A model for the dynamics of human lymphatic filariasis

In this paper, Bryan Gren fell, Edwin Michael and David Denham review the appropriateness of feline filariasis as a model of the population dynamics of human lymphatic filarial infection and disease. Because of the longevity of infection and our inability to measure the adult parasite population in humans, research in filariasis is particularly dependent on the use of laboratory animal models. We demonstrate that Brugia pahangi infection patterns in the cat closely parallel those of Brugia and Wuchereria in humans. Although primary infections in 'susceptible' cats are long-lived, repeatedly infected animals show evidence of concomitant immunity which prevents the establishment of later cohorts of infective larvae. Furthermore, there is some evidence from macro filarial length distributions of 'stunting' of adult worms during long-term repeat infections. Cats can also show an 'acute' response that spontaneously eliminates infections, and this appears to be due to a combination of intrinsic and dynamic mechanisms. As in humans, pathology in cat filariasis develops as a sequel to the asymptomatic microfilaremic state, largely as a result of re-expression of immunity. The relationship between macro filarial burdens and microfilariae in blood is positive but portrays a high degree of variability. The cat model provides an important tool for elucidating the relationships between infection, immunity and disease dynamics in lymphatic filariasis, and we conclude by suggesting directions for further work in this area.     

Animal models for the study of immunity in human filariasis

A major challenge to the development of vaccines against human lymphatic filariasis and onchocerciasis is to direct the immune response toward elimination of the early, prepathogenic larval stages and away from responses that mediate pathology. In this review, James Lok and David Abraham discuss the various animal models that have been used to investigate the pathways leading to immunity, immunological tolerance and chronic pathology in these diseases. Owing to the strict host specificities of the human-dwelling filariae, no single model serves to duplicate exactly all these aspects. Nevertheless, it has been possible to demonstrate a protective immune response invoked by and directed against incoming third-stage larvae of both lymphatic and skin-dwelling filariae. The fact that subsets of the sequelae of human filarial infection can be duplicated in animal systems should also aid in unravelling the mechanisms determining the course of infection and in ensuring that vaccine candidates do not produce an inappropriate immunopathological response. A proposed scheme for using animal models in screening candidates for a vaccine against Onchocerca volvulus is presented.     

Brugia malayi Asparaginyl - tRNA Synthetase Stimulates Endothelial Cell Proliferation,Vasodilation and Angiogenesis

A hallmark of chronic infection with lymphatic filarial parasites is the development of lymphatic disease which often results in permanent vasodilation and lymphedema, but all of the mechanisms by which filarial parasites induce pathology are not known. Prior work showed that the asparaginyl-tRNA synthetase (BmAsnRS) of Brugia malayi, an etiological agent of lymphatic filariasis, acts as a physiocrine that binds specifically to interleukin-8 (IL-8) chemokine receptors. Endothelial cells are one of the many cell types that express IL-8 receptors. IL-8 also has been reported previously to induce angiogenesis and vasodilation, however, the effect of BmAsnRS on endothelial cells has not been reported. Therefore, we tested the hypothesis that BmAsnRS might produce physiological changes in endothelial by studying the in vitro effects of BmAsnRS using a human umbilical vein cell line EA.hy926 and six different endothelial cell assays. Our results demonstrated that BmAsnRS produces consistent and statistically significant effects on endothelial cells that are identical to the effects of VEGF, vascular endothelial growth factor. This study supports the idea that new drugs or immunotherapies that counteract the adverse effects of parasite-derived physiocrines may prevent or ameliorate the vascular pathology observed in patients with lymphatic filariasis.     

Global eradication of lymphatic filariasis: the value of chronic disease control in parasite elimination programmes

The ultimate goal of the global programme against lymphatic filariasis is eradication through irrevocable cessation of transmission using 4 to 6 years of annual single dose mass drug administration. The costs of eradication, managerial impediments to executing national control programmes, and scientific uncertainty about transmission endpoints, are challenges to the success of this effort, especially in areas of high endemicity where financial resources are limited. We used a combined analysis of empirical community data describing the association between infection and chronic disease prevalence, mathematical modelling, and economic analyses to identify and evaluate the feasibility of setting an infection target level at which the chronic pathology attributable to lymphatic filariasis--lymphoedema of the extremities and hydroceles--becomes negligible in the face of continuing transmission as a first stage option in achieving the elimination of this parasitic disease. The results show that microfilaria prevalences below a threshold of 3.55% at a blood sampling volume of 1 ml could constitute readily achievable and sustainable targets to control lymphatic filarial disease. They also show that as a result of the high marginal cost of curing the last few individuals to achieve elimination, maximal benefits can occur at this threshold. Indeed, a key finding from our coupled economic and epidemiological analysis is that when initial uncertainty regarding eradication occurs and prospects for resolving this uncertainty over time exist, it is economically beneficial to adopt a flexible, sequential, eradication strategy based on controlling chronic disease initially.     

