Inferring transmission trees to guide targeting of interventions against visceral leishmaniasis and post–kala-azar dermal leishmaniasis

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 novel estimation methods are required. Here, we develop such methods to analyse 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 infectiousness of VL and PKDL, 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 <300m, and estimated average times from infector onset to secondary case infection were <4 months for 90% of VL infectors, but up to 2.75yrs for PKDL infectors. Estimated numbers of secondary VL cases per VL and PKDL case varied from 0-6 and were strongly correlated with the infector’s duration of symptoms. Counterfactual simulations suggest that prevention of PKDL could have reduced VL incidence by up to a quarter. 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.Significance StatementAlthough methods for analysing individual-level geo-located disease data have existed for some time, they have rarely been used to analyse endemic human diseases. Here we apply such methods to nearly a decade’s worth of uniquely detailed epidemiological data on incidence of the deadly vector-borne disease visceral leishmaniasis (VL) and its secondary condition, post-kala-azar dermal leishmaniasis (PKDL), to quantify the spread of infection around cases in space and time by inferring who infected whom, and estimate the relative contribution of different infection states to transmission. Our findings highlight the key role long diagnosis delays and PKDL play in maintaining VL transmission. This detailed characterisation of the spatiotemporal transmission of VL will help inform targeting of interventions around VL and PKDL cases.

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Insights from mathematical modelling and quantitative analysis on the proposed WHO 2030 targets for visceral leishmaniasis on the Indian subcontinent

Gates Open Research ◽

10.12688/gatesopenres.13073.1 ◽

2019 ◽

Vol 3 ◽

pp. 1651

Author(s):

Keyword(s):

Public Health ◽

Visceral Leishmaniasis ◽

Health Problem ◽

Indian Subcontinent ◽

Public Health Problem ◽

District Level ◽

World Health ◽

Kala Azar ◽

Health Organization ◽

The Impact

Visceral leishmaniasis (VL) is a neglected tropical disease (NTD) caused by Leishmania protozoa that are transmitted by female sand flies. On the Indian subcontinent (ISC), VL is targeted by the World Health Organization (WHO) for elimination as a public health problem by 2020, which is defined as <1 VL case (new and relapse) per 10,000 population at district level in Nepal and sub-district level in Bangladesh and India. WHO is currently in the process of formulating 2030 targets, asking whether to maintain the 2020 target or to modify it, while adding a target of zero mortality among detected cases. The NTD Modelling Consortium has developed various mathematical VL transmission models to gain insight into the transmission dynamics of VL, identify the main knowledge gaps, and predict the feasibility of achieving and sustaining the targets by simulating the impact of varying intervention strategies. According to the models, the current target is feasible at the appropriate district/sub-district level in settings with medium VL endemicities (up to 5 reported VL cases per 10,000 population per year) prior to the start of the interventions. However, in settings with higher pre-control endemicities, additional efforts may be required. We also highlight the risk that those with post-kala-azar dermal leishmaniasis (PKDL) may pose to reaching and sustaining the VL targets, and therefore advocate adding control of PKDL cases to the new 2030 targets. Spatial analyses revealed that local hotspots with high VL incidence remain. We warn that the current target provides a perverse incentive to not detect/report cases as the target is approached, posing a risk for truly achieving elimination as a public health problem although this is taken into consideration by the WHO procedures for validation. Ongoing modelling work focuses on the risk of recrudescence when interventions are relaxed after the elimination target has been achieved.

