Predicting lymphatic filariasis elimination in data-limited settings: A reconstructive computational framework for combining data generation and model discovery.

Although there is increasing importance placed on the use of mathematical models for the effective design and management of long-term parasite elimination, it is becoming clear that transmission models are most useful when they reflect the processes pertaining to local infection dynamics as opposed to generalized dynamics. Such localized models must also be developed even when the data required for characterizing local transmission processes are limited or incomplete, as is often the case for neglected tropical diseases, including the disease system studied in this work, viz. lymphatic filariasis (LF). Here, we draw on progress made in the field of computational knowledge discovery to present a reconstructive simulation framework that addresses these challenges by facilitating the discovery of both data and models concurrently in areas where we have insufficient observational data. Using available data from eight sites from Nigeria and elsewhere, we demonstrate that our data-model discovery system is able to estimate local transmission models and missing pre-control infection information using generalized knowledge of filarial transmission dynamics, monitoring survey data, and details of historical interventions. Forecasts of the impacts of interventions carried out in each site made by the models estimated using the reconstructed baseline data matched temporal infection observations and provided useful information regarding when transmission interruption is likely to have occurred. Assessments of elimination and resurgence probabilities based on the models also suggest a protective effect of vector control against the reemergence of LF transmission after stopping drug treatments. The reconstructive computational framework for model and data discovery developed here highlights how coupling models with available data can generate new knowledge about complex, data-limited systems, and support the effective management of disease programs in the face of critical data gaps.

The Interruption of Transmission of Onchocerciasis in Abia, Anambra, Enugu, and Imo States, Nigeria: The Largest Global Onchocerciasis Stop-Treatment Decision to Date.

Onchocerciasis causes severe morbidity in sub-Saharan Africa. Abia, Anambra, Enugu, and Imo states of Nigeria were historically classified meso- or hyperendemic and eligible for ivermectin mass drug administration (MDA). After ≥25 years of annual and biannual MDA, serological and entomological assessments were conducted to determine if Onchocerca volvulus transmission was interrupted. Dried blood spots collected in October 2020 from ≥3167 children 5-9 years old in each state were screened for O. volvulus-specific Ov16 antibody by enzyme-linked immunosorbent assay. Additionally, 52,187 Simulium damnosum heads (≥8845 per state) collected over 12 months between 2021 and 2022 were tested by pooled polymerase chain reaction (PCR) for O-150 DNA. Among seven seropositive children, four were found for follow-up skin snip PCR to confirm active infection. Three were negative and the fourth was excluded as he was visiting from an endemic state. The final seroprevalence estimates of each state had 95% upper confidence limits (UCL) < 0.1%. All fly pools were negative by O-150 PCR, giving a 95% UCL infective fly prevalence < 0.05% in each state. Each state therefore met the World Health Organization epidemiological and entomological criteria for stopping MDA effective January 2023. With 18.9 million residents eligible for MDA, this marked the largest global onchocerciasis stop-treatment decision to date.

A Mixed-Methods Evaluation of Mainstreaming Mass Drug Administration for Schistosomiasis and Soil-Transmitted Helminthiasis in Four Districts of Nigeria.

In Nigeria, mass drug administration (MDA) for schistosomiasis (SCH) and soil-transmitted helminthiasis (STH) has often been coordinated with other programs that receive greater external funding. As these programs reach stop MDA milestones, SCH and STH programs will likely need to transition implementation, or "mainstream," to domestic support. A mixed-methods study was conducted in four districts before (2021) and after (2022) mainstreaming to evaluate its impact on MDA coverage. Household surveys were done in 30 villages per district pre- and post-mainstreaming. All selected communities were eligible for STH treatment; around a third were eligible for SCH treatment. Mass drug administration was primarily conducted in schools. A total of 5,441 school-aged children were included in pre-mainstreaming and 5,789 were included in post-mainstreaming. Mass drug administration coverage was heterogeneous, but overall, mebendazole coverage declined nonsignificantly from 81% pre-mainstreaming to 76% post-mainstreaming (P = 0.09); praziquantel coverage declined significantly from 73% to 55% (P = 0.008). Coverage was significantly lower among unenrolled children or those reporting poor school attendance in nearly every survey. For the qualitative component, 173 interviews and 74 focus groups were conducted with diverse stakeholders. Respondents were deeply pessimistic about the future of MDA after mainstreaming and strongly supported a gradual transition to full government ownership. Participants formulated recommendations for effective mainstreaming: clear budget allocation by governments, robust and targeted training, trust building, and comprehensive advocacy. Although participants lacked confidence that SCH and STH programs could be sustained after reductions in external support, initial results indicate that MDA coverage can remain high 1 year into mainstreaming.

