Under the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted seven rounds of mass drug administration (MDA) from 2000–2006. The World Health Organization recommends systematic post-MDA surveillance using Transmission Assessment Surveys (TAS) for epidemiological assessment of recent LF transmission. We compared the effectiveness of two survey designs for post-MDA surveillance: a school-based survey of children aged 6–7 years, and a community-based survey targeting people aged ≥8 years. In 2016, we conducted a systematic school-based TAS in all elementary schools (N = 29) and a cluster survey in 28 villages on the two main islands of American Samoa. We collected information on demographics and risk factors for infection using electronic questionnaires, and recorded geo-locations of schools and households. Blood samples were collected to test for circulating filarial antigen (CFA) using the Alere Filariasis Test Strip. For those who tested positive, we prepared slides for microscopic examination of microfilaria and provided treatment. Descriptive statistics were performed for questionnaire variables. Data were weighted and adjusted to account for sampling design and sex for both surveys, and for age in the community survey. The school-based TAS (n = 1143) identified nine antigen-positive children and found an overall adjusted CFA prevalence of 0. 7% (95% CI: 0. 3–1. 8). Of the nine positive children, we identified one microfilariaemic 7-year-old child. The community-based survey (n = 2507,711 households) identified 102 antigen-positive people, and estimated an overall adjusted CFA prevalence of 6. 2% (95% CI: 4. 5–8. 6). Adjusted village-level prevalence ranged from 0–47. 1%. CFA prevalence increased with age and was higher in males. Of 86 antigen-positive community members from whom slides were prepared, 22 (25. 6%) were microfilaraemic. School-based TAS had limited sensitivity (range 0–23. 8%) and negative predictive value (range 25–83. 3%) but had high specificity (range 83. 3–100%) and positive predictive value (range 0–100%) for identifying villages with ongoing transmission. American Samoa failed the school-based TAS in 2016, and the community-based survey identified higher than expected numbers of antigen-positive people. School-based TAS was logistically simpler and enabled sampling of a larger proportion of the target population, but the results did not provide a good indication of the overall CFA prevalence in older age groups and was not sensitive at identifying foci of ongoing transmission. The community-based survey, although operationally more challenging, identified antigen-positive individuals of all ages, and foci of high antigen prevalence. Both surveys confirmed recrudescence of LF transmission.
Lymphatic filariasis (LF) is a neglected tropical disease caused by Wuchereria bancrofti and Brugia species of helminth worms. The disease is transmitted by mosquito vectors including Aedes, Anopheles, Culex and Mansonia species. Globally, an estimated 68 million people are infected; with 36 million microfilaemic people and 36 million people who are disabled or disfigured because of complications including lymphoedema, elephantiasis and scrotal hydrocoeles [1]. In 2000, the World Health Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF), which aims to eliminate LF as a public health problem by 2020. The GPELF includes two strategies, (i) to interrupt transmission of LF by conducting mass drug administration (MDA) in all disease endemic regions, and (ii) morbidity management and disability prevention for infected people [2]. The GPELF is estimated to have delivered 6. 2 billion treatments to over 820 million people since its inception [3]. Prior to the formation of the GPELF, the Pacific Programme to Eliminate LF (PacELF) was formed in 1999 to support 22 Pacific Island Countries and Territories in the Western Pacific Region [4]. As of 2017, Cook Islands, Niue, the Marshall Islands, Tonga and Vanuatu have successfully achieved elimination targets established by WHO [5]. WHO recommends conducting Transmission Assessment Surveys (TAS) in children aged 6–7 years for epidemiological assessment of transmission after the completion of MDA [2]. A minimum of two TAS are recommended at 2–3 year intervals, until the absence of transmission can be validated. The first TAS is designed to be conducted at least six months after the final round of MDA to decide if MDA can be stopped, while subsequent TAS are conducted to establish the absence of ongoing transmission. The rationale for choosing children aged 6–7 years as the target population for TAS is because they were born during or after MDA, and any infection in this population would most likely indicate recent and/or ongoing transmission. Transmission is considered not sustainable when the mean antigen (Ag) prevalence in an evaluation unit drops below the TAS threshold. Critical cut-off values are thresholds below which transmission is considered not sustainable and depend on the filarial parasite and vector. Critical cut-off values are calculated so that the likelihood of an evaluation unit passing is at least 75% if true Ag prevalence is 0. 