Advances and challenges in predicting the impact of lymphatic filariasis elimination programmes by mathematical modelling

Abstract

Mathematical simulation models for transmission and control of lymphatic filariasis are useful tools for studying the prospects of lymphatic filariasis elimination. Two simulation models are currently being used. The first, EPIFIL, is a population-based, deterministic model that simulates average trends in infection intensity over time. The second, LYMFASIM, is an individual-based, stochastic model that simulates acquisition and loss of infection for each individual in the simulated population, taking account of individual characteristics. For settings like Pondicherry (India), where Wuchereria bancrofti infection is transmitted by Culex quinquefasciatus, the models give similar predictions of the coverage and number of treatment rounds required to bring microfilaraemia prevalence below a level of 0.5%. Nevertheless, published estimates of the duration of mass treatment required for elimination differed, due to the use of different indicators for elimination (EPIFIL: microfilaraemia prevalence < 0.5% after the last treatment; LYMFASIM: reduction of microfilaraemia prevalence to zero, within 40 years after the start of mass treatment). The two main challenges for future modelling work are: 1) quantification and validation of the models for other regions, for investigation of elimination prospects in situations with other vector-parasite combinations and endemicity levels than in Pondicherry; 2) application of the models to address a range of programmatic issues related to the monitoring and evaluation of ongoing control programmes. The models' usefulness could be enhanced by several extensions; inclusion of different diagnostic tests and natural history of disease in the models is of particular relevance.

Figure 1

Transmission cycle of lymphatic filariasis with density-dependent mechanisms. This figure shows the life cycle of Wuchereria bancrofti, the main parasitic cause of lymphatic filariasis. The adult worms (macrofilariae) are located in the lymphatic system of the human host, where they live for 5–10 years [24, 37]. After mating with male worms, female worms can produce millions of microfilariae (mf), which can be found in the bloodstream and have a lifespan of 6–24 months [32]. A mosquito that takes a blood meal may engorge some mf. Inside the mosquito, mf develop in about 12 days into L3 stage larvae (L3), which are infectious to humans. When the mosquito takes another blood meal, the L3 can enter the human body and some will migrate to the lymphatic system and will develop into mature adult worms. The immature period lasts about 6–12 months [38]. Mf cannot develop into adult worms without passing through the developmental stages in the mosquito. Larval development and mosquito survival are density-dependent [17, 18]. Two possible mechanisms of acquired immunity are shown [20].

Figure 2

Comparison of model predictions of microfilaraemia prevalence by age with observed data, before the start of vector control (1981) in Pondicherry, India. (A) LYMFASIM predictions for models with anti-L3 immunity (solid line), anti-fecundity immunity (dashed line), and a model variant without immunity (dot-dashed line); the latter model did not fit the data and was therefore rejected. Source: [24]. (B) EPIFIL predictions of a model with acquired immunity. Source: [11]. Symbols in both graphs indicate the observed prevalence levels with corresponding confidence intervals.

Figure 3

LYMFASIM predictions of the coverage and number of yearly mass treatment rounds with ivermectin that are required for lymphatic filariasis elimination in Pondicherry, India. Precontrol microfilaraemia prevalence was assumed to be 8.5%. Elimination was said to occur if zero microfilaraemia prevalence is reached 40 years after the start of treatment, with 99% probability. A single treatment with ivermectin (200 μg/kg) was assumed to sterilize 77% of female worms permanently and to kill all microfilariae. Results are shown for two variants of the LYMFASIM model for Pondicherry, differing with respect to the assumed immune mechanism (solid line – anti-L3 immunity; broken line – anti-fecundity immunity). Source: [30].

Figure 4

EPIFIL predictions of the impact of mass treatment, vector control and their combination on trends in microfilaraemia prevalence. Predictions were made with the EPIFIL simulation model as quantified for Pondicherry (but ignoring acquired immunity), assuming a precontrol microfilaraemia prevalence of 10%. The plot shows the impact of mass treatment alone (5 rounds of annual mass treatment with diethylcarbamazine + albendazole, with a coverage of 80%), vector control alone (assuming a 90% reduction in biting rate during 5 years), and the combination of the two. Reprinted from [28], with permission from Elsevier.