Enhanced efficacy of sequential administration of Albendazole for the clearance of Wuchereria bancrofti infection: Double blind RCT

Till today, there is no effective treatment protocol for the complete clearance of Wuchereria bancrofti (W.b) infection that causes secondary lymphoedema. In a double blind randomized control trial (RCT), 146 asymptomatic W. b infected individuals were randomly assigned to one of the four regimens for 12 days, DEC 300 mg + Doxycycline 100 mg coadministration or DEC 300 mg + Albendazole 400 mg co-administration or DEC 300 mg + Albendazole 400 mg sequential administration or control regimen DEC 300 mg and were followed up at 13, 26 and 52 weeks post-treatment for the clearance of infection. At intake, there was no significant variation in mf counts (F(3,137)=0.044; P=0.988) and antigen levels (F(3,137)=1.433; P=0.236) between the regimens. Primary outcome analysis showed that DEC + Albendazole sequential administration has an enhanced efficacy over DEC + Albendazole co-administration (80.6 Vs 64.7%), and this regimen is significantly different when compared to DEC + doxycycline co-administration and control (P<0.05), in clearing microfilaria in 13 weeks. Secondary outcome analysis showed that, all the trial regimens were comparable to control regimen in clearing antigen (F(3, 109)=0.405; P=0.750). Therefore, DEC + Albendazole sequential administration appears to be a better option for rapid clearance of W. b microfilariae in 13 weeks time. (Clinical trials.gov identifier – NCT02005653)

Effect of a single dose of diethylcarbamazine, albendazole or both on the clearance of Wuchereria bancrofti microfilariae and antigenaemia among microfilaria carriers: A randomized trial.

Background. Lymphatic filariasis is a major vector-borne parasitic disease. The global programme to eliminate lymphatic filariasis was launched in 1997 and currently over 570 million people are covered under it in 48 countries. Mass annual single-dose drug administration of diethylcarbamazine (DEC), co-administrated with albendazole for 5–6 years and mass distribution of diethylcarbamazine-fortified salt are the two strategies for elimination of filariasis. Methods. Asymptomatic volunteers residing in Puducherry, India were screened for microfilaria (mf) by examining nocturnal thick blood smears. Those testing positive were randomly assigned to receive a single dose of DEC (6 mg/kg body weight) or albendazole 400 mg or both. Participants were hospitalized for 5 days. Membrane filtration count was used to assess microfilaraemia and ELISA (Og4C3) assay to measure circulating filarial antigens (CFA). Measurements were done before treatment and at 1, 2 and 3 years post-treatment. Viability of the adult worms was assessed by looking for the filarial dance sign (FDS) using ultrasound examination of the scrotum in men with hydrocele. Results. Fifty-four microfilaraemic individuals were studied. The mf prevalence started decreasing only by day 180 posttreatment in the DEC group but much earlier in the other two groups (day 30 in the albendazole and day 90 in the DEC with albendazole group). The decrease in mf was marginal (17.6%, 26.3% and 27.8%, respectively) by the end of year 1 posttreatment, but significant (96.7%, 78.6% and 93.3%, respectively) by the end of year 2 post-treatment (p<0.05). By the end of year 3, the level decreased to 80% in the DEC, 90% in the albendazole and to 100% in the DEC and albendazole groups. However, the mf intensity decreased © The National Medical Journal of India 2010 Vector Control Research Centre, Department of Health Research (ICMR), Indira Nagar, Puducherry 605006, India S. L. HOTI, S. P. PANI, P. VANAMAIL, K. ATHISAYA MARY, L. K. DAS, P. K. DAS Correspondence to S. L. HOTI; slhoti@yahoo.com significantly (by 39%; p<0.05) by day 7 post-treatment in both the DEC and DEC with albendazole groups, but only by day 30 in the albendazole group. In all the drug groups, the prevalence as well as intensity of CFA returned to pretreatment levels by the end of year 3 post-treatment. Conclusion. Annual single-dose administration of all the 3 drug regimens significantly reduced antigenaemia levels. There were no significant differences in the efficacy and overall pattern of CFA clearance between the 3 drug regimens.

Burden of chikungunya in India: estimates of disability adjusted life years (DALY) lost in 2006 epidemic.