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Impact of Changes in Detection Effort on Control of Visceral Leishmaniasis in the Indian Subcontinent

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz644 ◽

2019 ◽

Vol 221 (Supplement_5) ◽

pp. S546-S553 ◽

Cited By ~ 1

Author(s):

Luc E Coffeng ◽

Epke A Le Rutte ◽

Johanna Muñoz ◽

Emily R Adams ◽

Joaquin M Prada ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Indian Subcontinent ◽

Case Detection ◽

Population Coverage ◽

Duration Of Symptoms ◽

True Incidence ◽

Detection Delay ◽

Incidence And Mortality ◽

And Control ◽

The Impact

Abstract Background Control of visceral leishmaniasis (VL) on the Indian subcontinent relies on prompt detection and treatment of symptomatic cases. Detection efforts influence the observed VL incidence and how well it reflects the underlying true incidence. As control targets are defined in terms of observed cases, there is an urgent need to understand how changes in detection delay and population coverage of improved detection affect VL control. Methods Using a mathematical model for transmission and control of VL, we predict the impact of reduced detection delays and/or increased population coverage of the detection programs on observed and true VL incidence and mortality. Results Improved case detection, either by higher coverage or reduced detection delay, causes an initial rise in observed VL incidence before a reduction. Relaxation of improved detection may lead to an apparent temporary (1 year) reduction in VL incidence, but comes with a high risk of resurging infection levels. Duration of symptoms in detected cases shows an unequivocal association with detection effort. Conclusions VL incidence on its own is not a reliable indicator of the performance of case detection programs. Duration of symptoms in detected cases can be used as an additional marker of the performance of case detection programs.

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Visceral Leishmaniasis-HIV coinfection as a predictor of increased leishmania transmission at the village level in Bihar, India.

10.1101/2020.09.24.20200709 ◽

2020 ◽

Author(s):

Kristien Cloots ◽

Pia Marino ◽

Sakib Burza ◽

Naresh Gill ◽

Marleen Boelaert ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Negative Binomial ◽

Indian Subcontinent ◽

Random Effect ◽

Public Health Problem ◽

Negative Binomial Regression ◽

Village Level ◽

Kala Azar ◽

Rate Ratios ◽

The Village

Background: Visceral leishmaniasis (VL) is on the verge of being eliminated as a public health problem in the Indian subcontinent. Although Post kala azar dermal leishmaniasis (PKDL) is recognized as an important reservoir of transmission, we hypothesized that patients with VL coinfected with Human Immunodeficiency Virus (HIV) may also be important reservoirs of sustained leishmania transmission. We therefore investigated to what extent cases of PKDL or VL−HIV are associated with VL incidence at the village level in Bihar, India. Methods: VL, VL−HIV, and PKDL case data from six districts within the highly VL endemic state of Bihar, India were collected through the Kala Azar Management Information System for the years 2014−2019. Multivariate analysis was done using negative binomial regression controlling for year as a fixed effect and block (subdistrict) as a random effect. Findings: Presence of VL−HIV and PKDL cases were both associated with a more than twofold increase in VL incidence at village level, with Incidence Rate Ratios (IRR) of 2.16 (95% CI 1.81−2.58) and 2.37 (95% CI 2.01−2.81) for VL−HIV and PKDL cases respectively. A sensitivity analysis showed the strength of the association to be similar in each of the six included subdistricts. Conclusions: These findings indicate the importance of VL−HIV patients as infectious reservoirs, and suggest that they represent a threat equivalent to PKDL patients towards the VL elimination initiative on the Indian subcontinent, therefore warranting a similar focus.

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The potential impact of human visceral leishmaniasis vaccines on population incidence

10.1101/2020.05.05.20090480 ◽

2020 ◽

Author(s):

Epke A le Rutte ◽

Luc E Coffeng ◽

Stefano Malvolti ◽

Paul M. Kaye ◽

Sake J de Vlas

Keyword(s):

