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Mapping and monitoring for a lymphatic filariasis elimination program: a systematic review

Abstract Lymphatic filariasis (LF) is targeted for elimination by the year 2020. The Global Programme for Elimination of LF (GPELF) aims to achieve elimination by interrupting transmission through annual mass drug administration (MDA) of albendazole with ivermectin or diethylcarbamazine. The program has successfully eliminated the disease in 11 of the 72 endemic countries, putting in enormous efforts on systematic planning and implementation of the strategy. Mapping areas endemic for LF is a pre-requisite for implementing MDA, monitoring and evaluation are the components of programme implementation. This review was undertaken to assess how the mapping and impact monitoring activities have evolved to become more robust over the years and steered the LF elimination programme towards its goal. The findings showed that the WHO recommended mapping strategy aided 17 countries to delimit, plan and implement MDA in only those areas endemic for LF thereby saving resources. Availability of serological tools for detecting infection in humans (antigen/antibody assays) and molecular xenomonitoring (MX) in vectors greatly facilitated programme monitoring and evaluation in endemic countries. Results of this review are discussed on how these existing mapping and monitoring procedures can be used for re-mapping of unsurveyed and uncertain areas to ensure there is no resurgence during post-MDA surveillance. Further the appropriateness of the tests (Microfilaria (Mf)/antigenemia (Ag)/antibody(Ab) surveys in humans or MX of vectors for infection) used currently for post-MDA surveillance and their role in the development of a monitoring and evaluation strategy for the recently WHO recommended triple drug regimen in MDA for accelerated LF elimination are discussed.


Introduction
Lymphatic filariasis (LF) is one of the neglected tropical diseases (NTD) caused by three species of filarial worm: Wuchereria bancrofti, Brugia malayi, and Brugia timori. As of 1997, the disease was prevalent in 72 tropical and sub-tropical countries of the world. 1 In 1997, the World Health Assembly 2 declared elimination of LF as a public health problem. Subsequently, the World Health Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) in 2000 to achieve elimination by 2020. 3 The elimination program has two components 1) interruption of transmission; and 2) morbidity management and disability prevention. For interruption of transmission, the strategy is annual single dose mass drug administration (MDA) of albendazole in combination with diethylcarbamazine (DEC) or ivermectin (IVM) to the LF endemic population. The program encompasses the following sequence of steps: 4 1) map LF endemic areas (>1% of antigenemia (Ag), among 50-100 individuals (>15 years), from two communities of an endemic district); 5 2) deliver MDA for a minimum of 5 years with an effective coverage of 65%; 3) conduct a transmission-assessment survey (TAS); 4 4) conduct post-MDA surveillance; 5) develop a dossier that documents the achievement of elimination targets; and 6) independent validation of the claim that elimination criteria have been achieved.
Mapping the areas endemic for LF is the pre-requisite for the countries to plan and implement the elimination program. The next step is to implement MDA in endemic areas for a minimum of 5 years with an effective coverage of 65%. The program is to be monitored every 6 months post-MDA by assessing filarial infection (microfilaria [Mf]/Ag) in sentinel and spot check sites. If the prevalence of Mf in all the sentinel and in the randomly selected spot check sites are <1%, TAS is conducted to decide on stopping or continuing MDA. The TAS's decision to stop or continue MDA is based on a pre-determined number of Ag positives below which transmission is expected to be interrupted and hence MDA can be stopped, if not MDA is continued for another two rounds. TAS is repeated twice at 2-3 year intervals (post-MDA surveillance) to assess if transmission interruption is sustained after cessation of MDA following TAS 1. After successfully passing all the three TASs, a dossier is submitted to the WHO, which validates the claim of elimination made by the country and once validated, WHO acknowledges LF elimination in that country. As of 2017, 51 of the 72 LF endemic countries have fully implemented MDA, and WHO acknowledged after post-MDA validation in 11 countries, that LF is no longer a public health problem. 6 As GPELF is nearing its end game in many endemic countries it would be useful to do a comprehensive assessment of the mapping and monitoring activities used so far and to see how they been improvised to help in upscaling and assessing the impact of the program. Such a review would also be helpful to provide an insight on the methods that could be used in future for 1) remapping areas that are unsurveyed and not under MDA and areas bordering endemic districts; and 2) in identifying the appropriate sensitive tool that would detect ongoing transmission during post-MDA surveillance or validation phase. With this background, a systematic review of the literature on use of mapping and monitoring methods for LF elimination is undertaken.