BACKGROUND & OBJECTIVES: During 2006, chikungunya emerged as a major ever known epidemic in India. Disability adjusted life years (DALY) is an appropriate summary measure of population health to express epidemiological burden of diseases. We estimated the burden due to suspected chikungunya using DALYs for the first time and compared between the states and also with the burden due to other vector-borne diseases in India. The economic burden was also assessed in terms of productivity loss. METHODS: Data on the reported cases of fever/suspected cases of chikungunya from different states during 2006 in India were used. Years lived with disability (YLD) were calculated for non-fatal cases to estimate DALY. Since the disability weight for chikungunya is not available, the weights available for rheumatic arthritis, comparable to the disease outcome of chikungunya were used for the estimation. The burden was estimated for both acute and chronic cases. It is considered that about 11.5% of cases were reported to have extended morbidity with persisting arthralgia. For acute disease, the average duration of illness was considered to be nine days and for chronic cases it was six months on an average. The productivity loss due to income foregone by the working class was calculated using minimum official wage. RESULTS: National burden of chikungunya was estimated to be 25,588 DALYs lost during 2006 epidemic, with an overall burden of 45.26 DALYs per million. It varied from 0.01 to 265.62 per million in different states. Karnataka alone contributed as high as 55% of the national burden. Persistent arthralgia was found to impose heavy burden, accounting for 69% of the total DALYs. The productivity loss in terms of income foregone was estimated to be a minimum of Rs. 391 million. INTERPRETATION & CONCLUSION: The chikungunya epidemic in the year 2006 imposed heavy epidemiological burden and productivity loss to the community. The burden of chikungunya in terms of DALY was estimated for the first time. In view of re-emergence and spread of this infection in recent times it is warranted for derivation of disability weight for different health states of chikungunya to facilitate realistic estimates of DALYs. Quality epidemiological data from surveillance system to monitor vector-borne and zoonotic diseases would pave way for more realistic estimates of burden. The productivity loss in-terms of income foregone could be minimal as the estimation was made by using the minimum wage fixed by the government although the actual loss is expected to be higher.

The plight of chronic filarial lymphoedema patients in choice of health care and health care providers in Pondicherry, India.

Lymphatic filariasis has a wide spectrum of clinical manifestations with asymptomatic parasite carriers at one end and irreversible lymphoedema of extremities at the other. Irreversible lymphoedema of extremities is one of the disabling conditions that drive the affected patients to seek treatment from various systems of medicines and health care providers. This study attempts to map the care seeking pattern and behaviour of patients with chronic filarial lymphoedema of lower limbs in an urban area. Consecutive filarial lymphoedema patients from the VCRC filariasis clinic were recruited for the study. A pre-tested semi-structured questionnaire was used for interrogation of the patients. A total of 56 lymphoedema patients participated in the study. Majority (94.6%) of the patients sought medical management only. There was no difference (P>0.05) between the proportion of patients attending government (37.5%) and private (44.3%) medical care facilities There was also no difference in the proportion of patients' first consultations in private or government health care facilities. About 57.1% patients approaching governmental institutions opted for primary/secondary health care system. No particular sequential pattern of seeking health care was observed and the 56 study subjects followed 40 treatment-seeking routes by switching from one care provider to the other. The causes of not coming to the clinic for further check-up were 'no acute attacks' (30.4%), 'reduction in oedema volume' (21.7%), 'advised treatment being taken at home' (26.1%) and 'loss of daily wages' (21.7%). The study highlights the need to involve the private medical sector in morbidity management of filarial lymphoedema and to make governmental health facilities more accessible and user-friendly.

Locomotor disability in bancroftian filarial lymphoedema patients.

Disability prevention in cases with lymphatic filarial disease has been a research priority in view of the current programme on global elimination of lymphatic filariasis. This is also important for estimation of disease burden, impact evaluation, developing strategy for morbidity management and rehabilitation for lymphoedema patients in the endemic countries. In this communication, we are presenting the results of quantification of functional limitations of lower extremities with lymphoedema caused due to bancroftian filariasis by objective assessment of movement of joints and power of muscles in the affected legs. A total of 81 consecutive lymphoedema patients attending a filariasis clinic in Pondicherry urban locality were recruited for the study. Assessment for restriction of movement of joints and loss of power of muscles was carried out as in Manual for doctors to evaluate permanent physical impairment, prescribed by an expert group of WHO and Ministry of Health, Govt. of India on evaluation for permanent disability. Of the cases assessed, 40% in grade-I, 55% in grade-II, 77.3% in grade-III and 94.7% in grade-IV lymphoedema cases had functional limitations either in joint movements or power of muscles or both. The effective loss of locomotor/function (combined loss of joint movement and power of muscles in %) increased with stage of lymphoedema (grade-I-4.3+7.4, grade-II-7.0+8.4, grade-III-15.4+14.8 and grade IV- 33.2+22.8). The degree of loss varied significantly between the grades (P< 0.0001). The methodology used in this study can be adapted to evaluate the impact of the morbidity management component of strategy for Elimination of Lymphatic Flariasis (ELF) programme. This study will also enable researchers for fine-tuning the method for estimating disease burden and, to develop and evaluate strategies for morbidity management/rehabilitation of filarial lymphoedema patients.

