Lymphatic Filariasis In Africa Research Articles

Brugia malayi Glycoproteins Detected by the Filariasis Test Strip Antibody AD12.1.

Rapid and accurate prevalence mapping of lymphatic filariasis (LF) is necessary to eliminate this disfiguring and disabling neglected tropical disease. Unfortunately, rapid tests such as the filariasis test strip (FTS) for Wuchereria bancrofti, the causative agent of LF in Africa, can cross-react with antigens circulating in some persons infected by the African eye worm, Loa loa, rendering the test unreliable in eleven co-endemic nations. The intended target of the FTS is a heavily glycosylated W. bancrofti circulating filarial antigen (Wb-CFA). Previously, we determined that the FTS monoclonal antibody, AD12.1, which detects a carbohydrate epitope on Wb-CFA, also detects multiple L. loa proteins in cross-reactive sera from persons with loiasis. Since the carbohydrate epitope recognized by AD12.1 is present on glycoproteins of other parasitic nematodes, including Brugia species, it is unclear why reactive glycoproteins are not detected in infections with other filarial parasites. To gain a better understanding of the proteins recognized by the FTS diagnostic antibody, we used proteomics and lectin array technology to characterize filarial glycoproteins that are bound by the AD12.1 antibody using Brugia malayi as a model. Distinct but overlapping sets of AD12 glycoproteins were identified from somatic and excretory/secretory worm products. One of the identified proteins, Bm18019 was confirmed as a secreted AD12-reactive glycoprotein by in-gel proteomics and immunoassays. Based on lectin binding patterns, Brugia AD12-reactive glycoproteins express glycans including core fucose, galactose, N-acetylglucosamine and galactose (β1-3)N-acetylgalactosamine in addition to the epitope recognized by AD12.1. None of the lectins that bound B. malayi AD12 glycoproteins had affinity for the Wb-CFA, highlighting a key difference between it and other AD12 glycoproteins. B. malayi somatic and excretory/secretory proteins are similar to L. loa antigens found in FTS-positive human sera, bolstering the hypothesis that circulating L. loa AD12 antigens result from worm tissue damage or death. The difference in glycan and protein composition between the Wb-CFA and other AD12 glycoproteins can be used to differentiate LF from cross-reactive loiasis.

English

Wuchereria bancrofti has been reported to cause 90% of all cases of lymphatic filariasis in Africa. wolbachia endosymbiot infect a wide range of insects and nematodes. This study was conducted in 48 settlements (8 from each division). A total of 2003 mosquitoes was pooled into 120 clusters from the 48 settlements in The Gambia. Polymerase chain reaction (PCR) was used to detect the presence of Wolbachia and filarial nematode and further differentiate Wolbachia into super groups among the positive samples. The level of association between Wolbachia and the genera of anthropophilic mosquitoes in The Gambia was also determined. Microscopic results showed 64.9% Anopheles, 32.0% Culex, 3.0% Aedes. PCR showed that, 34.17% of Wolbachia in the mosquito obtained varied among the three mosquito genera, with highest being among Anopheles. Only Wolbachia super group B was identified in Culex and Aedes. The purpose of this study carried out in The Gambia was to describe the most common mosquito species and to identify, by means of PCR, their association with the Wolbachia bacteria and the presence of nematodes responsible for filiariasis, in order to understand the role that this bacterium plays in the chain of filarial transmission. Key words: Wuchereria bancrofti, Filariasis, Anopheles gambiae, Culex quinquefasciatus, elephantiasis.

Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d'Ivoire: An Open-label Randomized Controlled Trial.

