Comparative Safety Surveillance of Triple (IDA) Versus Dual Therapy (DA) in Mass Drug Administration for Elimination of Lymphatic Filariasis in Kenya: A Cohort Event Monitoring Study.

INTRODUCTION: Dual diethylcarbamazine and albendazole (DA) therapy is the standard mass drug administration (MDA) regimen for lymphatic filariasis in Kenya. Following the recent World Health Organization recommendation, Kenya piloted triple therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) in MDA. OBJECTIVE: We conducted a community-based, observational, cohort event monitoring study to compare the types, frequency, severity, and predictors of adverse events following dual versus triple therapy in 20,421 eligible residents. METHODS: Residents in Kilifi (n = 10,010) and Mombasa counties (n = 10,411) received DA and IDA through MDA campaigns, respectively. Adverse events were actively monitored through house-to-house visits on days 1, 2, and 7 after MDA. Any clinical events reported before and after MDA were cross-checked and verified to differentiate pre-existing events from MDA-associated adverse events. RESULTS: Overall, 5807 and 3102 adverse events were reported by 2839 and 1621 individuals in the IDA and DA groups, respectively. The incidence of experiencing one or more adverse events was significantly higher (p < 0.0001) in the IDA group (27.3%; 95% confidence interval [CI] 26.4-28.2) than in the DA group (16.2%; 95% CI 15.5-16.9). Dizziness (15.9% vs 5.9%) and drowsiness (10.1% vs 2.6%) were the most common adverse events and significantly higher in the IDA group compared with the DA group (p < 0.0001). Most adverse events were mild or moderate with a few severe cases (IDA = 0.05%; 95% CI 0.35-0.78, DA = 0.03%; 95% CI 0.14-0.60). Female sex, obesity, taking three or more diethylcarbamazine or ivermectin tablets, and having pre-existing clinical symptoms were significant predictors of adverse events following IDA treatment. CONCLUSIONS: Ivermectin, diethylcarbamazine, and albendazole as a combination is as safe and well tolerated as DA to use in MDA campaigns with no serious life-threatening adverse events. Systemic mild-to-moderate adverse events with a few severe cases and transient adverse events are more common with IDA treatment than with DA treatment. Hence, integrating pharmacovigilance into a MDA program is recommended for the timely detection and management of adverse events.

Risk factors for lymphatic filariasis in two villages of the Democratic Republic of the Congo.

BACKGROUND: Little is known regarding risk factors for lymphatic filariasis (LF) in Central Africa. To expand on what is known, we studied the epidemiology of LF in two endemic villages in the Democratic Republic of the Congo. METHODS: Dependent variables were Wuchereria bancrofti antigenaemia detected with filarial test strips (FTS) and microfilaraemia detected by night blood smears. The following factors were investigated: sex, age, the use of bednets, the use of latrines, hunting, fishing and agricultural activities, history of treatment with anthelmintic drugs, overnight stays in the bush, population density, the number of household members, and distance to rivers. Mixed multivariate logistic regression models were used. RESULTS: Two hundred and fifty nine out of 820 (31.6%) of subjects aged ≥ 5 years had W. bancrofti antigenaemia and 11.8% (97/820) had microfilaraemia. Multivariable analysis of risk factors for antigenaemia demonstrated increased risk for males (aOR = 1.75, 95% CI: 1.20-2.53, P = 0.003), for older individuals (aOR = 9.12 in those aged > 35 years, 95% CI: 4.47-18.61, P < 0.001), for people not using bednets (aOR = 1.57, 95% CI: 1.06-2.33, P = 0.023), for farmers (aOR = 2.21, 95% CI: 1.25-3.90, P = 0.006), and for those who live close to a river (aOR = 2.78, 95% CI: 1.14-6.74, P = 0.024). Significant risk factors for microfilaraemia included age, male gender, overnight stay in the bush, and residence close to a river (aOR = 1.86, 2.01, 2.73; P = 0.011, 0.010, 0.041; for the three latter variables, respectively). People who reported having taken levamisole (n = 117) during the prior year had a significantly decreased risk of having filarial antigenaemia (aOR = 0.40, 95% CI: 0.21-0.76, P = 0.005). CONCLUSIONS: Age, sex, not using bednets, and occupation-dependent exposure to mosquitoes were important risk factors for infection with W. bancrofti in this study. The association with levamisole use suggests that the drug may have prevented filarial infections. Other results suggest that transmission often occurs outside of the village. This study provides interesting clues regarding the epidemiology of LF in Central Africa.