Tolerability and efficacy of a three-age class dosage schedule of Diethylcarbamazine citrate (DEC) in the treatment of microfilaria carriers of Wuchereria bancrofti and its implications in mass drug administration (MDA) strategy for elimination of lymphatic filariasis (LF).

A six-age class dosage schedule of Diethylcarbamazine (DEC) of 50mg (1-2 years), 100mg (3-4 years), 150mg (5-8 years), 200mg (9-11 years), 250mg (12-14 years) and 300mg for above 14 years is being adopted for annual single dose MDA for LF elimination treat Wuchereria bancrofti microfilaria carriers. In order to increase the community compliance as well as to make the distribution easier during MDA, a revised 3 age class dosage schedule of 100mg (2-4 years), 200mg (5-14 years) and 300mg for above 14 years was evaluated for its tolerability and efficacy. By this change, it was observed that the 4-8 years age class is receiving 50 mg higher and 11-14 years age class is receiving 50mg lesser dose compared to the earlier class schedule. Therefore, the safety aspect in the age class of 4-8 years and efficacy component in the age class of 11-14 years were assessed. Apparently "healthy" asymptomatic microfilaraemic volunteers between the age class of 4-8 and 11-14 years were recruited for the study. The incidence of side reaction in the 4-8 years age class was 50.0% with 150mg dose and 66.7% with 200mg (P>0.05). No life threatening adverse reactions was observed in any dosage schedule. Fever, headache and myalgia, the predominant adverse reactions were mild and similar in both schedules. The mean intensity of the three major specific adverse reactions (fever, headache and myalgia) also did not differ significantly (P>0.05). For the purpose of LF elimination, efficacy in terms of reduction in mean microfilaria load is important. In the 11-14 year age class considerable reduction in the geometric mean density (GMD) was observed by day 90 and 180 post-therapy in both groups (250mg group and 200mg group) compared to pre-therapy level. By day 360 post-therapy, the difference was statistically not significant (P>0.05) (reduction of 72.2% in 250mg and 69.6% reduction in 200mg). The reductions in GMD were statistically significant when compared to pre-therapy levels in both the old (250mg) and new (200mg) doses. Thus, three- age class dosage schedule is as safe and efficacious as the six- age class schedule.

Tolerability and efficacy of single dose diethylcarbamazine (DEC) alone or co-administration with Ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, South India.

The tolerability and efficacy of single dose DEC (12mg/kg body weight) or co-administration of DEC (6mg/kg body weight) with Ivermectin (200 or 400 mcg/kg of body weight) was studied in 60 asymptomatic W. bancrofti microfilariae (Mf) carriers following a double blind randomized design. The drugs were tolerated well. The incidence of adverse reactions of DEC (85.0%), DEC + Ivermectin 200mcg (95.0%) and DEC + Ivermectin 400mcg (100%) did not vary significantly (P>0.05). The mean score of adverse reaction intensity due to DEC + Ivermectin 200mcg (1.41) was significantly higher compared to DEC (0.61) (P<0.05). However, there was no significant difference between and DEC +Ivermectin 400mcg (0.89) and DEC + Ivermectin 200mcg (1.41) and DEC + Ivermectin 400mcg and DEC. The major adverse reactions were fever, headache and myalgia in all groups. The incidence and intensity of the adverse reactions were maximum between 24 to 48 hours of post therapy. The haematological and biochemical parameters did not vary significantly between pre and 7-day post therapy values in any of the study groups (P>0.05). Efficacy was measured in terms of proportion of cases clearing microfilaraemia completely and reduction in geometric mean parasite density in comparison to pre therapy levels. At the end of one year, DEC with Ivermectin 400mcg group showed significantly higher efficacy in complete clearance of Mf (94.4%) than that of DEC with Ivermectin 200mcg (60.0%) or DEC alone (52.6%) (P<0.05). However, no significant difference was observed in reduction of geometric mean Mf density (99.9%, 99.7%, 99.5% respectively). In all the groups, the tolerability and efficacy of the drugs were independent of host age and gender.

Comparison of an immunochromatographic card test with night blood smear examination for detection of Wuchereria bancrofti microfilaria carriers.

