How elimination of lymphatic filariasis as a public health problem in the Kingdom of Cambodia was achieved.

BACKGROUND: Endemicity of lymphatic filariasis (LF) in Cambodia was proven in 1956 when microfilariae were detected in mosquitos in the Kratié province. In 2001, an extensive study confirmed the presence of both Brugia malayi and Wuchereria bancrofti microfilariae. In 2003, the Ministry of Health established a national task force to develop policies and strategies for controlling and eliminating neglected tropical diseases (NTDs), with the goal of eliminating LF by 2015. This article summarizes the work accomplished to eliminate LF as a public health problem in Cambodia. METHODS: The National Program to Eliminate Lymphatic Filariasis made excellent progress in the goal towards elimination due to strong collaboration between ministries, intensive supervision by national staff, and advocacy for mobilization of internal and external resources. Mass drug administration (MDA) with diethylcarbamazine citrate and albendazole was conducted in six implementation units, achieving > 70% epidemiological coverage for five consecutive rounds, from 2005 to 2009. In 2006, in 14 provinces, healthcare workers developed a line list of lymphedema and hydrocele patients, many of whom were > 40 years old and had been affected by LF for many years. The national program also trained healthcare workers and provincial and district staff in morbidity management and disability prevention, and designated health centers to provide care for lymphedema and acute attack. Two reference hospitals were designated to administer hydrocele surgery. RESULTS: Effectiveness of MDA was proven with transmission assessment surveys. These found that less than 1% of school children had antigenemia in 2010, which fell to 0% in both 2013 and 2015. A separate survey in one province in 2015 using Brugia Rapid tests to test for LF antibody found one child positive among 1677 children. The list of chronic LF patients was most recently updated and confirmed in 2011-2012, with 32 lymphoedema patients and 17 hydrocele patients listed. All lymphedema patients had been trained on self-management and all hydrocele patients had been offered free surgery. CONCLUSIONS: Due to the success of the MDA and the development of health center capacity for patient care, along with benefits gained from socioeconomic improvements and other interventions against vector-borne diseases and NTDs, Cambodia was validated by the World Health Organization as achieving LF elimination as a public health problem in 2016.

Lymphatic pathology in asymptomatic and symptomatic children with Wuchereria bancrofti infection in children from Odisha, India and its reversal with DEC and albendazole treatment.

BACKGROUND: Once interruption of transmission of lymphatic filariasis is achieved, morbidity prevention and management becomes more important. A study in Brugia malayi filariasis from India has shown sub-clinical lymphatic pathology with potential reversibility. We studied a Wuchereria bancrofti infected population, the major contributor to LF globally. METHODS: Children aged 5-18 years from Odisha, India were screened for W. bancrofti infection and disease. 102 infected children, 50 with filarial disease and 52 without symptoms were investigated by lymphoscintigraphy and then randomized to receive a supervised single oral dose of DEC and albendazole which was repeated either annually or semi-annually. The lymphatic pathology was evaluated six monthly for two years. FINDINGS: Baseline lymphoscintigraphy showed abnormality in lower limb lymphatics in 80% of symptomatic (40/50) and 63·5% (33/52) of asymptomatic children. Progressive improvement in baseline pathology was seen in 70·8, 87·3, 98·6, and 98·6% of cases at 6, 12, 18, and 24 months follow up, while in 4·2, 22·5, 47·9 and 64·8%, pathology reverted to normal. This was independent of age (p = 0·27), symptomatic status (p = 0·57) and semi-annual/bi-annual dosing (p = 0·46). Six of eleven cases showed clinical reduction in lymphedema of legs. INTERPRETATION: A significant proportion of a young W. bancrofti infected population exhibited lymphatic pathology which was reversible with annual dosage of DEC and albendazole. This provides evidence for morbidity prevention & treatment of early lymphedema. It can also be used as a tool to improve community compliance during mass drug administration. TRIAL REGISTRATION: ClinicalTrials.gov No CTRI/2013/10/004121.

Filarial breast lump.

