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Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.

Soil-transmitted helminths are targeted for elimination as a public health problem. This study assessed whether, with high coverage, community-wide mass drug administration (MDA) could lead to transmission interruption. DeWorm3 is an open-label, community cluster-randomised controlled trial in Benin, India, and Malawi. In each country, a single governmental administrative unit (population ≥80 000 individuals) with soil-transmitted helminth endemicity and participation in at least five rounds of community-wide MDA for lymphatic filariasis, was divided into 40 clusters (population ≥1650 individuals), which were randomly assigned (1:1) to community-wide MDA versus school-based deworming. Laboratory personnel were masked to exposure status and all investigators were masked to post-baseline outcome data until unmasking. In all clusters, preschool-aged and school-aged children received school-based deworming as per national guidelines for 3 years. In intervention clusters, door-to-door community-wide MDA (a single oral dose of 400 mg albendazole) was delivered to all eligible individuals biannually by community drug distributors for 3 years. All individuals aged 12 months and older in India and Benin and aged 24 months and older in Malawi were eligible for treatment, except women in the first trimester of pregnancy, those with adverse reactions to benzimidazoles, those who were acutely ill or intoxicated, or those reporting treatment within the previous 2 weeks. The co-primary outcomes were individual-level prevalence and cluster-level transmission interruption (ie, weighted prevalence of predominant species of ≤2%) of the predominant soil-transmitted helminth species, assessed by quantitative PCR (qPCR) 24 months after the last round of MDA. The analysis set contained a subset of randomly selected participants per cluster who enrolled in the endline assessment, provided a stool sample, and had a qPCR result. All individuals who received treatment were eligible for inclusion in the safety population. This trial is registered with ClinicalTrials.gov (NCT03014167), and is active but not recruiting. Between Oct 10, 2017, and Feb 17, 2023, 120 clusters (40 clusters per country, comprising 357 716 individuals) were randomly assigned, 60 to community-wide MDA and 60 to school-based deworming. 184 030 (51·4%) individuals in the clusters at baseline were female, 173 663 (48·5%) were male, and 23 (<0·1%) were other. The analysis set consisted of 58 827 individuals in the control group and 58 554 in the intervention group 24 months after the cessation of all deworming, Necator americanus prevalence (the predominant species at all sites) in the community-wide MDA group was lower than the school-based deworming group in Benin (adjusted prevalence ratio [aPR] 0·44 [95% CI 0·34–0·58]), India (0·41 [0·32–0·52]), and Malawi (0·40 [0·34–0·46]). Transmission interruption was achieved for N americanus in 11 (55%) of 20 intervention clusters versus six (30%) of 20 control clusters in Benin (p=0·20), in one (5%) intervention cluster versus no control clusters in India (p=1·00), and in no clusters in either group in Malawi (p=1·00). 984 adverse events were reported among 487 participants over the study, of which 32 among 13 participants resulted in hospitalisation and were classified as serious adverse events (three of which were related to study procedures). Soil-transmitted helminth transmission interruption might be possible in focal geographies but does not appear to be programmatically feasible within the evaluated timeframe. Community-wide MDA should be considered as an alternative strategy to school-based deworming programmes to improve equity and outcomes in helminth-endemic areas. The Gates Foundation.

A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele and lymphedema is in need of being assessed. During 2000-2012, the MDA programme made remarkable achievements - a total of 6.37 billion treatments were offered and an estimated 4.45 billion treatments were consumed by the population living in endemic areas. Using a model based on empirical observations of the effects of treatment on clinical manifestations, it is estimated that 96.71 million LF cases, including 79.20 million microfilaria carriers, 18.73 million hydrocele cases and a minimum of 5.49 million lymphedema cases have been prevented or cured during this period. Consequently, the global prevalence of LF is calculated to have fallen by 59%, from 3.55% to 1.47%. The fall was highest for microfilaraemia prevalence (68%), followed by 49% in hydrocele prevalence and 25% in lymphedema prevalence. It is estimated that, currently, i.e. after 13 years of the MDA programme, there are still an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases and 16.68 million lymphedema cases. The MDA programme has resulted in significant reduction of the LF burden. Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet reached 100% geographic coverage is imperative to further reduce the number of microfilaraemia and chronic disease cases and to reach the global target of interrupting transmission of LF by 2020.

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. Clinicaltrials.gov registration number: NCT02899936.