Visceral Leishmaniasis ◽

Indian Subcontinent ◽

Public Health Problem ◽

Transmission Model ◽

Sand Flies ◽

Promising Tool ◽

Kala Azar ◽

Human Visceral Leishmaniasis ◽

Population Incidence ◽

Potential Impact

AbstractBackgroundHuman visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence.Methodology / Principal FindingsWe implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as public health problem. We show that the first two simulated vaccine characteristics can greatly reduce VL incidence. For these vaccines, an approximate 60% vaccine efficacy would lead to achieving the ISC elimination target (<1 VL case per 10,000 population per year) within 10 years’ time in a moderately endemic setting when vaccinating 100% of the population. Vaccinating VL cases to prevent the development of PKDL is a promising tool to sustain the low incidence elimination target after regular interventions are halted. Vaccines triggering the development of transient immunity protecting against infection lead to the biggest reduction in VL incidence, but booster doses are required to achieve perduring impact.Conclusions / SignificanceEven though vaccines are not yet available for implementation, their development should be pursued as their potential impact on transmission can be substantial, both in decreasing incidence at the population level as well as in sustaining the ISC elimination target when other interventions are halted.Author summaryVaccines for human visceral leishmaniasis (VL) are currently under development. In this study, we simulate VL transmission dynamics using mathematical models to explore the potential impact of vaccines on population-wide incidence. We show that some vaccines have high potential to reduce VL incidence, namely those that reduce the infectiousness of infected individuals to sand flies and those that reduce the chance of developing symptoms once infected. The effect of vaccines that lead to protection from infection is potentially the greatest, but depending on the duration of immunity, individuals would require booster doses to guarantee lifelong impact. Vaccines that prevent the development of post-kala-azar dermal leishmaniasis are a promising tool to sustain low VL incidence and prevent recrudescence of infection when regular interventions are halted. Our results strongly support the continued development of VL vaccines, as their potential impact on population incidence can be substantial.

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Visceral Leishmaniasis-HIV Coinfection as a Predictor of Increased Leishmania Transmission at the Village Level in Bihar, India

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.604117 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kristien Cloots ◽

Pia Marino ◽

Sakib Burza ◽

Naresh Gill ◽

Marleen Boelaert ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Negative Binomial ◽

Indian Subcontinent ◽

Random Effect ◽

Public Health Problem ◽

Negative Binomial Regression ◽

Village Level ◽

Kala Azar ◽

Rate Ratios ◽

The Village

BackgroundVisceral leishmaniasis (VL) is on the verge of being eliminated as a public health problem in the Indian subcontinent. Although Post-kala-azar dermal leishmaniasis (PKDL) is recognized as an important reservoir of transmission, we hypothesized that VL patients co-infected with Human Immunodeficiency Virus (HIV) may also be important reservoirs of sustained leishmania transmission. We therefore investigated to what extent cases of PKDL or VL-HIV are associated with VL incidence at the village level in Bihar, India.MethodsVL, VL-HIV, and PKDL case data from six districts within the highly VL-endemic state of Bihar, India were collected through the Kala-Azar Management Information System for the years 2014–2019. Multivariate analysis was done using negative binomial regression controlling for year as a fixed effect and block (subdistrict) as a random effect.FindingsPresence of VL-HIV+ and PKDL cases were both associated with a more than twofold increase in VL incidence at village level, with Incidence Rate Ratios (IRR) of 2.16 (95% CI 1.81–2.58) and 2.37 (95% CI 2.01–2.81) for VL-HIV+ and PKDL cases respectively. A sensitivity analysis showed the strength of the association to be similar in each of the six included subdistricts.ConclusionsThese findings indicate the importance of VL-HIV+ patients as infectious reservoirs for Leishmania, and suggest that they represent a threat equivalent to PKDL patients towards the VL elimination initiative on the Indian subcontinent, therefore warranting a similar focus.

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Relapse after Treatment with Miltefosine for Visceral Leishmaniasis Is Associated with Increased Infectivity of the Infecting Leishmania donovani Strain

mBio ◽

10.1128/mbio.00611-13 ◽

2013 ◽

Vol 4 (5) ◽

Cited By ~ 26

Author(s):

Keshav Rai ◽

Bart Cuypers ◽

Narayan Raj Bhattarai ◽

Surendra Uranw ◽

Maya Berg ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Treatment Failure ◽