Search criteria
All published articles in national and international peerreviewed journals were searched. Searches were made in PUBMED MEDLINE database with key words like "lymphatic filariasis" in combination with "monitoring," "mapping," "infection," "disease," "MDA," "antigeneamia," "antibody," "ICT," "FTS," "Wb123," "Mf" (or "microfilaria"), "vector infection," and "xenomonitoring" using Boolean operators like "and" and "or." Attempts were made to download the full articles and the back reference lists in these articles were searched for additional studies.

Eligibility criteria
For a study to be eligible for the review it should either have carried out mapping or monitored/measured impact evaluation with respect to MDA or both in terms of filarial infection (Mf/Ag/Ab) in humans or disease in humans or infection in vectors.
monitoring alone and five both on mapping and monitoring aspects of LF.
The results of this review on mapping and monitoring of LF are presented in accordance with different phases of the program (pre-MDA, during MDA and post-MDA). While one would expect mapping to be undertaken mostly prior to implementation of MDA, it was observed that mapping was also done in the during-and post-MDA phases. As for monitoring, the studies included in this review assessed only the impact of MDA and not on coverage or compliance aspects of MDA.

Mapping
The majority (86%; 37/43) of the studies on mapping were conducted prior to implementation of MDA, mainly to delimit areas that required MDA. Of these 37 studies, 23 (62%) were from Africa, 5 (14%) from South East Asia, 6(16%) from the Americas and 3 (8%) from the Eastern Mediterranean region.
The WHO mapping guidelines 5 for LF endemic areas (preferably an implementation unit (IU)/district) recommended a two stage sampling method of examining 50-100 individuals aged >15 years (conveniently sampled) for filarial antigen from two communities purposively selected from the IU/district. If the Ag prevalence is found to be ≥1%, the IU/ district is considered for MDA.

Pre-MDA
The details of the pre-MDA mapping studies that were carried out to assess if MDA is required are given in Table 1. The review showed that most African countries used the WHO recommended mapping method for delimiting areas requiring MDA. [60][61][62][63][64][65][66][67][68] The surveys were conducted among adults and or children aged 5-15 years across the studies spanning over countries. In addition to these surveys, a few studies used Mf surveys (current and historic data), key informant techniques [69][70][71][72][73][74][75][76][77][78] for assessing LF endemicity. In four studies,   The data collected in an earlier study (Brandao et al, 2011), was used to identify the areas with high infection foci, applying kernel density approach on household level data. This method rapidly detected areas with highest concentration of infected cases and assisted the programme towards planning, monitoring, and surveillance of filariasis elimination activities.
Infection in children/adolescents in combination with SRI showed that the localities where the children most exposed to filarial transmission were clustered and precisely measured the relationship between social deprivation and the prevalence of infection among children. Mf, Ag and or disease surveys were used to map areas requiring MDA. [79][80][81][82] In Rwanda, mapping showed that there was only one Ag positive case in all five districts that were surveyed and this helped in declaring that LF was not a public health problem and therefore MDA was deferred thereby saving money and other humane efforts. 63 In the countries of the African region, starting with rapid assessment procedures (Ag survey and key informant interviews on LF symptoms) for delimiting areas endemic for LF, the progress made on mapping of LF has been tremendous. A few studies mapped the distribution of LF 61,62,66,83,84 using Mf and or Ag surveys and showed that the LF was more widely spread than it was previously thought in those countries. Few studies went further to carry out spatial analysis of the filarial prevalence data collected for mapping through a spatial sampling grid with 50 km distance between sampled locations and predicted LF prevalence at 25 km distance. 60,77,[85][86][87] Studies that carried out mapping of LF in Oncho coendemic area helped the program to produce LF distribution maps 80,82 with areas having Ag rates >1% and recommended inclusion of albendazole with the monotherapy of ivermectin to aid elimination of LF in these areas. 65 Subsequently, as the countries in the African region were known to be co-endemic for NTDs like loasis, soil transmitted helminthic diseases, schistosomiasis and podoconiosis, attempts were made to map all these under one roof and this paved the way for an integrated mapping approach to understand the extent of distribution of diseases, and implementing control programs. Integrated mapping of LF with podoconiosis led to efficient use of resources and helped in rapidly delimiting large geographical areas. This approach was popular among the health staff in Ethiopia. 