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Background: The Bangladesh Lymphatic Filariasis (LF) Elimination Programme has made significant progress in interrupting transmission through mass drug administration (MDA) and has now focussed its efforts on scaling up managing morbidity and preventing disability (MMDP) activities to deliver the minimum package of care to people affected by LF clinical conditions. This paper highlights the Bangladesh LF Programme’s success in conducting a large-scale cross-sectional survey to determine the number of people affected by lymphoedema and hydrocoele, which enabled clinical risk maps to be developed for targeted interventions across the 34 endemic districts (19 high endemic; 15 low endemic). Methodology/Principal findings: In the 19 high endemic districts, 8,145 community clinic staff were trained to identify and report patients in their catchment area. In the 15 low endemic districts, a team of 10 trained field assistants conducted active case finding with cases reported via a SMS mHealth tool. Disease burden and prevalence maps were developed, with morbidity hotspots identified at sub-district level based on a combination of the highest prevalence rates per 100,000 and case-density rates per square kilometre (km2). The relationship between morbidity and baseline microfilaria (mf) prevalence was also examined. In total 43,678 cases were identified in the 19 high endemic districts; 30,616 limb lymphoedema (70.1%; female 55.3%), 12,824 hydrocoele (29.4%), and 238 breast/female genital swelling (0.5%). Rangpur Division reported the highest cases numbers and prevalence of lymphoedema (26,781 cases, 195 per 100,000) and hydrocoele (11661 cases, 169.6 per 100,000), with lymphoedema predominately affecting females (n = 21,652). Rangpur and Lalmonirhat Districts reported the highest case numbers (n = 11,199), and prevalence (569 per 100,000) respectively, with five overlapping lymphoedema and hydrocoele sub-district hotspots. In the 15 low endemic districts, 732 cases were identified; 661 lymphoedema (90.2%; female 39.6%), 56 hydrocoele (7.8%), and 15 both conditions (2.0%). Spearman’s correlation analysis found morbidity and mf prevalence significantly positively correlated (r = 0.904; p<0.01). Conclusions/Significance: The Bangladesh LF Programme has developed one of the largest, most comprehensive country databases on LF clinical conditions in the world. It provides an essential database for health workers to identify local morbidity hotspots, deliver the minimum package of care, and address the dossier elimination requirements. [ABSTRACT FROM AUTHOR]

Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lead to high macrofilaricidal efficacy in a variety of preclinical models and in humans. As part of an effort to stimulate the discovery and development of new macrofilaricides, particularly for onchocerciasis, research has recently been devoted to the development of new formulations that would afford high oral bioavailability of FBZ, paving the way for potential clinical development of this repurposed drug for the treatment of human filariases. This review summarizes the background information that led to this program and summarizes some of the lessons learned from it. [ABSTRACT FROM AUTHOR]

