Swaminathan Subramanian

Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study

BACKGROUND Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. METHODS We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. FINDINGS In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. INTERPRETATION Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual countrys programme. FUNDING Bill & Melinda Gates Foundation.

Operational feasibility of lot quality assurance sampling (LQAS) as a tool in routine process monitoring of filariasis control programmes.

Lot quality assurance sampling (LQAS) with two‐stage sampling plan was applied for rapid monitoring of coverage after every round of mass drug administration (MDA). A Primary Health Centre (PHC) consisting of 29 villages in Thiruvannamalai district, Tamil Nadu was selected as the study area. Two threshold levels of coverage were used: threshold A (maximum: 60%; minimum: 40%) and threshold B (maximum: 80%; minimum: 60%). Based on these thresholds, one sampling plan each for A and B was derived with the necessary sample size and the number of allowable defectives (i.e. defectives mean those who have not received the drug). Using data generated through simple random sampling (SRSI) of 1750 individuals in the study area, LQAS was validated with the above two sampling plans for its diagnostic and field applicability. Simultaneously, a household survey (SRSH) was conducted for validation and cost‐effectiveness analysis. Based on SRSH survey, the estimated coverage was 93.5% (CI: 91.7–95.3%). LQAS with threshold A revealed that by sampling a maximum of 14 individuals and by allowing four defectives, the coverage was ≥60% in >90% of villages at the first stage. Similarly, with threshold B by sampling a maximum of nine individuals and by allowing four defectives, the coverage was ≥80% in >90% of villages at the first stage. These analyses suggest that the sampling plan (14,4,52,25) of threshold A may be adopted in MDA to assess if a minimum coverage of 60% has been achieved. However, to achieve the goal of elimination, the sampling plan (9, 4, 42, 29) of threshold B can identify villages in which the coverage is <80% so that remedial measures can be taken. Cost‐effectiveness analysis showed that both options of LQAS are more cost‐effective than SRSH to detect a village with a given level of coverage. The cost per village was US

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

76.18 under SRSH. The cost of LQAS was US

Role of modified CDC miniature light-traps as an alternative method for sampling adult anophelines (Diptera: Culicidae) in the national mosquito surveillance programme in India

65.81 and 55.63 per village for thresholds A and B respectively. The total financial cost of classifying a village correctly with the given threshold level of LQAS could be reduced by 14% and 26% of the cost of conventional SRSH method.

Lymphatic Filariasis Transmission Risk Map of India, Based on a Geo-Environmental Risk Model

Abstract.  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.

Predicting lymphatic filariasis transmission and elimination dynamics using a multi-model ensemble framework

The efficiency of modified CDC miniature light-traps for sampling adult mosquitoes was evaluated in comparison with indoor resting, outdoor resting, indoor man-landing and outdoor man-landing collections in the hilly district of Koraput, Orissa, India. Overall, light-traps captured 78% of adult mosquitoes collected by all methods. Of the 16 anopheline species recorded in the study area, light-traps effectively sampled 13, contributing about 72% of the total anophelines collected by all methods. Light-traps also caught a large number of female Culex vishnui Theobald (96%). As fully-fed mosquitoes were predominant (82%) and caught alive, light-traps can be used to catch large numbers of vector mosquitoes for studies on vector prevalence, distribution, vector incrimination and also for laboratory bioassays. Light-trap and indoor resting collections revealed similar seasonal trends in numbers of Anopheles culicifacies Giles, A. fluviatilis James, A. jeyporiensis James, A. vagus Doenitz, and A. splendidus Koidzumi. Age-structure of the samples did not vary significantly between the two methods. Light-traps could be used as an alternative to daytime indoor resting collections to monitor the seasonal fluctuations in the abundance and parity rates of these species. The light-trap collections correlated with indoor and outdoor man-landing collections of A. jeyporiensis and the outdoor man-landing collections of A. maculatusTheobald in measuring seasonal trends. Light-trap collections can thus be used as a substitute for man-landing collections of A. jeyporiensis and A. maculatus.

Application of a household-based molecular xenomonitoring strategy to evaluate the lymphatic filariasis elimination program in Tamil Nadu, India