Lymphatic filariasis (LF), a mosquito-borne parasitic disease caused by three species of filarial worms, was first detected in Niue, a small Pacific Island nation of approximately 1,600 people, in 1954. After extensive efforts involving multiple rounds of Mass Drug Administration, Niue was validated by the World Health Organization (WHO) as having e4liminated LF as a public health problem in 2016. However, no surveillance has been conducted since validation to confirm infection rates have remained below WHO's elimination threshold. WHO has encouraged an integrated approach to disease surveillance and integrating LF post-validation surveillance (PVS) with existing surveys is an anticipated recommendation of the upcoming WHO LF-PVS guidelines. This paper describes a protocol for the implementation of an integrated approach to LF-PVS in Niue as cost-efficient and operationally feasible means of monitoring the disease in the population. The LF-PVS will be implemented as part of a planned national population-based WHO STEPwise approach to non-communicable disease (NCD) risk factor surveillance (STEPS) in Niue. Integration between the LF-PVS and STEPS will occur at multiple points, including during pre-survey community awareness raising and engagement, when obtaining informed consent, during the collection of demographics, risk factor, and location data, and when collecting finger-prick blood samples (for glucose as part of the STEPS survey and LF as part of the LF-PVS). The primary outcome measure for LF transmission will be antigen positivity. Microfilaria slides will be prepared for any antigen-positive cases. Dried blood spots will be prepared for all participants for Multiplex Bead Assays-based analysis to detect anti-filarial antibodies. We estimate a total sample size of 1,062 participants aged 15-69, representing approximately 66% of the population. The results of this study will provide insight into the status of LF in Niue and evaluate the advantages, challenges, and opportunities offered by integrated approaches to disease surveillance.

The Global Programme to Eliminate Lymphatic Filariasis has made significant gains through mass drug administration (MDA) of Ivermectin/Albendazole. Periodic evaluation of the MDA programme in lymphatic filariasis elimination is particularly useful in determining end points for stopping the programme. This is a follow-up study that sought to examine the effects of additional time and MDA intake on antigenemia seroreversion in persons who had previously tested positive for LF using the Filarial Test Strip (FTS) and the TropBio ELISA over a period of 1-5 years. A total of 542 individuals, from the Kassena Nankana East Municipal (N = 340) and Nabdam districts (N = 202) in the Upper East Region of Ghana, who had previously tested either positive (N = 446) or negative (N = 96) for FTS-CFA, participated in the study. Two follow-up visits were conducted; 1-4 years (follow-up-1) and 2-5 years (follow-up-2) after the baseline visit. Of the 446 FTS-CFA positives, 175 (39.2%) did not receive additional MDA (ivermectin/Albendazole) after the baseline visit. Overall, from the two follow-up visits, 159/175 (90.9%) FTS-CFA+ participants who did not receive any additional Ivermectin/Albendazole and 226 out of the 271 (83.4%) with additional MDA treatment became CFA negative. A total of 120 randomly selected baseline FTS-CFA+ samples were tested with Og4C3 TropBio ELISA and only 44/120 (36.7%) were found positive. Of these 44 participants, 12 (27.3%) completely became CFA negative and an additional 18 (40.9%) had reduced antigen levels during the follow-up. Likewise, all three previously/baseline microfilariae positive persons had become amicrofilaremic. In the present work, it has been shown that >90% of the previous CFA positive individuals seroreverted in 1 to 5 years post-baseline without additional MDA. The FTS is a more sensitive diagnostic tool that plausibly detects residual CFA in blood. The impact and influence of time as compared to additional ivermectin/Albendazole intake, on CFA seroreversion in this study was significant (p < 0.001).

Brugia malayi is the most common cause of lymphatic filariasis (LF) in Indonesia. A zoophilic ecotype that infects both humans and animals occur in Belitung District in Indonesia. The district received five annual rounds of mass drug administration (MDA) between 2006 and 2010 and passed three transmission assessment surveys (TAS) in subsequent years. However, a survey in five villages in 2021 showed a microfilaria (Mf) prevalence of 2.1% in humans. The reappearance of B. malayi infection in humans may be due to reintroduction from animal reservoirs. The goal of this study was to determine B. malayi prevalence in potential reservoir hosts and to improve the identification of filarial Mf found in animals. Venous blood was collected from 291 cats, 41 dogs, and 163 crab-eating macaques (Macaca fascicularis) from areas with and without human B. malayi infection. B. malayi Mf were detected by microscopy in 1.4%, 7.3% and 13.5% of the samples, respectively. The geometric mean Mf density varied from 133 Mf/mL(dogs) to 255 Mf/mL (macaques). While Brugia Mf were easily differentiated from Dirofilaria Mf by microscopy, the morphological differentiation between B. malayi and B. pahangi was not reliable. qPCR detected B. malayi DNA in blood from 4.1% of cats, 2.4% dogs, and 13.5% macaques. In addition, infections or co-infection with B. pahangi (cats, dogs) or D. immitis (dogs) were detected. A novel Dirofilaria species was morphologically identified in 20.3% of macaques. Microscopy was less accurate for detection and species identification of Mf than qPCR. The presence of B. malayi Mf in animals represents a challenge for the elimination of LF in some areas in Indonesia. More research is needed to better understand B. malayi transmission between animals and humans in endemic areas like Belitung where routine MDA may not be sufficient to eliminate LF.