Single nucleotide polymorphisms in the angiogenic and lymphangiogenic pathways are associated with lymphedema caused by Wuchereria bancrofti.

BACKGROUND: Lymphedema (LE) is a chronic clinical manifestation of filarial nematode infections characterized by lymphatic dysfunction and subsequent accumulation of protein-rich fluid in the interstitial space-lymphatic filariasis. A number of studies have identified single nucleotide polymorphisms (SNPs) associated with primary and secondary LE. To assess SNPs associated with LE caused by lymphatic filariasis, a cross-sectional study of unrelated Ghanaian volunteers was designed to genotype SNPs in 285 LE patients as cases and 682 infected patients without pathology as controls. One hundred thirty-one SNPs in 64 genes were genotyped. The genes were selected based on their roles in inflammatory processes, angiogenesis/lymphangiogenesis, and cell differentiation during tumorigenesis. RESULTS: Genetic associations with nominal significance were identified for five SNPs in three genes: vascular endothelial growth factor receptor-3 (VEGFR-3) rs75614493, two SNPs in matrix metalloprotease-2 (MMP-2) rs1030868 and rs2241145, and two SNPs in carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) rs8110904 and rs8111171. Pathway analysis revealed an interplay of genes in the angiogenic/lymphangiogenic pathways. Plasma levels of both MMP-2 and CEACAM-1 were significantly higher in LE cases compared to controls. Functional characterization of the associated SNPs identified genotype GG of CEACAM-1 as the variant influencing the expression of plasma concentration, a novel finding observed in this study. CONCLUSION: The SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development.

Changes in Antibody Levels during and following an Episode of Acute Adenolymphangitis (ADL) among Lymphedema Patients in Léogâne, Haiti.

INTRODUCTION: Episodes of acute adenolymphangitis (ADL) are often the first clinical sign of lymphatic filariasis (LF). They are often accompanied by swelling of the affected limb, inflammation, fever, and general malaise and lead to the progression of lymphedema. Although ADL episodes have been studied for a century or more, questions still remain as to their etiology. We quantified antibody levels to pathogens that potentially contribute to ADL episodes during and after an episode among lymphedema patients in Léogâne, Haiti. We estimated the proportion of ADL episodes hypothesized to be attributed to specific pathogens. METHODS: We measured antibody levels to specific pathogens during and following an ADL episode among 41 lymphedema patients enrolled in a cohort study in Léogâne, Haiti. We calculated the absolute and relative changes in antibody levels between the ADL and convalescent time points. We calculated the proportion of episodes that demonstrated a two-fold increase in antibody level for several bacterial, fungal, and filarial pathogens. RESULTS: Our results showed the greatest proportion of two-fold changes in antibody levels for the carbohydrate antigen Streptococcus group A, followed by IgG2 responses to a soluble filarial antigen (BpG2), Streptococcal Pyrogenic Exotoxin B, and an antigen for the fungal pathogen Candida. When comparing the median antibody level during the ADL episode to the median antibody level at the convalescent time point, only the antigens for Pseudomonas species (P-value = 0.0351) and Streptolysin O (P-value = 0.0074) showed a significant result. CONCLUSION: Although our results are limited by the lack of a control group and few antibody responses, they provide some evidence for infection with Streptococcus A as a potential contributing factor to ADL episodes. Our results add to the current evidence and illustrate the importance of determining the causal role of bacterial and fungal pathogens and immunological antifilarial response in ADL episodes.

Bancroftian elephantiasis in Nilphamari, Bangladesh.

The parasitic nematodes Wuchereria bancrofti, causes a dreadful disease in humans known as lymphatic filariasis, which afflicts more than 250 million people in tropical countries. Twelve districts with about 20 million people are endemic out of 64 districts in Bangladesh affecting more on Northern districts. This study was done in the Nilphamari, Kisorgonj and Sayedpur Thana under Nilphamari district, which is the most endemic for filariasis. In the present study, nineteen unions were investigated. Average 1.34% people were infected with filariasis (0.87% male and 1.81% female) out of 2,32,005 populations in those area. The highest percentage of infected unions was Alam Biditor (1.35%) under Kisorgonj Thana and lowest infected unions was Khatamadhupur (0.21%) under Sayedpur Thana. Among the affected people, 69.48% were poor, 28.88% were middle class and 1.63% was rich. The age group, 26-45 years, showed the highest rate (53.07%) of infection and the age group, 6-15 years, showed the lowest rate (1.92%) of infection. The relationships between infection status of male and female were statistically significant.

