Heritable Factors Play a Major Role in Determining Host Responses to \u3ci\u3eWuchereria bancrofti\u3c/i\u3e Infection in an Isolated South Pacific Island Population

Background. It is increasingly recognized that host genetic factors may play an important role in determining the outcome of filarial infections. To test this hypothesis in bancroftian lymphatic filariasis, pedigree data were collected twice during an 18-year period from an isolated Polynesian population living on a Pacific island where lymphatic filariasis is endemic. Methods. Using variance-component analysis, we examined the contribution of shared genetic and environmental effects on host clinical and immune responses to filarial infection, along with potential confounding determinants. Results. Sex was found to have a negligible influence on heritability estimates, but shared-household effects accounted for up to 32% of host variability. After accounting for these shared-household effects, heritability estimates suggested that levels of microfilariae and circulating adult worm antigen, as well as host eosinophil and immunoglobulin G antibody responses to larval and adult worm antigens, were highly heritable (range of heritability estimates, 0.15-0.84). Conclusions. These data provide evidence of a key role for genetic factors in determining the host response to filarial infections in humans and emphasize the complexity of the relationships among the host, parasite, and environment

Characterization of microflora in Latin-style cheeses by next-generation sequencing technology

Background Cheese contamination can occur at numerous stages in the manufacturing process including the use of improperly pasteurized or raw milk. Of concern is the potential contamination by Listeria monocytogenes and other pathogenic bacteria that find the high moisture levels and moderate pH of popular Latin-style cheeses like queso fresco a hospitable environment. In the investigation of a foodborne outbreak, samples typically undergo enrichment in broth for 24 hours followed by selective agar plating to isolate bacterial colonies for confirmatory testing. The broth enrichment step may also enable background microflora to proliferate, which can confound subsequent analysis if not inhibited by effective broth or agar additives. We used 16S rRNA gene sequencing to provide a preliminary survey of bacterial species associated with three brands of Latin-style cheeses after 24-hour broth enrichment. Results Brand A showed a greater diversity than the other two cheese brands (Brands B and C) at nearly every taxonomic level except phylum. Brand B showed the least diversity and was dominated by a single bacterial taxon, Exiguobacterium, not previously reported in cheese. This genus was also found in Brand C, although Lactococcus was prominent, an expected finding since this bacteria belongs to the group of lactic acid bacteria (LAB) commonly found in fermented foods. Conclusions The contrasting diversity observed in Latin-style cheese was surprising, demonstrating that despite similarity of cheese type, raw materials and cheese making conditions appear to play a critical role in the microflora composition of the final product. The high bacterial diversity associated with Brand A suggests it may have been prepared with raw materials of high bacterial diversity or influenced by the ecology of the processing environment. Additionally, the presence ofExiguobacterium in high proportions (96%) in Brand B and, to a lesser extent, Brand C (46%), may have been influenced by the enrichment process. This study is the first to define Latin-style cheese microflora using Next-Generation Sequencing. These valuable preliminary data will direct selective tailoring of agar formulations to improve culture-based detection of pathogens in Latin-style cheese

A PCR Assay for the Detection of Wuchereria bancrofti in Blood

To identify Wuchereria bancrofti DNA sequences that could be used as the basis for a simple and rapid parasite detection assay, a genomic library of W. bancrofti was constructed and screened for highly repeated DNA. The repeat found with the highest copy number was 195 basepairs (bps) long, 77% AT, and 300 copies per haploid genome. This sequence was designated the Ssp I repeat because it has a unique recognition site for that restriction endonuclease in all or most of the repeat copies. The Ssp I repeat DNA family is dispersed, genus-specific, and exists in all of the different geographic isolates of W. bancrofti tested. Based on DNA sequence analysis of this repeat, we have developed an assay to detect very small quantities of W. bancrofti DNA using the polymerase chain reaction (PCR). With this PCR assay, the Ssp I repeat was detected in as little as 1 pg of W. bancrofti genomic DNA (about 1% of the DNA in one microfilaria) added to 100 pA of human blood. The PCR assay also amplified Ssp I repeat DNA from geographic isolates of W. bancrofti from around the world but not from other species of filariae or from human or mosquito DNA. Microfilaria-positive human blood samples collected in Mauke, Cook Islands were shown to be Ssp I PCR-positive, while microfilaria-negative samples were PCR-negative. The specificity and sensitivity of the Ssp I PCR assay indicates that this approach has significant potential for improved screening of large human populations for active W. bancrofti infection

Integrated Implementation of Programs Targeting Neglected Tropical Diseases through Preventive Chemotherapy: Proving the Feasibility at National Scale

In 2006, the United States Agency for International Development established the Neglected Tropical Disease (NTD) Control Program to facilitate integration of national programs targeting elimination or control of lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis and blinding trachoma. By the end of year 3, 12 countries were supported by this program that focused first on disease mapping where needed, and then on initiating or expanding disease-specific programs in a coordinated/integrated fashion. The number of persons reached each year increased progressively, with a cumulative total during the first three years of 98 million persons receiving 222 million treatments with donated drugs valued at more than $1.4 billion. Geographic coverage increased substantially for all these infections, and the program has supported training of more than 220,000 persons to implement the programs. This current experience of the NTD Control Program demonstrates clearly that an integrated approach to control or eliminate these five neglected diseases can be effective at full national scale

Determinants of Success in National Programs to Eliminate Lymphatic Filariasis: a Perspective Identifying Essential Elements and Research Needs