68,88 A large NTD survey integrating mapping for LF, schistosomiasis and STH in three states of Sudan 89 established that an estimated population of 1.2 and 1.4 million individuals were eligible for regular MDA with preventive chemotherapy (PCT) to treat STH and schistosomiasis respectively, and that 1.3 million individuals residing in Central-and Eastern Equatoria required MDA for LF. This integrated mapping approach cut costs and saved time with the same man-power efforts. 64 Yet another approach called Micro stratification overlapped mapping (MOM) in Congo 76 helped the program authorities to take extra precautions in handling serious adverse events that may take place due to co-endemicity of LF and loasis. In Nigeria, a similar approach using historical data helped in producing a series of maps to assist in maximizing existing interventions, cost effective usage of resources as the LF elimination programme scaled up. 81 Countries such as Ghana, Uganda and India used the historical data (Mf, Ag), for predicting LF prevalence in the uncertain and un-surveyed areas using geo-statistical models 67,69,[90][91][92][93] and showed the heterogeneous distribution of LF for the respective countries, indicating the possibility on the risk of occurrence of LF even in the probably non-endemic areas. Three studies from India used Mf prevalence to identify districts for MDA. [71][72][73] Mapping data along with social deprivation index (SDI) and socio-environmental composite risk index (SRI) were used in Haiti to specifically map LF risk in urban areas 74,75,78 and to see clustering of infection. Two studies tested a confirmatory mapping tool against the WHO recommended mapping strategy mainly to assess whether those areas in Ethiopia and Tanzania 94,95 with uncertain endemicity (one Ag positive among 200 adults; 45 in Ethiopia and 11 in Tanzania) needed to be included for MDA. This tool tested a sample of 320 children aged 9-14 years, from 30 schools selected based on probability proportional to estimated population size in a Woreda (a district) to find areas requiring MDA. The results showed that while only 3 out of 45 in Ethiopia and none of the 11 from Tanzania required MDA, thereby saving time and the resources by preventing MDA in areas where there was no evidence of transmission.

During MDA
Mapping during MDA (Table 2) was useful in re-assessing the geographic limits of LF and identifying new LF endemic areas that were either not surveyed, or classified as uncertain or non-endemic earlier. [96][97][98] It was observed that in India, 113 of the 190 districts, which were not surveyed earlier and not included for MDA, were identified to be having varying risk of transmission. As the elimination goal is nearing, the National Vector-Borne Disease Control Programme (NVBDCP) is in the process of validating these findings before bringing these districts under MDA net. Mf and entomological surveys conducted in the sentinel villages of the Gampha district of Sri Lanka after 5 rounds of MDA showed ongoing transmission 99 and recommended continuation of further rounds of MDA. In another study in Malawi that had already undergone 5 rounds of MDA for LF elimination is co-endemic for oncho and malaria, it was felt that the intervention programmes against these diseases could have impacted the transmission of LF. Therefore, to identify the high-risk areas of LF, a multiple intervention score map (MISM), that is based on weighted sum of individual intervention One district, Gampaha Mf and vector infection prevalence (MX) >3 years The study assessed the current status of LF after five rounds of MDA in two sentinel and one spot check site using GIS. While the Mf prevalence ranged between 0.5% and 3.4% in sentinel sites, vector infection by xenomonitoring ranged between 0 and 32.4%, indicating that transmission is on-going and therefore may need to intensify further rounds of MDA. Six LF-Oncho coendemic districs Ag prevalence All ages This study quantified the geographical extent of LF (MDA), Oncho (MDA), Bednets and IRS interventions impacting LF and produced a multiple intervention score map (MISM-weighted sum of individual intervention score). Districts were classified into four groups based on baseline LF prevalence and MISM. High coverage areas included the LF-onchocerciasis endemic areas in the southern region of the country and areas along the shores of Lake Malawi, where malaria vector control had been prioritised. Three districts with high baseline LF prevalence measures but low coverage of multiple interventions were identified and considered to be most at risk of ongoing transmission or re-emergence. In this analysis, six districts were identified as priority districts for additional interventions, with a further five being identified as having low prevalence and high intervention coverage, suggesting that they should be prioritised for post-MDA surveillance and move to the elimination phase (Continued) scores was used. This score was useful in identifying areas with high and low coverage of LF impacting interventions. It was shown that those areas with low coverage with high baseline LF prevalence were identified and considered to be with high risk of transmission or re-emergence. 100 Another study 101 attempted morbidity mapping to estimate lymphedema burden in Malawi after 5 rounds of MDA, observed that as there was no standardized method for collection of morbidity data, the morbidity burden due to LF could be grossly underestimated.

