The contribution of agricultural insecticide use to increasing insecticide resistance in African malaria vectors.

The fight against malaria is increasingly threatened by failures in vector control due to growing insecticide resistance. This review examines the recent primary research that addresses the putative relationship between agricultural insecticide use and trends in insecticide resistance. To do so, descriptive evidence offered by the new research was categorized, and additional factors that impact the relationship between agricultural insecticide use and observed insecticide resistance in malaria vectors were identified. In 23 of the 25 relevant recent publications from across Africa, higher resistance in mosquito populations was associated with agricultural insecticide use. This association appears to be affected by crop type, farm pest management strategy and urban development.

Ross, macdonald, and a theory for the dynamics and control of mosquito-transmitted pathogens.

Ronald Ross and George Macdonald are credited with developing a mathematical model of mosquito-borne pathogen transmission. A systematic historical review suggests that several mathematicians and scientists contributed to development of the Ross-Macdonald model over a period of 70 years. Ross developed two different mathematical models, Macdonald a third, and various "Ross-Macdonald" mathematical models exist. Ross-Macdonald models are best defined by a consensus set of assumptions. The mathematical model is just one part of a theory for the dynamics and control of mosquito-transmitted pathogens that also includes epidemiological and entomological concepts and metrics for measuring transmission. All the basic elements of the theory had fallen into place by the end of the Global Malaria Eradication Programme (GMEP, 1955-1969) with the concept of vectorial capacity, methods for measuring key components of transmission by mosquitoes, and a quantitative theory of vector control. The Ross-Macdonald theory has since played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention.

Host immune constraints on malaria transmission: insights from population biology of within-host parasites.

BACKGROUND: Plasmodium infections trigger complex immune reactions from their hosts against several life stages of the parasite, including gametocytes. These immune responses are highly variable, depending on age, genetics, and exposure history of the host as well as species and strain of parasite. Although the effects of host antibodies that act against gamete stages in the mosquito (due to uptake in the blood meal) are well documented, the effects of host immunity upon within-host gametocytes are not as well understood. This report consists of a theoretical population biology-based analysis to determine constraints that host immunity impose upon gametocyte population growth. The details of the mathematical models used for the analysis were guided by published reports of clinical and animal studies, incorporated plausible modalities of immune reactions to parasites, and were tailored to the life cycl es of the two most widespread human malaria pathogens, Plasmodium falciparum and Plasmodium vivax. RESULTS: For the same ability to bind and clear a target, the model simulations suggest that an antibody attacking immature gametocytes would tend to lower the overall density of transmissible mature gametocytes more than an antibody attacking the mature forms directly. Transmission of P. falciparum would be especially vulnerable to complete blocking by antibodies to its immature forms since its gametocytes take much longer to reach maturity than those of P. vivax. On the other hand, antibodies attacking the mature gametocytes directly would reduce the time the mature forms can linger in the host. Simulation results also suggest that varying the standard deviation in the time necessary for individual asexual parasites to develop and produce schizonts can affect the efficiency of production of transmissible gametocytes. CONCLUSIONS: If mature gametocyte density determines the probability of transmission, both Plasmodium species, but especially P. falciparum, could bolster this probability through evasion or suppression of host immune responses against the immature gametocytes. However, if the long term lingering of mature gametocytes at low density in the host is also important to ensure transmission, then evasion or suppression of antibodies against the mature stages would bolster probability of transmission as well.

Foetal haemoglobin and the dynamics of paediatric malaria.

BACKGROUND: Although 80% of malaria occurs in children under five years of age, infants under six months of age are known to have low rates of infection and disease. It is not clear why this youngest age group is protected; possible factors include maternal antibodies, unique nutrition (breast milk), and the presence of foetal haemoglobin (HbF). This work aims to gain insight into possible mechanisms of protection, and suggest pathways for focused empirical work, by modelling a range of possible effects of foetal haemoglobin and other red blood cell (RBC) developmental changes on parasite dynamics in infants. METHODS: A set of ordinary differential equations was created to investigate the leading hypotheses about the possible protective mechanisms of HbF-containing red blood cells, in particular whether HbF suppresses parasite population growth because parasite multiplication in individual RBCs is lower, slower or absent. The model also incorporated the intrinsic changes in blood volume and haematocrit that occur with age, and the possibility of parasite affinities for HbF-containing RBCs or reticulocytes. RESULTS: The model identified several sets of conditions in which the infant remained protected, or displayed a much slower growth of parasitaemia in the first few months of life, without any intervening immune response. The most protective of the hypothesized mechanisms would be the inhibition of schizont division in foetal RBCs so that fewer merozoites are produced. The model showed that a parasite preference for HbF-containing RBCs increases protective effects for the host, while a preference for reticulocytes has little effect. CONCLUSIONS: The results from this simple model of haematological changes in infants and their effects on Plasmodium falciparum infection dynamics emphasize the likely importance of HbF and RBC number as an explanatory factor in paediatric malaria, and suggest a framework for organizing related empirical research.