Epidemiology and immunopathology of bancroftian filariasis

Human lymphatic filariasis affects 120 million people worldwide. Although the disease is considered to be potentially erradicable by the World Health Organization, comprehensive studies on epidemiological aspects as well as mechanisms of pathology development are still premature. The following review summarizes currently available data on these topics and ends by discussing the latest control strategies.     

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.     

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.     

Kinetics of T cell cytokine gene expression in gerbils after a primary subcutaneous Brugia pahangi infection

The majority of patients infected with lymphatic filariae are microfilaremic but tend to manifest little obvious pathology because of the infections. Data collected from the Mongolian gerbil-Brugia spp. model for human lymphatic filariasis suggest this experimental animal model system most closely represents this patient group and will be useful in studying immunological parameters associated with chronic infections. This article reports the quantitation of interleukin (IL)-4, IL-5, IL-10, IL-13, and interferon (IFN)-gamma messenger RNA (mRNA) in gerbils after a primary subcutaneous infection with Brugia pahangi. Chronically infected gerbils showed elevated IL-4 in all tissues, compared with earlier time points, linking this Th2 cytokine to the downregulation of responsiveness, which develops in gerbils and humans. Both IL-5 and IL-13 mRNA expression were transient in all tissues. The peak in IL-5 at 14-28 days postinfection reflects the peak of peripheral eosinophilia observed in B. pahangi-infected gerbils. Little IFN-gamma mRNA was reported from chronically infected gerbils. The data collected thus far suggest that the expression profile of many of the measured cytokines in B. pahangi-infected gerbils reflects what is seen in an important subset of humans infected with lymphatic filariae, the microfilaremic, asymptomatic patient.     

Spatial modelling of individual-level parasite counts using the negative binomial distribution

We present a spatial model for the mean and correlation of highly dispersed count data, and apply it to individual-level counts of the nematode Wuchereria bancrofti, a parasite of humans which causes the disease lymphatic filariasis. Our model uses the negative binomial distribution, whose shape parameter is a convenient index of over-dispersion. Spatial association is quantified in terms of a characteristic length, which has an intuitive interpretation as the distance over which correlation decreases by half. Demographic surveillance and mapping enable us to include individual-level covariates such as age and sex. We discuss the distinctive features of our model and interpret the results in terms of the epidemiology of lymphatic filariasis and possible implications for control programmes.     

The Elimination of Lymphatic Filariasis: A Strategy for Poverty Alleviation and Sustainable Development - Perspectives from the Philippines

BACKGROUND: Within the Philippines areas endemic for lymphatic filariasis are in regions with the highest incidence of poverty. Out of a total of 79 provinces, 39 have a higher poverty incidence than the national average and 30 of these 39 provinces are endemic for lymphatic filariasis. DISCUSSION: Recognizing that provinces endemic for lymphatic filariasis (LF) are also the poorest provinces, the elimination of lymphatic filariasis in these areas presents significant opportunities to reduce poverty and inequalities in health. The implementation of an effective national programme for the elimination of lymphatic filariasis will provide means for sustainable development at national, local and community levels. SUMMARY: The elimination of lymphatic filariasis as a public health problem is a 20-year strategic plan for the world community, with the vision of all endemic communities free of transmission of lymphatic filariasis by 2020 and with the commitment to ensure the delivery of quality technologies and human services to eliminate lymphatic filariasis worldwide through a multi-stakeholder global alliance of all endemic countries. This global goal of elimination of lymphatic filariasis is a significant opportunity for partnerships - a world with less poverty through sustainable development and free from the scourge of lymphatic filariasis.     