Lymphatic filariasis is one of the most debilitating and disfiguring scourges among all diseases. This report presents a case of a woman with recurrent breast nodularity after being previously operated for a suspected breast neoplasm. We would like to highlight the issue of similar clinical presentation of a filarial breast lump and other breast lesions leading to inappropriate therapy.

Protective effect of diethylcarbamazine inhibits NF-κB activation in isoproterenol-induced acute myocardial infarction rat model through the PARP pathway.

The present study investigated the protective effect of diethylcarbamazine in inhibiting nuclear factor (NF)-κB activation in isoproterenol­induced acute myocardial infarction (AMI) rats through the poly ADP ribose polymerase (PARP) pathway. Male albino Wistar rats were injected subcutaneously with isoproterenol (100 mg/kg/day) for 2 days to induce an AMI model. Diethylcarbamazine (50 mg/kg) was administered by gavage for 12 days prior to the isoproterenol-induced AMI. It was noted that diethylcarbamazine significantly inhibited AMI­induced casein kinase and lactate dehydrogenase levels, and reduced the AMI­induced wet heart weight to body weight ratio in AMI rats. Diethylcarbamazine treatment significantly weakened reactive oxygen species production and reduced the levels of tumor necrosis factor (TNF)­α, interleukin­6 and NF­κB/p65 in AMI rats. Western blotting demonstrated that diethylcarbamazine significantly suppressed the AMI­induced inducible nitric oxide synthase (iNOS), transforming growth factor (TGF)­ß1, cyclooxygenase­2 (COX­2) and PARP protein expression in AMI rats. The results demonstrated that the protective effect of diethylcarbamazine inhibited isoproterenol­induced AMI through the suppression of inflammation, iNOS, TGF­ß1, COX­2 and the PARP pathway, and revealed the clinical potential of diethylcarbamazine for therapeutic and clinical applications.

Multiple frailty model for clustered interval-censored data with frailty selection.

Interval-censored time-to-event data often occur in studies of diseases where the symptoms of interest are not directly observable but require lab examinations for detection. Furthermore, the independence assumption among observations may not be valid if they are from clusters. Some methods have been developed for analysing clustered interval-censored data with a shared frailty to account for overall heterogeneity. In this paper, we propose a multiple frailty proportional hazards model, where we not only account for the baseline heterogeneity and effect variation across clusters for predictors, but also quantify the probabilities of the existence of such frailties. This proposed model will be especially useful for analysing multi-center randomised clinical trials for HIV, infections or progression-free survival in oncology studies.

Mathematical modelling of lymphatic filariasis elimination programmes in India: required duration of mass drug administration and post-treatment level of infection indicators.

BACKGROUND: India has made great progress towards the elimination of lymphatic filariasis. By 2015, most endemic districts had completed at least five annual rounds of mass drug administration (MDA). The next challenge is to determine when MDA can be stopped. We performed a simulation study with the individual-based model LYMFASIM to help clarify this. METHODS: We used a model-variant for Indian settings. We considered different hypotheses on detectability of antigenaemia (Ag) in relation to underlying adult worm burden, choosing the most likely hypothesis by comparing the model predicted association between community-level microfilaraemia (Mf) and antigenaemia (Ag) prevalence levels to observed data (collated from literature). Next, we estimated how long MDA must be continued in order to achieve elimination in different transmission settings and what Mf and Ag prevalence may still remain 1 year after the last required MDA round. The robustness of key-outcomes was assessed in a sensitivity analysis. RESULTS: Our model matched observed data qualitatively well when we assumed an Ag detection rate of 50 % for single worm infections, which increases with the number of adult worms (modelled by relating detection to the presence of female worms). The required duration of annual MDA increased with higher baseline endemicity and lower coverage (varying between 2 and 12 rounds), while the remaining residual infection 1 year after the last required treatment declined with transmission intensity. For low and high transmission settings, the median residual infection levels were 1.0 % and 0.4 % (Mf prevalence in the 5+ population), and 3.5 % and 2.0 % (Ag prevalence in 6-7 year-old children). CONCLUSION: To achieve elimination in high transmission settings, MDA must be continued longer and infection levels must be reduced to lower levels than in low-endemic communities. Although our simulations were for Indian settings, qualitatively similar patterns are also expected in other areas. This should be taken into account in decision algorithms to define whether MDA can be interrupted. Transmission assessment surveys should ideally be targeted to communities with the highest pre-control transmission levels, to minimize the risk of programme failure.

