Modelling the use of insecticide-treated cattle to control tsetse and Trypanosoma brucei rhodesiense in a multi-host population.

We present a mathematical model for the transmission of Trypanosoma brucei rhodesiense by tsetse vectors to a multi-host population. To control tsetse and T. b. rhodesiense, a proportion, ψ, of cattle (one of the hosts considered in the model) is taken to be kept on treatment with insecticides. Analytical expressions are obtained for the basic reproduction number, R0n in the absence, and R(0n)(T) in the presence of insecticide-treated cattle (ITC). Stability analysis of the disease-free equilibrium was carried out for the case when there is one vertebrate host untreated with insecticide. By considering three vertebrate hosts (cattle, humans and wildlife) the sensitivity analysis was carried out on the basic reproduction number (R(0n)(T)) in the absence and presence of ITC. The results show that R(03)(T) is more sensitive to changes in the tsetse mortality. The model is then used to study the control of tsetse and T. b. rhodesiense in humans through application insecticides to cattle either over the whole-body or to restricted areas of the body known to be favoured tsetse feeding sites. Numerical results show that while both ITC strategies result in decreases in tsetse density and in the incidence of T. b. rhodesiense in humans, the restricted application technique results in improved cost-effectiveness, providing a cheap, safe, environmentally friendly and farmer based strategy for the control of vectors and T. b. rhodesiense in humans.

The risk of Aedes aegypti breeding and premises condition in South Mexico.

A recent innovation instrumented for the Dengue Prevention and Control program in Mexico is the use of the premises condition index (PCI) as an indicator of risk for the vector Aedes aegypti infestation in dengue-endemic localities of Mexico. This paper addresses whether further improvements for the dengue control program could be made if the prevalence and productivity of Ae. aegypti populations could be reliably predicted using PCI at the household level, as well as medium-sized neighborhoods. We evaluated the use of PCI to predict the infestation with Aedes aegypti (breeding sites and immature productivity) in Merida, Mexico. The study consisted of a cross-sectional survey based on a cluster-randomized sampling design. We analyzed the statistical association between Aedes infestation and PCI, the extent to which the 3 components of PCI (house maintenance, and tidiness and shading of the patio) contributed to the association between PCI and infestation and whether infestation in a given premises was also affected by the PCI of the surrounding ones. Premises with the lowest PCI had significantly lower Aedes infestation and productivity; and as PCI scores increased infestation levels also tended to increase. Household PCI was significantly associated with Ae. aegypti breeding, largely due to the effect of patio untidiness and patio shade. The mean PCI within the surroundings premises also had a significant and independent explanatory power to predict the risk for infestation, in addition to individual PCI. This is the 1st study in Mexico showing evidence that premises condition as measured by the PCI is related to Ae. aegypti breeding sites and immature productivity. Results suggest that PCI could be used to streamline surveys to inform control efforts at least where Ae. aegypti breeds outdoors, as in Merida. The effect of individual premises, neighborhood condition, and the risk of Aedes infestation imply that the risk for dengue vector infestation can only be minimized by the mass effect at the community level.

Reconstructing historical changes in the force of infection of dengue fever in Singapore: implications for surveillance and control.

OBJECTIVE: To reconstruct the historical changes in force of dengue infection in Singapore, and to better understand the relationship between control of Aedes mosquitoes and incidence of classic dengue fever. METHODS: Seroprevalence data were abstracted from surveys performed in Singapore from 1982 to 2002. These data were used to develop two mathematical models of age seroprevalence. In the first model, force of infection was allowed to vary independently each year, while in the second it was described by a polynomial function. Model-predicted temporal trends were analysed using linear regression. Time series techniques were employed to investigate periodicity in predicted forces of infection, dengue fever incidence and mosquito breeding. FINDINGS: Force of infection estimates showed a significant downward trend from 1966, when vector control was instigated. Force of infection estimates from both models reproduced significant increases in the percentage and average age of the population susceptible to dengue infections. Importantly, the year-on-year model independently predicted a five to six year periodicity that was also displayed by clinical incidence but absent from the Aedes household index. CONCLUSION: We propose that the rise in disease incidence was due in part to a vector-control-driven reduction in herd immunity in older age groups that are more susceptible to developing clinical dengue.