Relapse Rate ◽

Leishmania Donovani ◽

Indian Subcontinent ◽

Drug Susceptibility ◽

Current View ◽

Content Type ◽

Control Programs ◽

Kala Azar

ABSTRACTLeishmania donovaniis an intracellular protozoan parasite that causes leishmaniasis, which can range from a self-healing cutaneous disease to a fatal visceral disease depending on the infecting species. Miltefosine is currently the latest and only oral antileishmanial that came out of drug discovery pipelines in the past few decades, but recent reports indicate a significant decline in its efficacy against visceral leishmaniasis (also known as kala-azar) in the Indian subcontinent. This relapse rate of up to 20% within 12 months after treatment was shown not to be related to reinfection, drug quality, drug exposure, or drug-resistant parasites. We therefore aimed to assess other phenotypes of the parasite that may affect treatment outcome and found a significant association between the number of metacyclic parasites, parasite infectivity, and patient treatment outcome in the Indian subcontinent. Together with previous studies on resistance ofL. donovaniagainst pentavalent antimonials, these data suggest that the infectivity of the parasite, or related phenotypes, might be a more determinant factor for treatment failure in visceral leishmaniasis than drug susceptibility, warranting a reassessment of our current view on treatment failure and drug resistance in leishmaniasis and beyond.IMPORTANCEThe high miltefosine relapse rate poses a major challenge for the current Kala-Azar Elimination Program in the Indian subcontinent and other leishmaniasis control programs worldwide. This relapse rate could not be related to reinfection, drug-resistant parasites, or reduced treatment quality. Here we report that an increased infectivity of the parasite is associated with miltefosine relapse of visceral leishmaniasis (VL) patients. These results supplement those obtained with antimonial-resistantL. donovaniwhere an increased infectivity was also observed. This challenges the current view ofLeishmaniadrug susceptibility being the biggest parasitic factor that contributes to treatment failure in leishmaniasis. These selected more infectious parasites may pose an additional burden to leishmaniasis control programs, highlighting the importance of multifaceted control measures to achieve leishmaniasis elimination in the Indian subcontinent and other regions where leishmaniasis is endemic.

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Detection of asymptomatic Leishmania infection in Bangladesh by antibody and antigen diagnostic tools shows an association with post–kala-azar dermal leishmaniasis (PKDL) patients

Parasites & Vectors ◽

10.1186/s13071-021-04622-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Sophie I. Owen ◽

Faria Hossain ◽

Prakash Ghosh ◽

Rajashree Chowdhury ◽

Md. Sakhawat Hossain ◽

...

Keyword(s):

Indian Subcontinent ◽

Quantitative Polymerase Chain Reaction ◽

Strong Association ◽

Asymptomatic Infection ◽

Diagnostic Tools ◽

Leishmania Infection ◽

Kala Azar ◽

Antigen Elisa ◽

History Of ◽

Index Cases

Abstract Background Asymptomatic Leishmania infections outnumber clinical infections on the Indian subcontinent (ISC), where disease reservoirs are anthroponotic. Diagnostics which detect active asymptomatic infection, which are suitable for monitoring and surveillance, may be of benefit to the visceral leishmaniasis (VL) elimination campaign on the ISC. Methods Quantitative polymerase chain reaction (qPCR), loop-mediated isothermal amplification (LAMP), and the direct agglutination test (DAT) were carried out on blood samples, and the Leishmania antigen ELISA was carried out on urine samples collected from 720 household and neighbouring contacts of 276 VL and post–kala-azar dermal leishmaniasis (PKDL) index cases, with no symptoms or history of VL or PKDL, in endemic regions of Bangladesh between September 2016 and March 2018. Results Of the 720 contacts of index cases, asymptomatic infection was detected in 69 (9.6%) participants by a combination of qPCR (1.0%), LAMP (2.1%), DAT (3.9%), and Leishmania antigen ELISA (3.3%). Only one (0.1%) participant was detected positive by all four diagnostic tests. Poor agreement between tests was calculated using Cohen’s kappa (κ) statistics; however, the Leishmania antigen ELISA and DAT in combination captured all participants as positive by more than one test. We find evidence for a moderately strong association between the index case being a PKDL case (OR 1.94, p = 0.009), specifically macular PKDL (OR 2.12, p = 0.004), and being positive for at least one of the four tests. Conclusions Leishmania antigen ELISA on urine detects active asymptomatic infection, requires a non-invasive sample, and therefore may be of benefit for monitoring transmission and surveillance in an elimination setting in combination with serology. Development of an antigen detection test in a rapid diagnostic test (RDT) format would be of benefit to the elimination campaign.