Developmental allometry and paediatric malaria.

WHO estimates that 80% of mortality due to malaria occurs among infants and young children. Though it has long been established that malaria disproportionately affects children under age five, our understanding of the underlying biological mechanisms for this distribution remains incomplete. Many studies use age as an indicator of exposure, but age may affect malaria burden independently of previous exposure. Not only does the severity of malaria infection change with age, but the clinical manifestation of disease does as well: younger children are more likely to suffer severe anaemia, while older children are more likely to develop cerebral malaria. Intensity of transmission and acquired immunity are important determinants of this age variation, but age differences remain consistent over varying transmission levels. Thus, age differences in clinical presentation may involve inherent age-related factors as well as still-undiscovered facets of acquired immunity, perhaps including the rates at which relevant aspects of immunity are acquired. The concept of "allometry" - the relative growth of a part in relation to that of an entire organism or to a standard - has not previously been applied in the context of malaria infection. However, because malaria affects a number of organs and cells, including the liver, red blood cells, white blood cells, and spleen, which may intrinsically develop at rates partly independent of each other and of a child's overall size, developmental allometry may influence the course and consequences of malaria infection. Here, scattered items of evidence have been collected from a variety of disciplines, aiming to suggest possible research paths for investigating exposure-independent age differences affecting clinical outcomes of malaria infection.

Revisiting the basic reproductive number for malaria and its implications for malaria control.

The prospects for the success of malaria control depend, in part, on the basic reproductive number for malaria, R0. Here, we estimate R0 in a novel way for 121 African populations, and thereby increase the number of R0 estimates for malaria by an order of magnitude. The estimates range from around one to more than 3,000. We also consider malaria transmission and control in finite human populations, of size H. We show that classic formulas approximate the expected number of mosquitoes that could trace infection back to one mosquito after one parasite generation, Z0(H), but they overestimate the expected number of infected humans per infected human, R0(H). Heterogeneous biting increases R0 and, as we show, Z0(H), but we also show that it sometimes reduces R0(H); those who are bitten most both infect many vectors and absorb infectious bites. The large range of R0 estimates strongly supports the long-held notion that malaria control presents variable challenges across its transmission spectrum. In populations where R0 is highest, malaria control will require multiple, integrated methods that target those who are bitten most. Therefore, strategic planning for malaria control should consider R0, the spatial scale of transmission, human population density, and heterogeneous biting.

Using the entomological inoculation rate to assess the impact of vector control on malaria parasite transmission and elimination.

BACKGROUND: Prior studies have shown that annual entomological inoculation rates (EIRs) must be reduced to less than one to substantially reduce the prevalence of malaria infection. In this study, EIR values were used to quantify the impact of insecticide-treated bed nets (ITNs), indoor residual spraying (IRS), and source reduction (SR) on malaria transmission. The analysis of EIR was extended through determining whether available vector control tools can ultimately eradicate malaria. METHOD: The analysis is based primarily on a review of all controlled studies that used ITN, IRS, and/or SR and reported their effects on the EIR. To compare EIRs between studies, the percent difference in EIR between the intervention and control groups was calculated. RESULTS: Eight vector control intervention studies that measured EIR were found: four ITN studies, one IRS study, one SR study, and two studies with separate ITN and IRS intervention groups. In both the Tanzania study and the Solomon Islands study, one community received ITNs and one received IRS. In the second year of the Tanzania study, EIR was 90% lower in the ITN community and 93% lower in the IRS community, relative to the community without intervention; the ITN and IRS effects were not significantly different. In contrast, in the Solomon Islands study, EIR was 94% lower in the ITN community and 56% lower in the IRS community. The one SR study, in Dar es Salaam, reported a lower EIR reduction (47%) than the ITN and IRS studies. All of these vector control interventions reduced EIR, but none reduced it to zero. CONCLUSION: These studies indicate that current vector control methods alone cannot ultimately eradicate malaria because no intervention sustained an annual EIR less than one. While researchers develop new tools, integrated vector management may make the greatest impact on malaria transmission. There are many gaps in the entomological malaria literature and recommendations for future research are provided.

Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty.

BACKGROUND: The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. METHODS: Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models. RESULTS: Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT) for malaria was estimated, and a policy of multiple first-line therapies (MFTs) was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases. CONCLUSIONS: At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.

Spatial patterns in discordant diagnostic test results for Chagas disease: links to transmission hotspots.

Diagnosis of Chagas disease is hindered by discordance between screening and confirmatory test results for Trypanosoma cruzi infection. In periurban Arequipa, Peru, spatial analysis revealed that individuals with discordant test results are spatially clustered in hotspots of T. cruzi transmission, suggesting that discordant results likely represent true infections in this setting.

Host control of malaria infections: constraints on immune and erythropoeitic response kinetics.

The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time

The multiplicity of malaria transmission: a review of entomological inoculation rate measurements and methods across sub-Saharan Africa.

Plasmodium falciparum malaria is a serious tropical disease that causes more than one million deaths each year, most of them in Africa. It is transmitted by a range of Anopheles mosquitoes and the risk of disease varies greatly across the continent. The "entomological inoculation rate" is the commonly-used measure of the intensity of malaria transmission, yet the methods used are currently not standardized, nor do they take the ecological, demographic, and socioeconomic differences across populations into account. To better understand the multiplicity of malaria transmission, this study examines the distribution of transmission intensity across sub-Saharan Africa, reviews the range of methods used, and explores ecological parameters in selected locations. It builds on an extensive geo-referenced database and uses geographical information systems to highlight transmission patterns, knowledge gaps, trends and changes in methodologies over time, and key differences between land use, population density, climate, and the main mosquito species. The aim is to improve the methods of measuring malaria transmission, to help develop the way forward so that we can better assess the impact of the large-scale intervention programmes, and rapid demographic and environmental change taking place across Africa.

Environmental factors associated with the malaria vectors Anopheles gambiae and Anopheles funestus in Kenya.

BACKGROUND: The Anopheles gambiae and Anopheles funestus mosquito species complexes are the primary vectors of Plasmodium falciparum malaria in sub-Saharan Africa. To better understand the environmental factors influencing these species, the abundance, distribution and transmission data from a south-eastern Kenyan study were retrospectively analysed, and the climate, vegetation and elevation data in key locations compared. METHODS: Thirty villages in Malindi, Kilifi and Kwale Districts with data on An. gambiae sensu strict, Anopheles arabiensis and An. funestus entomological inoculation rates (EIRs), were used as focal points for spatial and environmental analyses. Transmission patterns were examined for spatial autocorrelation using the Moran's I statistic, and for the clustering of high or low EIR values using the Getis-Ord Gi* statistic. Environmental data were derived from remote-sensed satellite sources of precipitation, temperature, specific humidity, Normalized Difference Vegetation Index (NDVI), and elevation. The relationship between transmission and environmental measures was examined using bivariate correlations, and by comparing environmental means between locations of high and low clustering using the Mann-Whitney U test. RESULTS: Spatial analyses indicated positive autocorrelation of An. arabiensis and An. funestus transmission, but not of An. gambiae s.s., which was found to be widespread across the study region. The spatial clustering of high EIR values for An. arabiensis was confined to the lowland areas of Malindi, and for An. funestus to the southern districts of Kilifi and Kwale. Overall, An. gambiae s.s. and An. arabiensis had similar spatial and environmental trends, with higher transmission associated with higher precipitation, but lower temperature, humidity and NDVI measures than those locations with lower transmission by these species and/or in locations where transmission by An. funestus was high. Statistical comparisons indicated that precipitation and temperatures were significantly different between the An. arabiensis and An. funestus high and low transmission locations. CONCLUSION: These finding suggest that the abundance, distribution and malaria transmission of different malaria vectors are driven by different environmental factors. A better understanding of the specific ecological parameters of each malaria mosquito species will help define their current distributions, and how they may currently and prospectively be affected by climate change, interventions and other factors.