Immunomodulatory effect of diethylcarbamazine citrate plus filarial excretory-secretory product on rat hepatocarcinogenesis.

Diethylcarbamazine citrate (DEC) had a significance in anti-filarial chemotherapy, while excretory-secretory product (ES) is released from adult filarial females. The target of the current study was to examine the immunomodulatory effect of DEC, Setaria equina ES or a combination of them on rat hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN). In vitro effect of combined DEC and ES or ES alone on lipopolysaccharide (LPS)-stimulated rat peripheral blood mononuclear cells (PBMCs) was tested through IFN-γ assay in culture supernatants. In addition, single or repeated doses of DEC, ES or DEC+ES have been applied in white albino rats to test the effect on HCC. Levels of IFN-γ and anti-ES IgG antibodies in rat serum were assayed using ELISA. Hemolytic complement activity (CH50) was determined in serum while the concentration of nitric oxide (NO) was assayed in liver tissue. The infiltration of NK cells as well as the expression of MHC Iproliferating cell nuclear antigen (PCNA), inducible NO synthase (iNOS), Bcl2 and p53 were determined using immunohistochemistry. There was a dose-dependent increase in IFN-γ after in vitro exposure to DEC+ES. Repeated ES doses increased NO concentration (p<0.05) and expression of iNOS but reduced CH50 (p<0.001), while repeated DEC+ES doses could increase anti-ES IgG (p<0.01), IFN-γ level (p<0.05) and NK cell infiltration. The same treatments could also reduce the expression of MHC I expression, PCNA, Bcl2 and p53. This study has shown immunomodulatory and protective effects of DEC+ES repeated doses on rat HCC.

Effect of diethylcarbamazine citrate and Setaria equina excretory-secretory material on rat hepatocellular carcinoma.

Diethylcarbamazine citrate (DEC) has been known for its efficacy to eradicate bancroftian filariasis in Egypt and other countries in the world. One of the known effects was to decrease the level of circulating filarial antigen in the patient's serum. The target of this study was to examine the effect of DEC, excretory-secretory (ES) material from the filarial parasite Setaria equina or a combination of both on the status of oxidative stress and pathogenesis of rat hepatocellular carcinoma (HCC) induced by diethylnitrosamine and 2-acetylaminofluorene. This could be tested in vitro using nitroblue tetrazolium reduction test for measuring the level of superoxide anion (O2(•-)) released from rat peritoneal macrophages. For in vivo test, a single dose before induction of carcinogenesis or continually repeated doses with DEC, ES or DEC + ES was used. Exposure of macrophages to ES could lead to a significant decrease (p < 0.01) in O2(•-) release, while DEC (200 µM) could modulate such effect with significant increase (p < 0.05). Pathogenesis of liver cancer and treatment were evaluated using histological investigation, level of antioxidant and liver function enzymes. Repeated ES doses could increase the activity of antioxidant enzymes, especially the catalase enzyme and show a protective effect on liver architecture. DEC could modulate the later effects when combined with ES. No significant effect on the liver function enzymes after treatment was observed. Nuclear factor κB was found to be localized only in the cytoplasm after single and repeated treatments with ES. This study could indicate the effect of S. equina ES as antioxidant against rat HCC, while DEC could modulate such effect when combined with it.

A longitudinal analysis of the effect of mass drug administration on acute inflammatory episodes and disease progression in lymphedema patients in Leogane, Haiti.