The Global Program to Eliminate Lymphatic Filariasis (GPELF) is a program that aims to eliminate lymphatic filariasis by 2030. The GPELF strategy is based on interrupting transmission using mass drug administration (MDA) and, in parallel, managing morbidity cases. However, it has been seen that there is a shortage of research in the literature and public policies regarding this last pillar. In this study, we reviewed the literature and available information regarding the burden of filarial morbidity. In addition, we identified that in the Americas, the implementation of structured services with regard to morbidity assistance in the Americas was scarce. We formed a review that aimed to assess the pathogenesis, epidemiology, repercussions, and treatment of filarial morbidity in countries in the Americas where lymphatic filariasis is endemic. Structured searches were carried out on PubMed, LILACS, Scopus, and Web of Science databases without time and language restrictions. Three reviewers evaluated the 2150 studies and performed data extraction, and quality assessment by assigning scores to the studies found. The current literature and available information on the burden of filarial morbidity, as well as the implementation of structured services with regard to morbidity assistance in the Americas, were all found to be scarce. Now that this knowledge gap has been identified, both health services and researchers need to seek the implementation and enhancement of the maintenance of GPELF strategies that relate to the morbidity pillar.

Sensitive diagnostic tools that signal lymphatic filariasis (LF) transmission are needed to monitor the progress of LF elimination programs. Anti-filarial antibody (Ab) markers could be more sensitive than antigen (Ag) point-of-care tests for monitoring LF transmission in some settings. This study aimed to investigate the sensitivity of anti-filarial Abs for detecting signals of LF transmission in Samoa by i) investigating the sensitivity and specificity of Ab to identify Ag-positives; ii) estimating the average number needed to test (NNTestav) to identify LF-seropositives (seropositive for Ag and/or any Ab), and iii) compare the efficiency of the different serological indicators by target age group and sampling design. A community-based serological survey of participants aged ≥5 years was conducted 1.5-3.5 months following the first round of triple-drug mass drug administration in Samoa in 2018, covering 35 primary sampling units (PSUs) (30 randomly selected and five purposively selected 'suspected hotspots'). Ag-positivity was detected using Alere Filariasis Test Strips, and Ab-seropositivity (Bm14, Wb123, Bm33 Abs) were measured using multiplex bead assays. Seroprevalence was adjusted for study design and standardised for age and gender. NNTestav was calculated using the formula 1/p, where p was the adjusted seroprevalence for each subgroup. Of 3795 participants (mean age: 20.7; 51.2% female), 1892 (49.9%) were LF-seropositive. If Ag alone was used to identify LF-seropositives, only 5% (117/1892) would be identified. Of the three Ab seromarkers, Bm14 Ab had the highest area under the Receiver-Operating Characteristic Curve ([ROC]=0.88) to classify participants as Ag-positive, followed by Wb123 Ab (ROC=0.83) and Bm33 Ab (ROC=0.76). Participants aged ≥10 years had lower NNTestav compared to participants aged 5-9 years for all seromarkers. NNTestav was lower in purposively versus randomly selected PSUs. All Ab seromarkers had high ROC values to classify patients as Ag-positive and may be useful tools for LF surveillance in some settings. However, further research is required to fully understand how best Ab serosurveillance can be incorporated into LF elimination programmes.

Parasite host switches may trigger disease emergence, but prehistoric host ranges are often unknowable. Lymphatic filariasis and loiasis are major human diseases caused by the insect-borne filarial nematodes Brugia , Wuchereria and Loa . Here we show that the genomes of these nematodes and seven tropical bird lineages exclusively share a novel retrotransposon, AviRTE, resulting from horizontal transfer (HT). AviRTE subfamilies exhibit 83–99% nucleotide identity between genomes, and their phylogenetic distribution, paleobiogeography and invasion times suggest that HTs involved filarial nematodes. The HTs between bird and nematode genomes took place in two pantropical waves, >25–22 million years ago (Myr ago) involving the Brugia / Wuchereria lineage and >20–17 Myr ago involving the Loa lineage. Contrary to the expectation from the mammal-dominated host range of filarial nematodes, we hypothesize that these major human pathogens may have independently evolved from bird endoparasites that formerly infected the global breadth of avian biodiversity. Lymphatic filariasis and loiasis are diseases caused by insect-borne filarial nematodes. Here, Suh et al . identify a retrotransposon that is present in the genomes of these nematodes and seven tropical bird lineages, indicating two waves of horizontal gene transfer around 17–25 million years ago.