Integrated Prevalence Assessment of Wuchereria bancrofti and Onchocerca volvulus in Three Co-Endemic Districts of Gambella Region, Ethiopia.

Lymphatic filariasis (LF) and onchocerciasis (OV) are among the neglected tropical diseases (NTD) targeted for elimination in Ethiopia. We used a transmission assessment survey (TAS-1) to evaluate the serological status of OV in three co-endemic districts in Gambella simultaneously. During May and June 2019, blood samples were collected from 6- to 7-year-old children who were randomly selected through standard community-based TAS methodology. Children were tested for both circulating filarial antigen (CFA) for LF via filariasis test strip and for Onchocerca volvulus 16 (Ov16) antibody for OV via laboratory-based ELISA. A total of 3,377 children from 150 villages in the three districts were tested; 1,823 (54.0%) were male. All three districts had CFA results below the critical threshold for stopping LF mass drug administration (MDA). In contrast, 40 children (1.2%) were positive for Ov16 antibody, well above the WHO's OV stop MDA threshold of 0.1%. The integrated assessment indicated two programmatic decisions: stop MDA for LF and continue MDA for OV. Accordingly, albendazole MDA was discontinued in the districts but ivermectin MDA continued. This integrated assessment showed that a random sample for TAS can give important information about OV transmission status in co-endemic areas.

Two Nigerian States (Plateau and Nasarawa) Have Eliminated Transmission of Human Onchocerciasis-A Report of Post-Ivermectin Mass Drug Administration Surveillance.

Transmission of Onchocerca volvulus (causing "river blindness") was interrupted in two states of Nigeria (Plateau and Nasarawa) in 2017 in accordance with 2016 WHO guidelines. Ivermectin mass drug administration was halted in January 2018, and posttreatment surveillance activities were conducted over a 3-year period. Vector Simulium damnosum s.l. flies were collected during the 2019 (39 sites) and 2020 (42 sites) transmission seasons. Head pools were tested by polymerase chain reaction for the presence of third-stage O. volvulus larvae; 15,585 flies were all negative, demonstrating an infective rate of < 1/2,000 with 95% confidence. In 2021, the Nigerian Federal Ministry of Health declared the two-state area as having eliminated transmission. Plateau and Nasarawa states are the first of 30 endemic states in Nigeria to have met the WHO criteria for onchocerciasis elimination. Post-elimination surveillance will need to continue given the risk of reintroduction of transmission from neighboring states.

Impact of Three to Five Rounds of Mass Drug Administration on Schistosomiasis and Soil-Transmitted Helminths in School-Aged Children in North-Central Nigeria.