5%, and no more than 5% if the true Ag prevalence is ≥1% [2]. In regions with endemic W. bancrofti and where transmission is dominated by Aedes spp. mosquitoes, the TAS threshold is based on an Ag prevalence of 1%. Recent studies have highlighted the limitations of relying solely on Ag-based TAS of young children as a post-MDA surveillance tool, especially as prevalence reaches low levels, and detection of any residual transmission becomes increasingly challenging. For example, in Sri Lanka, TAS of children aged 6–7 years were less sensitive at detecting low-level transmission compared to community-based surveys of people aged ≥10 years, antibody detection in school children aged 6–7 years, or xenomonitoring [6]. In American Samoa, where LF is endemic, W. bancrofti is the only known species of filarial worm, transmitted by both day and night biting Aedes spp. mosquitos. Ae. polynesiensis, the dominant vector, is highly efficient and day-biting [7]. In 1999, the Ag prevalence using rapid immunochromatographic test (ICT) was estimated to be 16. 5% [8,9]. Under PacELF, the American Samoa Department of Health delivered seven rounds of MDA during 2000–2006. In 2007, Ag prevalence by ICT in a community-based survey had declined to 2. 3% with microfilaria prevalence of 0. 5% [8,9]. Another round of MDA was recommended by the WHO Western Pacific Region Technical Advisory group Meeting held in 2008 [10], but was not conducted at large-scale due to logistical reasons [8,11]. School-based TAS are recommended in regions (e. g. American Samoa) where net school enrolment is ≥75% [2]. The sample size and threshold for TAS are designed to estimate Ag prevalence for the entire evaluation unit. Thus, TAS may not be able to detect small and highly focal residual clusters of transmission, particularly if there is significant spatial variation in prevalence within an evaluation unit. In addition, the age group (6–7 years) tested in TAS is likely to have lower prevalence than older ages, making it even more difficult to detect residual foci. In American Samoa, TAS-1 (conducted in 2011–2012) identified two Ag-positive children, and TAS-2 (conducted in 2015) identified one Ag-positive child. The Ag-positive children identified during both TAS all attended the same school. As the number of Ag-positive children identified was below the critical cut-off of six, American Samoa passed both TAS-1 [12] and TAS-2 [13]. Despite passing two TAS, recent community-based seroprevalence studies and molecular xenomonitoring studies of mosquitoes provided evidence of low-level but widespread ongoing transmission [14,15]. In a retrospective study of serum samples collected from adults in 2010, Ag (Og4C3) positive samples were identified from participants living across the main island of Tutuila, with higher Ag prevalence in two localised areas. One of these areas included the school where the Ag-positive children were identified during TAS-1 and TAS-2 [14]. A subsequent study in 2014 confirmed ongoing transmission within the two localised areas by identifying high Ag prevalence and microfilaraemic individuals. In addition, Ag prevalence (ICT) of 1. 1% (95% CI 0. 2–3. 1) was found in children aged 7–13 years who attended the school where Ag-positive children were identified in TAS-1 and TAS-2 [14,16]. The above findings raise concerns about the suitability of school-based TAS for post-MDA surveillance, not only in American Samoa but globally. In 2016, we conducted a study to compare the effectiveness of two survey designs for post-MDA surveillance: a school-based TAS of children aged 6–7 years and a community-based survey of individuals aged ≥8 years. We also evaluated the use of school-based TAS results as indicators of community-level Ag prevalence and/or foci of ongoing transmission. American Samoa was an optimal study site for answering these operational research questions for two reasons: (i) there had been no MDA since 2007 and any infection in children aged ≤9 years would have been acquired after the last round of MDA, and (ii) evidence from recent studies were highly suggestive of ongoing LF transmission [14–16]. In this paper, we report our key findings and discuss their implications for strengthening of TAS for post-MDA surveillance.