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) and podoconiosis are neglected tropical diseases (NTDs) that pose a significant physical, social and economic burden to endemic communities. Patients affected by the clinical conditions of LF (lymphoedema and hydrocoele) and podoconiosis (lymphoedema) need access to morbidity management and disability prevention (MMDP) services. Clear estimates of the number and location of these patients are essential to the efficient and equitable implementation of MMDP services for both diseases. Methodology/Principle findings: A community-based cross-sectional study was conducted in Ethiopia using the Health Extension Worker (HEW) network to identify all cases of lymphoedema and hydrocoele in 20 woredas (districts) co-endemic for LF and podoconiosis. A total of 612 trained HEWs and 40 supervisors from 20 districts identified 26,123 cases of clinical morbidity. Of these, 24,908 (95.3%) reported cases had leg lymphoedema only, 751 (2.9%) had hydrocoele, 387 (1.5%) had both leg lymphoedema and hydrocoele, and 77 (0.3%) cases had breast lymphoedema. Of those reporting leg lymphoedema, 89.3% reported bilateral lymphoedema. Older age groups were more likely to have a severe stage of disease, have bilateral lymphoedema and to have experienced an acute attack in the last six months. Conclusions/Significance: This study represents the first community-wide, integrated clinical case mapping of both LF and podoconiosis in Ethiopia. It highlights the high number of cases, particularly of leg lymphoedema that could be attributed to either of these diseases. This key clinical information will assist and guide the allocation of resources to where they are needed most. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is best known for the disabling and disfiguring clinical conditions that infected patients can develop; providing care for these individuals is a major goal of the Global Programme to Eliminate LF. Methods of locating these patients, knowing their true number and thus providing care for them, remains a challenge for national medical systems, particularly when the endemic zone is a large urban area. Methodology/Principle findings: A health community-led door-to-door survey approach using the SMS reporting tool MeasureSMS-Morbidity was used to rapidly collate and monitor data on LF patients in real-time (location, sex, age, clinical condition) in Dar es Salaam, Tanzania. Each stage of the phased study carried out in the three urban districts of city consisted of a training period, a patient identification and reporting period, and a data verification period, with refinements to the system being made after each phase. A total of 6889 patients were reported (133.6 per 100,000 population), of which 4169 were reported to have hydrocoele (80.9 per 100,000), 2251 lymphoedema-elephantiasis (LE) (43.7 per 100,000) and 469 with both conditions (9.1 per 100,000). Kinondoni had the highest number of reported patients in absolute terms (2846, 138.9 per 100,000), followed by Temeke (2550, 157.3 per 100,000) and Ilala (1493, 100.5 per 100,000). The number of hydrocoele patients was almost twice that of LE in all three districts. Severe LE patients accounted for approximately a quarter (26.9%) of those reported, with the number of acute attacks increasing with reported LE severity (1.34 in mild cases, 1.78 in moderate cases, 2.52 in severe). Verification checks supported these findings. Conclusions/Significance: This system of identifying, recording and mapping patients affected by LF greatly assists in planning, locating and prioritising, as well as initiating, appropriate morbidity management and disability prevention (MMDP) activities. The approach is a feasible framework that could be used in other large urban environments in the LF endemic areas. [ABSTRACT FROM AUTHOR]

Background: Individuals with high intensity of Loa loa are at risk of developing serious adverse events (SAEs) post treatment with ivermectin. These SAEs have remained unclear and a programmatic impediment to the advancement of community directed treatment with ivermectin. The pathogenesis of these SAEs following ivermectin has never been investigated experimentally. The Loa/baboon (Papio anubis) model can be used to investigate the pathogenesis of Loa-associated encephalopathy following ivermectin treatment in humans. Methods: 12 baboons with microfilarial loads > 8,000mf/mL of blood were randomised into four groups: Group 1 (control group receiving no drug), Group 2 receiving ivermectin (IVM) alone, Group 3 receiving ivermectin plus aspirin (IVM + ASA), and Group 4 receiving ivermectin plus prednisone (IVM + PSE). Blood samples collected before treatment and at Day 5, 7 or 10 post treatment, were analysed for parasitological, hematological and biochemical parameters using standard techniques. Clinical monitoring of animals for side effects took place every 6 hours post treatment until autopsy. At autopsy free fluids and a large number of standard organs were collected, examined and tissues fixed in 10% buffered formalin and processed for standard haematoxylin-eosin staining and specific immunocytochemical staining. Results: Mf counts dropped significantly (p<0.05) in all animals following ivermectin treatment with reductions as high as (89.9%) recorded; while no significant drop was observed in the control animals. Apart from haemoglobin (Hb) levels which recorded a significant (p = 0.028) drop post treatment, all other haematological and biochemical parameters did not show any significant changes (p>0.05). All animals became withdrawn 48 hours after IVM administration. All treated animals recorded clinical manifestations including rashes, itching, diarrhoea, conjunctival haemorrhages, lymph node enlargement, pinkish ears, swollen face and restlessness; one animal died 5 hours after IVM administration. Macroscopic changes in post-mortem tissues observed comprised haemorrhages in the brain, lungs, heart, which seen in all groups given ivermectin but not in the untreated animals. Microscopically, the major cellular changes seen, which were present in all the ivermectin treated animals included microfilariae in varying degrees of degeneration in small vessels. These were frequently associated with fibrin deposition, endothelial changes including damage to the integrity of the blood vessel and the presence of extravascular erythrocytes (haemorrhages). There was an increased presence of eosinophils and other chronic inflammatory types in certain tissues and organs, often in large numbers and associated with microfilarial destruction. Highly vascularized organs like the brain, heart, lungs and kidneys were observed to have more microfilariae in tissue sections. The number of mf seen in the brain and kidneys of animals administered IVM alone tripled that of control animals. Co-administration of IVM + PSE caused a greater increase in mf in the brain and kidneys while the reverse was noticed with the co-administration of IVM + ASA. Conclusions: The treatment of Loa hyper-microfilaraemic individuals with ivermectin produces a clinical spectrum that parallels that seen in Loa hyper-microfilaraemic humans treated with ivermectin. The utilization of this experimental model can contribute to the improved management of the adverse responses in humans. [ABSTRACT FROM AUTHOR]

