A systematic review of alternative surveillance approaches for lymphatic filariasis in low prevalence settings: Implications for post-validation settings

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Abstract

Due to the success of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) many countries have either eliminated the disease as a public health problem or are scheduled to achieve this elimination status in the coming years. The World Health Organization (WHO) recommend that the Transmission Assessment Survey (TAS) is used routinely for post-mass drug administration (MDA) surveillance but it is considered to lack sensitivity in low prevalence settings and not be suitable for post-validation surveillance. Currently there is limited evidence to support programme managers on the design of appropriate alternative strategies to TAS that can be used for post-validation surveillance, as recommended by the WHO. We searched for human and mosquito LF surveillance studies conducted between January 2000 and December 2018 in countries which had either completed MDA or had been validated as having eliminated LF. Article screening and selection were independently conducted. 44 papers met the eligibility criteria, summarising evidence from 22 countries and comprising 83 methodologically distinct surveillance studies. No standardised approach was reported. The most common study type was community-based human testing (n = 42, 47.2%), followed by mosquito xenomonitoring (n = 23, 25.8%) and alternative (non-TAS) forms of school-based human testing (n = 19, 21.3%). Most studies were cross-sectional (n = 61, 73.5%) and used non-random sampling methods. 11 different human diagnostic tests were described. Results suggest that sensitivity of LF surveillance can be increased by incorporating newer human diagnostic tests (including antibody tests) and the use of mosquito xenomonitoring may be able to help identify and target areas of active transmission. Alternative sampling methods including the addition of adults to routine surveillance methods and consideration of community-based sampling could also increase sensitivity. The evidence base to support post-validation surveillance remains limited. Further research is needed on the diagnostic performance and cost-effectiveness of new diagnostic tests and methodologies to guide policy decisions and must be conducted in a range of countries. Evidence on how to integrate surveillance within other routine healthcare processes is also important to support the ongoing sustainability of LF surveillance.

Author summary

Lymphatic filariasis (LF) is a mosquito-borne disease, which can result in complications including swelling affecting the limbs (lymphoedema) or scrotum (hydrocele). LF can be eliminated by mass drug administration (MDA) which involves whole communities taking drug treatment at regular intervals. After MDA programmes, country programmes conduct the Transmission Assessment Survey (TAS), which tests school children for LF. It is important to continue testing for LF after elimination because there can be a 10-year period between becoming infected and developing symptoms, but it is thought that the use of TAS in such settings is likely to be too expensive and also not sensitive enough to detect low-level infections. Our study assesses the results from 44 studies in areas of low LF prevalence that have investigated methods of surveillance for LF which differ from the standardised TAS approach. These include both human and mosquito studies. Results show that there is currently no standardised approach to testing, but that surveillance can be made more sensitive through the use of new diagnostic tests, such as antibody testing, and also by targeting higher risk populations. However, further research is needed to understand whether these approaches work in a range of settings and whether they are affordable on the ground.

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Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease

K. Ramaiah, Eric A. Ottesen (2014)

Introduction Lymphatic filariasis (LF) is a disease of the poor that is prevalent in 73 tropical and sub-tropical countries. LF is caused by three species of filarial worms – Wuchereria bancrofti, Brugia malayi and B. timori – and is transmitted by multiple species of mosquitoes. The disease is expressed in a variety of clinical manifestations, the most common being hydrocele and chronic lymphedema/elephantiasis of the legs or arms. People affected by the disease suffer from disability, stigma and associated social and economic consequences. Marginalized people, particularly those living in areas with poor sanitation and housing conditions are more vulnerable and more affected by the disease. Estimates made in 1996 indicated that 119 million people were infected with LF at that time, 43 million of them having the clinical manifestations (principally lymphedema and hydrocele) of chronic LF disease [1]. Earlier severe resource constraints and lack of operationally feasible strategies in the endemic countries left a significant proportion of the LF endemic population living unprotected and exposed to the risk of LF infection. Despite a long-standing and gloomy outlook for these individuals, the situation turned around dramatically in the 1990s for 2 principal reasons: 1) advances made in point-of-care diagnostics and 2) the finding of the long-term effectiveness of anti-filarial drugs given in single doses that permitted development of the strategy of annual two-drug, single-dose mass drug administration (MDA) to control/eliminate LF [2], [3]. As LF had already been postulated to be an eradicable disease [4] and with the success experienced in LF elimination activities in China [5] and elsewhere, the World Health Assembly (WHA) in May 1997 formulated resolution WHA 50.29 urging all endemic countries to increase their efforts and determination to control and eliminate LF. In response, the WHO was able to launch the Global Programme to Eliminate LF (GPELF) in the year 2000, largely because the manufacturers of albendazole (ALB) and ivermectin, two of the principal drugs used in the GPELF MDAs, donated these drugs for as long as needed to eliminate LF [3]. The principal strategy of the programme has been two-fold: 1) to implement MDA programmes in all endemic areas to achieve total interruption of transmission and (2) to provide effective morbidity management in order to alleviate the suffering in people already affected by filarial disease. The GPELF targets elimination of LF, at least as a public health problem, by the year 2020 [6]. The programme to implement MDAs targeting LF (GPELF) completed 13 years of operations in 2012 [7]. With its ambitious goal to eliminate LF by the year 2020, it is essential that progress toward this goal be assessed repeatedly in order to set benchmarks to guide future programmatic planning. How to define and assess this progress remains a challenge, but two strategies have been suggested. The first is to measure reduction in the burden of LF disease (i.e., hydrocele, lymphedema, microfilaraemia and associated subclinical disease) over the past 13 years – i.e., a clinical perspective; the second is to measure reduction in the risk of acquiring infection for populations living in (formerly) endemic areas – i.e., an epidemiologic perspective. In the present report we have pursued the first alternative – to model the decreased burden of LF (defined for the purposes of our calculations as hydrocele, lymphedema, and microfilaraemia) in order to assess the progress towards LF elimination from inception of the MDA programme through 2012 (i.e., during GPELF's first 13 years). In a parallel study, others have recently modeled the programme's progress from the alternative, risk-of-infection viewpoint (Hooper et al., submitted). Methods A simple ‘force-of-treatment’ model was formulated to estimate the impact of MDA on LF infection and disease. Model parameters: Individual countries and regions as the geographic units of assessment The GPELF aims to provide MDA (using ALB+either ivermectin or diethylcarbamazine [DEC]) to entire endemic populations at yearly intervals for 4–6 years. Such a programme, if implemented effectively (i.e. treating at least 65% of the total population during each MDA), is expected to interrupt transmission and eliminate LF [8]. Because the status of MDA activities in all of the 73 endemic countries at the time of this analysis (through 2012) ranged from no MDA at all in some countries to full completion of the MDAs in others, for the present study each country was evaluated separately. First, programme impact was determined for each endemic country; then, the burden of LF remaining in each of the five endemic WHO regions – Southeast Asia (SEAR), Africa (AFR), Western Pacific (WPR), Eastern Mediterranean (EMR) and America (AMR) - was calculated by summing the remaining LF burden for all the endemic countries within each region. Model parameters: Key elements in assessing programme progress Calculating progress of the MDA programme under GPELF – whether by burden or risk estimates – is affected by a number of important specific factors, namely; (1) the number of countries that have successfully completed implementing the MDA programme, (2) the number of countries currently implementing the programme and the geographical coverage or proportion of the endemic population targeted so far in each country, (3) the treatment coverage of the population targeted for MDA in each country, and (4) the duration of the programme (i.e., the number of rounds of MDA implemented) in each country. For the present analysis, all of these data have been sourced from the WHO PC data bank [9]. Model parameters: Calculation of the decrease in LF burden to assess programme progress There are 3 essential steps to assessing the decrease of LF burden since 2000: first, the establishment of the LF base-line burden (in 2000); then, estimation of the MDA impact for countries or IUs where MDAs have taken place during 2000–2012; and, finally, estimation of current burden for countries or IUs where no MDA has taken place. (i) Establishment of base-line data The MDA programme under GPELF was started in the year 2000. To quantify the impact of the MDA programme, first, a base-line disease burden was estimated, considering the year 2000 as the base-line year. After extensive review of the literature in the mid-1990s, Michael et al. (1996) [1] and Michael and Bundy (1997) [10] estimated the LF prevalence and burden for different endemic regions. LF epidemiology is such that, without specific intervention or environment-altering measures, prevalence is unlikely to change over a short period (few years) of time. Hence, for this work the LF prevalence during 1996 to 2000 period is considered to remain unchanged. However, the absolute number of people affected by the disease will have increased because of population growth in the endemic areas. Taking the above factors into account, the base-line LF burden was estimated by extrapolating the prevalence data defined earlier [1] to the population of the endemic countries in the year 2000 (Table 1). As the LF burden estimation for individual countries was not always possible due to paucity and availability of data on prevalence, base-line LF burden estimates were made following the earlier approach of Michael et al. (1996) [1], and utilizing the convention that all the endemic countries for which no specific information was available, within each endemic region, have an approximately similar average prevalence of microfilaraemia and chronic disease. 10.1371/journal.pntd.0003319.t001 Table 1 Burden of LF in 1996 and 2000 considered as base-line to understand the impact of MDA (2000–2012) under GPELF. LF burden 1996 LF burden 2000 WHO Region Total Population endemic countries Mf carriers Lymphoedema cases Hydrocele cases Total infected Total Population endemic countries Mf carriers Lymphoedema cases Hydrocele cases Total infected SEAR 1335 41.91 9.49 14.53 61.86 1506 47.40 10.74 16.47 70.00 AFR 474 25.78 4.31 9.43 37.06 568 30.91 5.17 11.31 44.44 WPR 1113 11.14 1.52 1.87 13.32 1261 12.62 1.72 2.12 15.10 EMR 100 0.0598 0.0100 0.0199 0.0897 116 0.0700 0.0117 0.0233 0.1050 AMR 179 0.1252 0.0179 0.0179 0.1610 199 0.1397 0.0200 0.0200 0.1796 Total 3200 79.01 15.35 25.87 112.50 3650 91.14 17.66 29.94 129.82 All figures in millions. The 1996 estimates were based on the work done by Michael et al. (1996). The 1996 data were extrapolated to the populations of each endemic country in 2000 to derive the baseline estimated for GPELF. (ii) Estimation of MDA impact on LF burden for all countries or IUs with MDA in place Since the decrease in LF burden is a direct result of the treatment provided to populations during the MDA, the model to estimate this burden decrease can be described as a ‘force-of-treatment’ model (see below). To quantify this force-of-treatment, a ‘treatment index’ (TI) was constructed. The TI is defined as the average number of treatments taken by persons in areas included in MDA. It takes into account three key parameters – the size of the population targeted, the treatment coverage and the number of rounds of MDA implemented. These data can be sourced from the WHO PC data bank [9]. The TI is calculated as the total number of treatments consumed divided by the size of the population of IUs included in MDA. How to interpret what the TI implies about the effect of the programme's MDAs on LF burden can be determined from considering the empiric observations reported in earlier studies of endemic populations treated with the same treatment regimens as those used in the current MDAs; these were reviewed and are summarized below and in Figures 1 and 2. 