Role of streptococcal infection in the acute pathology of lymphatic filariasis

Growing evidence suggest that secondary bacterial, mainly streptococcal, infections contribute significantly to recurrent episodes of acute adenolymphangitis (ADL) of filarial origin. We examined the role of group A streptococci in the progression of lymphedema in Polynesian patients with filariasis-related ADL (22 cases) or chronic pathology (10 cases), or with erysipela (10 patients) and, as controls, in 20 healthy adults. Antistreptolysin O (ASLO) and anti-streptodornase B (ASDB) titers were systematically determined in parallel to parasitological and biochemical tests. ASLO and ASDB assays were positive in 100% of erysipela, 75% of filarial ADL as compared to 50% of chronic pathology and 39% of healthy controls. Interestingly, by opposition to ASLO titers which were not significantly different between the four groups, ASDB titers were higher in ADL (p = 0.019) and erysipela (p = 0.002) than in controls. These results support the hypothesis that recurrent streptococcal infections may have an important role in the pathogenesis of ADL in lymphatic filariasis.     

Mapping of lymphatic filariasis in Nepal

BACKGROUND: Human infection with Wuchereria bancrofti causes a disabling parasitic disease known as lymphatic filariasis, which is a major public health and socio-economic problem in many parts of the world. At the onset of the study, little was known of the distribution of filariasis and its current importance as a public health problem in Nepal. METHODS: Epidemiological mapping was undertaken to determine the prevalence of infection by Wuchereria bancrofti in 37 districts of Nepal between July to December 2001. The study population above 15 years of age was selected, and the immunochromatographic test (ICT Filariasis) was used to screen for circulating filarial antigen (CFA). RESULTS: The overall prevalence of lymphatic filariasis from a 4,488-sample population was 13% and 33/37 districts were found to be endemic. On the basis of geographical data, the highest number of cases was found at altitudes between 500-700 m; however, a substantial number of infected individuals were found in the highly populated Kathmandu valley, at altitudes between 900-1,500 metres where transmission appears to take place. Prevalence rates above 20% were found in 11 districts (with the highest rate of 40%), 6-19% were found in 15 districts, and 0.1-5% were in 7 districts.Information on people's knowledge, attitudes and behaviour towards filariasis was also collected by means of a structured questionnaire, which is presented and discussed in the study. CONCLUSIONS: This is the most extensive study of lymphatic filariasis undertaken to date in Nepal. The study indicates that the prevalence of infection is far greater that was previously reported and that lymphatic filariasis should be a much higher health priority than currently given.     

Diagnosis and treatment of lymphatic filariasis

The lymphatic filariases, Wuchereria bancrofti, Brugia malayi, and B. timori, infect nearly 100 million people throughout the tropics, but mainly in Africa and southeast Asia. Over 900 million people live in endemic, areas at risk to the infection. The filarial parasites reproduce slowly, whereas their mosquito vectors are quickly-reproducing opportunists. Thus, although vector control can reduce the risk of transmission, the parasite itself would seem a more vulnerable target for prolonged attack. In this article, Felix Partono discusses the clinical diagnosis of f lariasis and argues that the disease can be effectively controlled by attacking the parasites in infected communities, using diethyl-carbamazine (DEC) as the drug of choice.     

Towards elimination of lymphatic filariasis in India

The global initiatives to eliminate lymphatic filariasis as a public health problem by the year 2020 have generated a great deal of debate in India, the largest endemic country. This has led to a shift in the focus from control to elimination of the disease. Although the campaign to eliminate filariasis has begun, much more needs to be done. Several recent research studies have provided an insight into various operational issues and prospects of elimination of lymphatic filariasis. In this article, the current scenario, recent research results, logistics and the prospects of eliminating lymphatic filariasis in India will be discussed.     

The economic burden of lymphatic filariasis in India

Lymphatic filariasis affects 119 million people living in 73 countries, with India accounting for 40% of the global prevalence of infection. Despite its debilitating effects, lymphatic filariasis is given very low control priority. One of the reasons for this is paucity of information on the economic burden of the disease. Recent studies in rural areas of south India have shown that the treatment costs and loss of work time due to the disease are considerable. Based on the results of these studies, Kapa Ramaiah et al. here estimate the annual economic loss because of lymphatic filariasis for India and discuss the implications of their findings.     