Ciência no século XIX: a contribuição brasileira para a descoberta do agente etiológico da filariose linfática / Science in the nineteenth century: the Brazilian contribution to the discovery of the etiologic agent of lymphatic filariasis

As contribuições de todos os povos para as artes de cura, ao longo de séculos, constituem a história da medicina universal. O estudo sobre as origens e o desenvolvimento dos conhecimentos médicos na história de pesquisas e descobertas leva à constatação da importância do papel de cientistas brasileiros natos ou por adoção. O objetivo deste trabalho foi ressaltar contribuições para a descoberta do agente etiológico da filariose bancroftiana. Destacam-se nomes como Otto Wucherer, Paterson e Silva Lima, que, nos primórdios do Brasil Império, criaram um modelo investigativo médico que, posteriormente, ficou conhecido como Escola Tropicalista Baiana.

Post-kidney transplantation lymphocele due to a lymphatic filariasis.

Lymphocele is a well-known complication of renal transplantation. Presenting symptoms are nonspecific; most patients are entirely asymptomatic. Herein, we have reported a case of lymphocele due to an asymptomatic lymphatic Wuchereria bancrofti filariasis with deterioration of graft function. A 53-year-old man with end-stage renal disease secondary to vascular disease was admitted 40 days after transplantation with vague, isolated abdominal pain. An abdomen and pelvis ultrasound examination demonstrated a cystic structure in the renal hilus. Graft function deteriorated, so the patient underwent puncture of the lymphocele followed by povidone iodine sclerotherapy. In the percutaneous drainage, we noted a fine whitish strand 4-mm thick similar to the shape of the stent, a part of which seemed to go into the transplantation fossa. Parasitological examination showed an adult female worm of W bancrofti measuring 6 cm. The test for microfilaremia was negative. The patient was treated for 10 days with a combination of Ivermectin and Albendazole associated with Doxycycline. The collection rapidly decreased after worm treatment. This case describes a post-renal transplantation lymphocele due to asymptomatic lymphatic filariasis.

Evidence for the exacerbation of lymphedema of geochemical origin, podoconiosis, by onchocerciasis.

The study was conducted to investigate a variation in the distribution of endemic elephantiasis previously determined to be of geochemical origin in three neighbouring and essentially homogenous villages, Bambili, Bambui and Finge of the Bambui Health District of NW Cameroon. A total of 301 subjects were examined for onchocerciasis and lymphatic filariasis in the area using standard procedures. The onchocercal microfilarial prevalence varied from 6.5% in Bambili through 20.4% in Bambui to 60.4% in Finge. The onchocercal serological prevalence based on IgG4 detection followed a similar trend. By contrast, blood microfilariae were absent in the area as verified by use of sensitive techniques. The community prevalence of elephantiasis varied from 1.1% in Bambili to 4.4% in Bambui and 10.4% in Finge. The correlation between the parasitological prevalence of onchocerciasis and the prevalence of lymphedema in the three villages was strong (r=0.99, p<0.05). We confirm that the elephantiasis in the area is of geochemical origin and the results suggest that it is being exacerbated by onchocercal lymphadenitis.

Lymphatic filariasis.

(1) Lymphatic filariasis is a set of parasitic diseases that are endemic in tropical and subtropical regions and can be disabling in the long term. (2) The standard antiparasitic drug for adults is oral diethylcarbamazine. Ivermectin is an alternative, especially for patients with intercurrent onchocercosis or loasis.

Collecting baseline information for national morbidity alleviation programs: different methods to estimate lymphatic filariasis morbidity prevalence.