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000. To understand why some national programs have been more successful than others, a panel of individuals with expertise in LF elimination efforts met to assess available data from programs in 8 countries. The goal was to identify: 1) the factors determining success for national LF elimination programs (defined as the rapid, sustained reduction in microfilaremia/ antigenemia after repeated mass drug administration [MDA]); 2) the priorities for operational research to enhance LF elimination efforts. Of more than 40 factors identified, the most prominent were 1) initial level of LF endemicity; 2) effectiveness of vector mosquitoes; 3) MDA drug regimen; 4) population compliance. Research important for facilitating program success was identified as either biologic (i.e., [1] quantifying differences in vectorial capacity; [2] identifying seasonal variations affecting LF transmission) or programmatic (i.e., [1] identifying quantitative thresholds, especially the population compliance levels necessary for success, and the antigenemia or microfilaremia prevalence at which MDA programs can stop with minimal risk of resumption of transmission; [2] defining optimal drug distribution strategies and timing; [3] identifying those individuals who are “persistently non- compliant” during MDAs, the reasons for this non-compliance and approaches to overcoming it). While addressing these challenges is important, many key determinants of program success are already clearly understood; operationalizing these as soon as possible will greatly increase the potential for national program success

National Mass Drug Administration Costs for Lymphatic Filariasis Elimination

Lymphatic filariasis (LF), commonly known as elephantiasis, is a profoundly disfiguring parasitic disease caused by thread-like nematode worms. This disease can often be disabling, thus reducing the potential productivity of the affected individuals. The WHO places the number of people at risk in 83 countries at 1.307 billion. This study was undertaken in seven countries—Burkina Faso, Ghana, Egypt, Tanzania, the Philippines, the Dominican Republic, and Haiti—using a common protocol to determine the costs of mass drug administration (MDA) programs to interrupt transmission of infection with LF, because there is lack of sufficient information about the costs of these programs. The results demonstrate that LF MDA is affordable and relatively inexpensive when compared to other public health programs. In the context of initiatives for integrating programs for the control and elimination of neglected tropical diseases, this study adds specifically to the relatively scarce body of information about the costs of MDA programs for LF. It also adds to the general knowledge about the application of methods that can be used to estimate the costs and cost-effectiveness of an integrated approach

The Effect of Azithromycin on Ivermectin Pharmacokinetics—A Population Pharmacokinetic Model Analysis

This paper describes the use of a modeling and simulation approach to explore a reported pharmacokinetic interaction between two drugs (ivermectin and azithromycin), which along with albendazole, are being developed for combination use in neglected tropical diseases. This approach is complementary to more traditional pharmacokinetic and safety studies that need to be conducted to support combined use of different health interventions. A mathematical model of ivermectin pharmacokinetics was created and used to simulate multiple trials, and the probability of certain outcomes (very high peak blood ivermectin levels when given in combination) was determined. All simulated peak blood levels were within ranges known to be safe and well tolerated. Additional field studies are needed to confirm these findings

The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years

Lymphatic filariasis (LF) is a vector-borne, chronically disabling parasitic infection causing elephantiasis, lymphedema, and hydrocele. The infection is endemic in 83 countries worldwide, with more than 1.2 billion people at risk and 120 million already infected. Since 1998, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has targeted elimination of LF by 2020. In its first 8 operational years, the program has scaled-up to provide more than 1.9 billion treatments through annual, single-dose mass drug administration (MDA) to ∼570 million individuals living in 48 LF-endemic countries. Not only do the GPELF drugs prevent the spread of LF, they also stop the progression of disease in those already infected. In addition, since two of the three drugs used for LF elimination have broad anti-parasite properties, treated populations are freed from both intestinal worms and from skin infections with onchocerca, lice, and scabies. To better understand the public health benefit of this ongoing global health initiative, we undertook an analysis of Programme data made available to WHO by participating countries. Our conservative estimates show that the GPELF has had an unprecedented public health impact on both LF and other neglected tropical diseases; it justly deserves the accolade of ‘a best buy’ in global health

A Multicenter Evaluation of Diagnostic Tools to Define Endpoints for Programs to Eliminate Bancroftian Filariasis

Successful mass drug administration (MDA) campaigns have brought several countries near the point of Lymphatic Filariasis (LF) elimination. A diagnostic tool is needed to determine when the prevalence levels have decreased to a point that MDA campaigns can be discontinued without the threat of recrudescence. A six-country study was conducted assessing the performance of seven diagnostic tests, including tests for microfilariae (blood smear, PCR), parasite antigen (ICT, Og4C3) and antifilarial antibody (Bm14, PanLF, Urine SXP). One community survey and one school survey were performed in each country. A total of 8,513 people from the six countries participated in the study, 6,443 through community surveys and 2,070 through school surveys. Specimens from these participants were used to conduct 49,585 diagnostic tests. Each test was seen to have both positive and negative attributes, but overall, the ICT test was found to be 76% sensitive at detecting microfilaremia and 93% specific at identifying individuals negative for both microfilariae and antifilarial antibody; the Og4C3 test was 87% sensitive and 95% specific. We conclude, however, that the ICT should be the primary tool recommended for decision-making about stopping MDAs. As a point-of-care diagnostic, the ICT is relatively inexpensive, requires no laboratory equipment, has satisfactory sensitivity and specificity and can be processed in 10 minutes—qualities consistent with programmatic use. Og4C3 provides a satisfactory laboratory-based diagnostic alternative