BackgroundImproved drug regimens are needed to accelerate elimination of lymphatic filariasis in Africa. This study determined whether a single co-administered dose of ivermectin plus diethylcarbamazine plus albendazole [IDA] is noninferior to standard 3 annual doses of ivermectin plus albendazole (IA) used in many LF-endemic areas of Africa.MethodsTreatment-naive adults with Wuchereria bancrofti microfilaremia in Côte d’Ivoire were randomized to receive a single dose of IDA (n = 43) or 3 annual doses of IA (n = 52) in an open-label, single-blinded trial. The primary endpoint was the proportion of participants who were microfilaria (Mf) negative at 36 months. Secondary endpoints were Mf clearance at 6, 12, and 24 months; inactivation of adult worm nests; and safety.ResultsAt 36 months posttreatment with IDA, 18/33 (55%; 95% CI, 38–72%) cleared Mf versus 33/42 (79%; 67–91%) with IA (P = .045). At 6 and 12 months IDA was superior to IA in clearing Mf (89% [77–99%] and 71% [56–85%]), respectively, versus 34% (20–48%) and 26% (14–42%) (P < .001). IDA was equivalent to IA at 24 months (61% [45–77%] vs 54% [38–72%]; P = .53). IDA was superior to IA for inactivating adult worms at all time points. Both treatments were well tolerated, and there were no serious adverse events.ConclusionsA single dose of IDA was superior to 2 doses of IA in reducing the overall Mf burden by 24 months. Reinfection may have contributed to the lack of sustained clearance of Mf with IDA.Clinical Trials RegistrationNCT02974049.

Significant decline in lymphatic filariasis associated with nationwide scale-up of insecticide-treated nets in Zambia

Lymphatic filariasis (LF) is a mosquito-borne disease, broadly endemic in Zambia, and is targeted for elimination by mass drug administration (MDA) of albendazole and diethylcarbamazine citrate (DEC) to at-risk populations. Anopheline mosquitoes are primary vectors of LF in Africa, and it is possible that the significant scale-up of malaria vector control over the past decade may have also impacted LF transmission, and contributed to a decrease in prevalence in Zambia. We therefore aimed to examine the putative association between decreasing LF prevalence and increasing coverage of insecticide-treated mosquito nets (ITNs) for malaria vector control, by comparing LF mapping data collected between 2003–2005 and 2009–2011 to LF sentinel site prevalence data collected between 2012 and 2014, before any anti-LF MDA was started. The coverage of ITNs for malaria was quantified and compared for each site in relation to the dynamics of LF. We found a significant decrease in LF prevalence from the years 2003–2005 (11.5% CI95 6.6; 16.4) to 2012–2014 (0.6% CI95 0.03; 1.1); at the same time, there was a significant scale-up of ITNs across the country from 0.2% (CI95 0.0; 0.3) to 76.1% (CI95 71.4; 80.7) respectively. The creation and comparison of two linear models demonstrated that the geographical and temporal variation in ITN coverage was a better predictor of LF prevalence than year alone. Whilst a causal relationship between LF prevalence and ITN coverage cannot be proved, we propose that the scale-up of ITNs has helped to control Anopheles mosquito populations, which have in turn impacted on LF transmission significantly before the scale-up of MDA. This putative synergy with vector control has helped to put Zambia on track to meet national and global goals of LF elimination by 2020.

Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection.

Severe adverse reactions have been observed in individuals with Loa loa infection treated with either diethylcarbamazine (DEC), the drug of choice for loiasis, or ivermectin (IVM), which is used in mass drug administration programs for control of onchocerciasis and lymphatic filariasis in Africa. In this study, posttreatment clinical and immunologic reactions were compared following single-dose therapy with DEC or IVM to assess whether these reactions have the same underlying pathophysiology. Twelve patients with loiasis and microfilarial counts <2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 µg/kg). Clinical and laboratory assessments were performed at 4, 8, 24, 48, and 72 hours and 5, 7, 9, and 14 days posttreatment. Posttreatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours posttreatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum interleukin 5 levels and eosinophil activation, as assessed by surface expression of CD69 and serum levels of eosinophil granule proteins, were increased posttreatment in both groups. Despite differences in eosinophil and lymphocyte counts during the first 24 hours posttreatment, the overall pattern of hematologic and immunologic changes suggest that posttreatment reactions following DEC and IVM share a common pathophysiology. NCT01593722.

Reducing the population requiring interventions against lymphatic filariasis in Africa.

Reducing the population requiring interventions against lymphatic filariasis in Africa.

Predicting the current and future potential distributions of lymphatic filariasis in Africa using maximum entropy ecological niche modelling.