10.1371/journal.pntd.0003319.g001 Figure 1 Empiric observations defining the relationship between number of treatments per person and % reduction in Mf prevalence 1 year later. 10.1371/journal.pntd.0003319.g002 Figure 2 Empiric observations defining the relationship between number of treatments and % reduction in hydrocele prevalence 1 year later. For microfilaraemia, two of the principal anti-filaria drugs used in MDA campaigns – DEC and ivermectin – have been recognized to exhibit remarkable, rapid effects on decreasing microfilaraemia. The anti-microfilarial effect of both drugs is further fortified when they are administered in combination with ALB, a broad spectrum anti- helminth drug that affects both adult worm viability and production of microfilariae [11]. The impact of treatment on microfilaraemia is evident from the first round of MDA and increases with each round of treatment year after year. While one round of mass treatment has been reported to reduce the Mf prevalence (assessed ∼1 yr post treatment) by 26% to 41%, 5–6 rounds led to 88%–90% reduction [12]–[21]. A review by de Kraker et al. (2006) [22] highlighted that both the drug combinations used in GPELF – ALB+DEC and ALB+ivermectin – strongly reduce the LF infection levels, but even 4–6 rounds of single-dose DEC alone can cause reduction of mf prevalence by as much as 86% [13], [23]. Hence, in the present effort to establish the relationship between the number of treatments and the % reduction in microfilaraemia prevalence, results were included from all the community level studies that administered annual single dose treatment (Figure 1), regardless of the specific MDA regimen employed. This empirically derived relationship between the number of treatments given and the decrease in microfilaraemia prevalence (Figure 1), in fact, defines the relationship between the TI and mf prevalence, since the TI is the population-level equivalent of the number of treatments administered at the individual-level. For microfilaraemia, there is a steady increase in reduction of prevalence as the treatment index increases, such that the reduction was close to 95% at a treatment index of about 6.0. For hydrocele, a similar review was undertaken of available information on the effect that treatment with anti-filarial drugs has on hydrocele prevalence [13], [24]–[29]. Treatment with DEC single dose was common to all of the studies providing results that were used in the analyses. Only one study each evaluated single dose of DEC+ivermectin [13] and ivermectin alone [29] and in both the studies the impact of these drugs was similar to that of DEC. The number of treatments given in these studies ranged from 2 to 12 and in most of the studies treatments were given at yearly or half-yearly interval. A model fitting the non-linear relationship (Fig. 2) was used to define the relationship between the number of treatments and % reduction in prevalence of hydrocele - again, defining the TI for the effect of MDA on hydrocele prevalence (Figure 2). This reduction increased progressively up to 4 treatments, but beyond that the treatment appears to have little additional impact; also, the maximum reduction seen with repeated treatments was approximately 60% (Figure 2). For lymphedema, different from microfilaraemia and hydrocele, information is scanty on the impact of annual MDA on lymphedema. Studies in Indonesia [30], [31], China [32], and Polynesia [24], all showed reduction in lymphedema prevalence, but all used more prolonged courses or different treatment regimens from those used in the GPELF MDAs. Post-GPELF, three studies evaluated the impact of MDA on lymphedema. In Ghana, one round of MDA with ivermectin and ALB showed no impact on lymphedema [33]. Administration of annual, single-dose DEC for 4 years in Papua New Guinea reduced the lymphedema prevalence by 20% [13]. Seven years of treatment in India showed 14% reduction in lymphedema prevalence in communities treated with annual DEC and 15% reduction in communities treated with ivermectin [29]. In light of these outcomes, a cautious and conservative approach was adopted for estimating the impact of MDA; it is postulated that for a TI of ≥3 (equivalent to nearly 4 rounds of MDA) lymphedema prevalence will be reduced by not more than 14%, the least reduction observed with annual MDA [29]. A TI 1.9 billion treatments were delivered, prevented 7.4 million cases of hydrocele and 4.3 million cases of lymphedema. While these estimates on the number of hydrocele cases prevented are similar to the estimates in the present study, there is less agreement on the number of lymphedema cases prevented. The estimated 5.49 million lymphedema cases prevented in this study, after 13 years of MDA and delivery of 6.37 billion treatments, was lower, likely because of both the different strategies for calculating the effects and the conservative approach adopted in assessing the impact of MDA on lymphedema. The estimated 5.49 million lymphedema cases prevented in this study was a minimum number, and the actual reduction may be much higher. Of the various factors influencing the outcome of MDA programmes, treatment coverage is particularly important [8]. In this study, the impact of MDA was assessed using the reported treatment coverage – i.e. the treatment coverage reported by the country level programme managers and compiled in WHO's PC data bank [9]. There are, however, a number of reports suggesting that the programme-reported treatment coverage in the South-east Asia region, particularly in India, may be higher than the actual treatment coverage in the communities. For example, while programme-reported treatment coverage in India was generally in the range of 58% to 90%, various independent studies showed treatment coverage that varied widely and ranged from 90% in different parts of the country [58]–[74]. The data from these published studies give rise to an average ‘evaluated’ treatment coverage rate of 51.0%, less than the 71.33% average reported national coverage [9]. Since the TI used to calculate programme impact in our model incorporates programme coverage, it is necessary to understand the effect of this difference between reported and evaluated coverage. For India, the TI based on reported coverage was 5.27, but only 4.21 when based on ‘evaluated’ coverage – a difference of 20%. Interestingly, however, when those different TI's were applied to the model (Figs. 1 & 2), the effect was minimal, because for TI's >4, little or no additional benefit was achieved on the 3 parameters measured (microfilaraemia, hydrocele, lymphedema/elephantiasis). In other words, the initial rounds of MDA will exert greater impact on these manifestations compared to later rounds, a finding already reported empirically and shown in various studies [12], [13], [15], [17]–[20]. However, if the treatment coverage rate is high, a higher TI can be achieved in the early rounds of the programme, and fewer rounds of MDA may be required to maximize both impact and cost-effectiveness. It is possible that preventive chemotherapy as well as other interventions implemented against other vector-borne diseases have added to the impact of LF MDA and caused further reduction in LF burden in some countries. Principal among these other interventions are the ivemectin distribution under the African Programme for Onchocrciasis Control (APOC) and the malaria control measures of insecticide treated nets (ITN) and indoor residual spraying (IRS). Currently, ivermectin is distributedfor onchocerciasis control in as many as 26 countries in Africa, covering nearly 130 million population [75]. Most of the 26 countries are co-endemic for LF also and while less than half of this LF-endemic population is under specific treatment as part of the GPELF, many are likely receiving benefit from the ivermectin being used for onchocerciasis control, as has been demonstrated specifically in a number of countries in West Africa [76]–[80]. Similarly, the malaria control measures have been shown to reduce LF transmission considerably and remain promising adjuncts to the MDA of the GPELF activities [81]–[83]. While these coincident intervention measures have, and will continue to have, positive impact on the LF elimination efforts, quantification of their impact remains a daunting challenge. The reduction in LF burden achieved during the GPELF's first 13 years is almost certainly higher than shown through our analyses both because of the additional, on-going intervention measures and because of our conservative approach to estimating the impact on chronic disease. Though, there can be little question that impressive gains in decreasing LF burden have been achieved as a result of 13 years of MDA in the GPELF, still, however, a considerable burden of LF remains – estimated at 36.45 million Mf cases, 16.68 million cases of lymphedema and 19.43 million cases of hydrocele (Table 4). Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet started is absolutely necessary to reduce the number of microfilaraemia cases and transmission. Such an extension of MDA will also reduce a proportion of hydrocele and lymphedema cases, but the burden of LF disease needs also to be approached directly. Techniques for effective morbidity management – both medical and surgical – are available but not nearly so widely implemented as they could or should be. The present model's calculations take into consideration only those burden-reducing benefits coming pari passu with MDA implementation. When appropriate morbidity management strategies are finally introduced and accelerated, the burden of LF disease will fall even more dramatically (and the model can be adapted accordingly).

