Lymphatic filariasis elimination in the Pacific: PacELF replicating Japanese success

Japan successfully eliminated lymphatic filariasis and other parasitic diseases through community-driven, integrated nationwide campaigns undertaken during the 1960s and 1970s. The campaigns also created a cadre of experienced clinicians, scientists and public health workers with excellent technical and operational knowledge and a positive attitude towards filariasis elimination. These factors, and the humanitarian desire to improve health in neighbouring nations, influenced Japan to support filariasis control efforts overseas, starting in the 1970s and continuing through to the inception of the Pacific Programme to Eliminate Lymphatic Filariasis (PacELF) in 1999. The unique community-driven, self-help approach of Japan to disease control and health improvement profoundly influenced the activities of PacELF. PacELF is demonstrating that the successful national disease-elimination model in Japan can be extended to the regional level.     

Lymphatic filariasis: what mice can tell us

Human lymphatic filariasis is a major tropical disease in which clinical manifestations range from asymptomatic microfilaraemia to chronic pathology. Investigative immunological research into this disease is hampered by the fact that mice are refractory to the full developmental cycle of this parasitic nematode. However, studies using either single-stage infections or immunocompromised mice have greatly added to our knowledge of the filarial-induced immune pathways leading to protective immunity, pathology and immunological tolerance. In this review, Rachel Lawrence discusses the recent advances in our understanding of the immunology of lymphatic filariasis using the mouse model.     

Lymphatic filariasis: new insights into an old disease

Lymphatic filariasis has afflicted people in the tropical areas of the world for thousands of years but even up to comparatively recent times it has been poorly understood and its importance under recognised. In the last 2 decades or so there has been a flurry of activity in filariasis research, which has provided new insights into the global problem of filariasis, the pathogenesis of filarial disease, diagnosis and control.     

Lymphatic filariasis and Brugia timori: prospects for elimination

Brugia timori is a pathogenic filarial nematode of humans, replacing the closely related species Brugia malayi on some islands in eastern Indonesia. Recent studies on Alor island show that, locally, B. timori is still of great public health importance, causing mainly acute filarial fever and chronic lymphedema. PCR-based assays to detect parasite DNA, in addition to assays for detecting specific antibodies that have been originally developed for B. malayi, can be used efficiently as diagnostic tools for B. timori. In the framework of the Global Program to Eliminate Lymphatic Filariasis, a single annual dose of diethylcarbamazine, in combination with albendazole, was found to reduce the prevalence and density of microfilaraemia persistently. Therefore, elimination of B. timori appears to be achievable.     

Lymphatic filariasis elimination in the Dominican Republic: History,progress, and remaining steps

Lymphatic filariasis (LF) is a mosquito-transmitted parasitic disease that is a leading cause of disability globally. The island of Hispaniola, which the Dominican Republic shares with Haiti, accounts for approximately 90% of LF cases in the Americas region. In 1998, the Dominican Ministry of Public Health created the Program to Eliminate Lymphatic Filariasis (PELF) with the goal of eliminating LF transmission by 2020. Baseline mapping revealed 19 (12% of total) endemic municipalities clustered into three geographic foci (Southwest, La Ciénaga and East), with a total at-risk population of 262,395 people. Beginning in 2002, PELF sequentially implemented mass drug administration (MDA) in these foci using albendazole and diethylcarbamazine (DEC). In total, 1,174,050 treatments were given over three to five annual rounds of house-to-house MDA per focus with a median coverage of 81.7% (range 67.4%–92.2%). By 2018, LF antigen prevalence was less than 2% in all foci, thus meeting criteria to stop MDA and begin post-treatment surveillance (PTS). This success has been achieved against a shifting landscape of limited domestic funding, competing domestic public health priorities, and sporadic external donor support. Remaining steps include the need to scale-up morbidity management and disability prevention services for LF and to continue PTS until LF transmission is interrupted across Hispaniola.     

Lymphatic filariasis in Papua New Guinea: interdisciplinary research on a national health problem

Bancroftian filariasis is a major public health problem in Papua New Guinea, where the level of transmission by the mosquito vector, human infection rates and clinical morbidity are among the highest in the world. Coordinated research efforts within the country, involving the disciplines of epidemiology, vector biology, immunology and genetics, have led to new insights into the ecology and pathogenesis of human lymphatic filariasis. Recent work using this knowledge base should be helpful in assessing local and global strategies aimed at eliminating Wuchereria bancrofti and in guiding research that will facilitate achievement of this goal.     