Nasarawa and Plateau states of north-central Nigeria have implemented programs to control schistosomiasis (SCH) and soil-transmitted helminths (STH) in children since the 1990s. Statewide mapping surveys were conducted in 2013, when 11,332 school-aged children were sampled from 226 schools. The local government areas (LGAs) then received varying combinations of mass drug administration (MDA) for the next 5 years. We revisited 196 (87%) schools in 2018 plus an additional six (202 schools in total), sampling 9,660 children. We calculated overall prevalence and intensity of infection and evaluated associations with gender; age; behaviors; water, sanitation, and hygiene (WASH); and treatment regimen. Urine heme detection dipsticks were used for Schistosoma hematobium in both surveys, with egg counts added in 2018. Stool samples were examined by Kato-Katz for Ascaris lumbricoides, Trichuris trichiura, Schistosoma mansoni, and hookworm. Schistosomiasis prevalence among sampled students dropped from 12.9% (95% confidence interval [CI]: 11.1-14.9%) to 9.0% (95% CI: 7.5-10.9%), a statistically significant change (P < 0.05). In 2018, eight LGAs still had > 1% of children with heavy-intensity schistosome infections. Prevalence of STH infection did not significantly change, with 10.8% (95% CI: 9.36-12.5%) of children positive in 2013 and 9.4% (95% CI: 8.0-10.9%) in 2018 (P = 0.182). Heavy-intensity STH infections were found in < 1% of children with hookworm, and none in children with A. lumbricoides or T. trichiura in either study. The WASH data were collected in 2018, indicating 43.6% of schools had a latrine and 14.4% had handwashing facilities. Although progress is evident, SCH remains a public health problem in Nasarawa and Plateau states.

Assessing Hypoendemic Onchocerciasis in Loa loa Endemic Areas of Southeast Nigeria.

Nigeria changed its goal for onchocerciasis from control to transmission elimination. Under the control program, ivermectin mass drug administration (MDA) focused only on hyper/meso-endemic local government areas (LGAs) identified by Rapid Epidemiological Mapping of Onchocerciasis as having ≥ 20% nodule rates. Because transmission is likely in some LGAs where nodule rates are < 20%, the new elimination paradigm requires MDA expansion. Determining which hypoendemic areas require MDA, termed onchocerciasis elimination mapping, is a major challenge. In 2016, we studied 19 ivermectin-naive hypoendemic LGAs in southern Nigeria that bordered LGAs under MDA. Fifty adults and 50 children (aged 5-10 years) were tested in 110 villages for onchocerciasis IgG4 antibody using an Ov16 rapid diagnostic test (RDT). A 10% subset of subjects provided a blood spot for confirmatory Ov16 ELISA. The mean prevalence of RDT positives was 0.5% in the 5,276 children tested (village range, 0.0-4.0%) versus 3.3% in 5,302 adults (village range, 0.0-58.0%). There was 99.3% agreement between the Ov16 RDT and ELISA. Six different MDA launch thresholds were applied to the RDT results based on different recommendations by the Nigeria Onchocerciasis Elimination Committee and the Onchocerciasis Technical Advisory Subgroup of the WHO. Mass drug administration targets for the same area varied tenfold by threshold chosen, from one LGA (population to be treated 221,935) to 13 LGAs (population 2,426,987). Because the Ov16 threshold selected will have considerable cost and resource implications, the decision to initiate MDA should incorporate entomological data demonstrating onchocerciasis transmission.

The Interruption of Transmission of Human Onchocerciasis by an Annual Mass Drug Administration Program in Plateau and Nasarawa States, Nigeria.