BACKGROUND: At present, two diagnostic tests--Og4C3 ELISA and an immunochromatographic card test (ICT)--are available to detect circulating filarial antigens of Wuchereria bancrofti in serum/whole blood samples collected during the day. We aimed to assess the sensitivity of the new format card test 'NOW ICT Filariasis' in detecting microfilaria carriers of W. bancrofti in comparison with conventional microscopic techniques and Og4C3 ELISA. METHODS: A total of 200 persons were selected from two villages following a quota sampling design (100 in each village). The required number of houses was selected using a systematic sampling procedure with a random start of the first household. Blood samples were taken from all the available persons in each selected house until the quota of 100 was reached. The new format ICT test, Og4C3 ELISA and night blood smear examination for microfilaria were carried out following standard procedures. RESULTS: The sensitivity of the new format ICT test was 100% among microfilaria carriers (detected by both early and late readings). The kappa statistic measure of agreement between the two readings of all the samples (n =200) tested was 0.811 (p<0.05). The new format test also reported 25% of microfilaria-negative individuals as being positive for circulating filarial antigens. However, the diagnostic lines were not stable beyond 10 minutes (particularly in the case of amicrofilaraemic persons). Though there was an overall agreement between the results of ICT and Og4C3 tests (kappa =0.612; p< 0.05), the sensitivity of the Og4C3 test was lower than that of ICT. CONCLUSION: The new format ICT test is highly sensitive in detecting microfilaria carriers in endemic communities. Improvement in the format to provide stable diagnostic lines, specificity of the format and cost of the test kit are to be considered before its large-scale use.

The preferential site of adult Wuchereria bancrofti: an ultrasound study of male asymptomatic microfilaria carriers in Pondicherry, India.

BACKGROUND: The traditional method of detection of microfilaria in night blood specimens for the diagnosis of Wuchereria bancrofti infection is being replaced with circulating filarial antigen in day blood specimens, which has a high sensitivity. However, both methods are indirect tests to detect the presence of adult worms in vivo. Localization of adult worms in vivo in their natural habitat may help in understanding better the end-point of drug treatment, the adulticidal action of antifilarial drugs, and in locating the site of lymphatic pathology. We used ultrasound examination to assess the preferential location of adult worms in an area endemic for lymphatic filariasis. METHODS: Ultrasound examination was done in 36 asymptomatic male carriers of Wuchereria bancrofti microfilaria to detect the location of adult worms. Both sides of the scrotum (root of the scrotum, epididymis, spermatic cord, testis and the adjoining area), lymphatic vessels and inguinal, popliteal, axillary and epitrochlear lymph nodes were examined using a 7.5 MHz probe in real-time B mode. RESULTS: The 'filaria dance sign (FDS)' suggesting the presence of adult worms was observed in 22 carriers (61%). The preferential site of location of the adult worms was the intrascrotal juxtatesticular lymphatic vessels in 'nests' along the lymphatic vessels of the epididymis, spermatic cord and paratesticular region. The number of nests varied between 1 and 4 with a mean size of 0.3 cm2. In 95% of cases, localization of the worms was unilateral. The mean microfilaria (SD) count-positive cases for those with the filarial dance sign (264 [199]) was significantly higher (p<0.05) than for the negative cases (171 [196]). CONCLUSION: Ultrasound visualization of adult worms of Wuchereria bancrofti in vivo is possible and confirms the concept that the worms have their own territory and reside in 'nests'. The preferential site of localization of the adult worms in men is the intrascrotal juxtatesticular lymphatic vessels.

Lambdacyhalothrin treated bed nets as an alternative method of malaria control in tribal villages of Koraput District, Orissa State, India.

A village scale trial was carried out to evaluate the efficacy of bed-nets impregnated with lambdacyhalothrin, at the dose of 0.025 g/m2, in reducing malaria transmission in villages of Koraput District of Orissa, India, inhabited by tribals. The nets were distributed before peak transmission season. There was an overall decline in the parasite rate in all the age groups, six months after the supply of impregnated nets while the same increased in control village and in a village where untreated nets were supplied. The vector densities (resting and man landing) were lower in the treated village as compared to untreated and control villages throughout the study period. The reduction in the parasite rate was consistent when the reimpregnation was done at six monthly interval and the same tend to increase when the gap between the two impregnations was increased to one year. Though malaria incidence was reduced, transmission was not completely interrupted during the study period, due to outdoor transmission. The insecticidal effect of bednets was retained upto six months. Washing of bednets by the community did not affect the efficacy. The acceptance and usage was better with impregnated nets as compared to ordinary nets.

Preliminary evaluation on safety aspects in mosquito net impregnation with lambdacyhalothrin.

