Mathematical modelling of lymphatic filariasis elimination programmes in India: required duration of mass drug administration and post-treatment level of infection indicators.

BACKGROUND: India has made great progress towards the elimination of lymphatic filariasis. By 2015, most endemic districts had completed at least five annual rounds of mass drug administration (MDA). The next challenge is to determine when MDA can be stopped. We performed a simulation study with the individual-based model LYMFASIM to help clarify this. METHODS: We used a model-variant for Indian settings. We considered different hypotheses on detectability of antigenaemia (Ag) in relation to underlying adult worm burden, choosing the most likely hypothesis by comparing the model predicted association between community-level microfilaraemia (Mf) and antigenaemia (Ag) prevalence levels to observed data (collated from literature). Next, we estimated how long MDA must be continued in order to achieve elimination in different transmission settings and what Mf and Ag prevalence may still remain 1 year after the last required MDA round. The robustness of key-outcomes was assessed in a sensitivity analysis. RESULTS: Our model matched observed data qualitatively well when we assumed an Ag detection rate of 50 % for single worm infections, which increases with the number of adult worms (modelled by relating detection to the presence of female worms). The required duration of annual MDA increased with higher baseline endemicity and lower coverage (varying between 2 and 12 rounds), while the remaining residual infection 1 year after the last required treatment declined with transmission intensity. For low and high transmission settings, the median residual infection levels were 1.0 % and 0.4 % (Mf prevalence in the 5+ population), and 3.5 % and 2.0 % (Ag prevalence in 6-7 year-old children). CONCLUSION: To achieve elimination in high transmission settings, MDA must be continued longer and infection levels must be reduced to lower levels than in low-endemic communities. Although our simulations were for Indian settings, qualitatively similar patterns are also expected in other areas. This should be taken into account in decision algorithms to define whether MDA can be interrupted. Transmission assessment surveys should ideally be targeted to communities with the highest pre-control transmission levels, to minimize the risk of programme failure.

River Blindness: Mathematical Models for Control and Elimination.

Human onchocerciasis (river blindness) is one of the few neglected tropical diseases (NTDs) whose control strategies have been informed by mathematical modelling. With the change in focus from elimination of the disease burden to elimination of Onchocerca volvulus, much remains to be done to refine, calibrate and validate existing models. Under the impetus of the NTD Modelling Consortium, the teams that developed EPIONCHO and ONCHOSIM have joined forces to compare and improve these frameworks to better assist ongoing elimination efforts. We review their current versions and describe how they are being used to address two key questions: (1) where can onchocerciasis be eliminated with current intervention strategies by 2020/2025? and (2) what alternative/complementary strategies could help to accelerate elimination where (1) cannot be achieved? The control and elimination of onchocerciasis from the African continent is at a crucial crossroad. The African Programme for Onchocerciasis Control closed at the end of 2015, and although a new platform for support and integration of NTD control has been launched, the disease will have to compete with a myriad of other national health priorities at a pivotal time in the road to elimination. However, never before had onchocerciasis control a better arsenal of intervention strategies as well as diagnostics. It is, therefore, timely to present two models of different geneses and modelling traditions as they come together to produce robust decision-support tools. We start by describing the structural and parametric assumptions of EPIONCHO and ONCHOSIM; we continue by summarizing the modelling of current treatment strategies with annual (or biannual) mass ivermectin distribution and introduce a number of alternative strategies, including other microfilaricidal therapies (such as moxidectin), macrofilaricidal (anti-wolbachial) treatments, focal vector control and the possibility of an onchocerciasis vaccine. We conclude by discussing challenges, opportunities and future directions.

Concurrence of dermatological and ophthalmological morbidity in onchocerciasis.

Prevalence of skin and eye disorders in African onchocerciasis (river blindness) is well documented. However, less is known about their joint occurrence. Information on concurrence may improve our understanding of disease pathogenesis and is required to estimate the disease burden of onchocerciasis. We analysed data from 765 individuals from forest villages in the Kumba and Ngambe Health districts, Cameroon. These data were collected in 1998, as baseline data for the evaluation of the African Programme for Onchocerciasis Control. Concurrence of symptoms was assessed using logistic regression. Onchocerciasis was highly endemic in the study population (63% nodule prevalence among males aged ≥20). Considerable overall prevalences of onchocercal visual impairment (low vision or blindness: 4%), troublesome itch (15%), reactive skin disease (19%), and skin depigmentation (25%) were observed. The association between onchocercal visual impairment and skin depigmentation (OR 9.0, 95% CI 3.9-20.8) was partly explained by age and exposure to infection (OR 3.0, 95% CI 1.2-7.7). The association between troublesome itch and reactive skin disease was hardly affected by adjustment (adjusted OR 6.9, 95% CI 4.2-11.1). Concluding, there is significant concurrence of morbidities within onchocerciasis. Our results suggest a possible role of host characteristics in the pathogenesis of depigmentation and visual impairment. Further, we propose a method to deal with concurrence when estimating the burden of disease.

Effectiveness of annual ivermectin treatment for Wuchereria bancrofti infection.