American Samoa is a US Territory in the South Pacific (14. 2710° South, 170. 1322° West), consisting of small inhabited islands with a total population of ~55,519 persons living in ~70 villages [17]. Over 90% of the population resides on the main island of Tutuila and the adjacent island of Aunu' u. The remote Manu' a islands were not included in this study as recent seroprevalence studies did not provide any evidence of local LF transmission [14]. This study consisted of two components: A) a school-based survey and B) a community-based survey. Each of the survey designs and sampling methods are described below. For the school-based survey, information sheets and consent forms were distributed to parents/guardians of all Grade 1 and 2 children approximately one week prior to scheduled school visits. All children with valid consent forms were included, and assent was sought from all participants. For the community-based survey, signed informed consent was obtained from adult participants or from parents/ guardians of those aged <18 years, along with verbal assent from minors. Ethics approvals for the study were granted by American Samoa Institutional Review Board and the Human Research Ethics Committee at the Australian National University (protocol number 2016/482). The study was conducted in collaboration with the American Samoa Department of Health and the American Samoa Community College. Official permissions for school and village visits were granted by the Department of Education and the Department of Samoa Affairs, respectively. All field activities were carried out in a culturally appropriate and sensitive manner with bilingual local field teams, and with verbal approval sought from village chiefs/ mayors prior to conducting the community surveys. Surveys were conducted in English or Samoan depending on the participants’ preference. The Institutional Review Board of the U. S. Centers for Disease Control and Prevention (CDC) determined CDC to be a non-engaged research partner.
We included all elementary schools (N = 29) on the two main islands of Tutuila and Aunu’u. Of 2180 Grade 1 and 2 students who were eligible to participate, 1143 (52. 4%) students returned signed consent forms and were included in the study. The average participation rate by school was 57% (range 18. 2–91. 7%). Table 2 summarises characteristics of participants included in the school-based TAS. Of the 1143 students, we identified nine Ag-positive children, equivalent to a crude CFA prevalence of 0. 8%. As the critical cut-off for passing TAS was fewer than six Ag-positive children, American Samoa failed the school-based TAS. The estimated overall CFA prevalence after adjusting for participation rates by school and sex was 0. 7% (95% CI: 0. 3–1. 8). The design effect for the school-based survey was 1. 9. Adjusted CFA prevalence in males was 0. 5% (95% CI: 0. 1–1. 9) and in females was 0. 9% (95% CI: 0. 4–2. 4). Valid FTS results were available for all 1143 (100%) children. Of the nine Ag-positive children, four (44. 4%) attended the same school in Pago Pago, and two (22. 2%) attended the same school in Nua. The other three Ag-positive children attended different schools located in the villages of Ili' ili, Nu' uuli and Faga' alu. Both Ag-positive children from the school in Nua lived in Fagali’i, one of the suspected hotspots identified in previous studies [14,16]. Seven (77. 8%) Ag-positive children were born in American Samoa and reported to have lived there for their entire lives, and two (22. 2%) were born in Samoa. Of the nine FTS-positive children, one (11. 1%) was microfilaraemic with Mf density of 1075 Mf/ml. The child was a 7 year old male who lived in Vaitogi, another potential hotspot identified in previous studies and attended the school where Ag-positive children were identified in TAS-1 and TAS-2. We visited all 30 selected PSUs and sampled 2507 persons from 711 households. The villages of Ili’ili and Pava’ia’i were split into two segments during the selection process, and both segments of these villages were selected for the survey. For the purposes of analyses, data from the different segments of each village were pooled, and results were presented for 28 villages (comprising 30 PSUs). The average household size was 6 (range 1–25) persons aged ≥8 years. We recruited participants from 77. 