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Effect of yearly mass drug administration with diethylcarbamazine and albendazole on bancroftian filariasis in Egypt: a comprehensive assessment.

Hanan Helmy, Reda M. R. Ramzy, Gary Weil … (2006)

Egypt was one of the first countries to implement a national programme to eliminate lymphatic filariasis based on WHO's strategy of repeated rounds of mass drug administration (MDA) with diethylcarbamazine and albendazole (target population, 2.5 million in 181 localities). We assessed the effect of five yearly rounds of MDA on filariasis in four sentinel villages in Egypt. We studied two areas with different infection rates before MDA: the Qalubyia study area had a low infection rate because of previous treatment with diethylcarbamazine; this was typical of most filariasis-endemic villages in Egypt before MDA. The Giza study area had a high baseline infection rate. We undertook repeated surveys in villages for treatment compliance and tests for microfilaraemia and circulating filarial antigenaemia, antibodies to filarial antigen Bm14 in schoolchildren, and infections in indoor-resting mosquitoes (assessed by PCR). MDA compliance rates were excellent (>80%). In Giza after MDA, prevalence rates of microfilaraemia and circulating filarial antigenaemia fell from 11.5% to 1.2%, and from 19.0% to 4.8%, respectively (p<0.0001). Corresponding rates in Qalubyia fell from 3.1% to 0% and 13.6% to 3.1%, respectively (p<0.0001). Rates of antifilarial antibody and circulating filarial antigenaemia in schoolchildren (aged about 7-8 years), fell from 18.3% to 0.2% (p<0.0001) and from 10.0% to 0.4% (p<0.0001) in Giza, respectively, and from 1.7% to 0% and 1.7% to 0% (both p=0.13) in Qalubyia, respectively. Mosquito infection rates fell from 3.07% (95% CI 2.38-3.88) to 0.19% (0.08-0.38) in Giza and from 4.37% (3.07-5.99) to 0% (0-0.05) in Qalubyia. MDA greatly affects variables related to infection (microfilaraemia and circulating filarial antigenaemia prevalence rates) and transmission (antifilarial antibodies in young children and mosquito infection rates). Our results suggest that after five rounds of MDA filariasis is likely to have been eliminated in most endemic localities in Egypt.