Mass drug treatment for lymphatic filariasis and onchocerciasis

This review summarizes the progress towards control of lymphatic filariasis (LF) and onchocerciasis, focussing on the impact of mass drug administration (MDA) programmes, in particular those that have developed following the donation of ivermectin and albendazole. The contrasting strategies and objectives of the different programmes are compared, and the impact on transmission, clinical disease and public health assessed. The constraints on programme success are: (i) the absence of a macrofilaricide, which can be used in a public health context; (ii) the sustainability of high coverage of ivermectin over many years in onchocerciasis control; and (iii) the problem of treatment in areas where Loa loa (tropical eye worm) is co-endemic with onchocerciasis because of the rare severe adverse events. LF programmes are expanding rapidly in over 30 countries, where circa 60 million people received treatments in 2002. No serious adverse events have been associated with MDAs for LF elimination. Research on new approaches to treatment using antibiotics are showing promising results in pilot settings because doxycyline has been shown to have long-term embryostatic effects and sustained reductions of microfilaria loads in onchocerciasis and bancroftian filariasis.     

Achievements and challenges of lymphatic filariasis elimination in Sierra Leone

BackgroundLymphatic filariasis (LF) is targeted for elimination in Sierra Leone. Epidemiological coverage of mass drug administration (MDA) with ivermectin and albendazole had been reported >65% in all 12 districts annually. Eight districts qualified to implement transmission assessment survey (TAS) in 2013 but were deferred until 2017 due to the Ebola outbreak (2014–2016). In 2017, four districts qualified for conducting a repeat pre-TAS after completing three more rounds of MDA and the final two districts were also eligible to implement a pre-TAS.Methodology/Principal findingsFor TAS, eight districts were surveyed as four evaluation units (EU). A school-based survey was conducted in children aged 6–7 years from 30 clusters per EU. For pre-TAS, one sentinel and one spot check site per district (with 2 spot check sites in Bombali) were selected and 300–350 persons aged 5 years and above were selected. For both surveys, finger prick blood samples were tested using the Filariasis Test Strips (FTS).For TAS, 7,143 children aged 6–7 years were surveyed across four EUs, and positives were found in three EUs, all below the critical cut-off value for each EU. For the repeat pre-TAS/pre-TAS, 3,994 persons over five years of age were surveyed. The Western Area Urban had FTS prevalence of 0.7% in two sites and qualified for TAS, while other five districts had sites with antigenemia prevalence >2%: 9.1–25.9% in Bombali, 7.5–19.4% in Koinadugu, 6.1–2.9% in Kailahun, 1.3–2.3% in Kenema and 1.7% - 3.7% in Western Area Rural.Conclusions/SignificanceEight districts in Sierra Leone have successfully passed TAS1 and stopped MDA, with one more district qualified for conducting TAS1, a significant progress towards LF elimination. However, great challenges exist in eliminating LF from the whole country with repeated failure of pre-TAS in border districts. Effort needs to be intensified to achieve LF elimination.     

Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3

Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.     

Mass drug administration to eliminate lymphatic filariasis in India

Mass drug administration (MDA) to eliminate lymphatic filariasis is already in place in 32 out of 83 endemic countries. Expansion of the MDA programme to other countries and within large countries such as India is necessary to achieve the goal of lymphatic filariasis elimination. However, expansion and sustenance of the global campaign to eliminate lymphatic filariasis requires commitment and allocation of funds by governments and donor agencies. This could be achieved, at least to some extent, by highlighting the benefits of the programme in relation to costs. On the basis of various studies in south India, this article assesses the costs, effectiveness and economic and social benefits of the MDA programmes aimed at eliminating lymphatic filariasis.     

Immune dynamics in the pathogenesis of human lymphatic filariasis

Despite the longstanding recognition of the spectral nature of human disease due to lymphatic filariasis, immunologists interested in pathogenesis have mostly examined patients classified as being at either one extreme pole or the other. While the clinically asymptomatic individuals with microfilaremia who sit at one pole always have active infection, it has been difficult to define who else on the clinical spectrum is actively infected with living adult worms. In this review, David Freedman discusses how the ability to measure circulating filarial antigen in patient serum has advanced our ability to understand the immunopathogenesis of lymphatic filariasis by improving the precision of patient classification. Recent work suggests that the presence (or absence) of antigenemia, rather than overt clinical manifestations of disease, is closely associated with specific cytokine responses. A framework for patient classification based on these findings is proposed.     