6% of the selected households, and 83. 2% (range 14. 3–100%) of eligible household members (aged ≥8 years). On average, 16. 8% of eligible household members were not recruited, and non-response was mostly associated with household members being absent at the time of visit, rather than refusal to participate. We recruited 1,140 (45. 5%) males and 1,367 (54. 5%) females (Table 3). Of the 2507 participants tested, 11 (0. 4%) had invalid tests and were excluded from analyses (Tables 1 & 3). Of the 2496 participants with valid tests, 102 were Ag-positive, equivalent to an overall crude CFA prevalence of 4. 1%. Of the 102 FTS-positive persons, 79 were male (crude CFA prevalence 7. 0%) and 23 were female (crude CFA prevalence 1. 7%), and this difference was statistically significant (p<0. 001). The original target sample size for the community-based survey, calculated based on an expected CFA prevalence of 1%, was 4620. After the first two weeks of recruitment, the observed CFA prevalence (~4%) was significantly higher than anticipated, and it was determined that a smaller target sample size of 2981 would provide adequate statistical power (Table 4). The age and sex distribution of the community-based survey participants and the general population of American Samoa are presented in Fig 3, showing that the survey included proportionately more females but provided a good representation of all age groups. After adjusting for the survey design, and age and sex distribution of American Samoa, the overall adjusted CFA prevalence was 6. 2% (95% CI: 4. 5–8. 6). The design effect for the community-based survey was 4. 2. The adjusted CFA prevalence by age and sex in the selected villages are presented in Fig 4A. Notably, in children aged 8–9 years, who were born after MDA had stopped, the adjusted CFA prevalence was 2. 2% (95% CI: 0. 8–6. 1). Of the 102 FTS-positive individuals, we were able to prepare slides for 86 (84. 3%) participants. Of these, 22 (25. 6%) were microfilaraemic, of whom 19 (86. 4%) were male (Fig 4B). The geometric mean Mf density was 60. 7 Mf/ml (range 5. 6–916. 7 Mf/ml). Adjusted village-level CFA prevalence varied from 0% to 47. 1% (Table 4 and Fig 5). Of the 28 villages, Ag-positive individuals were identified in the majority of villages, and only 6 (21. 5%) villages had no Ag-positive individuals. Microfilaraemic people identified from the community survey were dispersed throughout the island and lived in 10 of the 28 selected villages. Of the 22 microfilaraemic people, six (27. 3%) lived in Vaitogi (focal area with ongoing transmission identified in previous studies), the same village as the Mf-positive school child. Ag-positive school children from the school-based survey lived in four (14. 3%) of the 28 villages included in the community-based survey and attended school in three villages (10. 7%). A total of six villages (21. 4%) were identified as communities where Ag-positive children lived and/or attended school. Three (33. 3%) and two (22. 2%) Ag-positive children identified in the school-based survey, respectively, lived in and attended school in villages that were not selected for this survey; these data were therefore not included in the analysis of sensitivity, specificity, PPV and NPV. Table 5 shows the sensitivity, specificity, PPV and NPV for using Ag-positive children as indicators of villages with adjusted CFA prevalence of greater than 1%, 2%, 5%, 10%, and 20%. These findings suggest that follow-up of Ag-positive school children would have identified areas of transmission with high specificity (>73% for all scenarios), but low sensitivity (<24% for all scenarios), even if we considered villages where Ag-positive lived and/or attended school. Ag-positive children were a poor indicator of villages with higher prevalence (10 or 20%), with PPV of 25% or less for any of the scenarios tested.