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A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration

Ramakrishna Rao, Kumara Nagodavithana, Sandhya Samarasekera … (2014)

Introduction Lymphatic filariasis (LF, caused by the mosquito borne filarial nematodes Wuchereria bancrofti, Brugia malayi, and B. timori), is a major public-health problem in many tropical and subtropical countries. The latest summary from the World Health Organization (WHO) reported that 56 of 73 endemic countries have implemented mass drug administration (MDA) with a combination of two drugs (albendazole with either ivermectin or diethycarbamazine), and 33 countries have completed 5 or more rounds of MDA in some implementation units [1]. With more than 4.4 billion doses of treatment distributed between 2000 and 2012, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) is easily the largest public health intervention to date based on MDA. Bancroftian filariasis was highly endemic in Sri Lanka in the past [2]–[4]. The Sri Lankan Ministry of Health' Anti Filariasis Campaign (AFC) used a variety of methods to reduce filarial infection rates to low levels by 1999 [5], [6]. Sri Lanka was one of the first countries to initiate a LF elimination program based on GPELF guidelines [7]. The AFC provided annual MDA with diethylcarbamazine alone for three years starting in 1999. This was followed by five annual rounds of MDA with albendazole plus diethylcarbamazine in all 8 endemic districts (implementation units, IU) between 2002 and 2006. Various types of surveillance have been conducted by AFC and other groups since the MDA program ended in 2006 [8]–[12]. Post-MDA surveillance results (based on detection of microfilariae or Mf in human blood by microscopy) have consistently shown Mf rates much lower than the target value of 1% in all endemic areas [13]. The AFC also conducted school-based surveys for filarial antigenemia in 2008 according to WHO guidelines active at that time. Approximately 600 children were tested for circulating filarial antigenemia (CFA) in 30 schools in each of the 8 endemic districts, and no positive tests were observed (unpublished data, Sri Lanka Ministry of Health). WHO guidelines emphasize that LF elimination programs should provide care for people with acute and chronic clinical manifestations of filariasis [7], and the AFC has an excellent network of clinics that is devoted to this activity [13]. The present study represents a significant expansion of earlier post-MDA surveillance activities in Sri Lanka. Transmission assessment surveys (TAS) were performed according to current WHO guidelines [14], [15] for sampling primary school children to detect filarial antigenemia in each district. While TAS results may be useful for deciding whether MDA can be stopped, TAS cannot guarantee that LF transmission has been interrupted in evaluation units (EUs), which are typically districts with populations that may exceed 1 million. Therefore we conducted more intensive surveillance activities in smaller areas (Public Health Inspector “PHI” areas) that were considered to be at high risk for persistent filariasis to complement the TAS program. Provisional targets have been proposed for documenting the interruption of filariasis transmission based on studies of the effects of MDA in Egypt, which also has LF transmitted by Culex mosquitoes [16]. Targets proposed for treated populations after at least five years of effective MDA were 0.35 in two assays performed on different days were considered to be positive for antibody to Bm14. Microfilaria (Mf) testing was performed for people with positive filarial antigen tests (in community household surveys, school surveys, and TAS) with three-line blood smears (60 µl total volume of night blood tested). Detection of filarial DNA in mosquitoes Mosquitoes were sorted by experienced technicians. Blood fed, gravid, and semi-gravid Culex quinquefaciatus mosquitoes were identified by morphology and sorted into 4 pools of 20 mosquitoes per collection site. Two hundred and seventy-seven pools of mosquitoes (mean pool size of 17) were collected and tested from Peliyagodawatta in the pilot study that was performed in 2008. Approximately 200 pools were tested from each PHI area in later surveys. W. bancrofti DNA was detected in mosquito pools by qPCR as previously described [16], [20]. DNA isolation and PCR analysis for samples from the 2008 pilot study were performed by AFC personnel together with Washington University technicians in St. Louis. All subsequent PCR work was conducted by AFC personnel in the AFC laboratory in Colombo. Data collection and data management Demographic information including age, gender, documentation of informed consent, and a history of compliance with the previously administered MDA program was collected and entered into personal digital assistants (PDA) (Dell Axim ×51, Dell Inc. Round Rock, TX or HP iPAQ 211, Hewlett Packard, Palo Alto, CA) using a preloaded survey questionnaire. Participant data, specimen ID, and test results were linked using preprinted barcode labels as described by Gass et al [21]. AFC deployed 2 or 3 teams for blood collection and 2 or 3 teams for mosquito collection in each PHI, and teams were comprised of a mixture of personnel from the district and from AFC headquarters. Data collected by multiple teams were synchronized at AFC headquarters, and data were transferred to a laptop computer using LF field office data manager software designed by the Lymphatic Filariasis Support Center, Taskforce for Global Health, Decatur, GA. Transferred files were merged to create a master database, which was backed up using an external hard drive. Specimens and laboratory test results were linked to study subject numbers (or to trap site and pool number for mosquito data) using barcodes. Deidentified, cleaned data were transferred into Excel files (Microsoft Corp., Redmond, WA) for analysis at AFC and at Washington University. Spatial analysis GPS coordinates for human and mosquito sampling sites were plotted using ArcGIS 10.2.1 (ESRI, Redlands, CA) to show the location of households surveyed and mosquito trapping sites for each PHI. Waypoints were color coded to show the infection status of household residents and mosquitoes from these collection sites. School-based Transmission Assessment Surveys (TAS) TAS were performed in all 8 endemic districts in late 2012 or early 2013 according to WHO guidelines. The TAS program used districts as evaluation units (EUs) in 5 cases. However, 3 districts or areas with large populations (Colombo district plus Colombo town, Gampaha, and Galle) were each divided into two EUs for TAS. All EUs met criteria for conducting TAS by having completed 5 rounds of MDA in 2006 with high MDA compliance rates (>80%). All sentinel and spot check sites in each district had Mf prevalence rates well below 1% for several years prior to TAS. Since Sri Lanka has high primary school attendance rates (>95%), TAS surveys used the