly speaking, it is not even clear whether both VL and cutaneous leishmaniasis would be considered. Similarly to tuberculosis–HIV co-infection, successful management and control of VL–HIV co-infection will hinge on the effective coordination of both VL and HIV programs [15]. Coordination at the global level is likely to foster successful integration of national programs [15]. For instance, in Ethiopia—which has the highest VL–HIV co-infection rates—the national VL guidelines recommend routine ART for all VL cases, but the HIV/ART guidelines will follow the international HIV clinical staging system (only mentioning “atypical disseminated leishmaniasis;” http://www.who.int/hiv/pub/guidelines/ethiopia_art.pdf). The same is true in other VL-endemic countries such as India and Uganda. In contrast, VL is an AIDS-defining condition in the national ART guidelines in Brazil and Kenya. As to Sudan and South Sudan, both “atypical disseminated leishmaniasis” and VL are included. We call upon WHO to address this inconsistency and hope this can be rectified by the next revision of the WHO guidelines.

Diagnostic methods for visceral leishmaniasis (VL) require invasive specimen sampling. Urine is a potential noninvasive alternative and in the present study the diagnostic performance of direct agglutination test (DAT), based on a freeze dried antigen, and rK39 strip test (InBios, Bio-Rad) on specimens collected in Sudan was assessed. RK39 test had a sensitivity of 72.1% and a specificity of 76.9% on urine and DAT sensitivity was 62.8% and its specificity 69.2%, using initial diagnosis (VL diagnosis was confirmed on clinical and serological basis) as reference in both cases. Tests agreements were fair. Both rK39 as well DAT have potential in diagnosing VL using urine, but results are currently not as good as on the Indian sub-continent.

BackgroundConfirmatory diagnosis of visceral leishmaniasis (VL), as well as diagnosis of relapses and test of cure, usually requires examination by microscopy of samples collected by invasive means, such as splenic, bone marrow or lymph node aspirates. This causes discomfort to patients, with risks of bleeding and iatrogenic infections, and requires technical expertise. Molecular tests have great potential for diagnosis of VL using peripheral blood, but require well-equipped facilities and trained personnel. More user-friendly, and field-amenable options are therefore needed. One method that could meet these requirements is loop-mediated isothermal amplification (LAMP) using the Loopamp Leishmania Detection Kit, which comes as dried down reagents that can be stored at room temperature, and allows simple visualization of results.Methodology/Principal findingsThe Loopamp Leishmania Detection Kit (Eiken Chemical Co., Japan), was evaluated in the diagnosis of VL in Sudan. A total of 198 VL suspects were tested by microscopy of lymph node aspirates (the reference test), direct agglutination test-DAT (in house production) and rK28 antigen-based rapid diagnostic test (OnSite Leishmania rK39-Plus, CTK Biotech, USA). LAMP was performed on peripheral blood (whole blood and buffy coat) previously processed by: i) a direct boil and spin method, and ii) the QIAamp DNA Mini Kit (QIAgen). Ninety seven of the VL suspects were confirmed as cases by microscopy of lymph node aspirates. The sensitivity and specificity for each of the tests were: rK28 RDT 98.81% and 100%; DAT 88.10% and 78.22%; LAMP-boil and spin 97.65% and 99.01%; LAMP-QIAgen 100% and 99.01%.Conclusions/SignificanceDue to its simplicity and high sensitivity, rK28 RDT can be used first in the diagnostic algorithm for primary VL diagnosis, the excellent performance of LAMP using peripheral blood indicates that it can be also included in the algorithm for diagnosis of VL as a simple test when parasitological confirmatory diagnosis is required in settings that are lower than the reference laboratory, avoiding the need for invasive lymph node aspiration.

Leishmaniasis, a vector-borne disease, remains one of the most significant parasitic disease with potential outbreak and high mortality. Despite improvements in living standards and health infrastructure, there has been a territorial expansion in the incidence and lethality of the disease. However, evidence regarding its control, prevention, and eradication remains limited. Given an understanding of the present status of the disease, this study assesses the trends and patterns in the incidence and mortality of this endemic in India from 1990 to 2019. This study obtained Visceral Leishmaniasis (VL) incidence and mortality data (1990–2019) from the Global Burden of Disease (GBD) study 2019, provided by the Institute for Health Metrics and Evaluation (IHME). To capture the overall changes and sex-specific changes in ASIRs and ASMRs of VL, joinpoint regression analysis was employed for all ages by using joinpoint regression programme version 4.5.0.1. Age-period-cohort analysis is used to estimate the net age, period, and cohort effects on the incidence and mortality of VL from observed age-specific incidence and mortality rates. The APC model was implemented using Stata 16.0, and its fit was assessed using Akaike’s Information Criterion (AIC) and Bayesian Information Criterion (BIC). Findings indicate a significant decline in the age-specific incidence and mortality rates for both sex. The highest annual percentage decline in VL incidence and mortality was observed during 2011–2016 for both males and females. (Table 1). Results from the age effect show that the risk of VL incidence and mortality among both genders decreased sharply with advancing age. Period effect indicated a sharp decline in incidence and mortality risk from the period 1990–94 to 2000–04. The cohorts effect showed that compared to earlier birth cohort (1900–04),, the relative risk (RR) of VL incidence increased by 1.5 in male and 1.7 times in females in more recent birth cohort (2015–19), whereas mortality risk decreased by 48% among females. Findings highlight a notable reduction in VL incidence and mortality in the country. The age pattern in the incidence and mortality rates indicates the need for age-specific attention while performing preventive measures and comprehensive strategies. Moreover, strengthening large-scale screening, vector control measures, and public health education is essential to sustain VL elimination efforts.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-025-10751-7.

BACKGROUNDThere are three main forms of leishmaniasis in humans: cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), and mucocutaneous leishmaniasis. The prevalence of human leishmaniasis varies widely in different countries and different regions of the same country. To date, there is no overall estimation of the prevalence of human leishmaniasis in Sudan.AIMTo determine the pooled prevalence of human leishmaniasis and the disease risk factors among Sudanese citizens.METHODSFrom all articles written in English or Arabic languages conducted before the 4th of August 2021 from [Scopus, Web of Science, PubMed, and MEDLINE, African Journals Online (AJOL), ResearchGate, direct Google search, Google Scholar, and universities websites], just 20 articles with a total of 230960 participants were eligible for this study. Data synthesis and analysis were done using STATA software, version 16. EndNote citation manager version X9.3.3 and Reference Citation Analysis (RCA) were used to remove the duplicated studies and manage the citation respectively. RESULTSThe overall pooled prevalence of human leishmaniasis in Sudan was 21% (with confidence interval 12%-30%). CL was the most common type of leishmaniasis in Sudan, with a pooled prevalence of 26% followed by VL (18%). Nevertheless, the pooled prevalence of human leishmaniasis in Sudan was higher in males compared with females (60% vs 40%). The current results revealed that the people in the age group between 15 and 44 were the most affected group (60%), and central Sudan has the highest pooled prevalence of human leishmaniasis (27%) compared with other regions of Sudan. Finally, the prevalence of human leishmaniasis seems to decrease with time.CONCLUSIONThis study showed that human leishmaniasis infection is still endemic in many regions in Sudan and highly prevalent in central and eastern Sudan, and CL is the most prevalent in the country. Males and adults were more susceptible to infection compared with females and children. However, the human leishmaniasis prevalence decreased relatively over time.