Bacteriological studies of blood, tissue fluid, lymph and lymph nodes in patients with acute dermatolymphangioadenitis (DLA) in course of ‘filarial’ lymphedema

Filarial lymphedema is complicated by frequent episodes of dermatolymphangioadenitis (DLA). Severe systemic symptoms during attacks of DLA resemble those of septicemia. The question we asked was whether bacterial isolates can be found in the peripheral blood of patients during the episodes of DLA. Out of 100 patients referred to us with ‘filarial’ lymphedema 14 displayed acute and five subacute symptoms of DLA. All were on admission blood microfilariae negative but had a positive test in the past. Blood bacterial isolates were found in nine cases, four acute (21%) and five subacute (26%). In 10 acute cases blood cultures were found negative. Six blood isolates belonged to Bacilli, four to Cocci and one was Sarcina. To identify the sites of origin of bacterial dissemination, swabs taken from the calf skin biopsy wounds and tissue fluid, lymph and lymph node specimens were cultured. Swabs from the calf skin biopsy wound contained isolates in nine (47%) cases. They were Bacilli in nine, Cocci in three, Acinetobacter and Erwinia in two cases. Tissue fluid was collected from 10 patients and contained Bacilli in four (40%) and Staphylococci in three (30%). Lymph was drained in four patients and contained isolates in all samples (100%). They were Staphylococcus epidermis, xylosus and aureus, Acinetobacter, Bacillus subtilis and Sarcina. Three lymph nodes were biopsied and contained Staphylococcus chromogenes, xylosus, Enterococcus and Bacillus cereus. In six cases the same phenotypically defined species of bacteria were found in blood and limb tissues or fluids. In the ‘control’ group of patients with lymphedema without acute or subacute changes all blood cultures were negative. Interestingly, swabs from biopsy wound of these patients contained isolates in 80%, tissue fluid in 68%, lymph in 70% and lymph nodes in 58% of cases. In healthy controls, tissue fluid did not contain bacteria, and lymph isolates were found only in 12% of cases. This study demonstrates that patients with acute episodes of DLA reveal bacteriemia in a high percentage of cases. Diversity of blood and tissue bacterial isolates in these patients points to a breakdown of the skin immune barrier in lymphedema and subsequently indiscriminate bacterial colonization of deep tissues and spread to an blood circulation. © 1999 Elsevier Science B.V. All rights reserved

Changes in cytokine, filarial antigen, and DNA levels associated with adverse events following treatment of lymphatic filariasis

Mild to moderate adverse events (AEs) are common after treatment of lymphatic filariasis (LF) and pose a major challenge for the global LF elimination program. We studied changes in cytokine levels and filarial worm components in plasma of subjects with and without AEs following treatment of LF. Participants (n = 24) were hospitalized and monitored for AEs following treatment. Cytokines (27), filarial DNA, circulating filarial antigen (CFA), and immune complexes were measured in plasma samples collected before and after treatment. Levels for 16 cytokines increased after treatment in individuals with moderate AEs compared to individuals with no and/or mild AEs. These included 3 major proinflammatory cytokines (interleukin 6, tumor necrosis factor α, and interleukin 1β). Eotaxin-1 levels were elevated at baseline in individuals who developed moderate AEs after treatment; thus, eotaxin-1 is a potential biomarker for AE risk. CFA and filarial DNA levels increased more in individuals with moderate AEs after treatment than in people with no/mild AEs. Increases in cytokine, filarial DNA, and CFA levels were associated with development of AEs following treatment of LF. Improved understanding of the pathogenesis of AEs may lead to improved methods for their prevention or management that could increase compliance in elimination programs

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin—originating solely from a single microorganism isolated at the Kitasato Intitute, Tokyo, Japan from Japanese soil—has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin’s passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a “wonder” drug

Decreased Prevalence of Lymphatic Filariasis among Diabetic Subjects Associated with a Diminished Pro-Inflammatory Cytokine Response (CURES 83)

Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates of sero-positivity of LF among diabetic subjects was carried out (n = 1416) as part of the CURES study. There was a significant decrease in the prevalence of LF among diabetic subjects (both newly diagnosed [5.7%] and those under treatment [4.3%]) compared to pre-diabetic subjects [9.1%] (p = 0.0095) and non-diabetic subjects [10.4%] (p = 0.0463). A significant decrease in filarial antigen load (p = 0.04) was also seen among diabetic subjects. Serum cytokine levels of the pro-inflammatory cytokines—IL-6 and GM-CSF—were significantly lower in diabetic subjects who were LF positive, compared to those who were LF negative. There were, however, no significant differences in the levels of anti-inflammatory cytokines—IL-10, IL-13 and TGF-β—between the two groups. Although a direct causal link has yet to be shown, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished pro-inflammatory cytokine response in Asian Indians with diabetes and concomitant LF