A preliminary evaluation was undertaken on the safety aspects in mosquito net impregnation with lambdacyhalothrin, on the operators and users of the treated nets. The detection by HPLC of one of the principal metabolites of lambdacyhalothrin, 3-phenoxy benzoic acid (3-PBA) in blood samples of the users and operators in very small quantities (0.01 to 0.02 ng/microliters) showed that absorption of the insecticide was minimum. Clinical examination and analysis of different biochemical parameters in blood and serum samples showed in spite of the minimal absorption of the insecticide, there was no immediate adverse effect.

Microlevel epidemiological variations in malaria & its implications on control strategy.

Microlevel epidemiological variations in designing malaria control strategies were studied. Quantitative and qualitative variations were observed between two physiographic zones and between four different ecotypes within the zones of the Koraput district. While the peak transmission occurred in rainy season in the 600 m plateau (Jeypore zone), the same was observed in cold season in 150 m plateau (Malkangiri zone). The age specific parasite prevalence indicated a high degree of transmission and high level of acquired immunity in top- and foot-hill villages of both zones as compared to plain and riverine villages. Transmission was perennial in top-hill and foot-hill villages while it was of short period (indicated by infant parasite rate) in others. Since the period and intensity of transmission vary, an uniform residual insecticidal spray schedule as followed at present is not necessary. Majority of fever patients in top-hill villages were positive for Plasmodium falciparum and therefore may be treated for malaria without slide collection and examination. Evaluations may be done by sample surveys. These steps can optimize the malaria control operation in the district.

Parasitological aspects of malaria persistence in Koraput district Orissa, India.

A sample survey in 37 villages covering 10,733 people in 1986-87 in the Koraput district, Orissa showed that the malaria prevalence is of a much higher order than that reported by the National Malaria Eradication Programme (annual parasite incidence between 14.3 and 26.8 during 1981-86). Out of 833 positives detected 714 had Plasmodium falciparum, 86 had P. vivax, 12 had P. malariae and 21 had mixed infections. There were 650 asymptomatic parasite carriers and 127 gametocyte carriers. The infant parasite rate was 15.82 per cent and average enlarged spleen (AES) in 2 to 9 yr old children was 1.98. In a year round fever survey in 22 villages, 5520 blood smears were collected and 1364 were found positive for malaria, with 77.3 per cent P. falciparum. In a mass blood survey conducted in a labour camp at an irrigation project, 610 people were examined, and 181 were positive. Nearly 40 per cent of migrants and 22 per cent of locals were positive, P. falciparum being dominant.

Malaria & other common ailments among upper Bonda tribals in Koraput district, Orissa.

A malariometric survey carried out among the upper Bonda tribals of Koraput district showed that malaria is the major cause of morbidity followed by worm infestation and malnutrition. A total of individuals 1,409 (32.2% of the population) were sampled and 771 were found positive for malaria parasites. Plasmodium falciparum was the predominant parasite (73.7%) followed by P. vivax (10.6%) and P. malariae (5.2%) among the positive cases. Mixed infection was observed in 10.5 per cent of positive individuals. The infant parasite rate was 60.0 per cent and the average enlarged spleen among the children between 2-9 yr was 2.11. The age specific parasite rate indicated high degree transmission and high level of acquired resistance among the tribals.

Prevalence of bancroftian filariasis & its control by single course of diethyl carbamazine in a rural area in Tamil Nadu.

The prevalence of microfilaraemia, clinical spectrum of bancroftian filariasis and vector potential were studied in Vettavalam village in North Arcot district of Tamil Nadu. The effectiveness of selective therapy with diethyl carbamazine (DEC) in controlling filariasis in rural areas was also evaluated. The prevalence of microfilaraemia (mf rate) and disease (disease rate) was found to be 11.7 and 11.09 per cent respectively. Hydrocele was the dominant clinical sign in males and lymphoedema in females. The density of the vector Culex quinquefasciatus was 25.44 females/man-hour, and the infection and infectivity rates were 18.16 and 1.09 per cent respectively. All mf carriers detected after the mass blood survey were given a single course of DEC at the dosage of 6 mg/kg of body wt/day for 12 days. Only 61.6 per cent of them took the full course of DEC treatment. DEC therapy brought down the mf rate from 11.7 to 5.84 per cent after one month. In the absence of further treatment, there was no significant change in mf prevalence after one year.

Detection of Plasmodium ovale in Koraput district, Orissa state.

We report for the first time the detection of P. ovale infection in three patients in two hilly villages of Koraput district, Orissa state, India. The identification of the parasite was confirmed by the Imperial Colleage of Science and Technology, London.