Plateau and Nasarawa states in central Nigeria were endemic for onchocerciasis. The rural populations of these two states received annual ivermectin mass drug administration (MDA) for a period of 8-26 years (1992-2017). Ivermectin combined with albendazole was given for 8-13 of these years for lymphatic filariasis (LF); the LF MDA program successfully concluded in 2012, but ivermectin MDA continued in areas known to have a baseline meso-/hyperendemic onchocerciasis. In 2017, serological and entomological assessments were undertaken to determine if MDA for onchocerciasis could be stopped in accordance with the current WHO guidelines. Surveys were conducted in 39 sites that included testing 5- to < 10-year-old resident children by using ELISA for OV16 IgG4 antibodies, and Onchocerca volvulus O150 pooled polymerase chain reaction (PCR) testing of Simulium damnosum s.l. vector heads. Only two of 6,262 children were OV16 positive, and none of 19,056 vector heads were positive for parasite DNA. Therefore, both states were able to meet WHO stop-MDA thresholds of an infection rate in children of < 0.1% and a rate of infective blackflies of <1/2,000, with 95% statistical confidence. Transmission of onchocerciasis was declared interrupted in Plateau and Nasarawa states by the Federal Ministry of Health, and 2.2 million ivermectin treatments/year were stopped in 2018. Post-treatment Surveillance was launched focusing on entomological monitoring on borders with neighboring onchocerciasis-endemic states. An apparent positive impact of the LF MDA program on eliminating hypo-endemic onchocerciasis was observed. This is the first stop-MDA decision for onchocerciasis in Nigeria and the largest single stop-MDA decision for onchocerciasis yet reported. This achievement, along with the process used in adapting and implementing the 2016 WHO stop-MDA guidelines, will be important as a potential model for decision makers and national onchocerciasis elimination committees in other African countries that are charged with advancing their programs.

The Galabat-Metema cross-border onchocerciasis focus: The first coordinated interruption of onchocerciasis transmission in Africa.

BACKGROUND: Onchocerciasis transmission across international borders is not uncommon, yet a coordinated cross border stops mass drug administration (MDA) decision has not been documented. METHODS/PRINCIPLE FINDINGS: The Galabat-Metema focus involves neighboring districts on the border between Sudan and Ethiopia. Mass drug administration (MDA) was provided once and subsequently twice per year in this focus, with twice-per-year beginning in Ethiopia's Metema subfocus in 2016 and in the Sudan's Galabat subfocus in 2008. Ov16 ELISA-based serosurveys were conducted in 6072 children under 10 years of age in the Metema subfocus in 2014, and 3931 in the Galabat in 2015. Between 2014 and 2016, a total of 27,583 vector Simulium damnosum flies from Metema and 9,148 flies from Galabat were tested by pool screen PCR for Onchocerca volvulus O-150 DNA. Only 8 children were Ov16 seropositive (all in the Metema subfocus); all were negative by skin snip PCR. The upper limit of the 95% confidence interval (UCL) for Ov16 seropositive was <0.1% for the overall focus and 0.14 positive fly heads per 2000 (UCL = 0.39/2000). However, an entomological 'hotspot' was detected on the Wudi Gemzu river in Metema district. The hotspot was confirmed when 4 more positive fly pools were found on repeat testing in 2017 (1.04 L3/2000 flies (UCL = 2.26/2000). Information exchange between the two countries led to stopping MDA in a coordinated fashion in 2018, with the exception of the hotspot at Wudi Gemzu, where MDA with ivermectin was increased to every three months to hasten interruption of transmission. CONCLUSION: Coordinated stop MDA decisions were made by Sudan and Ethiopia based on data satisfying the World Health Organization's criteria for interruption of onchocerciasis transmission. Definitions of entomological 'hotspots' and buffer zones around the focus are proposed.

Comparison of Reported and Survey-Based Coverage in Onchocerciasis Programs over a Period of 8 Years in Cameroon and Uganda.

Mass drug administration (MDA) with ivermectin must reach a high treatment coverage (90% of the eligible population) if onchocerciasis is to be eliminated. Questions have been raised as to whether reported treatment figures reaching such high coverage are reliable. Sample surveys are proposed as the method of choice for "validating" reported coverage figures. The purpose of this study was to compare the district-level MDA coverage reported by programs with contemporaneous surveys of randomly selected respondents living in those same districts. Over an 8-year period, 19,219 households were selected using multistage random sampling; 38,433 adult male and female heads of those households were asked about their recent ivermectin MDA treatment experience. District coverage reports were considered "accurate" if they fell within the 95% CIs determined by the corresponding district's survey. Ninety-eight treatment rounds were evaluated over an 8-year period. Overall, the reported coverage of 96.5% (range: 68-100%) was significantly higher than the 92.5% surveyed coverage (range: 62.1-99.6%, 95% CI: 91.9-93.2%). However, only 20% of districts reported significantly higher coverage than surveys, 68% of district program reports were judged as accurate, and 12% of districts reported significantly lower coverage figures than their corresponding surveys. Eighty-eight percent of districts reported coverage ≥ 90% threshold for success, compared with 97% of surveys that included 90% in their 95% CIs. We conclude that when analyzed statistically at the district level, most surveys verified the reported coverage.