Lymphatic filariasis: a method to identify subclinical lower limb change in PNG adolescents

Lymphedema related to lymphatic filariasis (LF) is a disabling condition that commonly manifests in adolescence. Fifty-three adolescents, 25 LF infected and 28 LF non-infected, in age and sex-matched groups, using the Binax ICT rapid card test for filarial antigen were recruited to the study. None of the participants had overt signs of lymphedema. Lymphedema assessment measures were used to assess lower limb tissue compressibility (tonometry), limb circumference (tape measure), intra- and extra-cellular fluid distribution (bioimpedance) and joint range of motion (goniometry). The mean tonometric measurements from the left, right, and dominant posterior thighs were significantly larger in participants with LF compared to participants who had tested negative for LF (p = 0.005, p = 0.004, and p = 0.003, respectively) indicating increased tissue compressibility in those adolescents with LF. ROC curve analysis to define optimal cut-off of the tonometry measurements indicated that at 3.5, sensitivity of this potential screening test is 100% (95%-CI = 86.3%, 100%) and specificity is 21.4% (95%-CI = 8.3%, 41.0%). It is proposed that this cut-off can be used to indicate tissue change characteristic of LF in an at-risk population of PNG adolescents. Further longitudinal research is required to establish if all those with tissue change subsequently develop lymphedema. However, thigh tonometry to identify early tissue change in LF positive adolescents may enable early intervention to minimize progression of lymphedema and prioritization of limited resources to those at greatest risk of developing lifetime morbidity.     

Lymphatic filariasis in children: clinical features, infection burdens and future prospects for elimination

Lymphatic filariasis (LF), a common parasitic infection in tropical countries, causes lymphoedema of limbs, hydrocele and acute attacks of dermato-lymphangio-adenitis. Recent advances in diagnosis have helped to recognize that LF infection is often acquired in childhood. Newly available diagnostic techniques like sensitive antigen and antibody assays, Doppler ultrasonography and lymphoscintigraphy have helped to understand the subclinical pathology caused by this infection, which was hitherto generally believed to be irreversible. Recent studies indicate that drugs used in the mass drug administration (MDA) programme under GPELF are capable of reversing the sub-clinical lymphatic damage in children and provide benefits other than interruption of transmission. Albendazole and ivermectin used in MDA are effective against soil-transmitted helminthic infections common in children in LF endemic areas. Thus MDA had other 'beyond LF' benefits in treated children including increased appetite, weight gain, greater learning ability and concentration, better school attendance and prevention of anaemia. MDA should no longer be viewed as a measure for interrupting transmission alone. Recent findings of reversibility of early lymphatic pathology in treated children indicate that both MDA and 'foot-hygiene' measures are effective strategies in preventing and managing morbidity. Programme managers should effectively utilize this information to strengthen their advocacy efforts to achieve high and sustainable coverage in MDA.     

Lymphatic filariasis epidemiology in Samoa in 2018: Geographic clustering and higher antigen prevalence in older age groups