cluster method to sample students in 30–35 randomly selected schools per EU[15]. Systematic selection of school children was performed with Survey Sample Builder software, SSB.V.2.1 (http://www.ntdsupport.org/resources/transmission-assessment-survey-sample-builder). The TAS sampling strategy required filarial antigen testing of approximately 1500 primary grade children in each EU. Blood samples were collected with One Touch Ultra Soft lancet holders with disposable lancets (LifeScan, Inc., Milpitas, CA). Finger prick blood was collected into capillary tubes provided with the BinaxNow Filariasis cards, and 100 µl of blood was added directly to sample application pads of the cards according to the manufacturer's instructions. Tests were performed in the school auditorium, library, or health screening station immediately after blood collection, and read at 10 minutes. Antigen test results (positive or negative) were recorded manually using preprinted data collection forms. Children with positive filarial antigen tests were tested for microfilaremia with night blood smears as described above. Data analysis We used the software program PASW Statistics 18 (SPSS, now IBM Corporation, Armonk, NY) and JMP (SAS, Cary, NC). The Chi-square test was used to assess the significance of differences in categorical variables such as antigenemia rates. The correlation between human and mosquito infection parameters was analyzed by the Spearman rank test. Logistic regression was used to assess the independence of risk factors for filarial antigenemia. Graphs were produced with GraphPad Prism V. software (La Jolla, CA). Filarial DNA rates (maximum likelihood estimates with 95% confidence intervals) were calculated with PoolScreen 2.02 [22], [23]. To sharpen the analysis of risk factors for filarial infection, we limited the analysis to 14 PHI areas where one or more people had positive filarial antigen tests. All analyses were performed assuming simple random sampling for simplicity of exposition. A generalized linear mixed model was used to estimate design effects of household-based cluster sampling used in community surveys. This analysis was performed with data from the two PHIs with the highest surveyed CFA rates. Ethical review The study protocol for comprehensive surveillance in PHIs was reviewed and approved by institutional review boards at Washington University School of Medicine and at the University of Kelaniya in Sri Lanka (FWA 00013225). Prior to school surveys (both PHI surveys and TAS), study personnel held preliminary meetings with school principals and officials from the Sri Lankan Ministry of Education about the goals and procedures for the study. They also met with parents or guardians to discuss the study design and the significance of the study. Printed participant information sheets and written consent forms were provided to participants (or to parents/guardians) in Sinhalese, Tamil and English. Written consent was obtained from adults. Participation of minors required written consent from at least one parent or guardian plus assent by the child/minor. Consent was also documented electronically into PDAs by study personnel prior to collection of health information or blood samples. TAS surveys used preprinted paper forms for parental consent and other forms for data collection (school name, child name, age, sex, and CFA result). Results Community survey results Nineteen PHI surveys were conducted in 8 districts and in Colombo town between March 2011 and July 2013. Demographic information for survey participants is provided in Table 1, and results are summarized in Table 2 and Figure 1. Community CFA rates were 2% in 5 of 19 PHIs. Microfilaremia rates were 5%. Only three of 137 children with positive antibody tests (out of 6198 children tested for antibody from all 19 PHI areas) had positive CFA tests, and all three of these children were Mf negative. Antifilarial antibodies in community surveys Community antibody testing was performed in a subset of PHIs that were surveyed in the comprehensive surveillance study (Table S1). Although CFA and Mf rates in these communities were below provisional target levels, community antibody rates were high in all of these PHIs, and this probably reflects high infection rates that were present in these areas prior to implementation of the national MDA program. Relationships between different human filariasis parameters in community and school surveys Human filariasis parameters tended to be significantly correlated with each other [e.g., community Mf rate vs. community CFA rate (r = 0.63, P = 0.0018), school CFA rate vs. school antibody rate (r = 0.5, P = 0.0142), and community CFA rate vs. school CFA rate (r = 0.69; P = 0.0006)]. Transmission assessment survey results More than 17,000 primary grade school children were tested in TAS in 337 schools located in 11 EUs in 8 districts and in Colombo town (Table 5). The numbers of positive CFA tests were well below the TAS threshold level of 18 (critical cut-off value) in all EUs. Thus all EUs “passed” TAS including the coastal Galle District EU, where high rates for filariasis markers were noted in two PHI study areas. None of the 16 children with positive CFA tests in TAS surveys had microfilaremia. All CFA-positive children were treated with anti-filarial medications and follow-up surveys are in progress or planned to further assess people in areas with positive children. 10.1371/journal.pntd.0003281.t005 Table 5 Transmission assessment survey (TASa) results from 11 evaluation units (EUs) in 8 districtsb in in Sri Lanka. Evaluation Unit Population size/EU Number of primary grade schools included Number of primary grade children tested Number of children positive for filarial antigenemiac Colombo-RDHS 1,761,010 30 1716 2 (0.12, 0.03–0.4) Colombo-city 557,356 30 1555 2 (0.13, 0.04–0.4) Gampaha I 898,731 30 1642 1 (0.06, 0.01–0.3) Gampaha II 1,426,944 30 1462 0 (0) Kalutara 1,237,676 30 1585 4 (0.3, 0.10–0.6) Galle I 719,911 31 1557 7 (0.45, 0.22–0.9) Galle II 347,027 31 1543 0 (0) Matara 815,625 30 1591 0 (0) Puttalam 766,469 30 1583 0 (0) Kurunegala 1,629,958 35 1692 0 (0) Hambantota 607,404 30 1553 0 (0) Total 10,768,112 337 17479 16 (0.1, 0.06–0.1) a The critical cutoff value for assessing interruption of transmission was 18 in all EUs. b The 8 endemic districts were MDA implementation units. c BinaxNOW Filariasis tests were used for detection of filarial antigenemia. Data shown are the number of positive tests (% positive and 95% CI). Filarial DNA rates in mosquitoes Almost 3,900 pools (20 mosquitoes per pool) of blood fed, gravid or semi-gravid mosquitoes collected in 19 PHI areas were tested for filarial DNA by qPCR (Table 6). Filarial DNA rates exceeded the target of 0.25% in 10 of 19 PHIs. Mosquitoes from both PHIs surveyed in Galle district and one in Matara district had parasite DNA rates of more than 1%, and these rates were comparable to those seen in some filariasis endemic areas in Egypt with continued filariasis transmission following one or two rounds of MDA [24]. Upper confidence limits for filarial DNA rates were ≥1% in 5 of 19 PHIs surveyed. On the other hand, three of 19 PHIs surveyed had no positive mosquito pools. Most of the other filariasis parameters were also low in these PHIs. Mosquito DNA samples from Wattala were retested by qPCR at Washington University and confirmed to be negative. 