Using estimates for the anthelmintic efficacy of a single dose of ivermectin in the treatment of lymphatic filariasis patients, Anton Plaisier, Wilma Stolk, Gerrit van Oortmarssen and Dik Habbema here present and discuss model predictions of the impact of a five-year programme of annual community treatment on the intensity of infection. They show that the effectiveness of such programmes in terms of reductions in the microfilarial density depends critically on the treatment coverage and the pattern of attendance at repeated mass administrations. Improving these factors will possibly be more important than improving the efficacy of ivermectin by increasing its dosage or by adding other drugs.

Regulation of anti-filarial IgE by infection pressure.

In lymphatic filariasis, specific IgG4 responses to the parasite and their relationship with infection have been studied extensively, but only a few studies have concentrated on anti-filarial and total IgE. Here we have investigated the role of filarial infection pressure on production of IgE by considering length of exposure (age), filarial endemicity and parasitological status. Antibody levels were determined in 366 individuals, who were resident in 3 villages in South-Sulawesi, Indonesia, with varying degrees of filarial transmission intensity, as indicated by the prevalence of Brugia malayi microfilaraemia (0.7%, 9% and 32%, respectively). Anti-filarial IgE levels were significantly lower in the low transmission village than in the areas with intermediate and high filarial transmission; however, in the latter village a remarkable suppression of specific IgE was found. Microfilaria-positive individuals showed elevated levels of total IgE, but suppression of specific IgE, which has been reported before. Taken together, these observations suggest that 2 opposing mechanisms regulate anti-parasite IgE expression: increasing experience of filarial infection stimulates specific IgE, but antibody levels become specifically suppressed when microfilariae or adult worms develop. Using a simple mathematical model, we illustrate how anti-filarial IgE increases with parasite antigen up to a threshold level, but levels off and becomes down-regulated after the threshold is exceeded.

Meta-analysis of age-prevalence patterns in lymphatic filariasis: no decline in microfilaraemia prevalence in older age groups as predicted by models with acquired immunity.

The role of acquired immunity in lymphatic filariasis is uncertain. Assuming that immunity against new infections develops gradually with accumulated experience of infection, models predict a decline in prevalence after teenage or early adulthood. A strong indication for acquired immunity was found in longitudinal data from Pondicherry, India, where Mf prevalence was highest around the age of 20 and declined thereafter. We reviewed published studies from India and Subsaharan Africa to investigate whether their age-prevalence patterns support the models with acquired immunity. By comparing prevalence levels in 2 adult age groups we tested whether prevalence declined at older age. For India, comparison of age groups 20-39 and 40+ revealed a significant decline in only 6 out of 53 sites, whereas a significant increase occurred more often (10 sites). Comparison of older age groups provided no indication that a decline would start at a later age. Results from Africa were even more striking, with many more significant increases than declines, irrespective of the age groups compared. The occurrence of a decline was not related to the overall Mf prevalence and seems to be a chance finding. We conclude that there is no evidence of a general age-prevalence pattern that would correspond to the acquired immunity models. The Pondicherry study is an exceptional situation that may have guided us in the wrong direction.

Assessing density dependence in the transmission of lymphatic filariasis: uptake and development of Wuchereria bancrofti microfilariae in the vector mosquitoes.

Understanding density dependence in the transmission of lymphatic filariasis is essential for assessing the prospects of elimination. This study seeks to quantify the relationship between microfilaria (Mf) density in human blood and the number of third stage (L3) larvae developing in the mosquito vectors Aedes polynesiensis Marks and Culex quinquefasciatus Say (Diptera: Culicidae) after blood-feeding. Two types of curves are fitted to previously published data. Fitting a linearized power curve through the data allows for correction for measurement error in human Mf counts. Ignoring measurement error leads to overestimation of the strength of density dependence; the degree of overestimation depends on the accuracy of measurement of Mf density. For use in mathematical models of transmission of lymphatic filariasis, a hyperbolic saturating function is preferable. This curve explicitly estimates the Mf uptake and development at lowest Mf densities and the average maximum number of L3 that can develop in mosquitoes. This maximum was estimated at 23 and 4 for Ae. polynesiensis and Cx. quinquefasciatus, respectively.

The dynamics of Wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India.

This paper presents a model-based analysis of longitudinal data describing the impact of integrated vector management on the intensity of Wuchereria bancrofti infection in Pondicherry, India. The aims of this analysis were (1) to gain insight into the dynamics of infection, with emphasis on the possible role of immunity, and (2) to develop a model that can be used to predict the effects of control. Using the LYMFASIM computer simulation program, two models with different types of immunity (anti-L3 larvae or anti-adult worm fecundity) were compared with a model without immunity. Parameters were estimated by fitting the models to data from 5071 individuals with microfilaria-density measurement before and after cessation of a 5-year vector management programme. A good fit, in particular of the convex shape of the age-prevalence curve, required inclusion of anti-L3 or anti-fecundity immunity in the model. An individual's immune-responsiveness was found to halve in approximately 10 years after cessation of boosting. Explanation of the large variation in Mf-density required considerable variation between individuals in exposure and immune responsiveness. The mean life-span of the parasite was estimated at about 10 years. For the post-control period, the models predict a further decline in Mf prevalence, which agrees well with observations made 3 and 6 years after cessation of the integrated vector management programme.