During MDA
Of the 19 studies conducted during MDA phase, 6, 7, 3, 2 and 1 were from African, Southeast Asian, Western Pacific, Americas and eastern Mediterranean regions respectively (Table 3). In eleven studies, the impact of MDA had been measured in terms of reduction in Mf Ag or Ab or filarial disease prevalence [102][103][104][105][106][107][108][109][110][111][112] in humans. Seven studies, two from India, 113,114 two from Tanzania, 115,116 one each from Haiti, 117 Nigeria, 118 Samoa, 119 and Egypt 120 monitored infection (xenomonitoring/dissection) in vectors in addition to infection in humans (MF/Ag/Ab). Studies in the African, 118 East Mediterranean, 120 and South East Asian 107,114,117 regions which used human and vector infection indicators have concluded that 4-6 rounds of MDA may not be sufficient to interrupt transmission. While the study from Nigeria 118 concluded that additional interventions (like more frequent MDA treatments and insecticidal bed nets) were necessary particularly for those sentinel villages that had baseline Ag prevalence >25%, systematic noncompliance to MDA was the reason for on-going transmission in Haiti which led to two additional MDA rounds. 117 The studies that had used vector infection prevalence in addition to Mf/Ag/Ab 117,119,120 have suggested that MX is a powerful tool in assessing the impact of MDA and that both Ab in humans and the MX tool could be used to measure on-going transmission.
Few studies that had measured Ab prevalence alone or in addition to Mf/Ag in children 105,108,115,116 indicated that    measuring Ab in children is a better indicator to assess interruption of transmission as it also measures exposure to infective bites in addition to infection with adult worms. It was suggested that measuring Ab instead of Ag alone may be helpful in identifying areas with residual infections. 105 Studies that used disease prevalence to measure the impact of MDA 104,106,110 suggested that 10 rounds of MDA had helped in reducing the overall disease prevalence to low levels. A study from Papua New Guinea showed that after four rounds of MDA, the acute filarial morbidity reduced significantly from the pre-treatment levels and that the reduction was higher in those areas that had higher transmission indices compared to those with lower figures. 106 In a community trial from India, it was found that seven rounds of MDA with DEC alone prevented incidence of new hydrocele cases and resolved the manifestation in a proportion of already affected individuals in addition to reducing the levels of Mf and transmission indices in the communities. 104 Assessment of occurrence of systemic symptoms 102 following a 5th round of MDA and providing free symptomatic treatment was expected to motivate people to report symptoms and seek care. However, the authors concluded that from a programmatic perspective, treatment of these systemic symptoms might not be necessary, because most of the individuals surveyed did not report these symptoms as a barrier to participating in future MDA.
Few studies have reported only the current situation of LF (Mf/Ag/Ab/disease) after six to seven rounds of MDA 103,104,110,[112][113][114] in the endemic areas and found that Mf prevalence were still above the 1% threshold. To interrupt the on-going transmission in spite of several rounds of MDA, these studies recommend the need for additional efforts by program authorities to improve the coverage of the program and better monitoring and evaluation procedures.
One study assessed the possibility of integrating antibody testing for LF and oncho, which has highlighted the complexities that may arise in making a decision on stopping MDA particularly in LF-oncho co-endemic areas of Africa. 111 Another study 109 observed that 7 years of monotherapy with ivermectin has not reduced Mf prevalence in a oncho-LF co-endemic area and therefore to achieve significant reduction, the authors suggested that albendazole be added to the program particularly in LF endemic areas. In another oncho-LF co-endemic area 118 the study showed that while Mf and Ag rates were reduced by 83% and 67%, the mosquito infection and infectivity rates were reduced by 86% and 76% compared to the baseline. As this was a LF-oncho co-endemic area, regarding the decision of stopping MDA, it was suggested that if LF transmission was found to be interrupted, albendazole could be stopped and the MDA could continue only with ivermectin with simultaneous post-MDA surveillance for LF for resurgence. If it is found that oncho transmission also has been interrupted, an integrated surveillance can be planned for post-MDA surveillance.