Analysis of risk factors for T. brucei rhodesiense sleeping sickness within villages in south-east Uganda.

BACKGROUND: Sleeping sickness (HAT) caused by T.b. rhodesiense is a major veterinary and human public health problem in Uganda. Previous studies have investigated spatial risk factors for T.b. rhodesiense at large geographic scales, but none have properly investigated such risk factors at small scales, i.e. within affected villages. In the present work, we use a case-control methodology to analyse both behavioural and spatial risk factors for HAT in an endemic area. METHODS: The present study investigates behavioural and occupational risk factors for infection with HAT within villages using a questionnaire-based case-control study conducted in 17 villages endemic for HAT in SE Uganda, and spatial risk factors in 4 high risk villages. For the spatial analysis, the location of homesteads with one or more cases of HAT up to three years prior to the beginning of the study was compared to all non-case homesteads. Analysing spatial associations with respect to irregularly shaped geographical objects required the development of a new approach to geographical analysis in combination with a logistic regression model. RESULTS: The study was able to identify, among other behavioural risk factors, having a family member with a history of HAT (p = 0.001) as well as proximity of a homestead to a nearby wetland area (p < 0.001) as strong risk factors for infection. The novel method of analysing complex spatial interactions used in the study can be applied to a range of other diseases. CONCLUSION: Spatial risk factors for HAT are maintained across geographical scales; this consistency is useful in the design of decision support tools for intervention and prevention of the disease. Familial aggregation of cases was confirmed for T. b. rhodesiense HAT in the study and probably results from shared behavioural and spatial risk factors amongmembers of a household.

A dominant lethal genetic system for autocidal control of the Mediterranean fruitfly.

The Sterile Insect Technique (SIT) used to control insect pests relies on the release of large numbers of radiation-sterilized insects. Irradiation can have a negative impact on the subsequent performance of the released insects and therefore on the cost and effectiveness of a control program. This and other problems associated with current SIT programs could be overcome by the use of recombinant DNA methods and molecular genetics. Here we describe the construction of strains of the Mediterranean fruit fly (medfly) harboring a tetracycline-repressible transactivator (tTA) that causes lethality in early developmental stages of the heterozygous progeny but has little effect on the survival of the parental transgenic tTA insects. We show that these properties should prove advantageous for the implementation of insect pest control programs.

Estimating the burden of rhodesiense sleeping sickness during an outbreak in Serere, eastern Uganda.

BACKGROUND: Zoonotic sleeping sickness, or HAT (Human African Trypanosomiasis), caused by infection with Trypanosoma brucei rhodesiense, is an under-reported and neglected tropical disease. Previous assessments of the disease burden expressed as Disability-Adjusted Life Years (DALYs) for this infection have not distinguished T.b. rhodesiense from infection with the related, but clinically distinct Trypanosoma brucei gambiense form. T.b. rhodesiense occurs focally, and it is important to assess the burden at the scale at which resource-allocation decisions are made. METHODS: The burden of T.b. rhodesiense was estimated during an outbreak of HAT in Serere, Uganda. We identified the unique characteristics affecting the burden of rhodesiense HAT such as age, severity, level of under-reporting and duration of hospitalisation, and use field data and empirical estimates of these to model the burden imposed by this and other important diseases in this study population. While we modelled DALYs using standard methods, we also modelled uncertainty of our parameter estimates through a simulation approach. We distinguish between early and late stage HAT morbidity, and used disability weightings appropriate for the T.b. rhodesiense form of HAT. We also use a model of under-reporting of HAT to estimate the contribution of un-reported mortality to the overall disease burden in this community, and estimate the cost-effectiveness of hospital-based HAT control. RESULTS: Under-reporting accounts for 93% of the DALY estimate of rhodesiense HAT. The ratio of reported malaria cases to reported HAT cases in the same health unit was 133:1, however, the ratio of DALYs was 3:1. The age productive function curve had a close correspondence with the HAT case distribution, and HAT cases occupied more patient admission time in Serere during 1999 than all other infectious diseases other than malaria. The DALY estimate for HAT in Serere shows that the burden is much greater than might be expected from its relative incidence. Hospital based control in this setting appears to be highly cost-effective, highlighting the value of increasing coverage of therapy and reducing under-reporting. CONCLUSION: We show the utility of calculating DALYs for neglected diseases at the local decision making level, and emphasise the importance of improved reporting systems for acquiring a better understanding of the burden of neglected zoonotic diseases.