The spatial and temporal patterns of falciparum and vivax malaria in Perú: 1994-2006.

BACKGROUND: Malaria is the direct cause of approximately one million deaths worldwide each year, though it is both preventable and curable. Increasing the understanding of the transmission dynamics of falciparum and vivax malaria and their relationship could suggest improvements for malaria control efforts. Here the weekly number of malaria cases due to Plasmodium falciparum (1994-2006) and Plasmodium vivax (1999-2006) in Perú at different spatial scales in conjunction with associated demographic, geographic and climatological data are analysed. METHODS: Malaria periodicity patterns were analysed through wavelet spectral analysis, studied patterns of persistence as a function of community size and assessed spatial heterogeneity via the Lorenz curve and the summary Gini index. RESULTS: Wavelet time series analyses identified annual cycles in the incidence of both malaria species as the dominant pattern. However, significant spatial heterogeneity was observed across jungle, mountain and coastal regions with slightly higher levels of spatial heterogeneity for P. vivax than P. falciparum. While the incidence of P. falciparum has been declining in recent years across geographic regions, P. vivax incidence has remained relatively steady in jungle and mountain regions with a slight decline in coastal regions. Factors that may be contributing to this decline are discussed. The time series of both malaria species were significantly synchronized in coastal (rho = 0.9, P < 0.0001) and jungle regions (rho = 0.76, P < 0.0001) but not in mountain regions. Community size was significantly associated with malaria persistence due to both species in jungle regions, but not in coastal and mountain regions. CONCLUSION: Overall, findings highlight the importance of highly refined spatial and temporal data on malaria incidence together with demographic and geographic information in improving the understanding of malaria persistence patterns associated with multiple malaria species in human populations, impact of interventions, detection of heterogeneity and generation of hypotheses.

Strain theory of malaria: the first 50 years.

From the 1920s to the 1970s, a large body of principles and evidence accumulated about the existence and character of 'strains' among the Plasmodium species responsible for human malaria. An extensive research literature examined the degree to which strains were autonomous, stable biological entities, distinguishable by clinical, epidemiological or other features, and how this knowledge could be used to benefit medical and public health practice. Strain theory in this era was based largely on parasite phenotypes related to clinical virulence, reactions to anti-malarial drugs, infectivity to mosquitoes, antigenic properties and host immunity, latency and relapse. Here we review the search for a definition of 'strain', suggest how the data and discussion shaped current understandings of many aspects of malaria and sketch a number of specific connections with perspectives from the past 30 years.

Parasite prevalence: a static measure of dynamic infections.

The intensity of malaria transmission is often measured by looking at the fraction of individuals infected at a given point in time. However, malaria infections in individuals are dynamic, leading to uncertainty about whether a cross-sectional survey that represents a single snapshot in time is a useful representation of a temporally complex process. In this analysis, we examine the impact of parasite density fluctuations on the measurement of parasite prevalence. Our results show that parasite prevalence may be underestimated by 20% or more, depending on the sensitivity of parasite detection.

The risk of a mosquito-borne infection in a heterogeneous environment.

A common assumption about malaria, dengue, and other mosquito-borne infections is that the two main components of the risk of human infection--the rate at which people are bitten (human biting rate) and the proportion of mosquitoes that are infectious--are positively correlated. In fact, these two risk factors are generated by different processes and may be negatively correlated across space and time in heterogeneous environments. Uneven distribution of blood-meal hosts and larval habitat creates a spatial mosaic of demograPhic sources and sinks. Moreover, mosquito populations fluctuate temporally, forced by environmental variables such as rainfall, temperature, and humidity. These sources of spatial and temporal heterogeneity in the distribution of mosquito populations generate variability in the human biting rate, in the proportion of mosquitoes that are infectious, and in the risk of human infection. To understand how heterogeneity affects the epidemiology of mosquito-borne infections, we developed a set of simple models that incorporate heterogeneity in a stepwise fashion. These models predict that the human biting rate is highest shortly after the mosquito densities peak, near breeding sites where adult mosquitoes emerge, and around the edges of areas where humans are aggregated. In contrast, the proportion of mosquitoes that are infectious reflects the age structure of mosquito populations; it peaks where old mosquitoes are found, far from mosquito breeding habitat, and when mosquito population density is declining. Finally, we show that estimates for the average risk of infection that are based on the average entomological inoculation rate are strongly biased in heterogeneous environments.