Post-MDA
A total of 17 studies (eleven from South East Asia, three from Western Pacific, two from Africa and one from American regions) have reported the findings during the post-MDA monitoring phase. Of these, one additionally monitored pre-MDA period and another study monitored pre-, during-and post-MDA periods. These studies highlighted the importance of monitoring during different phases of MDA (Table 4).
As seen in pre-and during-MDA phases, studies in the post-MDA phase have also used Ag/Ab and vector infection indicators to monitor the LF situation. In a multicountry study (consisting of eleven countries) Chu et al. 121 reported that TAS protocol is a reliable strategy (either school-or community-based) to assess interruption of transmission. Similar observation was made in India 122 who reported the first successful TAS in Goa in India after nine rounds of MDA, mentioning that TAS is a scientific, practical, and effective evaluation tool for stopping MDA. The authors emphasized the importance of focal survey to identify the source of infection in communities with antigen-positive children to prevent resurgence in an area declared free from MDA.
A study from Ghana reported the existence of hotspots, despite 14 years of MDA, and attributed the persistence of hotspots to its high baseline Mf prevalence 123 and reported that more than the standard five to six rounds of MDAs, say up to 14 rounds were required to interrupt transmission. Another study 124 summarized the current situation of LF in Bangladesh through TAS conducted in 19 districts (which had undergone 5-12 rounds of MDA) and 15 low endemic districts (not given MDA). The results showed a significant reduction in prevalence of geographical distribution of infection across Bangladesh and attributed this to factors like good administrative development and health system infrastructure, relative political stability, strong political commitment and financial support, strong program management leadership and heightened awareness of morbidity in the endemic areas. The authors also suggested that districts that required more rounds of MDA had higher baseline Mf prevalence. Post-MDA surveillance in Cambodia 125 showed that all the endemic districts had undergone five rounds of MDA with >65% coverage and had passed even TAS 3 and is currently in the final stage of declaring LF elimination. The authors have attributed this success to the commitment of the government and effective implementation of MDA, monitoring and evaluation, and surveillance activities. MDA was successfully implemented even in forested and remote endemic areas through advocacy, sensitization of various departments, active participation of provincial-and centrallevel program personnel in MDA activities, and financial and related support from partners and stakeholders. In Nepal 126 it was shown that interruption of transmission was established in five of the ten endemic districts and in one EU of another district following successful TAS after six rounds of MDA, in-spite of not achieving the optimum coverage of 65% in three districts. In the remaining districts, MDA continued as they had a higher baseline Mf prevalence as reported in Bangladesh. 124 In Myanmar 127 the program initiated in one district in 2001 was up-scaled to 42 of the 45 endemic districts by 2014. This slow progress in upscaling was attributed to lack of funding, resources (eg training of basic health staff, advocacy materials), continued problems in procuring adequate quantities of DEC, as well as security-related issues. In spite of this, five districts declared interruption of transmission with two passing TAS 1 after 6-10 rounds of MDA and three districts that had passed TAS 2 after undergoing five rounds. In this study also, a predictive modeling approach showed that the decline in Mf prevalence was associated with the number of MDAs and initial Mf prevalence as observed in the above studies.
The PHC area in Thanjavur district, Tamil Nadu, India, 128 reported low levels of infection (community Mf and Ag prev-0.2%,and 2.3%, and Ag prevalence in 2-8 years old children was 0.12%) after eight rounds of MDA with spatially clustered infection both at household and community level. Based on this study MDA was stopped in this area. Results of a long-term community trial that evaluated the effectiveness of ten rounds of DEC or ivermectin alone in ten villages of the Villupuram district of Tamilnadu, India [129][130][131] concluded that ten rounds of MDA with DEC alone would be able to interrupt transmission of LF and achieve the objective of LF elimination. 129 Subsequent post-MDA study 130 in the same area indicated  The impact of 10 rounds of MDA (using DEC alone) on LF infection and transmission in 5 endemic communities of south India, were monitored and evaluated for 6 years after the overall Mf rate of the study communities was brought down to,1.0%, considered to be the safe and threshold level to stop MDA. Overall Mf prevalence (n=700) and vector infection rates (n=803-3520) showed a declining trend. Both Mf status in humans and infection in vectors were zero from 3rd year after stopping MDA. In only one village, community Mf rate was at 1.0% and Ag prevalence among 1-7 -year old children was 4.6% (n = 44) and vector infectivity rate during the sixth year was 0.1% (n = 852).