Background: Bangladesh had one of the highest burdens of lymphatic filariasis (LF) at the start of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) with an estimated 70 million people at risk of infection across 34 districts. In total 19 districts required mass drug administration (MDA) to interrupt transmission, and 15 districts were considered low endemic. Since 2001, the National LF Programme has implemented MDA, reduced prevalence, and been able to scale up the WHO standard Transmission Assessment Survey (TAS) across all endemic districts as part of its endgame surveillance strategy. This paper presents TAS results, highlighting the momentous geographical reduction in risk of LF and its contribution to the global elimination target of 2020. Methodology/Principal findings: The TAS assessed primary school children for the presence of LF antigenaemia in each district (known as an evaluation unit—EU), using a defined critical cut-off threshold (or ‘pass’) that indicates interruption of transmission. Since 2011, a total of 59 TAS have been conducted in 26 EUs across the 19 endemic MDA districts (99,148 students tested from 1,801 schools), and 22 TAS in the 15 low endemic non-MDA districts (36,932 students tested from 663 schools). All endemic MDA districts passed TAS, except in Rangpur which required two further rounds of MDA. In total 112 students (male n = 59; female n = 53), predominately from the northern region of the country were found to be antigenaemia positive, indicating a recent or current infection. However, the distribution was geographically sparse, with only two small focal areas showing potential evidence of persistent transmission. Conclusions/Significance: This is the largest scale up of TAS surveillance activities reported in any of the 73 LF endemic countries in the world. Bangladesh is now considered to have very low or no risk of LF infection after 15 years of programmatic activities, and is on track to meet elimination targets. However, it will be essential that the LF Programme continues to develop and maintain a comprehensive surveillance strategy that is integrated into the health infrastructure and ongoing programmes to ensure cost-effectiveness and sustainability. [ABSTRACT FROM AUTHOR]