Modelling the spatial distributions of human parasite species is crucial to understanding the environmental determinants of infection as well as for guiding the planning of control programmes. Here, we use ecological niche modelling to map the current potential distribution of the macroparasitic disease, lymphatic filariasis (LF), in Africa, and to estimate how future changes in climate and population could affect its spread and burden across the continent. We used 508 community-specific infection presence data collated from the published literature in conjunction with five predictive environmental/climatic and demographic variables, and a maximum entropy niche modelling method to construct the first ecological niche maps describing potential distribution and burden of LF in Africa. We also ran the best-fit model against climate projections made by the HADCM3 and CCCMA models for 2050 under A2a and B2a scenarios to simulate the likely distribution of LF under future climate and population changes. We predict a broad geographic distribution of LF in Africa extending from the west to the east across the middle region of the continent, with high probabilities of occurrence in the Western Africa compared to large areas of medium probability interspersed with smaller areas of high probability in Central and Eastern Africa and in Madagascar. We uncovered complex relationships between predictor ecological niche variables and the probability of LF occurrence. We show for the first time that predicted climate change and population growth will expand both the range and risk of LF infection (and ultimately disease) in an endemic region. We estimate that populations at risk to LF may range from 543 and 804 million currently, and that this could rise to between 1.65 to 1.86 billion in the future depending on the climate scenario used and thresholds applied to signify infection presence.

Can coverage of schistosomiasis and soil transmitted helminthiasis control programmes targeting school-aged children be improved? New approaches

Control programmes generally use a school-based strategy of mass drug administration to reduce morbidity of schistosomiasis and soil-transmitted helminthiasis (STH) in school-aged populations. The success of school-based programmes depends on treatment coverage. The community-directed treatment (ComDT) approach has been implemented in the control of onchocerciasis and lymphatic filariasis in Africa and improves treatment coverage. This study compared the treatment coverage between the ComDT approach and the school-based treatment approach, where non-enrolled school-aged children were invited for treatment, in the control of schistosomiasis and STH among enrolled and non-enrolled school-aged children. Coverage during the first treatment round among enrolled children was similar for the two approaches (ComDT: 80.3% versus school: 82.1%, P=0.072). However, for the non-enrolled children the ComDT approach achieved a significantly higher coverage than the school-based approach (80.0 versus 59.2%, P<0.001). Similar treatment coverage levels were attained at the second treatment round. Again, equal levels of treatment coverage were found between the two approaches for the enrolled school-aged children, while the ComDT approach achieved a significantly higher coverage in the non-enrolled children. The results of this study showed that the ComDT approach can obtain significantly higher treatment coverage among the non-enrolled school-aged children compared to the school-based treatment approach for the control of schistosomiasis and STH.

Ivermectin resistance and overview of the Consortium for AnthelminticResistance SNPs

Ivermectin (IVM) has transformed nematode parasite control in veterinary medicineand the control of some nematode infections in humans, such as onchocerciasais,lymphatic filariasis in Africa and strongyloidiasis. Unfortunately, IVMresistance is now a serious problem for parasite control in livestock and thereis a concern about resistance development and spread in nematode parasites ofhumans. IVM is believed to act by opening glutamate-gated chloride channels andGABA-gated channels in invertebrate neurons or muscle cells, leading tohyperpolarisation of the cells and to an inhibitory paralysis. However, in thefilarial nematodes, it is not altogether clear that the effect of IVM isconfined to these actions or even whether these are the most important.Alterations in some ligand-gated ion channel (LGIC) receptor subunits may play arole in the mechanisms of IVM resistance in some nematodes, but the evidencethat changes in LGICs are the most important cause of IVM resistance innematodes is far from clear. What is evident is that IVM is an excellentsubstrate for some ATP-binding cassette transporters, IVM selects for changes inexpression levels of ABC transporters, such as P-glycoproteins, and that alteredlevels of some ABC transporters contribute to IVM resistance. In addition, thereis growing evidence that IVM selects on β-tubulin, at least in somenematodes. Based on these various mechanisms, which contribute to IVMresistance, it may become possible to develop panels of molecular markers forIVM resistance in different nematode parasites. In order to stimulate thedevelopment of such markers, an international Consortium for AnthelminticResistance SNPs (CARS) has been developed to help coordinate marker development,advance our knowledge of helminth biology and possibly assist with thedevelopment of new anthelmintic molecules.

Ivermectin: does P-glycoprotein play a role in neurotoxicity?