10.1371/journal.pntd.0003281.t006 Table 6 Filarial DNA rates in Sri Lankan Culex quinquefasciatus mosquitoes by Public Health Inspector area. District PHI areaa PHI code Number of mosquitoes tested Number of pools tested b Number (%) of positive pools Filarial DNA rates in mosquitoes c Colombo Katukurunda C1 4000 200 3 (1.5) 0.07 (0.01–0.22) Sedawatta C2 4480 224 21 (9) 0.52 (0.31–0.80) Mattakkuliya C3 4000 200 13 (6.5) 0.34 (0.17–0.59) Borella C4 4000 200 26 (13) 0.69 (0.43–1.0) Gampaha Kelaniya G1 4320 216 22 (10) 0.54 (0.32–0.83) Wattala G2 4000 200 0 (0) 0 PeliyagodaW G3 4080 203 17 (8) 0.43 (0.24–0.71) Kalutara Panadura KA1 4000 200 9 (4.5) 0.23 (0.10–0.45) Kalutara N KA2 4080 204 28 (14) 0.74 (0.47–1.09) Galle Ambalangoda GL1 4000 200 52 (26) 1.49 (1.08–2.01) Unawatuna GL2 4000 200 54 (27) 1.56 (1.13–2.08) Matara Devinuwara M1 4160 208 9 (4) 0.22 (0.09–0.43) Weligama M2 4080 204 51 (25) 1.43 (1.03–1.92) Puttalam Chila town P1 4000 200 6 (3) 0.15 (0.05–0.34) Lunuwila P2 4160 208 0 (0) 0 Kurunegala Bamunawala KU1 4160 208 4 (1.9) 0.10 (0.02–0.25) Narammala KU2 4160 208 11 (5.2) 0.27 (0.13–0.50) Hambantota HT town H1 4000 200 0 (0) 0 Tanagalle H2 4080 204 2 (1) 0.05 (0.01–0.15) a Sentinel sites (PHIs) C3 and C4 were located in the city of Colombo. Sentinel site G3 is a PHFO area. b Each pool included 20 mosquitoes (blood fed, gravid and semigravid). c Filarial DNA was detected by qPCR. Rates of filarial DNA in mosquitoes (maximum likelihood and 95% CI) were estimated using PoolScreen2. Results are shown as pass (regular font), borderline (italics) or fail (bold) based on provisional endpoint criteria described in the Introduction. The percentages of positive mosquito trap sites were highly variable in different PHIs, and these rates were strongly correlated with percentages of pools positive for filarial DNA (r = 0.99, P 9) is to have an upper confidence limit of <2%. This target provides a very high level of confidence that the Mf rate will be less than 0.5% in the community with a much smaller sample size than what would be required for Mf testing. Additional studies will be needed to test the new proposed targets in different regions. We believe that these targets will be helpful for identifying areas that require continued surveillance. Next steps for areas that may have ongoing transmission following MDA Existing guidelines do not adequately address this issue. Four options to consider are resumption of MDA, implementation of test and treat programs, vector control, and watchful waiting. It may be difficult to justify resumption of MDA when Mf rates are well below 1% when one considers that many of those with persistent infections may have been noncompliant with MDA in the past. Test and treat campaigns may be more efficient for finding and treating those with persistent infections than MDA, and the Sri Lanka AFC has started to do this in Galle district. Our results suggest that adult males and people who do not recall having taken MDA in the past should be considered to be high priority target groups for test and treat programs. WHO has recommended vector control as a post MDA strategy [26]. Although vector control can be difficult to implement at the scale needed for LF elimination, surveillance results may identify hot spot areas where focused vector control may be feasible. Our finding that CFA rates were lower in people who reported using bed nets is interesting, although the logistic regression analysis suggested that lack of bed net use was not an independent risk factor for filarial infection. Bed nets are popular in Sri Lanka because of the mosquito nuisance factor and the risk of dengue. Beneficial effects of bed nets for LF have been reported from areas with Anopheles transmission [27], [28]. The Sri Lanka government should consider implementing a health education campaign to reinforce the popularity of bed nets and increase usage rates in areas with persistent LF. The longitudinal data from Peliyagodawatta are intriguing, because they suggest that some areas with filariasis parameters that do not meet our provisional criteria for interruption of transmission may spontaneously improve over time. Thus the strategy of watching, waiting, and retesting may be the best course of action for some areas with persistent LF. Other data from Peliyagodawatta on the natural history of filarial antigenemia in amicrofilaremic individuals in the post-MDA setting are reassuring. These results suggest that there is no pressing need to actively identify and treat asymptomatic and amicrofilaremic persons with positive filarial antigen tests following MDA. This is because the risk of such people developing microfilaremia is low, and antigenemia often clears over time without treatment. We believe that this study has contributed significant new information regarding post-MDA surveillance and low level persistence of filariasis following MDA. LF elimination is a dynamic process [29], and point estimates of persistent infection may be less important than trends over time. For this reason, we plan to restudy Peliyagodawatta and several other PHIs with elevated LF parameters three years after the evaluations described in this publication. Supporting Information Figure S1 Distribution of households and mosquito collection sites tested for filariasis in Chila Town PHI area in Puttalam district which has less evidence of persistent filariasis than Unawatuna PHI (shown in Fig 2). Panel A. Blue waypoints indicate households (HH) where all tested residents had negative filarial antigen tests; waypoints in red indicate houses with at least one infected subject (CFA positive). Panel B shows molecular xenomonitoring results. Trap sites with no mosquito pools positive for filarial DNA are shown in blue, and traps with one or more positive mosquito pools are shown in red. Filarial DNA was detected in mosquitoes collected in 10% of the traps in this PHI area. (TIFF) Click here for additional data file. Table S1 Community rates for circulating filarial antigenemia (CFA), microfilaremia (Mf), and IgG4 antibodies to filarial antigen Bm14 in selected public health inspector. (DOCX) Click here for additional data file. Table S2 Filarial infections by household and mosquito trap site in different Public Health Inspector (PHI) areas in Sri Lanka. (DOCX) Click here for additional data file. Checklist S1 STROBE statement. Checklist of items included in this cross-sectional study Rao et al., A Comprehensive Assessment of Persistent Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration. (DOC) Click here for additional data file.