Safety and Immunogenicity of DNA and MVA HIV-1 Subtype C Vaccine Prime-Boost Regimens: A Phase I Randomised Trial in HIV-Uninfected Indian Volunteers

STUDY DESIGN: A randomized, double-blind, placebo controlled phase I trial. METHODS: The trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of prime-boost vaccination regimens with either 2 doses of ADVAX, a DNA vaccine containing Chinese HIV-1 subtype C env gp160, gag, pol and nef/tat genes, as a prime and 2 doses of TBC-M4, a recombinant MVA encoding Indian HIV-1 subtype C env gp160, gag, RT, rev, tat, and nef genes, as a boost in Group A or 3 doses of TBC-M4 alone in Group B participants. Out of 16 participants in each group, 12 received vaccine candidates and 4 received placebos. RESULTS: Both vaccine regimens were found to be generally safe and well tolerated. The breadth of anti-HIV binding antibodies and the titres of anti-HIV neutralizing antibodies were significantly higher (p<0.05) in Group B volunteers at 14 days post last vaccination. Neutralizing antibodies were detected mainly against Tier-1 subtype B and C viruses. HIV-specific IFN-γ ELISPOT responses were directed mostly to Env and Gag proteins. Although the IFN-γ ELISPOT responses were infrequent after ADVAX vaccinations, the response rate was significantly higher in group A after 1(st) and 2(nd) MVA doses as compared to the responses in group B volunteers. However, the priming effect was short lasting leading to no difference in the frequency, breadth and magnitude of IFN-γELISPOT responses between the groups at 3, 6 and 9 months post-last vaccination. CONCLUSIONS: Although DNA priming resulted in enhancement of immune responses after 1(st) MVA boosting, the overall DNA prime MVA boost was not found to be immunologically superior to homologous MVA boosting. TRIAL REGISTRATION: Clinical Trial Registry CTRI/2009/091/00005

Epidemiology of lymphatic filariasis with special reference to urogenital-manifestations

Lymphatic filariasis (LF) is currently endemic in as many as 80 countries round the globe, particularly in the tropics and sub-tropics. Wuchereria bancrofti as a causative organism accounts for over 90% of the global burden. India contributes about 40% of the total global burden and accounts for about 50% of the people at the risk of infection. In India, states like Andhra Pradesh, Bihar, Gujarat, Kerala, Maharastra, Orissa, Tamil Nadu, Utter Pradesh and West Bengal contribute to about 95% of total burden. W. bancrofti is the predominant species accounting for about 98% of the national burden, widely distributed in 17 states and six union territories. Diethylcarbamazine (DEC) is an effective drug acting on the parasite (without report of resistance in past five decades) and mass annual single dose community drug administration with selective vector control could result in effective elimination of infection by interruption of transmission. The WHO has called for targeting filariasis elimination by 2020. India is the largest LF endemic country and has targeted the elimination of LF by 2015

Review Article: Epidemiology of lymphatic filariasis with special reference yo urogenital-manifestations

Lymphatic filariasis (LF) is currently endemic in as many as 80 countries round the globe, particularly in the tropics and sub-tropics. Wuchereria bancrofti as a causative organism accounts for over 90% of the global burden. India contributes about 40% of the total global burden and accounts for about 50% of the people at the risk of infection. In India, states like Andhra Pradesh, Bihar, Gujarat, Kerala, Maharastra, Orissa, Tamil Nadu, Utter Pradesh and West Bengal contribute to about 95% of total burden. W. bancrofti is the predominant species accounting for about 98% of the national burden, widely distributed in 17 states and six union territories. Diethylcarbamazine (DEC) is an effective drug acting on the parasite (without report of resistance in past five decades) and mass annual single dose community drug administration with selective vector control could result in effective elimination of infection by interruption of transmission. The WHO has called for targeting filariasis elimination by 2020. India is the largest LF endemic country and has targeted the elimination of LF by 2015

Treatment of microfilaraemia in asymptomatic brugian filariasis: the efficacy and safety of the combination of single doses of ivermectin and diethylcarbamazine