The macrocyclic lactone ivermectin (Mectizan®) is widely used for the control of human filarial infections, particularly as a donated product for onchocerciasis and lymphatic filariasis. In the case of control of lymphatic filariasis in Africa, it is used in combination with donated albendazole. In areas co-endemic for Onchocerciasis and Loa loa, serious adverse reactions have been observed in patients with apparently high microfilaria counts of Loa loa. Recent findings suggest that the severe central nervous system side effects seen in various vertebrates following ivermectin treatment may be due to an absence of, or functional deficiency in P-glycoprotein. P-glycoprotein is expressed in the apical membrane of brain capillary epithelial cells and is responsible for limiting the brain penetration of a range of compounds. Toxicity of ivermectin in some collie dogs may be explained by a 4-bp deletion mutation of the mdr1 gene resulting in a frame shift, generating stop codons that prematurely terminate synthesis of P-glycoprotein. Additionally, sub-populations of CF-1 identified as expressing reduced levels of P-glycoprotein exhibit increased toxicity to substrates of this transporter. Furthermore, while the traditional view of drug-drug interactions is alteration in drug clearance mediated through a change in hepatic drug metabolism, some of these changes may arise through competition for binding sites on P-glycoprotein in the blood-brain barrier, resulting in reduced extracellular efflux and enhanced CNS toxicity. In conclusion, P-glycoprotein is an integral component of the human blood brain barrier and plays a central role in limiting drug uptake into the brain. Altered expression or function of p-glycoprotein could conceivably allow elevation of brain concentrations of ivermectin and produce severe neurotoxicity. This might arise through a genetic polymorphism in p-glycoprotein or co-administration of ivermectin with a drug or foodstuff that might inhibit this efflux transporter.

The use of grid sampling methodology for rapid assessment of the distribution of bancroftian filariasis

The recent World Health Assembly Resolution to eliminate lymphatic filariasis as a public health problem once more brings to the fore the need for reliable data for the effective planning of disease control programmes. Most countries do not have data on the distribution of lymphatic filariasis and are therefore not in the position to initiate control programmes based on sound baseline data. We tested in Ghana in 1998–1999 a method for the Rapid Assessment of the Geographical Distribution of Bancroftian Filariasis (RAGFIL) that uses a spatial sampling grid with 50 km between sampled villages, rapid assessment surveys for filariasis prevalence in the sampled villages and spatial analysis to estimate the geographical distribution of filariasis throughout the study area. The prevalence contours obtained with the 50 × 50-km sampling grid were operationally similar to those obtained with a 25 × 25-km grid. The predicted prevalence was not statistically different from the sample survey prevalence in 57 independent villages and the 50 × 50-km grid appears adequate for rapid mapping of filariasis. For the purpose of filariasis mapping, the antigen test would seem a better diagnostic test than clinical examination for hydrocoele. We recommend that a regional approach to mapping be used because of the importance of cross-border foci as demonstrated by our findings from the north of Ghana. Application of the method will provide the minimal information required for effective planning of treatment programmes, and will facilitate estimation of the number of people to be treated. It will also help improve estimates of the number of people at risk and affected, and of the burden of disease due to lymphatic filariasis in Africa.

Mapping and estimating the population at risk from lymphatic filariasis in Africa

Lymphatic filariasis remains a major public health problem in Africa and is 1 of the World Health Organization's 6 diseases targeted for global eradication. However, no detailed maps of the geographical distribution of this disease exist, making it difficult to target control activities and quantify the population at risk. We hypothesized that the distribution of lymphatic filariasis is governed by climate. The climate at sites in Africa where surveys for lymphatic filariasis had taken place was characterized using computerized climate surfaces. Logistic regression analysis of the climate variables predicted with 76% accuracy whether sites had microfilaraemic patients or not. We used the logistic equation in a geographical information system to map risk of lymphatic filariasis infection across Africa, which compared favourably with expert opinion. Further validation with a quasi-independent data set showed that the model predicted correctly 88% of infected sites. A similar procedure was used to map risk of microfilaraemia in Egypt, where the dominant vector species differs from those in sub-Saharan Africa. By overlaying risk maps on a 1990 population grid, and adjusting for recent population increases, we estimate that around 420 million people will be exposed to this infection in Africa in the year 2000. This approach could be used to produce a sampling frame, based on estimated risk of microfilaraemia, for conducting filariasis surveys in countries that lack accurate distribution maps and thus save on costs.