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Background Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals. Methods We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases. Results We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission. Conclusions Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease. [ABSTRACT FROM AUTHOR]

Understanding of spatiotemporal transmission of infectious diseases has improved significantly in recent years. Advances in Bayesian inference methods for individual-level geo-located epidemiological data have enabled reconstruction of transmission trees and quantification of disease spread in space and time, while accounting for uncertainty in missing data. However, these methods have rarely been applied to endemic diseases or ones in which asymptomatic infection plays a role, for which additional estimation methods are required. Here, we develop such methods to analyze longitudinal incidence data on visceral leishmaniasis (VL) and its sequela, post-kala-azar dermal leishmaniasis (PKDL), in a highly endemic community in Bangladesh. Incorporating recent data on VL and PKDL infectiousness, we show that while VL cases drive transmission when incidence is high, the contribution of PKDL increases significantly as VL incidence declines (reaching 55% in this setting). Transmission is highly focal: 85% of mean distances from inferred infectors to their secondary VL cases were <300 m, and estimated average times from infector onset to secondary case infection were <4 mo for 88% of VL infectors, but up to 2.9 y for PKDL infectors. Estimated numbers of secondary cases per VL and PKDL case varied from 0 to 6 and were strongly correlated with the infector's duration of symptoms. Counterfactual simulations suggest that prevention of PKDL could have reduced overall VL incidence by up to 25%. These results highlight the need for prompt detection and treatment of PKDL to achieve VL elimination in the Indian subcontinent and provide quantitative estimates to guide spatiotemporally targeted interventions against VL. [ABSTRACT FROM AUTHOR]

Background: Age patterns in asymptomatic and symptomatic infection with Leishmania donovani, the causative agent of visceral leishmaniasis (VL) in the Indian subcontinent (ISC), are currently poorly understood. Age-stratified serology and infection incidence have been used to assess transmission levels of other diseases, which suggests that they may also be of use for monitoring and targeting control programmes to achieve elimination of VL and should be included in VL transmission dynamic models. We therefore analysed available age-stratified data on both disease incidence and prevalence of immune markers with the aim of collating the currently available data, estimating rates of infection, and informing modelling and future data collection. Methodology/Principal findings: A systematic literature search yielded 13 infection prevalence and 7 VL incidence studies meeting the inclusion criteria. Statistical tests were performed to identify trends by age, and according to diagnostic cut-off. Simple reversible catalytic models with age-independent and age-dependent infection rates were fitted to the prevalence data to estimate infection and reversion rates, and to test different hypotheses about the origin of variation in these rates. Most of the studies showed an increase in infection prevalence with age: from ≲10% seroprevalence (<20% Leishmanin skin test (LST) positivity) for 0-10-year-olds to >10% seroprevalence (>20% LST-positivity) for 30-40-year-olds, but overall prevalence varied considerably between studies. VL incidence was lower amongst 0-5-year-olds than older age groups in most studies; most showing a peak in incidence between ages 5 and 20. The age-independent catalytic model provided the best overall fit to the infection prevalence data, but the estimated rates for the less parsimonious age-dependent model were much closer to estimates from longitudinal studies, suggesting that infection rates may increase with age. Conclusions/Significance: Age patterns in asymptomatic infection prevalence and VL incidence in the ISC vary considerably with geographical location and time period. The increase in infection prevalence with age and peaked age-VL-incidence distribution may be due to lower exposure to infectious sandfly bites in young children, but also suggest that acquired immunity to the parasite increases with age. However, poor standardisation of serological tests makes it difficult to compare data from different studies and draw firm conclusions about drivers of variation in observed age patterns. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis (VL) is characterised by a high degree of spatial clustering at all scales, and this feature remains even with successful control measures. VL is targeted for elimination as a public health problem in the Indian subcontinent by 2020, and incidence has been falling rapidly since 2011. Current control is based on early diagnosis and treatment of clinical cases, and blanket indoor residual spraying of insecticide (IRS) in endemic villages to kill the sandfly vectors. Spatially targeting active case detection and/or IRS to higher risk areas would greatly reduce costs of control, but its effectiveness as a control strategy is unknown. The effectiveness depends on two key unknowns: how quickly transmission risk decreases with distance from a VL case and how much asymptomatically infected individuals contribute to transmission. Methodology/Principal findings: To estimate these key parameters, a spatiotemporal transmission model for VL was developed and fitted to geo-located epidemiological data on 2494 individuals from a highly endemic village in Mymensingh, Bangladesh. A Bayesian inference framework that could account for the unknown infection times of the VL cases, and missing symptom onset and recovery times, was developed to perform the parameter estimation. The parameter estimates obtained suggest that, in a highly endemic setting, VL risk decreases relatively quickly with distance from a case—halving within 90m—and that VL cases contribute significantly more to transmission than asymptomatic individuals. Conclusions/Significance: These results suggest that spatially-targeted interventions may be effective for limiting transmission. However, the extent to which spatial transmission patterns and the asymptomatic contribution vary with VL endemicity and over time is uncertain. In any event, interventions would need to be performed promptly and in a large radius (≥300m) around a new case to reduce transmission risk. [ABSTRACT FROM AUTHOR]