We conducted a longitudinal analysis of 117 lymphedema patients in a filariasis-endemic area of Haiti during 1995-2008. No difference in lymphedema progression between those who received or did not receive mass drug administration (MDA) was found on measures of foot (P = 0.24), ankle (P = 0.87), or leg (P = 0.46) circumference; leg volume displacement (P = 0.09), lymphedema stage (P = 0.93), or frequency of adenolymphangitis (ADL) episodes (P = 0.57). Rates of ADL per year were greater after initiation of MDA among both groups (P < 0.01). Nevertheless, patients who received MDA reported improvement in four areas of lymphedema-related quality of life (P ≤ 0.01). Decreases in foot and ankle circumference and ADL episodes were observed during the 1995-1998 lymphedema management study (P ≤ 0.01). This study represents the first longitudinal, quantitative, leg-specific analysis examining the clinical effect of diethylcarbamazine on lymphedema progression and ADL episodes.

Toward the elimination of lymphatic filariasis by 2020: treatment update and impact assessment for the endgame.

Lymphatic filariasis (LF) is an important public health problem endemic in 73 countries, where it is a major cause of acute and chronic morbidity and a significant impediment to socioeconomic development. It is targeted for elimination by 2020, through preventive chemotherapy using albendazole in combination with either ivermectin or diethylcarbamazine citrate. Preventive chemotherapy enables the regular and coordinated administration of safe, single-dose medications delivered through mass drug administration (MDA). Many countries are now scaling down MDA activities after achieving 100% geographic coverage and instituting monitoring and evaluation procedures to establish the impact of several consecutive rounds of MDA and determine if transmission has been interrupted. At the same time, countries yet to initiate MDA for elimination of LF will adopt improved mapping and coverage assessment protocols to accelerate the efforts for achieving global elimination by 2020. This review provides an update on treatment for LF and describes the current global status of the elimination efforts, transmission control processes and strategies for measuring impact and continuing surveillance after MDA has ceased.

Towards elimination of lymphatic filariasis: social mobilization issues and challenges in mass drug administration with anti-filarial drugs in Tamil Nadu, South India.

India is a signatory to World Health Assembly resolution for elimination of lymphatic filariasis (LF) and National Health Policy has set the goal of LF elimination by 2015. Annual mass drug administration (MDA) is ongoing in endemic districts since 1996-97. Compliance rate is a crucial factor in achieving elimination and was assessed in three districts of Tamil Nadu for 10th and 11th treatment rounds (TRs). An in-depth study assessed the impact of social mobilization by drug distributors (DDs) in two areas from each of the three districts. Overall coverage and compliance for assessed TRs were 76.3 and 67.7% which is below the optimum level to achieve LF elimination. Modifiable determinants continue to be the reason for non-consumption even in the 11th TR and 20.8% were systematic non-compliers. In 76.4% of the cases, DDs failed to adhere to three mandatory visits as per the guidelines. Number of visits by DDs in relation to low and high MDA coverage areas showed a significant relationship (P ≤ 0.000). MDA is limited to drug distribution alone and efforts by DDs in preparing the community were inadequate. Probable means to meet the challenges in preparation of the community is discussed.

Adverse reactions following mass drug administration with diethylcarbamazine in lymphatic filariasis endemic areas in the Northeast of Brazil / Reações adversas após tratamento em massa com dietilcarbamazina em áreas endêmicas de filariose linfática no nordeste do Brasil

INTRODUCTION: The Global Programme to Eliminate Lymphatic Filariasis was launched with the goal of eliminating this disease via the annual mass drug administration (MDA) of a single dose of antifilarial drugs. Adverse drug reactions following MDA are a major factor of poor treatment adherence in several countries. This study assessed the occurrence of adverse drug reactions (ADRs) following the first round of mass treatment in two communities treated with different dosages of diethylcarbamazine (DEC) in the City of Recife, Brazil. METHODS: Population-based cross-sectional surveys were conducted in a random sample of the population living in both communities (Areas I and II). The dose of DEC recommended by the WHO (6mg/kg) was calculated based on the individual's weight-for-age. In Area II, weight differences between the genders were also considered when determining dosage. Data were obtained through interviews conducted in the first 12 to 48h and on the 5th day after MDA during household visits. RESULTS: A total of 487 and 365 individuals were interviewed in Areas I and II, respectively. The prevalence of ADRs in Area I (23.6; 95%CI: 19.1-29.5) was higher than in Area II (16.2; 95%CI:11.9-21.5)(p=0.0078). The prevalence of ADRs among females was higher than in males in Area I (p=0.0021). In Area II, no significant difference between the genders was observed (p=0.1840). Age was not associated with ADRs in either area. CONCLUSIONS: Adjusting MDA dosage schedules according to weight-for-age and sex may be may contribute to reduce the occurrence of adverse drug reactions in the population.