(Continued) Results from this and other recent operational studies proved that singledose treatment with antifilarials is very effective at community level, feasible, logistically easier and cheap and hence a highly appropriate strategy to control or eliminate LF. Higher treatment coverage than that observed in this study and a few more than six cycles of treatment and more effective treatment tools/strategies may be necessary to reduce microfilaraemia to zero level in all communities, which may lead to elimination of LF.   lence rates ranged from 0-0.9% and 0-3.4%, respectively. Infection rates were significantly higher in males and lower in people who denied prior treatment. Antibody rates in school children exceeded 2% in ten study sites; the area that had the highest community and school CFA rates also had the highest school antibody rate (6.9%). Filarial DNA rates in mosquitoes exceeded 0.25% in 10 PHI areas. that 6 years of post-MDA monitoring and evaluation was adequate to discern the status of transmission interruption and for making an appropriate decision on certifying LF elimination.
Few studies have also evaluated the use of MX for confirming the findings of TAS and, also as a post-MDA surveillance tool. In a study from India, Ag-prevalence in children and vector infection indicators were used to assess the LF situation in one of the evaluation areas that stopped MDA (after 8 rounds). 128,132 The estimated vector infection rate based on xenomonitoring corroborated with the decision based on human infection for stopping MDA in this evaluation unit, suggesting that xenomonitoring could be a potential alternative to post-MDA surveillance or validation. Further, vector infection prevalence was reported to be higher in communities which were transmission hotspots (with Ag positive children). Similar observations were made in American Samoa 133 that detected parasite DNA in vector mosquitoes in the communities where Ag-positive persons were detected. In Bangladesh, one study 134 reported MX evaluation for transmission interruption in two areas; one previously endemic district that had stopped MDA (Panchagarh), and another part of a non-endemic district that reported transmission. In a study from Sri Lanka, in addition to TAS, a comprehensive surveillance (a package included cross-sectional community surveys for Mf and Ag, school surveys for Ag and Ab, besides xenomonitoring) was carried out to assess the LF situation 6 years after cessation of MDA in 19 Public Health Inspector (PHI) areas of the eleven EUs in eight districts. 135 The prevalence of infection in vector exceeded the provisional threshold of 0.25% in 10 of the 19 PHIs where the school-and community-based Ag-and Ab surveys reported <2% Ag and >2% Ab prevalence. Based on the results, the authors recommended use of antibody and MX testing as tools to complement TAS for post-MDA surveillance. Similarly, a study from Tanzania showed that in areas that had passed TAS, MX provided evidence of on-going transmission and this led to reinitiation of MDA for another two rounds in those areas. In a subsequent study from Sri Lanka, 136 MX indicated ongoing transmission (filarial DNA prevalence of 0.63% greater than the provisional threshold of 0.25% 135 ) in a coastal district 8 years post-MDA, although Mf prevalence (0.2%) was much lower than the threshold for stopping MDA (1%) proving xenomonitoring is more sensitive than TAS and Mf-survey.

Mapping and monitoring
Five studies reported on mapping and monitoring together (Table 5) during MDA (four studies) and post-MDA phase (one study).
In Haiti, of the five districts that were mapped as low endemic based on Ag survey prior to MDA, 137 transmission was on-going during MDA in three districts and a possibility of spatial dependency up to a distance of 20 m from an index case (an Ag-positive child). Spatial mapping of Mf prevalence (overall 31.5%, least 8.5%) after three rounds of MDA in four endemic districts of Andhra Pradesh in India showed spatial heterogeneity with non-interruption of transmission. 138 A study in Tanzania 139 showed that even after six rounds of MDA, transmission was on-going but at a lower level. However, the Ag prevalence in 6-7-yearolds had started showing a declining trend. One study, 140 using samples from a serum bank assessed the prevalence of LF Ag and Ab, 4 years after stopping MDA. They reported that while Ag prevalence was very low (0.8%), Ab prevalence (8.1%) was high as expected. It was seen that while Ag prevalence showed spatial variation, Ab prevalence did not. Another study 141 from Papua New Guinea that reviewed the district level distribution of MDA during 1980-2011, reported that targeting of districts by level of prevalence will strengthen the control program, facilitate monitoring of the disease trend and increase the likelihood of reaching the target of LF elimination by 2020.