Late-acting dominant lethal genetic systems and mosquito control.

BACKGROUND: Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality. RESULTS: We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality. CONCLUSION: Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease control.

Pupal surveys for Aedes aegypti surveillance and potential targeted control in residential areas of Mérida, México.

A mosquito larval-pupal survey was conducted in 1,160 households of the Mexican city of Mérida during the rainy season of 2003 to determine their differential productivity for Aedes aegypti. Larvae and pupae were detected in 15 broad categories of container types. All breeding sites were found in the patios (backyards) and were potentially rain filled. Ae. aegypti pupae were produced from all categories of breeding site, and no single container type was predominately responsible for pupal production. The most productive buckets comprised 42% of the pupae-positive containers and provided 34% of the total pupae collected. Pupal production in buckets, together with plastic rubbish, pet dishes and basins, utensils for cooking and washing, tires, and flowerpots, accounted for almost 87% of pupal production. However, the most important pupal producers had low infestation indices for immature forms, illustrating that the use of positive-container indices can underestimate the importance of certain breeding sites. Overall, 40% of containers that were observed harboring Ae. aegypti pupae were classified as disposable. The remaining containers were considered useful, although some were seldom used. The discussion focuses on the potential utility of the pupal survey for targeting control, and its resulting pupae-per-person entomological indicator, both for comparison with a theoretical threshold for dengue transmission and for targeting vector control in this Mexican city.

Treating cutaneous leishmaniasis patients in Kabul, Afghanistan: cost-effectiveness of an operational program in a complex emergency setting.

BACKGROUND: Although Kabul city, Afghanistan, is currently the worldwide largest focus of cutaneous leishmaniasis (CL) with an estimated 67,500 cases, donor interest in CL has been comparatively poor because the disease is non-fatal. Since 1998 HealthNet TPO (HNTPO) has implemented leishmaniasis diagnosis and treatment services in Kabul and in 2003 alone 16,390 were treated patients in six health clinics in and around the city. The aim of our study was to calculate the cost-effectiveness for the implemented treatment regimen of CL patients attending HNTPO clinics in the Afghan complex emergency setting. METHODS: Using clinical and cost data from the on-going operational HNTPO program in Kabul, published and unpublished sources, and discussions with researchers, we developed models that included probabilistic sensitivity analysis to calculate ranges for the cost per disability adjusted life year (DALY) averted for implemented CL treatment regimen. We calculated the cost-effectiveness of intralesional and intramuscular administration of the pentavalent antimonial drug sodium stibogluconate, HNTPO's current CL 'standard treatment'. RESULTS: The cost of the standard treatment was calculated to be 27 US dollars (95% C.I. 20-36) per patient treated and cured. The cost per DALY averted per patient cured with the standard treatment was estimated to be approximately 1,200 US dollars (761-1,827). CONCLUSION: According to WHO-CHOICE criteria, treatment of CL in Kabul, Afghanistan, is not a cost-effective health intervention. The rationale for treating CL patients in Afghanistan and elsewhere is discussed.

Managing insecticide resistance by mass release of engineered insects.