The geographical distribution of lymphatic filariasis infection in Malawi

Background

Papua New Guinea is the only endemic country in the Western Pacific Region that has not yet introduced a countrywide programme to eliminate lymphatic filariasis. However, on Misima Island in Milne Bay Province, government and private sectors have collaborated to implement a pilot elimination programme. Although interim evaluation indicated that the programme has been parasitologically successful, an appreciation that sustainable health gains depend on understanding and accommodating local beliefs prompted this qualitative study.

Methods

We investigated Misima community members knowledge and attitudes about lymphatic filariasis and the elimination programme. A combination of focus groups and key informant interviews were used to explore participants perceptions of health; knowledge of the aetiology and symptoms of filariasis, elephantiasis and hydrocele; attitudes towards the disease and mass drug distribution; and the social structure and decision-making protocols within the villages.

Results

Focus group discussions proved inferior to key informant interviews for gathering rich data. Study participants did not consider lymphatic filariasis ("pom") a major health problem but were generally positive about mass drug administration campaigns. A variety of conditions were frequently and incorrectly attributed to filariasis. Participants expressed the belief that individuals infected with filariasis always had visible manifestations of disease. A common misconception was that taking drugs during campaigns provided long-term immunity against disease. The role of mosquito vectors in transmission was not generally appreciated and certain clinical presentations, particularly hydrocele, were associated with supernatural forces. Multiple adverse events were associated with mass drug administration campaigns and most study participants mentioned community members who did not participate in campaigns.

Conclusion

Important issues requiring educational intervention and elimination activity modification in the Misima region were identified during this study. Research outcomes should assist Papua New Guinea in developing and implementing a national elimination strategy and inform discussions regarding the appropriateness of current elimination strategies.     

Albendazole sulphoxide concentrations in plasma of endemic normals from a lymphatic filariasis endemic region using liquid chromatography

A simple and sensitive reversed-phase isocratic HPLC method for the determination of albendazole and its metabolites has been developed. The mobile phase consisting of acetonitrile-water-perchloric acid (70%) (30:110:0.06 (v/v/v)) was pumped at a flow rate of 0.80 ml/min on a 5 microm, reverse phase, Discovery RPamide C16 column with UV detection at 290 nm. The calibration graphs were linear in the range of 0.05- 1 microg/ml for albendazole, albendazole sulphoxide and albendazole sulphone. The limit of quantification was 50 ng/ml for albendazole, 25 ng/ml for albendazole sulphoxide and 30 ng/ml for albendazole sulphone. The within-day and day-to-day coefficient of variation averaged 4.98 and 6.95% for albendazole, 3.83 and 6.83% for albendazole sulphoxide and 3.44 and 5.51% for albendazole sulphone, respectively. The mean extraction recoveries of albendazole, albendazole sulphoxide and albendazole sulphone were 79.25, 93.03 and 88.78%, respectively. The method was applied to determine the plasma levels of albendazole sulphoxide in endemic normals administered with albendazole during pharmacokinetic studies.     

Increased calcium intake reduces plasma cholesterol and improves vasorelaxation in experimental renal failure

Chronic renal failure (CRF) is associated with abnormal lipid metabolism and high prevalence of vascular complications. Calcium salts are commonly used in CRF as phosphate binders. Increased calcium intake may also lower plasma cholesterol and beneficially influence vascular tone. Therefore, we investigated the influence of increasing dietary calcium from 0.3% to 3.0% for 8 wk after 5/6 nephrectomy (NTX) on plasma cholesterol and mesenteric resistance vessel tone in male Sprague-Dawley rats. The groups were Sham, Sham-Calcium, NTX, and NTX-Calcium (n = 10-11). Blood pressure was modestly elevated after NTX, whereas the plasma creatinine, urea nitrogen, phosphate, and parathyroid hormone levels were clearly increased. The high-calcium diet suppressed plasma phosphate and parathyroid hormone but was without effect on blood pressure. The NTX resulted in 1.6-fold elevation in plasma total cholesterol and 40% reduction in high density-to-low density lipoprotein ratio (HDL/LDL). However, the lipid profile in NTX rats on the high-calcium diet did not differ from sham-operated controls. The endothelium-mediated relaxations induced by acetylcholine were impaired in NTX rats, whereas the response was normalized by a high-calcium diet. No differences in vasorelaxations by the endothelium-independent vasodilator nitroprusside were detected. In conclusion, improved vasorelaxation after a high-calcium diet could be due to reduced plasma total cholesterol and ameliorated HDL/LDL ratio, although decreased plasma phosphate and parathyroid hormone may also play a significant role in the vascular effects of increased calcium intake.