The lymphatic filariasis elimination program aims not only to stop transmission, but also to alleviate morbidity. Although geographically limited morbidity projects exist, few have been implemented nationally. For advocacy and planning, the program coordinators need prevalence estimates that are currently rarely available. This article compares several approaches to estimate morbidity prevalence: (1) data routinely collected during mapping or sentinel site activities; (2) data collected during drug coverage surveys; and (3) alternative surveys. Data were collected in Plateau and Nasarawa States in Nigeria and in 6 districts in Togo. In both settings, we found that questionnaires seem to underestimate the morbidity prevalence compared with existing information collected through clinical examination. We suggest that program managers use the latter for advocacy and planning, but if not available, questionnaires to estimate morbidity prevalence can be added to existing surveys. Even though such data will most likely underestimate the real burden of disease, they can be useful in resource-limited settings.

Community's knowledge and perceptions about filarial elephantiasis and hydrocele in coastal Orissa, India.

This study assesses people's knowledge and perceptions on transmission, prevention and eradication of elephantiasis and hydrocele, common manifestations of chronic lymphatic filariasis (LF). The assessment was done during mass drug administration (MDA) of the programme to eliminate LF in the State of Orissa, India. A household survey with pre-tested interview questionnaire was conducted in four LF endemic districts of Orissa state, India, where the MDA has been taken place. The sampling units (clusters of households) of the household survey are taken based on (1) urban/rural and (2) type of or absence of health facility. A total of 1,448 respondents were selected randomly. Majority of the respondents heard about elephantiasis and hydrocele. About one third of them know that mosquito bite is the cause of elephantiasis but very few people know about hydrocele. Around 50% of the respondent believed that elephantiasis could be cured completely, while almost 60% said that it could be totally removed from the community. But for hydrocele, more than 80% of respondents showed a positive approach for cure and nearly about 70% said that hydrocele could totally be eradicated from community. Various causes and methods of cure and prevention were suggested. Around 55% of respondents suggested that elephantiasis can be eradicated by taking medicine, but only 40% felt that hydrocele can be cured by taking medicine. Basic knowledge on LF is poor and relatively low proportion of people knows that LF can be eliminated by taking medicine. As there are plans to undertake further rounds of MDA in Orissa, people's knowledge has to be strengthened and perception and attitudes have to be addressed to achieve positive behavioural change, which eventually lead to higher compliance of MDA.

Knowledge and perceptions of filariasis in Colombo, Sri Lanka, among patients with chronic filarial lymphoedema.

Knowledge of filariasis and perceptions of the disease were explored among 413 lymphoedema cases attending two filariasis clinics in the Colombo district of Sri Lanka. The information was collected in interviews based on a pre-tested, interviewer-administered questionnaire. Only 15% of the patients had initially attributed their limb swelling to filariasis. Most knew that filariasis resulted from mosquito bites (81.1%) and that the disease is transmissible (59.8%) and preventable (74.3%). The majority did not know, or were uncertain, whether filariasis causes swelling of the breasts in females (68.5%), scrotal swelling (60.7%) or dry cough/breathlessness (62.7%). Most (60%) of the interviewees wrongly believed that chronic filarial lymphoedema could be cured, primarily by long-term treatment with diethylcarbamazine. Knowledge of filariasis was significantly associated with level of education (P<0.05). Curiously, compared with the male interviewees, the females interviewed were much less likely to say that filariasis was the cause of their initial swelling (P<0.001). Those who had suffered with the disease for more than 1 year were not significantly more knowledgeable about the disease than the interviewees who had developed symptomatic filariasis more recently. Knowledge about the symptoms of filariasis was generally poor in the study population. In order to dispel several common myths about the disease, health-education programmes, that are targeted both at the community in general and at primary-care providers, are clearly needed.

Natural course of lymphatic filariasis: insights from epidemiology, experimental human infections, and clinical observations.

Lymphatic filariasis has been described as a "spectral disease". Analysis of the natural course of infection in nonendemic individuals as well as experimental infections of "volunteers" suggests that the filarial parasites are not inherently aggressive infectious agents. Experimental infections of humans with infective larvae result in transient, low-level microfilaremia, if at all. Nonendemic individuals with limited exposure show no evidence of persistent infection or pathology. Nonendemic individuals exposed to repeated infections show accelerated pathology. It is tempting to speculate that normal, immunocompetent residents in an endemic area show either (a) no pathology (endemic normals) because they are subject to the relatively low levels of infection or (b) chronic pathology if they are repeatedly infected. It would appear that only those individuals rendered immunologically tolerant to filarial parasites become productively infected with the filarial parasites. The intensity of transmission may underlie the differences in clinical presentation seen in diverse global pockets of endemicity.