Transgenic crops producing insecticidal toxins are now widely used to control insect pests. The benefits of this method would be lost if resistance to the toxins spread to a significant proportion of the pest population. The primary resistance management method, mandatory in the United States, is the high-dose/ refuge strategy, requiring toxin-free crops as refuges near the insecticidal crops, and the use of toxin doses sufficiently high to kill insects heterozygous for a resistance allele, thereby rendering resistance functionally recessive. We propose that mass-release of harmless susceptible (toxin-sensitive) insects could substantially delay or even reverse the spread of resistance. Mass-release of such insects is an integral part of release of insects carrying a dominant lethal (RIDL), a method of pest control related to the sterile insect technique. We show by mathematical modeling that specific RIDL strategies could form an effective component of a resistance management strategy for plant-incorporated protectants and other toxins.

Rabies Control: Could Innovative Financing Break the Deadlock?

The neglected zoonotic diseases (NZDs) have been all but eradicated in wealthier countries but remain major causes of ill-health and mortality in over 80 countries across Africa, Asia, and Latin America. The nature of neglect for the NZDs has been ascribed, in part, to underreporting resulting in an underestimation of their global burden that, together with a lack of advocacy, downgrades their relevance to policy-makers and funding agencies. While this may be the case for many NZDs, for rabies this is not the case. The global burden estimates for rabies (931,600 DALYs) more than justify prioritizing rabies control building on the strong advocacy platforms, functioning at local, regional, and global levels (including the Global Alliance for Rabies Control), and commitments from WHO, OIE, and FAO. Simple effective tools for rabies control exist together with blueprints for operationalizing control, yet, despite elimination targets being set, no global affirmative action has been taken. Rabies control demands activities both in the short term and over a long period of time to achieve the desired cumulative gains. Despite the availability of effective vaccines and messaging tools, rabies will not be sustainably controlled in the near future without long-term financial commitment, particularly as disease incidence decreases and other health priorities take hold. While rabies control is usually perceived as a public good, public private partnerships could prove equally effective in addressing endemic rabies through harnessing social investment and demonstrating the cost-effectiveness of control. It is acknowledged that greater attention to navigating local realities in planning and implementation is essential to ensuring that rabies, and other neglected diseases, are controlled sustainably. In the shadows of resource and institutional limitations in the veterinary sector in low- and middle-income countries, sufficient funding is required so that top-down interventions for rabies can more explicitly engage with local project organization capacity and affected communities in the long term. Development Impact Bonds have the potential to secure the financing required to deliver effective rabies control.

Cost-estimate and proposal for a development impact bond for canine rabies elimination by mass vaccination in Chad.

Close to 69,000 humans die of rabies each year, most of them in Africa and Asia. Clinical rabies can be prevented by post-exposure prophylaxis (PEP). However, PEP is commonly not available or not affordable in developing countries. Another strategy besides treating exposed humans is the vaccination of vector species. In developing countries, the main vector is the domestic dog, that, once infected, is a serious threat to humans. After a successful mass vaccination of 70% of the dogs in N'Djaména, we report here a cost-estimate for a national rabies elimination campaign for Chad. In a cross-sectional survey in four rural zones, we established the canine : human ratio at the household level. Based on human census data and the prevailing socio-cultural composition of rural zones of Chad, the total canine population was estimated at 1,205,361 dogs (95% Confidence interval 1,128,008-1,736,774 dogs). Cost data were collected from government sources and the recent canine mass vaccination campaign in N'Djaména. A Monte Carlo simulation was used for the simulation of the average cost and its variability, using probability distributions for dog numbers and cost items. Assuming the vaccination of 100 dogs on average per vaccination post and a duration of one year, the total cost for the vaccination of the national Chadian canine population is estimated at 2,716,359 Euros (95% CI 2,417,353-3,035,081) for one vaccination round. A development impact bond (DIB) organizational structure and cash flow scenario were then developed for the elimination of canine rabies in Chad. Cumulative discounted cost of 28.3 million Euros over ten years would be shared between the government of Chad, private investors and institutional donors as outcome funders. In this way, the risk of the investment could be shared and the necessary investment could be made available upfront - a key element for the elimination of canine rabies in Chad.