Our study confirmed recrudescence of LF transmission in American Samoa 10 years after the last round of MDA. Through the school survey, we identified nine Ag-positive children (adjusted CFA prevalence 0. 7%), including a seven-year-old microfilaraemic child. The community survey identified 102 Ag-positive persons (adjusted CFA prevalence 6. 2%) and 22 microfilaraemic individuals. American Samoa failed school-based TAS in 2016, and the community-based survey identified higher numbers of Ag-positive people compared to Ag prevalence of 2. 3% (by ICT) in 2007 and 3. 2% (by Og4C3 Ag) in 2010 [8,14]. The adjusted CFA prevalence in the school-based survey of children aged 6–7 years (0. 7%) was significantly lower than the community-based survey of people aged ≥8 years (6. 2%), consistent with our knowledge that CFA prevalence is generally higher in older age groups. Our study identified advantages and limitations of using school-based versus community-based surveys. The school-based survey was logistically simpler, faster and cheaper, while the community-based survey was practically more challenging and time-consuming but provided more detailed information on estimates of community-level CFA prevalence, highlighted foci of high prevalence, and identified Ag- and Mf-positive people who are capable of perpetuating transmission. With the school-based survey, the identification of Ag-positive young children who have lived in American Samoa for their whole lives provided clear evidence of transmission within the past 6–7 years. The community survey also provided evidence of recent transmission by identifying Ag-positive children aged 8–9 years (adjusted CFA prevalence of 2. 2%, 95% CI 0. 8–6. 1), who were either born after the last round of MDA in 2008 or were too young to participate. In addition, the community-based survey provided detailed epidemiological information for a wider age range, including identification of older Ag-positive people who may serve an important reservoir of parasites and maintain transmission in the post-MDA setting [28]. Our results indicate that TAS conducted among young children (who have lower seroprevalence) may not be sufficiently sensitive to identify all areas of residual transmission (i. e where Ag-positive people aged ≥8 years were identified). This finding supports the conclusions of a recent study which modelled the efficiency of surveillance protocols based on the combination of ability to identify transmission foci, sample size required and high PPV, and found that testing of adults would be more efficient at detecting transmission in low prevalence settings compared to testing children aged 6–7 years [28]. The school-based TAS did not identify any difference in CFA prevalence between male and female young children. The community-based survey indicated that males (particularly those aged ≥20 years) had higher CFA prevalence and greater proportion of those who were Ag-positive had detectable microfilaria. Higher prevalence in adult males could be related to more time spent outdoors for work and recreation, and/or lower rates of participation in MDA [14,29]. Hormonal and pregnancy-mediated regulation of the immune system may also contribute to lower infection rates in females, particularly during the reproductive years [30]. The school-based survey was a systematic survey where all elementary schools on the two main islands were included. Overall, 52. 4% of our target population (6–7 year olds) participated in the survey, and we do not have reasons to suspect differences in Ag prevalence amongst those children who did not participate. The school-based survey identified two FTS-positive children living in Fagali’i, an area of known high LF transmission [16], and a cluster of four FTS-positive children who attended one school and lived in Fagatogo and Pago Pago. Considering that both villages of residence had low estimated CFA prevalence of 2. 7% and 2. 3%, respectively (below the overall estimated CFA prevalence of 6. 2%), the school-based clustering raises the possibility that transmission might be occurring in and around the school, particularly in the presence of a highly efficient day-biting vector [7]. The school-based survey had limited utility for detecting focal areas of ongoing transmission, (Table 5); while follow-up of villages where Ag-positive children lived or went to school might help identify areas of transmission with high specificity (range 83. 3–100%), the low sensitivity (range 0–23. 8%), PPV (0% in villages with >20% Ag prevalence) and NPV (range 25–83. 3%) suggests that even if further surveillance was conducted in all the villages where Ag-positive children lived and/or attended school, many high prevalence villages would still have been missed. The community-based survey was a modified WHO cluster survey, which is recommended for surveying large populations in resource-limited settings. By using a population representative sampling design and correcting for clustering during analyses [27,31], we believe our results are an accurate estimate of the country-wide CFA prevalence. The community-based survey demonstrated significant heterogeneity in CFA prevalence between villages, even in the very small and isolated island. Similar observations were made in the 2007 survey in American Samoa, and during post-MDA surveillance studies in other small island countries such as Sri Lanka and Samoa [6,8, 32]. A limitation of the survey design was that the school and community-based surveys were not completely geographically aligned because all schools were