Discussion
This review on mapping and monitoring of LF is based on 84 studies from 32 countries representing all WHO regions except the European region over two decades between 1997 and 2018. Most African countries followed the mapping protocol for delimitation in addition to historical data. Countries from other regions used WHO mapping strategy and other methods like the Key informant technique, 70 physical examination by health workers for chronic symptoms of filariasis, disease prevalence and Mf prevalence for mapping LF. The review has shown how the WHO mapping strategy that initially used convenience sampling design evolved to become a more robust 30-cluster-based design in line with the confirmatory mapping tool 94,95 to delimit areas requiring MDA. This confirmatory mapping tool tested Ag among older children aged 9-14 years in 30 randomly selected schools and was proved to be more  effective in low-prevalence settings. Though this tool is similar to the LF-TAS, the sample size requirement is only one-fourth of that of TAS and covers older children and is currently termed as "Mini-TAS." In the current scenario, where most LF endemic countries have completed at least five rounds of MDA, it is proposed to use this for remapping in uncertain and naive areas bordering the endemic districts or the unsurveyed areas that have the risk of LF transmission to help the country program to bring in or exclude those areas from the MDA net. However, the challenge will be to choose the appropriate test (Ag/Ab surveys in humans or MX for vector infection) for remapping to identify new transmission hotspots if any, and prevent resurgence during post-MDA surveillance. This review has highlighted how mapping helped in implementing the elimination program only in the areas known to be endemic for LF thereby preventing MDA in areas where the LF was non-endemic. Mf and Ag surveys were used in prioritizing areas requiring MDA and these data were subsequently used to visualize the extent of LF distribution. Accounting for the spatial component in these data with appropriate spatial models, LF prevalence was predicted up to a distance of 25-50 km around the surveyed locations to provide additional information on risk of LF to the program authorities to act upon. 60,90,93,[96][97][98] Such data also provided scientific evidence on the clustering nature of LF around a transmission/residual foci which again could be used to extend MDA or other supplementary interventions in those neighboring areas. In addition, mapping data collected over time from different countries were also useful for modeling the trends of LF prevalence accounting for the effect of climate change on parasite transmission. 91,92 The mapping initiative for LF also paved the way to integrate mapping of all NTDs (LF, podoconiosis, schistosomiasis, loasis and STH) which was proven to be cost effective and feasible while covering a large geographical area. 64,88,89,100,142 However, it could be logistically intensive and methodologically difficult due to the difference in the tests used and the target groups to be covered. As this is one of the important activities under the WHO road map 143 for implementing interventions against NTDs, the challenges for the endemic countries would be in terms of strong in-country leadership, man power and resources to conduct the surveys and application to capture the data to make it cost effective and feasible.
One of the reasons for the success of this large scale elimination program is attributed to the strong in-built component of monitoring and evaluation during-and post-MDA.
The review has shown that impact of MDA is generally measured in terms of Mf and Ag prevalence in humans. However, in recent times Ab prevalence in humans and MX for assessing parasite DNA in vectors are being used for the purpose in view of their high sensitivity in detecting exposure/transmission. It was observed that the WHO recommended strategy of 5-6 rounds of MDA was not sufficient in interrupting transmission 103,107,109,111,114,118,119,123 suggesting the requirement of additional interventions like frequent MDA treatments, distribution of insecticide treated nets and other localized vector control measures. 118 Additional efforts warranting improved MDA coverage and adequate monitoring by the implementing authorities were recommended. Non-interruption of transmission and persistence of hotspots in spite of several rounds of MDA (up to 12 rounds) were found to be significantly associated with high baseline prevalence of Mf or Ag 118,123,124 and systematic non-compliance to MDA. 117 These imply that the number of rounds required to reach the threshold of <1% Mf prevalence (or 2% Ag prevalence) cannot be generalized for all endemic areas. The success stories in Bangladesh 124 and Cambodia 125 indicated that in addition to the adequate MDA coverage, the reasons for success of the elimination program in a country is driven by 1) the commitment of the government and effective implementation of MDA even in remote areas; 2i) active participation of provincial-and central-level program personnel; 3) adequate financial and related support from stakeholders and partners; and 4) a rigorous monitoring and evaluation plan and post-MDA surveillance activities. The impact of MDA on LF disease, both chronic and acute forms were promising with not only reduction in the disease prevalence following 5-8 rounds of MDA but also in preventing new cases of hydrocele, thereby indirectly achieving the MMDP goals too. 104,106 In LF-oncho co-endemic areas, impact assessment surveys during MDA showed that several rounds of MDA with monotherapy of Ivermectin alone, 100, 107, 113 could not interrupt LF transmission and inclusion of albendazole in the subsequent rounds helped in reducing the Mf and Ag prevalence in humans and vector infection and infectivity rates significantly, respectively. 109,111 However, the decision on stopping MDA in such areas would imply stopping albendazole but continuing with ivermectin alone along with post-MDA surveillance to ensure there is no resurgence of the disease.