Development of antigen detection ELISA for the diagnosis of brugian and bancroftian filariasis using antibodies to recombinant filarial antigens Bm-SXP-1 and Wb-SXP-1

Antibodies specific to recombinant filarial antigens Wb-SXP-1 and Bm-SXP-1 have been used to develop a sandwich ELISA for the detection of circulating filarial antigen (CFA) in sera from patients with lymphatic filariasis caused by Wuchereria bancrofti of Brugia malayi. In patients with W. bancrofti infections, a high proportion of microfilaria (mf) positive (MF) and low proportions of patients with chronic pathology (CP) and endemic normals (EN) showed the presence of CFA. Similarly in patients with brugian infections a high proportion of mf positive individuals contained CFA while none of the patients with chronic pathology or endemic normals showed the presence of CFA. Sera from patients with other parasitic infections (OPI) like O. volvulus, Loa loa, Ascaris lumbricoides and from individuals residing in areas non-endemic to filariasis did not exhibit any reactivity. This assay shows promise for the detection of microfilaremic infections in lymphatic filariasis and its usefulness as a diagnostic tool especially in B. malayi infections, needs to be further evaluated.     

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.     

Proliferative responses of Brugia malayi TPX-1 and its epitopic peptide(29-43) in an endemic population of human lymphatic filariasis

Although the antioxidant thioredoxin peroxidase (TPX) is a putative target exploited in vaccine studies of lymphatic filariasis, the high sequence homology with host peroxiredoxins remains a great concern. The emergence of immunomics offers a powerful tool for novel vaccine design. Further, due to the cellular hypo-response in filariasis, analysis of T epitope repertoire becomes imperative in disease control. Here, we report the cellular responses of filarial TPX-1 and the identification of T epitope (29-43) in the host non-homologous region. The strong proliferative responses induced by the peptide mimetic in mice splenocytes and human PBMC's prove the existence of T epitope recognized in endemic population.     

Comparison of Three Quality of Life Instruments in Lymphatic Filariasis: DLQI,WHODAS 2.0, and LFSQQ

Background

The Global Program to Eliminate Lymphatic Filariasis aims to interrupt transmission of lymphatic filariasis and manage morbidity in people currently living with the disease. A component of morbidity management is improving health-related quality of life (HRQoL) in patients. Measurement of HRQoL in current management programs is varied because of the lack of a standard HRQoL tool for use in the lymphatic filariasis population.

Methodology/Principal Findings

In this study, the psychometric properties of three health status measures were compared when used in a group of lymphatic filariasis patients and healthy controls. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), the Dermatology Life Quality Index (DLQI), and the Lymphatic Filariasis Quality of Life Questionnaire (LFSQQ) were administered to 36 stage II and stage III lymphatic filariasis subjects and 36 age and sex matched controls in Kerala, India. All three tools yielded missing value rates lower than 10%, suggesting high feasibility. Highest internal consistency was seen in the LFSQQ (α = 0.97). Discriminant validity analysis demonstrated that HRQoL was significantly lower in the LF group than in controls for the WHODAS 2.0, DLQI, and LFSQQ, but total HRQoL scores did not differ between stage II and stage III lymphedema subjects. The LFSQQ total score correlated most strongly with the WHODAS 2.0 (r = 0.91, p<0.001) and DLQI (r = 0.81, p<0.001).

Conclusions/Significance

The WHODAS 2.0, DLQI, and LFSQQ demonstrate acceptable feasibility, internal consistency, discriminate validity, and construct validity. Based on our psychometric analyses, the LFSQQ performs the best and is recommended for use in the lymphatic filariasis population.     

Spatio-Temporal Distribution of Dengue and Lymphatic Filariasis Vectors along an Altitudinal Transect in Central Nepal

Background

Rapidly increasing temperatures in the mountain region of Nepal and recent reports of dengue fever and lymphatic filariasis cases from mountainous areas of central Nepal prompted us to study the spatio-temporal distribution of the vectors of these two diseases along an altitudinal transect in central Nepal.

Methodology/Principal Findings

We conducted a longitudinal study in four distinct physiographical regions of central Nepal from September 2011 to February 2012. We used BG-Sentinel and CDC light traps to capture adult mosquitoes. We found the geographical distribution of the dengue virus vectors Aedes aegypti and Aedes albopictus along our study transect to extend up to 1,310 m altitude in the Middle Mountain region (Kathmandu). The distribution of the lymphatic filariasis vector Culex quinquefasciatus extended up to at least 2,100 m in the High Mountain region (Dhunche). Statistical analysis showed a significant effect of the physiographical region and month of collection on the abundance of A. aegypti and C. quinquefasciatus only. BG-Sentinel traps captured significantly higher numbers of A. aegypti than CDC light traps. The meteorological factors temperature, rainfall and relative humidity had significant effects on the mean number of A. aegypti per BG-Sentinel trap. Temperature and relative humidity were significant predictors of the number of C. quinquefasciatus per CDC light trap. Dengue fever and lymphatic filariasis cases had previously been reported from all vector positive areas except Dhunche which was free of known lymphatic filariasis cases.