Systemic insecticides in dogs have been suggested as a public health intervention to prevent human cases of Zoonotic Visceral Leishmaniasis (ZVL). But, currently there are no systemic insecticides for dogs registered against zoo-anthropophilic pool blood feeding phlebotomine flies. We predict the impact of community-wide use of systemic insecticide in dog populations as a public health measure to control transmission of Leishmania infantum to humans using a mathematical model. We developed a Susceptible-Exposed-Infected (SEI) compartmental model to describe L. infantum transmission dynamics in dogs, with a vectorial capacity term to represent transmission between L. infantum-hosting dogs via phlebotomine flies. For Infected (I) dogs two levels of infectiousness were modelled, high infectiousness and low infectiousness. Human incidence was estimated through its relationship to infection in the dog population. We evaluated outcomes from a wide range of scenarios comprising different combinations of initial insecticide efficacy, duration of insecticide efficacy over time, and proportion of the dog population treated (60%, 70% & 80%). The same reduction in human infection incidence can be achieved via different combinations of insecticide efficacy, duration and dog coverage. For example, a systemic insecticide with an initial efficacy of 80% and 6 months above 65% efficacy would require treating at least 70% of the dogs to reduce the human infection incidence by 50%. Sensitivity analysis showed that the model outcome was most sensitive to baseline values of phlebotomine fly daily survival rate and insecticide coverage. Community-wide use of systemic insecticides applied to the “L. infantum canine reservoir” can significantly reduce human incidence of L. infantum infection. The results of this mathematical model can help defining the insecticide target product profile and how the insecticide should be applied to maximise effectiveness. [ABSTRACT FROM AUTHOR]

Background. Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods. This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results. The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10 000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions. The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks. [ABSTRACT FROM AUTHOR]

Background: With visceral leishmaniasis (VL) incidence at its lowest level since the 1960s, increasing attention has turned to early detection and investigation of outbreaks. Methods: Outbreak investigations were triggered by recognition of case clusters in the VL surveillance system established for the elimination program. Investigations included ascertainment of all VL cases by date of fever onset, household mapping and structured collection of risk factor data. Results: VL outbreaks were investigated in 13 villages in 10 blocks of 7 districts. Data were collected for 20,670 individuals, of whom 272 were diagnosed with VL between 2012 and 2019. Risk was significantly higher among 10–19 year-olds and adults 35 or older compared to children younger than 10 years. Outbreak confirmation triggered vector control activities and heightened surveillance. VL cases strongly clustered in tolas (hamlets within villages) in which > 66% of residents self-identified as scheduled caste or scheduled tribe (SC/ST); 79.8% of VL cases occurred in SC/ST tolas whereas only 24.2% of the population resided in them. Other significant risk factors included being an unskilled non-agricultural laborer, migration for work in a brick kiln, living in a kuccha (mud brick) house, household crowding, habitually sleeping outside or on the ground, and open defecation. Conclusions: Our data highlight the importance of sensitive surveillance with triggers for case cluster detection and rapid, careful outbreak investigations to better respond to ongoing and new transmission. The strong association with SC/ST tolas suggests that efforts should focus on enhanced surveillance in these disadvantaged communities. [ABSTRACT FROM AUTHOR]