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Nicholas Riches:

ORCID: http://orcid.org/0000-0002-1729-7635

Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Xavier Badia-Rius:

ORCID: http://orcid.org/0000-0002-3132-3350

Role: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – review & editing

Themba Mzilahowa: Role: Writing – review & editing

Louise A. Kelly-Hope: Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Patrick J. Lammie: Role: Editor

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Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date (Electronic): 12 May 2020

Publication date Collection: May 2020

Volume: 14

Issue: 5

Electronic Location Identifier: e0008289

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[1 ] Centre for Neglected Tropical Diseases, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

[2 ] Malaria Alert Centre, College of Medicine, Blantyre, Malawi

Task Force for Child Survival and Developmentorce for Global Health, UNITED STATES

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The authors have declared that no competing interests exist.

* E-mail: nicholas.riches@ 123456lstmed.ac.uk

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Nicholas Riches http://orcid.org/0000-0002-1729-7635

Xavier Badia-Rius http://orcid.org/0000-0002-3132-3350

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Publisher ID: PNTD-D-19-01432

DOI: 10.1371/journal.pntd.0008289

PMC ID: 7217451

PubMed ID: 32396575

SO-VID: 300b4157-b53a-485b-a966-72a769b9be50

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Date received : 4 September 2019

Date accepted : 13 April 2020

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A systematic review of alternative surveillance approaches for lymphatic filariasis in low prevalence settings: Implications for post-validation settings

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Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease

Effect of yearly mass drug administration with diethylcarbamazine and albendazole on bancroftian filariasis in Egypt: a comprehensive assessment.

A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration

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