Although combinations of ivermectin and diethylcarbamazine (DEC) have been shown to be superior to either drug alone in the suppression of bancroftian microfilariae, their efficacy against infections with Brugia malayi has never been investigated. The present, open trial is the first on the efficacy and safety of a combination of single doses of ivermectin and DEC when used against microfilaraemias of brugian filariasis. Twenty-one, asymptomatic but microfilaraemic (109-6934 microfilariae/ml blood, with a median of 841/ml) men, aged 18-48 years, each received oral doses of ivermectin (400 μg/kg) and DEC (6 mg/kg) as a single treatment. Twelve hours post-treatment, 96.5%-100% of the microflariae in each subject had been cleared and 12 of the subjects were amicrofilaraemic. A further reduction in microfilarial counts was evident 1 month post-treatment (mean clearance = 99.0%) and the counts continued to fall at least until the last follow-up, at 1 year post-treatment, when the mean clearance has 99.9 % and 13 (68.4%) of the 19 subjects then investigated were amicrofilaraemic. All subjects experienced adverse reactions of one form or another, lasting for up to 48 h post-treatment; these included fever, myalgia, headache, and lethargy. Postural hypotension was recorded in two subjects and dilated, inflamed lymphatic channels were seen in another two. The combination of ivermectin and DEC demonstrated a microfilaricidal effect superior to that of either drug used alone, both in the initial rapid clearance of microfilariae and in sustaining the effect for 1 year. This finding has important implications for the control of lymphatic filariasis

Effects of Obstetric Complications on Adolescent Postpartum Contraception and Rapid Repeat Pregnancy

STUDY OBJECTIVE: To determine whether complications during pregnancy or at delivery influence postpartum contraception choices and rapid repeat pregnancy rates in adolescent women. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This retrospective cohort study included 321 adolescents delivering at UMASS Memorial Healthcare. Complications during pregnancy and delivery along with subsequent contraception use were investigated. Postpartum contraception choice (long-acting reversible contraception [LARC] vs non-LARC) at either delivery, hospitalization discharge, or at postpartum outpatient appointment, and rapid repeat pregnancy rate (pregnancy confirmed within 12 months of index delivery), were analyzed according to pregnancy complications. Comparisons were made with chi2 and Fisher exact tests for categorical variables, and with Wilcoxon rank sum test for continuous variables. RESULTS: Of the study population, 27.7% (n = 89/321) used LARC in the postpartum period. The LARC and non-LARC patient populations differed significantly regarding history of abortion (P = .029), with no differences in obstetric complications between the groups. Of the population, 16.6% (n = 53/320) became pregnant again within 1 year of their index delivery. Those with a rapid repeat pregnancy had significantly increased gravidity (P = .002), parity (P = .003), number of previous spontaneous or therapeutic abortions (P = .026); they were also more like to have nonlive birth as a complication (P = .028), compared with those without repeat pregnancy. No other obstetrical complications were statistically significantly different between the compared groups. CONCLUSION: Obstetrical complications seem to have little effect on postpartum contraception choice or repeat pregnancy rate with the notable exception of nonlive birth being associated with rapid repeat pregnancy

The pharmacokinetics, safety and tolerability of the co-administration of diethylcarbamazine and albendazole

The pharmacokinetics, safety and tolerability of single, oral doses of diethylcarbamazine (DEC) and albendazole, given alone or in combination, were investigated in a double-blind, randomized and placebo-controlled trial involving 42 amicro� laraemic subjects living in an area of India where lymphatic � lariasis is endemic. The subjects (34 males and eight females, aged 18–52 years and weighing 46–66.5 kg ) were randomly allocated to one of the three drug groups. Fourteen were given just DEC (6 mg/kg ), another 14 were given just albendazole (400 mg) and the remaining 14 were given both DEC (6 mg/kg) and albendazole (400 mg). Blood samples for pharmacokinetic study were collected at speci� ed intervals before and after drug administration. Plasma concentrations of DEC and albendazole/albendazole sulphoxide were estimated using gas chromatography and HPLC, respectively. The safety and tolerability of the treatments were evaluated through clinical and laboratory assessments. Both the DEC and albendazole were well tolerated when given alone or in combination, no adverse events being observed. In all three treatment groups, the drugs were rapidly absorbed from the gastro–intestinal tract although there was marked inter-individual variation. The pharmacokinetics of DEC, albendazole and albendazole sulphoxide were similar, whether each drug was given alone or in combination. These results indicate that there is no adverse pharmacokinetic or pharmacodynamic reason why DEC and albendazole should not be co-administered to control lymphatic � filariasis