Background: With visceral leishmaniasis (VL) incidence at its lowest level since the 1960s, increasing attention has turned to early detection and investigation of outbreaks. Methods: Outbreak investigations were triggered by recognition of case clusters in the VL surveillance system established for the elimination program. Investigations included ascertainment of all VL cases by date of fever onset, household mapping and structured collection of risk factor data. Results: VL outbreaks were investigated in 13 villages in 10 blocks of 7 districts. Data were collected for 20,670 individuals, of whom 272 were diagnosed with VL between 2012 and 2019. Risk was significantly higher among 10–19 year-olds and adults 35 or older compared to children younger than 10 years. Outbreak confirmation triggered vector control activities and heightened surveillance. VL cases strongly clustered in tolas (hamlets within villages) in which > 66% of residents self-identified as scheduled caste or scheduled tribe (SC/ST); 79.8% of VL cases occurred in SC/ST tolas whereas only 24.2% of the population resided in them. Other significant risk factors included being an unskilled non-agricultural laborer, migration for work in a brick kiln, living in a kuccha (mud brick) house, household crowding, habitually sleeping outside or on the ground, and open defecation. Conclusions: Our data highlight the importance of sensitive surveillance with triggers for case cluster detection and rapid, careful outbreak investigations to better respond to ongoing and new transmission. The strong association with SC/ST tolas suggests that efforts should focus on enhanced surveillance in these disadvantaged communities. [ABSTRACT FROM AUTHOR]

Background On the Indian subcontinent, visceral leishmaniasis (VL) incidence is on track to reach elimination goals by 2020 in nearly all endemic districts. Although not included in official targets, previous data suggest post-kala-azar dermal leishmaniasis (PKDL) patients can act as an infection reservoir. Methods We conducted xenodiagnosis on 47 PKDL patients and 15 VL patients using laboratory-reared Phlebotomus argentipes. In direct xenodiagnosis, flies were allowed to feed on the patient's skin for 15 minutes. For indirect xenodiagnosis, flies were fed through a membrane on the patient's blood. Five days later, blood-fed flies were dissected and examined by microscopy and/or polymerase chain reaction (PCR). A 3-mm skin snip biopsy (PKDL) or venous blood (VL) was processed by quantitative PCR. Results Twenty-seven PKDL patients (57.4%) had positive results by direct and/or indirect xenodiagnosis. Direct was significantly more sensitive than indirect xenodiagnosis (55.3% vs 6.4%, P <.0001). Those with positive xenodiagnosis had median skin parasite loads >1 log10 unit higher than those with negative results (2.88 vs 1.66, P <.0001). In a multivariable model, parasite load, nodular lesions, and positive skin microscopy were significantly associated with positive xenodiagnosis. Blood parasite load was the strongest predictor for VL. Compared to VL, nodular PKDL was more likely and macular PKDL less likely to result in positive xenodiagnosis, but neither difference reached statistical significance. Conclusions Nodular and macular PKDL, and VL, can be infectious to sand flies. Active PKDL case detection and prompt treatment should be instituted and maintained as an integral part of VL control and elimination programs. [ABSTRACT FROM AUTHOR]

Background: Visceral Leishmaniasis (VL) is a neglected tropical disease that afflicts some of the poorest populations in the world including people living in the Bihar state of India. Due to efforts from local governments, NGOs and international organizations, the number of VL cases has declined in recent years. Despite this progress, the reservoir for transmission remains to be clearly defined since it is unknown what role post kala-azar dermal leishmaniasis (PKDL) and asymptomatic infections play in transmission. This information is vital to establish effective surveillance and monitoring to sustainably eliminate VL. Methodology/Principal Findings: We performed a longitudinal study over a 24-month period to examine VL transmission and seroconversion in households with VL, PKDL and asymptomatic infections in the Saran and Muzaffarpur districts of Bihar. During the initial screening of 5,144 people in 16 highly endemic villages, 195 cases of recently treated VL, 116 healthy rK39 positive cases and 31 PKDL cases were identified. Approximately half of the rK39-positive healthy cases identified during the initial 6-month screening period were from households (HHs) where a VL case had been identified. During the 18-month follow-up period, seroconversion of family members in the HHs with VL cases, PKDL cases, and rK39-positive individuals was similar to control HHs. Therefore, seroconversion was highest in HHs closest to the time of VL disease of a household member and there was no evidence of higher transmission in households with PKDL or healthy rK39-positive HHs. Moreover, within the PKDL HHs, (the initial 31 PKDL cases plus an additional 66 PKDL cases), there were no cases of VL identified during the initial screen or the 18-month follow-up. Notably, 23% of the PKDL cases had no prior history of VL suggesting that infection resulting directly in PKDL is more common than previously estimated. Conclusions/Significance: These observations argue that acute VL cases represent the major reservoir for transmission in these villages and early identification and treatment of VL cases should remain a priority for VL elimination. We were unable to obtain evidence that transmission occurs in HHs with a PKDL case. [ABSTRACT FROM AUTHOR]