included, but only 30 of the 70 PSUs were sampled, i. e. some children tested in the school-based survey lived in villages that were not selected for the community-based survey. However, as we surveyed a large proportion of the selected villages, and many villages are contiguous along the limited number of roads in American Samoa (Fig 5), geographical concordance between the two surveys is unlikely to be a major issue in this study. The reasons for recrudescence of LF in American Samoa are unclear but could be associated with a combination of factors including some areas of poor-coverage or systematic non-compliance during MDAs [33,34], travel and migration of people from other countries in the Pacific where LF transmission is still ongoing [14,29,34]. An outdoor lifestyle in the presence of highly efficient day and night biting mosquitoes could also have contributed to recrudescence, and lower target thresholds may need to be considered in such settings [7,15]. LF has a long prepatent period [35], leading to low prevalence in young children even when prevalence is high in adults [8]. Thus, it was unlikely that all the Ag-positive people of all ages identified in our study acquired infection between 2015 (when American Samoa passed TAS-2) and 2016 (when TAS-3 was failed). In hindsight, early signals of ongoing transmission were evident from the population-representative serological survey of adults conducted in 2010, and further studies in 2014 which confirmed high Ag prevalence and identified Mf positive individuals within two foci of residual transmission in American Samoa [14,16]. Ag-positive young children detected in TAS-1 and TAS-2 attended school in one of the foci identified by research studies, which could have provided early signals of focal transmission. A molecular xenomonitoring study conducted in 2011 also identified evidence of widespread low-grade infection [7], and findings were strongly geographically correlated with village-level human seroprevalence [15]. Taken together, these observations and the results of the current study indicate that, compared to current protocols and thresholds of TAS of 6–7 year old children, other surveillance strategies have the potential to detect ongoing transmission earlier and with greater geographic precision. Our findings therefore support the need for more sensitive and innovative post-MDA surveillance strategies to achieve elimination goals of the global programme. Surveillance strategies that warrant further consideration include community-based surveys of both adults and children, school-based surveys that include a wider age range, lowering the threshold for the current TAS protocol, spatially explicit surveillance strategies, adaptive or snowball sampling (e. g. testing household and/or community members of Ag-positive children), testing for antifilarial antibodies, molecular xenomonitoring, or a combination of these strategies. We do not currently have sufficient evidence to specifically recommend any of these strategies over another, and operational research will be required to provide robust guidance for future surveillance. However, inclusion of older individuals in surveillance strategies might enable earlier detection of Ag-positive people in American Samoa and in other Polynesian countries, with highly efficient day-biting vectors and similar age-specific prevalence curves. As countries approach the GPELF elimination targets, WHO recommends developing sustainable post-MDA surveillance strategies that are cost-efficient and can be integrated into routine surveillance activities [2,16]. Although community-based surveys can be operationally more challenging, surveillance activities could take advantage of opportunistic and cost-effective methods of targeting community members [16,28], such as testing high-risk occupation groups, screening at workplace clinics and antenatal clinics, or during routine health check-ups for chronic illnesses and school-based vaccination campaigns.
Lymphatic filariasis (LF) is caused by infection with filarial worms that are transmitted by mosquito bites. Globally, 68 million are infected, with ~36 million people disfigured and disabled by complications such as severe swelling of the legs (elephantiasis) or scrotum (hydrocele). The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through mass drug administration (MDA), and to control illness and suffering in affected persons by 2020. The World Health Organization recommends conducting Transmission Assessment Surveys (TAS) in school children aged 6–7 years, to determine if infection rates have dropped to levels where disease transmission is no longer sustainable. American Samoa made significant progress towards eliminating LF. Following seven rounds of MDA, American Samoa passed TAS in 2011–2012 and 2015, with antigen prevalence of <1%. Despite passing TAS, recent studies have provided evidence of ongoing disease transmission in American Samoa, questioning the suitability of TAS for conducting surveillance after MDA has stopped. We compared a school-based survey of children aged 6–7 years and a community-based survey targeting people aged ≥8 years as tools for conducting post-MDA surveillance of LF. Our study provides recommendations for strengthening of post-MDA surveillance as countries approach the GPELF elimination targets.
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Identifying residual transmission of lymphatic filariasis after mass drug administration: Comparing school-based versus community-based surveillance - American Samoa, 2016