Evaluation of Treatment Coverage and Enhanced Mass Drug Administration for Onchocerciasis and Lymphatic Filariasis in Five Local Government Areas Treating Twice Per Year in Edo State, Nigeria.

The western region of Edo state in southern Nigeria is highly endemic for onchocerciasis. Despite years of mass drug administration (MDA) with ivermectin (IVM), reports suggest persistently high prevalence of onchocerciasis, presumably because of poor coverage. In 2016, twice-per-year treatment with IVM (combined with albendazole for lymphatic filariasis in the first round where needed) began in five local government areas (LGAs) of Edo state. We undertook a multistage cluster survey within 3 months after each round of MDA to assess coverage. First-round coverage was poor: among 4,942 people of all ages interviewed from 145 clusters, coverage was 31.1% (95% confidence intervals [CI]: 24.1-38.0%). Most respondents were not offered medicines. To improve coverage in the second round, three LGAs were randomized to receive MDA through a "modified campaign" approach focused on improved supervision and monitoring. The other two LGAs continued with standard MDA as before. A similar survey was conducted after the second round, interviewing 3,362 people in 87 clusters across the five LGAs. Coverage was not statistically different from the first round (40.0% [95% CI: 31.0-49.0%]) and there was no significant difference between the groups (P = 0.7), although the standard MDA group showed improvement over round 1 (P < 0.01). The additional cost per treatment in the modified MDA was 1.6 times that of standard MDA. Compliance was excellent among those offered treatment. We concluded that poor mobilization, medicine distribution, and program penetration led to low coverage. These must be addressed to improve treatment coverage in Edo state.

Author Correction: Substantiating freedom from parasitic infection by combining transmission model predictions with disease surveys.

The original version of this Article contained an error in the spelling of Emily Griswold, which was incorrectly given as Emily Grisworld. This error has now been corrected in both the PDF and HTML versions of the Article.

In Southern Nigeria Loa loa Blood Microfilaria Density is Very Low Even in Areas with High Prevalence of Loiasis: Results of a Survey Using the New LoaScope Technology.

Ivermectin treatment can cause central nervous system adverse events (CNS-AEs) in persons with very high-density Loa loa microfilaremia (≥ 30,000 mf/mL blood). Hypoendemic onchocerciasis areas where L. loa is endemic have been excluded from ivermectin mass drug administration programs (MDA) because of the concern for CNS AEs. The rapid assessment procedure for L. loa (RAPLOA) is a questionnaire survey to assess history of eye worm. If ≥ 40% of respondents report eye worm, this correlates with ≥ 2% prevalence of very high-density loiasis microfilaremia, posing an unacceptable risk of CNS-AEs after MDA. In 2016, we conducted a L. loa study in 110 ivermectin-naïve, suspected onchocerciasis hypoendemic villages in southern Nigeria. In previous RAPLOA surveys these villages had prevalences between 10% and 67%. We examined 10,605 residents using the LoaScope, a cell phone-based imaging device for rapidly determining the microfilaria (mf) density of L. loa infections. The mean L. loa village mf prevalence was 6.3% (range 0-29%) and the mean individual mf count among positives was 326 mf/mL. The maximum individual mf count was only 11,429 mf/mL, and among 2,748 persons sampled from the 28 villages with ≥ 40% RAPLOA, the ≥ 2% threshold of very high Loa mf density could be excluded with high statistical confidence (P < 0.01). These findings indicate that ivermectin MDA can be delivered in this area with extremely low risk of L. loa-related CNS-AEs. We also concluded that in Nigeria the RAPLOA survey methodology is not predictive of ≥ 2% prevalence of very high-density L. loa microfilaremia.