INTRODUÇÃO: O Programa Global de Eliminação da Filariose Linfática foi lançado visando à eliminação da doença pela administração de medicamentos em massa (MDA). As reações adversas seguidas ao MDA são um importante fator de baixa adesão ao tratamento em vários países. Este estudo avaliou a ocorrência de reações adversas medicamentosas (ADRs) após a primeira dose de tratamento em massa em duas comunidades tratadas com diferentes doses de dietilcarbamazina (DEC), na Cidade de Recife, Brasil. MÉTODOS: Estudos transversais foram realizados em uma amostra aleatória da população de duas áreas (Áreas I e II). A dose de DEC recomendada pela OMS (6mg/kg) foi calculada com base em parâmetros populacionais de peso para a idade. Na Área II, diferenças de peso entre os sexos também foram consideradas no cálculo. Dados foram obtidos através de entrevistas nas primeiras 12 às 48h e 5º dia após o tratamento durante visitas domiciliares. RESULTADOS: Um total de 487 e 365 pessoas foi entrevistado nas Áreas I e II, respectivamente. A prevalência de ADRs na Área I (23,6; IC95%: 19,1-29,5) foi maior do que na Área II (16,2; IC 95%:11,9-21,5)(p=0,0078). Na Área I, a prevalência de ADRs foi maior nas mulheres do que nos homens (p=0,0021), não se observando diferença na Área II (p=0,1840). Idade não esteve associada à ADRs. CONCLUSÕES: Doses de tratamento em massa (MDA) ajustadas por peso para a idade e sexo parecem contribuir para redução da ocorrência de ADRs na população.

Mid-arm and epitrochlear lymphadenopathy: a clinico-radiological surprise.

An 18-year-old man presented with multiple subcutaneous nodules over the anteromedial aspect of his right lower arm. Based on findings of sonography, histopathology, circulating filarial antigen test, and therapeutic response to diethylcarbazine, a diagnosis of filarial lymphadenopathy affecting mid-arm nodes and epitrochlear lymph nodes was made.

Higher evening antiepileptic drug dose for nocturnal and early-morning seizures.

We describe 17 children with nocturnal or early-morning seizures who were switched to a proportionally higher evening dose of antiepileptic drugs and were retrospectively reviewed for seizure outcome and side effects. Of 10 children with unknown etiology, clinical presentation was consistent with nocturnal frontal lobe epilepsy (NFLE) in 5 and benign epilepsy with centrotemporal spikes (BECTS) in 3. After a mean follow-up of 5.3 months, 15 patients were classified as responders; 11 of these became seizure free (5 NFLE, 1 BECTS, 5 with structural lesions) and 4 (2 BECTS, 2 with structural lesions) experienced 75-90% reductions in seizures. Among two nonresponders, seizures in one had failed to resolve with epilepsy surgery. Nine subjects (53%) received monotherapy after dose modification, and none presented with worsening of seizures. Two complained of transient side effects (fatigue/somnolence). Differential dosing led to seizure freedom in 64.7% (11/17) of patients, and 88.2% (15/17) experienced ≥ 50% reductions in seizures.

Imported bancroftian filariasis: diethylcarbamazine response and benzimidazole susceptibility of Wuchereria bancrofti in dynamic cross-border migrant population targeted by the National Program to Eliminate Lymphatic Filariasis in South Thailand.