BackgroundSamoa conducted eight nationwide rounds of mass drug administration (MDA) for lymphatic filariasis (LF) between 1999 and 2011, and two targeted rounds in 2015 and 2017 in North West Upolu (NWU), one of three evaluation units (EUs). Transmission Assessment Surveys (TAS) were conducted in 2013 (failed in NWU) and 2017 (all three EUs failed). In 2018, Samoa was the first in the world to distribute nationwide triple-drug MDA using ivermectin, diethylcarbamazine, and albendazole. Surveillance and Monitoring to Eliminate LF and Scabies from Samoa (SaMELFS Samoa) is an operational research program designed to evaluate the effectiveness of triple-drug MDA on LF transmission and scabies prevalence in Samoa, and to compare the usefulness of different indicators of LF transmission. This paper reports results from the 2018 baseline survey and aims to i) investigate antigen (Ag) prevalence and spatial epidemiology, including geographic clustering; ii) compare Ag prevalence between two different age groups (5–9 years versus ≥10 years) as indicators of areas of ongoing transmission; and iii) assess the prevalence of limb lymphedema in those aged ≥15 years.MethodsA community-based cluster survey was conducted in 30 randomly selected and five purposively selected clusters (primary sampling units, PSUs), each comprising one or two villages. Participants were recruited through household surveys (age ≥5 years) and convenience surveys (age 5–9 years). Alere Filariasis Test Strips (FTS) were used to detect Ag, and prevalence was adjusted for survey design and standardized for age and gender. Adjusted Ag prevalence was estimated for each age group (5–9, ≥10, and all ages ≥5 years) for random and purposive PSUs, and by region. Intraclass correlation (ICC) was used to quantify clustering at regions, PSUs, and households.ResultsA total of 3940 persons were included (1942 children aged 5–9 years, 1998 persons aged ≥10 years). Adjusted Ag prevalence in all ages ≥5 years in randomly and purposively selected PSUs were 4.0% (95% CI 2.8–5.6%) and 10.0% (95% CI 7.4–13.4%), respectively. In random PSUs, Ag prevalence was lower in those aged 5–9 years (1.3%, 95% CI 0.8–2.1%) than ≥10 years (4.7%, 95% CI 3.1–7.0%), and poorly correlated at the PSU level (R-square = 0.1459). Adjusted Ag prevalence in PSUs ranged from 0% to 10.3% (95% CI 5.9–17.6%) in randomly selected and 3.8% (95% CI 1.3–10.8%) to 20.0% (95% CI 15.3–25.8%) in purposively selected PSUs. ICC for Ag-positive individuals was higher at households (0.46) compared to PSUs (0.18) and regions (0.01).ConclusionsOur study confirmed ongoing transmission of LF in Samoa, in accordance with the 2017 TAS results. Ag prevalence varied significantly between PSUs, and there was poor correlation between prevalence in 5–9 year-olds and older ages, who had threefold higher prevalence. Sampling older age groups would provide more accurate estimates of overall prevalence, and be more sensitive for identifying residual hotspots. Higher prevalence in purposively selected PSUs shows local knowledge can help identify at least some hotspots.     

Lymphatic filariasis in 2016 in American Samoa: Identifying clustering and hotspots using non-spatial and three spatial analytical methods

BackgroundAmerican Samoa completed seven rounds of mass drug administration from 2000–2006 as part of the Global Programme to Eliminate Lymphatic Filariasis (LF). However, resurgence was confirmed in 2016 through WHO-recommended school-based transmission assessment survey and a community-based survey. This paper uses data from the 2016 community survey to compare different spatial and non-spatial methods to characterise clustering and hotspots of LF.MethodNon-spatial clustering of infection markers (antigen [Ag], microfilaraemia [Mf], and antibodies (Ab [Wb123, Bm14, Bm33]) was assessed using intra-cluster correlation coefficients (ICC) at household and village levels. Spatial dependence, clustering and hotspots were examined using semivariograms, Kulldorf’s scan statistic and Getis-Ord Gi* statistics based on locations of surveyed households.ResultsThe survey included 2671 persons (750 households, 730 unique locations in 30 villages). ICCs were higher at household (0.20–0.69) than village levels (0.10–0.30) for all infection markers. Semivariograms identified significant spatial dependency for all markers (range 207–562 metres). Using Kulldorff’s scan statistic, significant spatial clustering was observed in two previously known locations of ongoing transmission: for all markers in Fagali’i and all Abs in Vaitogi. Getis-Ord Gi* statistic identified hotspots of all markers in Fagali’i, Vaitogi, and Pago Pago-Anua areas. A hotspot of Ag and Wb123 Ab was identified around the villages of Nua-Seetaga-Asili. Bm14 and Bm33 Ab hotspots were seen in Maleimi and Vaitogi-Ili’ili-Tafuna.ConclusionOur study demonstrated the utility of different non-spatial and spatial methods for investigating clustering and hotspots, the benefits of using multiple infection markers, and the value of triangulating results between methods.     

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.     

Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs.     

Rehabilitation in the Philippines

The international community has perspective and experience that will freshen our approaches to rehabilitation. Martin Grabois, MD^*, editor of this special section, has gathered articles written by experts from other countries. The intention is to stimulate thought, discussion, and action—and to broaden horizons.