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Application of an Improved Method for the Recombinant K39 Enzyme-Linked Immunosorbent Assay To Detect Visceral Leishmaniasis Disease and Infection in Bangladesh

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.12.12.1410-1415.2005 ◽

2005 ◽

Vol 12 (12) ◽

pp. 1410-1415 ◽

Cited By ~ 15

Author(s):

K. M. Kurkjian ◽

L. E. Vaz ◽

R. Haque ◽

C. Cetre-Sossah ◽

S. Akhter ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Immunosorbent Assay ◽

Leishmania Donovani ◽

Asymptomatic Infection ◽

Negative Control ◽

Original Method ◽

Cutoff Point ◽

Enzyme Linked Immunosorbent Assay ◽

Standard Curve ◽

Kala Azar

ABSTRACT Several serology-based immunoassays are used to diagnose visceral leishmaniasis (VL), a chronic protozoan parasitic disease caused by the Leishmania donovani complex. These tests are primarily designed to diagnose the most severe clinical form of VL, known as kala-azar. However, leishmanial infection is frequently asymptomatic and may manifest only as a positive serologic response or positive leishmanin skin test. We modified a previously described enzyme-linked immunosorbent assay (ELISA) that detects patient antibodies reactive with the recombinant Leishmania protein K39 (rK39) to confirm suspected kala-azar and to detect asymptomatic infection in a community study in Bangladesh. With the inclusion of a standard curve on each ELISA plate, the rK39 ELISA was more repeatable (kappa coefficient of agreement = 0.970) and more reliable compared to the original method (kappa = 0.587, P < 0.001). The cutoff point for a positive antibody response was chosen based on the 99th percentile of the ELISA distribution for the negative-control sera. However, we found that sera from all patients with active kala-azar yielded values more than twice the magnitude of this cutoff. Using receiver-operator characteristic curves, we determined a second cutoff value predictive of kala-azar. Using these criteria, the sensitivity and specificity of the modified ELISA for kala-azar were 97.0% and 98.9%, respectively, for sera from our study population. We hypothesize that individuals with antibody levels greater than the 99th percentile of the negative controls but less than the cutoff point for kala-azar have asymptomatic leishmanial infections.

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Transcriptional Blood Signatures for Active and Amphotericin B Treated Visceral Leishmaniasis in India

10.1101/554022 ◽

2019 ◽

Author(s):

Michaela Fakiola ◽

Om-Prakash Singh ◽

Genevieve Syn ◽

Toolika Singh ◽

Bhawana Singh ◽

...

Keyword(s):

Gene Expression ◽

Single Dose ◽

Visceral Leishmaniasis ◽

Amphotericin B ◽

Leishmania Donovani ◽

Indian Subcontinent ◽

Expression Patterns ◽

Disease Outbreaks ◽

Asymptomatic Infection ◽

Healthy Controls

AbstractAmphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days.Author SummaryVisceral leishmaniasis (VL), also known as kala-azar, is a potentially fatal disease caused by intracellular parasites of the Leishmania donovani species complex. VL is a serious public health problem in rural India, causing high morbidity and mortality, as well as major costs to local and national health budgets. Amphotericin B provides improved therapy for VL with single dose liposomal-encapsulated Ambisome, now affordable through WHO-negotiated price reductions, providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. By assessing immune responses to parasites in people infected with L. donovani, but with different clinical status, we can determine the requirements for immune cell development and predict which asymptomatic individuals, for example healthy individuals with high anti-leishmanial antibody levels, will progress to clinical VL. This will help in monitoring disease outbreaks. In this study we looked at global gene expression patterns in whole blood to try to understand more about asymptomatic infection, active VL, and the progress to cure in cases treated with single or multi-dose amphotericin B. The signatures of gene expression identified aid in our understanding of disease pathogenesis and provide novel targets for therapeutic intervention in the future.

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