The strategy adopted by a global program to interrupt transmission of lymphatic filariasis (LF) is mass drug administration (MDA) using chemotherapy. India also followed this strategy by introducing MDA in the historically known endemic areas. All other areas, which remained unsurveyed, were presumed to be nonendemic and left without any intervention. Therefore, identification of LF transmission risk areas in the entire country has become essential so that they can be targeted for intervention. A geo-environmental risk model (GERM) developed earlier was used to create a filariasis transmission risk map for India. In this model, a Standardized Filariasis Transmission Risk Index (SFTRI, based on geo-environmental risk variables) was used as a predictor of transmission risk. The relationship between SFTRI and endemicity (historically known) of an area was quantified by logistic regression analysis. The quantified relationship was validated by assessing the filarial antigenemia status of children living in the unsurveyed areas through a ground truth study. A significant positive relationship was observed between SFTRI and the endemicity of an area. Overall, the model prediction of filarial endemic status of districts was found to be correct in 92.8% of the total observations. Thus, among the 190 districts hitherto unsurveyed, as many as 113 districts were predicted to be at risk, and the remaining at no risk. The GERM developed on geographic information system (GIS) platform is useful for LF spatial delimitation on a macrogeographic/regional scale. Furthermore, the risk map developed will be useful for the national LF elimination program by identifying areas at risk for intervention and for undertaking surveillance in no-risk areas.

Use of a simple DNA extraction method for high-throughput detection of filarial parasite Wuchereria bancrofti in the vector mosquitoes

Highlights • No single mathematical model captures all features of parasite transmission dynamics.• Multi-model ensemble modelling can overcome biases of single models.• A multi-model ensemble of three lymphatic filariasis models is proposed and evaluated.• The multi-model ensemble outperformed the single models in predicting infection.• The ensemble approach may improve use of models to inform disease control policy.

Are alternative strategies required to accelerate the global elimination of lymphatic filariasis? Insights from mathematical models

Background The monitoring and evaluation of lymphatic filariasis (LF) has largely relied on the detection of antigenemia and antibodies in human populations. Molecular xenomonitoring (MX), the detection of parasite DNA/RNA in mosquitoes, may be an effective complementary method, particularly for detecting signals in low-level prevalence areas where Culex is the primary mosquito vector. This paper investigated the application of a household-based sampling method for MX in Tamil Nadu, India. Methods MX surveys were conducted in 2010 in two evaluation units (EUs): 1) a hotspot area, defined as sites with community microfilaria prevalence ≥1%, and 2) a larger area that also encompassed the hotspots. Households were systematically selected using a sampling interval proportional to the number of households in the EU. Mosquito pools were collected and analyzed by real-time polymerase chain reaction (qPCR). Two independent samples were taken in each EU to assess reproducibility of results. Follow-up surveys were conducted in 2012. Results In 2010, the proportion of positive pools in the hotspot EU was 49.3% compared to 23.4% in the overall EU. In 2012, pool positivity was significantly reduced to 24.3% and 6.5%, respectively (p<0.0001). Pool positivity based on independent samples taken from each EU in 2010 and 2012 were not significantly different except for the hotspot EU in 2012 (p = 0.009). The estimated prevalence of infection in mosquitoes, measured by PoolScreen, declined from 2.2–2.7% in 2010 to 0.6–1.2% in 2012 in the hotspot area and from 0.9–1.1% to 0.2–0.3% in the larger area. Conclusions The household-based sampling strategy for MX led to mostly reproducible results and supported the observed LF infection trends found in humans. MX has the potential to be a cost-effective, non-invasive monitoring and evaluation tool with sensitive detection of infection signals in low prevalence settings. Further investigation and application of this sampling strategy for MX are recommended to support its adoption as a standardized method for global LF elimination programs.

Usage pattern, physical integrity & insecticidal efficacy of long-lasting insecticidal nets in Odisha State, India

Molecular xenomonitoring of filariasis is the detection of filarial DNA in mosquitoes by PCR and a useful tool for monitoring transmission. DNA extraction coupled with PCR allows rapid detection of the presence or absence of the filarial parasite in vector mosquitoes compared to traditional method of manual dissection of the mosquito and observation for parasite under a microscope. A Tris–EDTA (TE) buffer-based boiling method of DNA extraction developed earlier by us was employed and explored for its suitability in the detection of Wuchereria bancrofti DNA in pools of Culex quinquefasciatus mosquitoes in real-time PCR assay. In this preliminary study, 1,000 laboratory-reared C. quinquefasciatus were made into 40 pools, each containing 25 mosquitoes spiked with 2mf. DNA from the first 20 pools was extracted using Qiagen DNeasy blood and tissue kit as standard, and the other 20 pools were subjected to TE buffer-based boiling method of DNA extraction. When the results (Ct values) obtained for DNA samples extracted by TE buffer-based boiling method were compared with that of the DNA samples extracted by the standard Qiagen method, they were found to be highly concordant without any significant difference (P = 0.9). Besides being cost- and time-effective, this protocol was found useful in extracting filarial DNA from two other mosquito genus Aedes and Anopheles, species of which have been reported as important vectors of W. bancrofti in other endemic regions of the world. Thus, TE buffer-based boiling method of DNA extraction is useful for the high-throughput detection of W. bancrofti in vector mosquitoes.