Current control strategies for onchocerciasis and lymphatic filariasis (LF) rely on prolonged yearly or twice-yearly mass administration of microfilaricidal drugs. Prospects for near-term elimination or eradication of these diseases would be improved by availability of a macrofilaricide that is highly effective in a short regimen. Flubendazole (FLBZ), a benzimidazole anthelmintic registered for control of human gastrointestinal nematode infections, is a potential candidate for this role. FLBZ has profound and potent macrofilaricidal effects in many experimental animal models of filariases and in one human trial for onchocerciasis after parental administration. Unfortunately, the marketed formulation of FLBZ provides very limited oral bioavailability and parenteral administration is required for macrofilaricidal efficacy. A new formulation that provided sufficient oral bioavailability could advance FLBZ as an effective treatment for onchocerciasis and LF. Short-term in vitro culture experiments in adult filariae have shown that FLBZ damages tissues required for reproduction and survival at pharmacologically relevant concentrations. The current study characterized the long-term effects of FLBZ on adult Brugia malayi by maintaining parasites in jirds for up to eight weeks following brief drug exposure (6–24 hr) to pharmacologically relevant concentrations (100 nM—10 μM) in culture. Morphological damage following exposure to FLBZ was observed prominently in developing embryos and was accompanied by a decrease in microfilarial output at 4 weeks post-exposure. Although FLBZ exposure clearly damaged the parasites, exposed worms recovered and were viable 8 weeks after treatment. [ABSTRACT FROM AUTHOR]

The nematodes Wuchereria bancrofti and Brugia spp. infect over 120 million people worldwide, causing lymphedema, elephantiasis and hydrocele, collectively known as lymphatic filariasis. Most infected individuals appear to be asymptomatic, but many exhibit sub-clinical manifestations including the lymphangiectasia that likely contributes to the development of lymphedema and elephantiasis. As adult worm excretory-secretory products (ES) do not directly activate lymphatic endothelial cells (LEC), we investigated the role of monocyte/macrophage-derived soluble factors in the development of filarial lymphatic pathology. We analyzed the production of IL-8, IL-6 and VEGF-A by peripheral blood mononuclear cells (PBMC) from naïve donors following stimulation with filarial ES products. ES-stimulated PBMCs produced significantly more IL-8, IL-6 and VEGF-A compared to cells cultured in medium alone; CD14+ monocytes appear to be the primary producers of IL-8 and VEGF-A, but not IL-6. Furthermore, IL-8, IL-6 and VEGF-A induced in vitro tubule formation in LEC Matrigel cultures. Matrigel plugs supplemented with IL-8, IL-6, VEGF-A, or with supernatants from ES-stimulated PBMCs and implanted in vivo stimulated lymphangiogenesis. Collectively, these data support the hypothesis that monocytes/macrophages exposed to filarial ES products may modulate lymphatic function through the secretion of soluble factors that stimulate the vessel growth associated with the pathogenesis of filarial disease. [ABSTRACT FROM AUTHOR]

Introduction: A clinically significant endemic focus of onchocerciasis existing in Esmeraldas Province, coastal Ecuador has been under an ivermectin mass drug administration program since 1991. The main transmitting vector in this area is the voracious blackfly, Simulium exiguum. This paper describes the assessments made that support the decision to cease mass treatment. Methodology and Principle Findings: Thirty-five rounds of ivermectin treatment occurred between 1991–2009 with 29 of these carrying >85% coverage. Following the guidelines set by WHO for ceasing ivermectin distribution the impact on parasite transmission was measured in the two vector species by an O-150 PCR technique standard for assessing for the presence of Onchocerca volvulus. Up to seven collection sites in three major river systems were tested on four occasions between 1995 and 2008. The infectivity rates of 65.0 (CI 39–101) and 72.7 (CI 42–116) in 1995 dropped to zero at all seven collection sites by 2008. Assessment for the presence of antibodies against O. volvulus was made in 2001, 2006, 2007 and 2008 using standard ELISA assays for detecting anti-Ov16 antibodies. None of total of 1810 children aged 1–15 years (between 82 and 98% of children present in the surveyed villages) tested in the above years were found to be carrying antibodies to this antigen. These findings were the basis for the cessation of mass drug treatment with ivermectin in 2009. Significance: This fulfillment of the criteria for cessation of mass distribution of ivermectin in the only known endemic zone of onchocerciasis in Ecuador moves the country into the surveillance phase of official verification for national elimination of transmission of infection. These findings indicate that ivermectin given twice a year with greater than 85% of the community can move a program to the final stages of verification of transmission interruption. [ABSTRACT FROM AUTHOR]