Conclusions/Significance

We conclude that dengue virus vectors have already established stable populations up to the Middle Mountains of Nepal, supporting previous studies, and report for the first time the distribution of lymphatic filariasis vectors up to the High Mountain region of this country. The findings of our study should contribute to a better planning and scaling-up of mosquito-borne disease control programmes in the mountainous areas of Nepal.     

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.     

Clinical and pathological aspects of filarial lymphedema and its management

Lymphatic filariasis, transmitted by mosquitoes is the commonest cause of lymphedema in endemic countries. Among 120 million infected people in 83 countries, up to 16 million have lymphedema. Microfilariae ingested by mosquitoes grow into infective larvae. These larvae entering humans after infected mosquito bites grow in the lymphatics to adult worms that cause damage to lymphatics resulting in dilatation of lymph vessels. This earliest pathology is demonstrated in adults as well as in children, by ultrasonography, lymphoscintigraphy and histopathology studies. Once established, this damage was thought to be irreversible. This lymphatic damage predisposes to bacterial infection that causes recurrent acute attacks of dermato-lymphangio-adenitis in the affected limbs. Bacteria, mainly streptococci gain entry into the lymphatics through 'entry lesions' in skin, like interdigital fungal infections, injuries, eczema or similar causes that disrupt integrity of skin. Attacks of dermato-lymphangio-adenitis aggravates lymphatic damage causing lymphedema, which gets worse with repeated acute attacks. Elephantiasis is a late manifestation of lymphatic filariasis, which apart from limbs may involve genitalia or breasts. Lymphedema management includes use of antifilarial drugs in early stages, treatment and prevention of acute attacks through 'limb-hygiene', antibiotics and antifungals where indicated, and physical measures to reduce the swelling. In selected cases surgery is helpful.     

Geographic and ecologic heterogeneity in elimination thresholds for the major vector-borne helminthic disease,lymphatic filariasis

Background

Large-scale intervention programmes to control or eliminate several infectious diseases are currently underway worldwide. However, a major unresolved question remains: what are reasonable stopping points for these programmes? Recent theoretical work has highlighted how the ecological complexity and heterogeneity inherent in the transmission dynamics of macroparasites can result in elimination thresholds that vary between local communities. Here, we examine the empirical evidence for this hypothesis and its implications for the global elimination of the major macroparasitic disease, lymphatic filariasis, by applying a novel Bayesian computer simulation procedure to fit a dynamic model of the transmission of this parasitic disease to field data from nine villages with different ecological and geographical characteristics. Baseline lymphatic filariasis microfilarial age-prevalence data from three geographically distinct endemic regions, across which the major vector populations implicated in parasite transmission also differed, were used to fit and calibrate the relevant vector-specific filariasis transmission models. Ensembles of parasite elimination thresholds, generated using the Bayesian fitting procedure, were then examined in order to evaluate site-specific heterogeneity in the values of these thresholds and investigate the ecological factors that may underlie such variability

Results

We show that parameters of density-dependent functions relating to immunity, parasite establishment, as well as parasite aggregation, varied significantly between the nine different settings, contributing to locally varying filarial elimination thresholds. Parasite elimination thresholds predicted for the settings in which the mosquito vector is anopheline were, however, found to be higher than those in which the mosquito is culicine, substantiating our previous theoretical findings. The results also indicate that the probability that the parasite will be eliminated following six rounds of Mass Drug Administration with diethylcarbamazine and albendazole decreases markedly but non-linearly as the annual biting rate and parasite reproduction number increases.

Conclusions

This paper shows that specific ecological conditions in a community can lead to significant local differences in population dynamics and, consequently, elimination threshold estimates for lymphatic filariasis. These findings, and the difficulty of measuring the key local parameters (infection aggregation and acquired immunity) governing differences in transmission thresholds between communities, mean that it is necessary for us to rethink the utility of the current anticipatory approaches for achieving the elimination of filariasis both locally and globally.

     

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.