Progress in the Mathematical Modelling of Visceral Leishmaniasis

Abstract

The leishmaniases comprise a complex of diseases characterised by clinical outcomes that range from self-limiting to chronic, disfiguring and stigmatising, to life-threatening. Diagnostic methods, treatments, and vector and reservoir control options exist, but deciding the most effective interventions requires a quantitative understanding of the population level infection and disease dynamics. The effectiveness of any set of interventions has to be determined within the context of operational conditions, including economic and political commitment. Mathematical models are the best available tools for studying quantitative systems crossing disciplinary spheres (biology, medicine, economics) within environmental and societal constraints.In 2005, the World Health Assembly and government health ministers of India, Nepal, and Bangladesh signed a Memorandum of Understanding to eliminate the life threatening form of leishmaniasis, visceral leishmaniasis (VL), on the Indian subcontinent by 2015 through a combination of early case detection, improved treatments, and vector control. The elimination target is <1/10,000 population at the district or subdistrict level compared to the current 20/10,000 in the regions of highest transmission.Towards this goal, this chapter focuses on mathematical models of VL, and the biology driving those models, to enable realistic predictions of the * Corresponding author Email address: orin.courtenay@warwick.ac.uk (Orin Courtenay)Preprint submitted to Advances in Parasitology July 18, 2016 best combination of interventions. Several key issues will be discussed which have affected previous modelling of VL and the direction future modelling may take. Current understanding of the natural history of disease, immunity (and loss of immunity), as well as stages of infection and their durations are considered particularly for humans, but also for dogs. Asymptomatic and clinical infection are discussed in the context of their relative roles in Leishmania transmission, as well as key components of the parasite-sandfly-vector interaction and intervention strategies including diagnosis, treatment and vector control. Gaps in current biological knowledge and potential avenues to improve model structures and mathematical predictions are identified. Underpinning the marriage between biology and mathematical modelling, the content of this chapter represents the first step towards developing the next generation of models for VL.

Spatio-temporal modelling of Leishmania infantum infection among domestic dogs: a simulation study and sensitivity analysis applied to rural Brazil

“…Ultimately, VL being a vector-borne disease means that infection events are driven by sand fly 296 biting behaviour and sand fly interactions with hosts. Accordingly, finding greater sensitivity 297 on infection prevalence when altering the parameters related to sand fly dynamics versus the 298 majority of parameters conditioned solely on dogs is not unexpected and is in agreement with 299 prior studies displaying the sensitivity of Leishmania transmission models to sand fly parameter 300 values [13,38]. Furthermore, the importance of understanding sand fly biology and biting be-301 haviours in relation to transmission probability and control has been underpinned by laboratory 302 experiments and observations in nature [32,[39][40][41][42].…”

“…In terms of canine VL, serological 34 studies undertaken in endemic areas of Brazil have found prevalence of L. infantum infection 35 to range from 25% [16] to more than 70% [17][18][19][20] depending on the diagnostic sample and 36 test employed. A consequence of the burden of L. infantum infection in the canine reservoir 37 is that Brazil has seen a steady rise in the number of human VL cases throughout the last 30 38 years [5,21]. A reported 3,500 human VL cases occur in the country per year, 90% of all VL 39 cases reported in the Americas [1,3], with the actual incidence (allowing for under-reporting) 40 estimated annually to be between 4,200 and 6,300 [1].…”

Elimination of visceral leishmaniasis in the Indian subcontinent: a comparison of predictions from three transmission models

“…All VL transmission models face the challenge of describing transmission of a disease with many key factors, such as the role of immunity and the contributions of individuals in different disease stages to transmission, basically remaining unknown (Rock et al, 2015, Rock et al, 2016, Le Rutte et al, 2016). Also the impact of IRS, the main intervention strategy, on sandfly densities remains debated.…”

“…Mathematical models capturing disease transmission dynamics and control measures have proven to be useful tools in predicting the feasibility of achieving elimination targets with existing strategies (Hollingsworth et al, 2015, Rock et al, 2015, Hirve et al, 2016, Rock et al, 2016). Deterministic VL transmission models have been developed previously based on the KalaNet dataset from Bihar (India) and Nepal (Stauch et al, 2011, Stauch et al, 2014).…”

Safety Analysis of Leishmania Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial

“…3,4 Statistical and mathematical models of Leishmania zoonotic transmission demonstrated that an effective canine-targeted vaccine would also control human disease. [5][6][7] Veterinarians in Brazil, the country with the greatest burden of zoonotic canine leishmaniasis (CanL), have been empirically using vaccination as immunotherapy to treat dogs as they were only recently awarded with the first drug available in Brazil to treat CanL, Miltefosine (Milteforan), licensed in 2017. Before that it had been illegal for veterinarians to treat dogs seropositive for CanL because of the risk of these animals failing treatment and promoting Leishmania transmission to people.…”