Crisis, what crisis? Control of Rhodesian sleeping sickness.

There is an urgent need for cost-effective strategies for the sustainable control of Trypanosoma brucei rhodesiense (Rhodesian) sleeping sickness, which is a fatal zoonotic disease that has caused devastating epidemics during the past century. Sleeping sickness continues to be controlled by crisis management, using active case detection, treatment and vector control - activities that occur only during major epidemics; during the intervening periods, farmers and communities must fend for themselves. There are several methods for assessing the burden of this disease and there is a series of farmer-led methodologies that can be applied to reduce the burden of human and animal trypanosomiases.

Using remote sensing and geographic information systems to identify villages at high risk for rhodesiense sleeping sickness in Uganda.

Geographic information systems (GIS) and remote sensing were used to identify villages at high risk for sleeping sickness, as defined by reported incidence. Landsat Enhanced Thematic Mapper (ETM) satellite data were classified to obtain a map of land cover, and the Normalised Difference Vegetation Index (NDVI) and Landsat band 5 were derived as unclassified measures of vegetation density and soil moisture, respectively. GIS functions were used to determine the areas of land cover types and mean NDVI and band 5 values within 1.5 km radii of 389 villages where sleeping sickness incidence had been estimated. Analysis using backward binary logistic regression found proximity to swampland and low population density to be predictive of reported sleeping sickness presence, with distance to the sleeping sickness hospital as an important confounding variable. These findings demonstrate the potential of remote sensing and GIS to characterize village-level risk of sleeping sickness in endemic regions.

Integrated control of vector-borne diseases of livestock--pyrethroids: panacea or poison?

Tick- and tsetse-borne diseases cost Africa approximately US$4-5 billion per year in livestock production-associated losses. The use of pyrethroid-treated cattle to control ticks and tsetse promises to be an increasingly important tool to counter this loss. However, uncontrolled use of this technology might lead to environmental damage, acaricide resistance in tick populations and a possible exacerbation of tick-borne diseases. Recent research to identify, quantify and to develop strategies to avoid these effects are highlighted.

Are insecticide-impregnated dog collars a feasible alternative to dog culling as a strategy for controlling canine visceral leishmaniasis in Brazil?

In a zoonotic visceral leishmaniasis (ZVL)-endemic area in Brazil, deltamethrin-impregnated collars (DMC) were fitted to 136 dogs for 5 months and significantly reduced the odds of increasing their anti-Leishmania antibody titer during this period by 50% (95% confidence interval 29-87%, P=0.01), as compared with a population of 97 uncollared dogs with pre-intervention prevalence within the same town. Mathematical modeling suggests that under typical Brazilian ZVL-endemic conditions, the epidemiological impact of community-wide DMC application should be greater than the currently practiced dog culling strategy, but that its impact will be dependent on collar coverage and loss rate. Both interventions should have a higher proportional impact in regions of lower endemicity, but the relative advantage of DMC over culling increases with transmission rate. Sensitivity analyses indicate that the impact of either intervention is not significantly affected by variation in the biology of the sandfly vector, but is greatly influenced by variation in dog mortality and serorecovery rates.

A threshold analysis of the cost-effectiveness of artemisinin-based combination therapies in sub-saharan Africa.