The implementation on the Thailand-Myanmar border of annual mass drug administration (MDA) of a single 6 mg/kg dose of diethylcarbamazine (DEC) plus 400mg albendazole, part of the National Program to Eliminate Lymphatic Filariasis (PELF), has been challenging. In particular, chain migration of cross-border Myanmar workers at risk for nocturnally periodic Wuchereria bancrofti infection can lead to imported bancroftian filariasis (IBF) in Thailand. IBF is targeted for multiple-dose MDA with 300 mg DEC, in addition to what is recommended by the World Health Organization (WHO). The dynamic Myanmar migrants in Phang-nga, southern Thailand were sampled to test whether the responsible W. bancrofti has a genetic predisposition of benzimidazole exposure, and IBF exhibits DEC susceptibility. The long-term migrants had more access to DEC. IBF in W. bancrofti antigenemic (microfilaremic vs. amicrofilaremic) short-term migrants exhibited susceptibility to a 300-mg single-dose DEC treatment. During the course of a 3-month follow-up, antigenemia was significantly reduced, but microfilaremia was fluctuated. Surprisingly, a newly recognized Mansonella infection co-existing among W. bancrofti-affected Myanmar migrants elicited microfilaremia clearance within a month after treatment. As a result of the presence of genetically stable W. bancrofti beta-tubulin (Wbtubb) gene responsible for benzimidazole susceptibility, IBF did not possess a genetic predisposition for benzimidazole exposure. Point mutations at positions Phe167Tyr and Phe200Tyr were not detected by Wbtubb locus-specific nested PCR and sequencing. This study has the potential to help guide not only the Thai/Myanmar PELF surveillance and monitoring of mass treatment impacts on W. bancrofti, but also the other endemic countries allied with the Global Program to Eliminate Lymphatic Filariasis (GPELF).

Antifilarial drugs, in the doses employed in mass drug administrations by the Global Programme to Eliminate Lymphatic Filariasis, reverse lymphatic pathology in children with Brugia malayi infection.

Lymphatic filariasis is increasingly viewed as the result of an infection that is often acquired in childhood. The lymphatic pathology that occurs in the disease is generally believed to be irreversible. In a recent study in India, Doppler ultrasonography and lymphoscintigraphy were used to explore subclinical pathology in 100 children from an area endemic for Brugia malayi infection. All the children investigated showed some evidence of current or previous filarial infection. Some were microfilaraemic but asymptomatic, some were amicrofilaraemic but had filarial disease or a past history of microfilaraemia and/or filarial disease, and the rest, though amicrofilaraemic, asymptomatic and without any history of microfilaraemia or filarial disease, were seropositive for antifilarial IgG(4) antibodies. All the children were treated every 6 months, with a single combined dose of diethylcarbamazine (6 mg/kg) and albendazole (400 mg), and followed up for 24 months. By the end of this period all but one of the children were amicrofilaraemic and the 'filarial dance sign' could not be detected in any of the 14 children who had initially been found positive for this sign. Although lymphoscintigraphy revealed lymph-node and lymph-vessel damage in 82% of the children at enrolment, in about 67% of the children this pathology was markedly reduced by the 24-month follow-up. These results indicate that the drug regimens used in the mass drug administrations run by the Global Programme to Eliminate Lymphatic Filariasis are capable of reversing subclinical lymphatic damage and can provide benefits other than interruption of transmission in endemic areas. The implications of these findings are presented and discussed.

Lymphadenovarix of the head-neck region--a rare presentation of Bancroftian filariasis.

Cystic swellings of the neck in children have limited differential diagnoses, often either lymphatic or vascular malformations. Other cystic inflammations can be the result of tuberculous abscesses, suppurated lymph nodes and actinomycosis. Microfilaria causing lmphadenovarix of head-neck region has not yet been described in the literature. A 10-year-old Indian boy presented with an asymptomatic cystic neck mass of 8 months duration. Aspiration of the swelling demonstrated numerous Wuchereria bancrofti microfilaria and the patient responded well to 6 weeks of daily anti-filarial treatment using diethylcarbamazine citrate (6mg kg(-1) day(-1)). This appears to be the first report of microfilariae-associated lymphadenovarix of head-neck region. Though rare, filariasis should be considered as a differential diagnosis for aberrant swellings where lymphatic filarids are endemic.