TAS, the decision-making tool for stopping or continuing MDA was adjudged to be a robust, scientific and reliable tool based on the results from 12 countries, 121 including India, 122 based on a single EU. Detection of filaria parasite DNA in vectors in areas with Ag-positive children, showed that the results of TAS and MX corroborate with each other, when the decision to continue MDA is to be made. However in a few countries, it was also shown that assessing the impact of MDA on transmission interruption was more accurate if Ag tests in TAS are complemented with Ab tests during post-MDA surveillance as they provide additional evidence of ongoing transmission/exposure in the community, particularly in children. 105,115,116,132,134 In some instances, even when both Ag (TAS) and Ab tests indicated interruption of transmission, vector infection prevalence through MX was found to be well above the provisional threshold level of 0.5% (indicating on-going transmission) suggesting that TAS may not be a sensitive tool in assessing complete interruption of transmission, 133,135,136,142 particularly during post-MDA surveillance. In view of this, it was recommended MX/Ab surveys may be used as a complementary tool for TAS to assess transmission, particularly during post-MDA surveillance and validation phases. 133,135,136,142 These observations suggest that though TAS is a powerful tool while making decisions on stopping MDA or not, it may or may not be very sensitive particularly during the post-MDA surveillance and validation phases when the transmission levels are very low. Therefore MX, a sensitive tool in detecting on-going transmission may also be done alongside so that there is added support to the results by TAS. However, implementing MX under programmatic mode will be a major challenge as the expertise and the facilities for running the molecular assays need to be made available at all implementation unit levels.
Currently, in order to eliminate LF in hard core areas with persisting transmission, WHO has recommended the use of triple drug regimen (IDA, Ivermectin + Diethylcarbamazine + Albendazole) for MDA towards accelerated elimination of LF by 2020. 6 While the monitoring and impact evaluation methods are in place for the existing LF elimination strategy of MDA with two drug regimens (DA, DEC + Albendazole), 4 the challenge will be to develop an appropriate monitoring and evaluation (M & E) strategy, as this strategy is expected to interrupt transmission with 2-3 rounds of MDA in the endemic areas. In addition to the appropriate indicators sensitive enough to measure the human infection levels and or vector infection/infectivity levels, the target population need to be examined and the diagnostic to be used in humans for assessing transmission interruption needs to be identified.

Conclusions
The review has highlighted the necessity of mapping for LF before a massive intervention program is to be implemented in large geographical area as it helps in identifying only those areas that require the intervention, thereby saving resources and man-power. If the area is endemic for other NTDs as well, an integrated mapping approach would be cost effective as well as feasible. For example in India, if an area is prone for dengue, chikungunya and LF, serological or MX surveys with appropriate test kits/ devices with good sampling designs can be used to carry out integrated mapping of these diseases at the same time sharing the man-power and other resources. 144 However, to include this as a part of a national program, a substantial investment has to be made in providing the infrastructure and training to personnel to carry out serological and MX surveys for the NTDs prevalent in the area. The review compared the performance of both serological (Ag/Ab) and molecular tools in assessing the status of LF transmission and highlighted that MX could play a major role in the context of M & E for LF. As most endemic countries under GPELF are progressing towards post-MDA surveillance, validation and elimination phases, M & E component needs to be revised/strengthened with appropriate tools either Ag complemented with Ab or MX for verifying the absence of transmission, assessing the risk of resurgence, identifying hotspots, particularly in the context of introduction of IDA as MDA for accelerated elimination.
With this holistic approach, national programs should take advantage of the existing serological tools and MX and incorporate them wherever necessary in their integrated vector management program to control, monitor and eliminate all vector borne diseases. And wherever possible both mapping of diseases and monitoring of interventions should adopt an integrated approach, to assess the current situation with minimum resources.

Disclosure
The authors report no conflicts of interest in this work.