Artemisinin-based combination therapies (ACTs) are generally regarded as vital in addressing the growing problem posed by the development of antimalarial resistance across sub-Saharan Africa. However, the costs of the new ACTs are likely to be significantly higher than current therapies. Therefore, it is important to examine formally the cost-effectiveness of the more effective yet more expensive ACTs before advocating a switch in policy. Importantly, any such economic evaluation must consider the temporal dynamics of drug resistance, and not just focus on the static question of whether switching today would be cost-effective at current levels of resistance, particularly since the development of new antimalarials in the future is so uncertain. However, predicting the future changes in drug resistance is a major difficulty in accurately quantifying the relative costs and health outcomes associated with different drug therapies over time. Here, we use a simple decision tree model to estimate the incremental cost-effectiveness of using ACTs, compared with persisting with current therapies, over 5-, 10-, and 15-year periods. We describe the dynamics of drug resistance using a general logistic growth function, in which the starting frequency of resistance and maximum growth may be altered. However, rather than make assumptions about the absolute rate at which resistance to ACTs will progress, we allow the ratio of the growth rate of resistance to ACTs relative to that of current therapies to vary. Defining the growth rate of ACT resistance in this manner allows us to calculate the threshold ratio at which ACTs would no longer appear cost-effective, for any starting conditions of resistance to current therapies and ACTs, and over any time period. The influence of uncertainty in other decision tree parameters on the threshold ratio values is also quantified, using Monte Carlo simulation techniques. This analysis shows that ACTs are more than 95% likely to be cost-effective under most conditions, other than very low levels of initial resistance to sulfadoxine/pyrimethamine and a five-year time frame. These predictions are conservative in that 95% certainty is a stringent decision rule favoring the rejection of new policies. The importance of other variables not included in the analysis for the robustness of the findings are discussed (e.g., consideration of the entire population at risk for malaria, the affordability of ACTs in specific settings, and the growth of resistance modeled according to population genetic parameters).

Controlling malaria using livestock-based interventions: a one health approach.

Where malaria is transmitted by zoophilic vectors, two types of malaria control strategies have been proposed based on animals: using livestock to divert vector biting from people (zooprophylaxis) or as baits to attract vectors to insecticide sources (insecticide-treated livestock). Opposing findings have been obtained on malaria zooprophylaxis, and despite the success of an insecticide-treated livestock trial in Pakistan, where malaria vectors are highly zoophilic, its effectiveness is yet to be formally tested in Africa where vectors are more anthropophilic. This study aims to clarify the different effects of livestock on malaria and to understand under what circumstances livestock-based interventions could play a role in malaria control programmes. This was explored by developing a mathematical model and combining it with data from Pakistan and Ethiopia. Consistent with previous work, a zooprophylactic effect of untreated livestock is predicted in two situations: if vector population density does not increase with livestock introduction, or if livestock numbers and availability to vectors are sufficiently high such that the increase in vector density is counteracted by the diversion of bites from humans to animals. Although, as expected, insecticide-treatment of livestock is predicted to be more beneficial in settings with highly zoophilic vectors, like South Asia, we find that the intervention could also considerably decrease malaria transmission in regions with more anthropophilic vectors, like Anopheles arabiensis in Africa, under specific circumstances: high treatment coverage of the livestock population, using a product with stronger or longer lasting insecticidal effect than in the Pakistan trial, and with small (ideally null) repellency effect, or if increasing the attractiveness of treated livestock to malaria vectors. The results suggest these are the most appropriate conditions for field testing insecticide-treated livestock in an Africa region with moderately zoophilic vectors, where this intervention could contribute to the integrated control of malaria and livestock diseases.

Patterns in age-seroprevalence consistent with acquired immunity against Trypanosoma brucei in Serengeti lions.

Trypanosomes cause disease in humans and livestock throughout sub-Saharan Africa. Although various species show evidence of clinical tolerance to trypanosomes, until now there has been no evidence of acquired immunity to natural infections. We discovered a distinct peak and decrease in age prevalence of T. brucei s.l. infection in wild African lions that is consistent with being driven by an exposure-dependent increase in cross-immunity following infections with the more genetically diverse species, T. congolense sensu latu. The causative agent of human sleeping sickness, T. brucei rhodesiense, disappears by 6 years of age apparently in response to cross-immunity from other trypanosomes, including the non-pathogenic subspecies, T. brucei brucei. These findings may suggest novel pathways for vaccinations against trypanosomiasis despite the notoriously complex antigenic surface proteins in these parasites.