Substantiating freedom from parasitic infection by combining transmission model predictions with disease surveys.

Stopping interventions is a critical decision for parasite elimination programmes. Quantifying the probability that elimination has occurred due to interventions can be facilitated by combining infection status information from parasitological surveys with extinction thresholds predicted by parasite transmission models. Here we demonstrate how the integrated use of these two pieces of information derived from infection monitoring data can be used to develop an analytic framework for guiding the making of defensible decisions to stop interventions. We present a computational tool to perform these probability calculations and demonstrate its practical utility for supporting intervention cessation decisions by applying the framework to infection data from programmes aiming to eliminate onchocerciasis and lymphatic filariasis in Uganda and Nigeria, respectively. We highlight a possible method for validating the results in the field, and discuss further refinements and extensions required to deploy this predictive tool for guiding decision making by programme managers.

The role of national committees in eliminating onchocerciasis.

National onchocerciasis elimination committees (NOECs) serve to help ministries of health complete the pathway to successful verification of elimination of onchocerciasis (river blindness), as outlined in the 2016 World Health Organization guidelines. These guidelines, however, only take effect when the country believes it has reached a point that elimination can be demonstrated, and do not address the preceding milestones. Therefore, NOECs can be of great help with guiding and tailoring earlier planning, programming and assessments to empower national programs to aggressively move toward their countries' elimination goals. In this article, we provide suggestions for organizing NOECs and examples of four such committees that have successfully operated in Africa and the Americas.

How are qualitative methods used in diabetes research? A 30-year systematic review.

We aimed to describe how qualitative methods are used in global research on diabetes and identify opportunities whereby qualitative methods could further benefit our understanding of the human experience of diabetes and interventions to address it. We conducted a systematic review of National Library of Medicine, EMBASE, and Web of Science electronic databases to identify original research articles that used qualitative methods to study diabetes between 1980 and 2011. We identified 554 eligible articles and categorised these by geographic region, year of publication, study population, study design, research question, qualitative data collection methods, and journal type. Results show low use of qualitative methods in diabetes research over the past 30 years. The majority of articles (75%) reported using substantive qualitative research, while mixed-methods research has remained underutilised. Eighty-five per cent of articles reported studies conducted in North America or Europe, with few studies in developing countries. Most articles reported recruiting clinic-based populations (58%). Over half (54%) of research questions focused on patient experience and 24% on diabetes management. Qualitative methods can provide important insights about socio-cultural aspects of disease to improve disease management. However, they remain underutilised for understanding the diabetes experience, especially in Africa and Asia and amongst non-clinic populations.

Criteria to Stop Mass Drug Administration for Lymphatic Filariasis Have Been Achieved Throughout Plateau and Nasarawa States, Nigeria.

Nigeria has the largest population at risk for lymphatic filariasis (LF) in Africa. This study used a transmission assessment survey (TAS) to determine whether mass drug administration (MDA) for LF could stop in 21 districts, divided into four evaluation units (EUs), of Plateau and Nasarawa States, Nigeria, after 8-12 years of annual albendazole-ivermectin treatment. A total of 7,131 first- and second-year primary school children (approximately 6-7 years old) were tested for LF antigen by immunochromatographic test (ICT) from May to June 2012. The target sample size of 1,692 was exceeded in each EU (range = 1,767-1,795). A total of 25 (0.4%) individuals were ICT positive, with the number of positives in each EU (range = 3-11) less than the TAS cutoff of 20, meaning that LF transmission had been reduced below sustainable levels. As a result, 3.5 million annual albendazole-ivermectin treatments were halted in 2013. Combined with the previous halt of MDA for LF in other parts of Plateau and Nasarawa, these are the first Nigerian states to stop LF MDA statewide. Posttreatment surveillance is ongoing to determine if LF transmission has been interrupted.