Malaria vaccine efficacy: the difficulty of detecting and diagnosing malaria.

New sources of funding have revitalized efforts to control malaria. An effective vaccine would be a tremendous asset in the fight against this devastating disease and increasing financial and scientific resources are being invested to develop one. A few candidates have been tested in Phase I and II clinical trials, and several others are poised to begin trials soon. Some studies have been promising, and others disappointing. It is difficult to compare the results of these clinical trials; even independent trials of the same vaccine give highly discrepant results. One major obstacle in evaluating malaria vaccines is the difficulty of diagnosing clinical malaria. This analysis evaluates the impact of diagnostic error, particularly that introduced by microscopy, on the outcome of efficacy trials of malaria vaccines and make recommendations for improving future trials.

An elaborated feeding cycle model for reductions in vectorial capacity of night-biting mosquitoes by insecticide-treated nets.

BACKGROUND: Insecticide Treated Nets (ITNs) are an important tool for malaria control. ITNs are effective because they work on several parts of the mosquito feeding cycle, including both adult killing and repelling effects. METHODS: Using an elaborated description of the classic feeding cycle model, simple formulas have been derived to describe how ITNs change mosquito behaviour and the intensity of malaria transmission, as summarized by vectorial capacity and EIR. The predicted changes are illustrated as a function of the frequency of ITN use for four different vector populations using parameter estimates from the literature. RESULTS: The model demonstrates that ITNs simultaneously reduce mosquitoes' lifespans, lengthen the feeding cycle, and by discouraging human biting divert more bites onto non-human hosts. ITNs can substantially reduce vectorial capacity through small changes to all of these quantities. The total reductions in vectorial capacity differ, moreover, depending on baseline behavior in the absence of ITNs. Reductions in lifespan and vectorial capacity are strongest for vector species with high baseline survival. Anthropophilic and zoophilic species are affected differently by ITNs; the feeding cycle is lengthened more for anthrophilic species, and the proportion of bites that are diverted onto non-human hosts is higher for zoophilic species. CONCLUSION: This model suggests that the efficacy of ITNs should be measured as a total reduction in transmission intensity, and that the quantitative effects will differ by species and by transmission intensity. At very high rates of ITN use, ITNs can generate large reductions in transmission intensity that could provide very large reductions in transmission intensity, and effective malaria control in some areas, especially when used in combination with other control measures. At high EIR, ITNs will probably not substantially reduce the parasite rate, but when transmission intensity is low, reductions in vectorial capacity combine with reductions in the parasite rate to generate very large reductions in EIR.

A stochastic model of immune-modulated malaria infection and disease in children.

We develop a simple three-state stochastic description of individual malaria infections that relates dynamics of disease and immune status to age and previous exposure, under different intensities of transmission. We apply the resulting individual-based community models to examine the effects of drug treatment and vaccination on the frequency and severity of disease in ensembles of children. The several broad qualitative similarities between our results and field observations include potential rebound effects following intervals of drug treatment.

Gametocytemia and fever in human malaria infections.

We examine the charts of 408 malaria-naive neurosyphilis patients given malaria therapy at the South Carolina USPHS facility, with daily records encompassing at least 93% of the duration of infection, and focus on the 152 patients infected with the St. Elizabeth strain of Plasmodium vivax, 82 with the McLendon strain of Plasmodium filciparum, 36 with the USPHS strain of Plasmodium malariae, and 15 with the Donaldson strain of Plasmodium ovale in whom gametocytes appeared before drug, or other, intervention. In P. vivax infections, fever and parasitemia were higher after gametocytes were first detected than before; in P. malariae infections, parasitemia was higher. In P. ovale infections, fever and parasitemia were similar before and after. In P. falciparum infections, fever, parasitemia, and fever frequency were lower after gametocytes were first detected than before. Parasitemia and temperature correlated in P. vivax infections, before and after gametocytes were first detected; parasitemia and temperature at first fever were not correlated in infections with any species. Gametocyte density correlated with parasitemia in P. malariae and sporozoite-induced P. falciparum and P. vivax infections. Fevers and detected gametocytemia coincided more often than expected by chance with P. vivax and P. ovale; fever temperature and gametocyte density were not correlated in infections with any species.