Geographic distribution of lymphatic filariasis in Haiti.

Although lymphatic filariasis is known to have been endemic in Haiti since at least the mid 1700s, a national filariasis survey has never been conducted. As a first step in the national program to eliminate filariasis, we collected blood in January-April 2001 from 50-250 school children (6-11 years old) in all 133 communes of the country using an adaptation of the lot quality assurance sampling method. Of 22,365 children tested, 901 (4.0%) were positive for circulating Wuchereria bancrofti antigen. When weighted by commune population, the overall national antigen prevalence in this age group was 7.3%. Infected children were found in 117 (87.9%) communes, the most heavily affected areas being concentrated in the northern part of the country. In only 16 (12.1%) communes were all 250 children antigen negative. Thus, W. bancrofti infection in Haiti is much more widespread than previously realized; virtually the entire population of the country may be considered at risk of infection.

Entry lesions in bancroftian filarial lymphoedema patients--a clinical observation.

The prevalence of entry lesions in limbs was significantly higher in limbs with filarial lymphoedema (80.88%) than in normal limbs (42.86%, P = 0.000012). Among the various entry lesions in the lymphoedematous limbs, the prevalence of web space intertrigo was significantly higher in those who had acute dermatolymphangioadenitis (ADLA) than those who did not have ADLA (P = 0.04). Entry lesions were present only in 25% of those not using footwear, while 84.3% of those using footwear regularly or irregularly had these lesions (P = 0.01). None of the patients with good limb hygiene had ADLA, while 64% of those with fair to poor limb hygiene had ADLA (P = 0.02). Since the majority of the entry lesions were asymptomatic, training of patients and health care givers to specifically look for and treat these along with advice for good limb hygiene practices should form an important component of foot care programme for optimum filarial morbidity management.

Detection of filaria-specific IgG4 antibodies using Brugia Rapid test in individuals from an area highly endemic for Brugia timori.

The filarial parasite Brugia timori is of great public health importance in some islands of Eastern Indonesia. To establish a simple serological test for the identification and post-treatment monitoring of areas endemic for B. timori, a rapid immunochromatographic dipstick test (Brugia Rapid, BR) was evaluated on microfilaraemic and amicrofilaraemic individuals. This test is based on the detection of anti-filarial IgG4 antibodies that react with a recombinant Brugia malayi antigen (BmR1). In our study area on Alor island the prevalence of microfilaraemia was 26%. With the BR test, 100% of 196 sera from microfilaraemic persons and 76% of 563 sera from amicrofilaraemic persons, either symptomatic or asymptomatic, reacted positive. All 50 control sera from areas non-endemic for lymphatic filariasis gave negative BR test results. This study showed that the BR test can be also used to detect antibodies against B. timori. Due to the high prevalence of IgG4 antibodies as detected by the BR test (81%), no significant correlation with the prevalence of microfilaraemia could be detected within the endemic village. The BR test also shows great promise to be employed as a monitoring tool for B. timori in the framework of the Global Program to Eliminate Lymphatic Filariasis (GPELF).

Community- and individual-level determinants of Wuchereria bancrofti infection in Leogane Commune, Haiti.

We conducted a school-based assessment of the geographic distribution of Wuchereria bancrofti infection in Leogane Commune, Haiti, using the immunochromatographic test. In multivariate analyses performed using generalized linear mixed models, children attending schools in the foothills and plains were 3.95 (95% confidence interval [CI] = 1.28-12.23) and 23.56 (95% CI = 8.99-61.79) times as likely to be infected, respectively, as children attending mountain schools. Infection prevalence decreased with increasing altitude, but some local foci of infection were detected at higher altitudes. Higher school tuition, a marker of socioeconomic status (SES), was not associated with decreased infection prevalence. Our results indicate that although the force of infection in Leogane Commune is greatest below 70 meters above sea level, higher altitude communities are not exempt from infection. Lymphatic filariasis (LF) elimination programs should consider extending infection mapping activities to presumed non-LF altitudes. In addition, higher SES does not confer protection against W. bancrofti infection.