Response to malaria epidemics in Africa.

Malaria epidemics affect nonimmune populations in many highland and semi-arid areas of Africa. Effective prevention of these epidemics is challenging, particularly in the highlands where predictive accuracy of indicators is not sufficiently high to allow decisions involving expensive measures such as indoor residual spraying of insecticides. Advances in geographic information systems have proved useful in stratification of areas to guide selective targeting of interventions, including barrier application of insecticides in transmission foci to prevent spread of infection. Because rainfall is associated with epidemics in semi-arid areas, early warning methods based on seasonal climate predictions have been proposed. For most areas, response measures should focus on early recognition of anomalies and rapid mass drug administration. Vector control measures are useful if abnormal transmission is highly likely and if they can be selectively implemented at the early stages of an outbreak

Early warning systems for malaria in Africa: from blueprint to practice.

Although the development of early warning systems for malaria has been advocated by international agencies and academic researchers for many years, practical progress in this area has been relatively modest. In two recent articles, Thomson et al. provide new evidence that models of malaria incidence that incorporate monitored or predicted climate can provide early warnings of epidemics one to five months in advance in semi-arid areas. Although the potential benefits of these models in terms of improved management of epidemics are clear, several technical and practical hurdles still need to be overcome before the models can be widely integrated into routine malaria-control strategies

Effect of environmental variables and kdr resistance genotype on survival probability and infection rates in Anopheles gambiae (s.s.).

BACKGROUND: Environmental factors, especially ambient temperature and relative humidity affect both mosquitoes and malaria parasites. The early part of sporogony is most sensitive and is affected by high temperatures and temperature fluctuation immediately following ingestion of an infectious blood meal. The aim of this study was to explore whether environmental variables such as temperature, together with the presence of the kdr insecticide resistance mutations, have an impact on survival probability and infection rates in wild Anopheles gambiae (s.s.) exposed and unexposed to a pyrethroid insecticide. METHODS: Anopheles gambiae (s.s.) were collected as larvae, reared to adults, and fed on blood samples from 42 Plasmodium falciparum-infected local patients at a health facility in mid-western Uganda, then exposed either to nets treated with sub-lethal doses of deltamethrin or to untreated nets. After seven days, surviving mosquitoes were dissected and their midguts examined for oocysts. Prevalence (proportion infected) and intensity of infection (number of oocysts per infected mosquito) were recorded for each group. Mosquito mortality was recorded daily. Temperature and humidity were recorded every 30 minutes throughout the experiments. RESULTS: Our findings indicate that apart from the effect of deltamethrin exposure, mean daily temperature during the incubation period, temperature range during the first 24 hours and on day 4 post-infectious feed had a highly significant effect on the risk of infection. Deltamethrin exposure still significantly impaired survival of kdr homozygous mosquitoes, while mean daily temperature and relative humidity during the incubation period independently affected mosquito mortality. Significant differences in survival of resistant genotypes were detected, with the lowest survival recorded in mosquitoes with heterozygote L1014S/L1014F genotype. CONCLUSIONS: This study confirmed that the early part of sporogony is most affected by temperature fluctuations, while environmental factors affect mosquito survival. The impact of insecticide resistance on malaria infection and vector survival needs to be assessed separately for mosquitoes with different resistance mechanisms to fully understand its implications for currently available vector control tools and malaria transmission

Exposure to deltamethrin affects development of Plasmodium falciparum inside wild pyrethroid resistant Anopheles gambiae s.s. mosquitoes in Uganda.

BACKGROUND: Pyrethroid resistance in African vector mosquitoes is a threat to malaria control. Resistant mosquitoes can survive insecticide doses that would normally be lethal. We studied effects of such doses on Plasmodium falciparum development inside kdr-resistant Anopheles gambiae s.s. in Uganda. METHODS: We collected An. gambiae s.s. homozygous for kdr-L1014S mutation, fed them on blood samples from 42 P. falciparum-infected local patients, then exposed them either to nets treated with sub-lethal doses of deltamethrin or to untreated nets. After seven days, we dissected 692 mosquitoes and examined their midguts for oocysts. Prevalence (proportion infected) and intensity of infection (number of oocysts per infected mosquito) were recorded for each group. RESULTS: Both prevalence and intensity of infection were significantly reduced in deltamethrin-exposed mosquitoes, compared to those exposed to untreated nets. With low doses (2.5-5.0 mg/m(2)), prevalence was reduced by 59% (95% CI = 22%-78%) and intensity by 41% (95% CI = 25%-54%). With high doses (10-16.7 mg/m(2)), prevalence was reduced by 80% (95% CI = 67%-88 %) and intensity by 34 % (95 % CI = 20%-46%). CONCLUSIONS: We showed that, with locally-sampled parasites and mosquitoes, doses of pyrethroids that are sub-lethal for resistant mosquitoes can interfere with parasite development inside mosquitoes. This mechanism could enable pyrethroid-treated nets to prevent malaria transmission despite increasing vector resistance

Forecasting malaria incidence from historical morbidity patterns in epidemic-prone areas of Ethiopia: a simple seasonal adjustment method performs best.

The aim of this study was to assess the accuracy of different methods of forecasting malaria incidence from historical morbidity patterns in areas with unstable transmission. We tested five methods using incidence data reported from health facilities in 20 areas in central and north-western Ethiopia. The accuracy of each method was determined by calculating errors resulting from the difference between observed incidence and corresponding forecasts obtained for prediction intervals of up to 12 months. Simple seasonal adjustment methods outperformed a statistically more advanced autoregressive integrated moving average method. In particular, a seasonal adjustment method that uses mean deviation of the last three observations from expected seasonal values consistently produced the best forecasts. Using 3 years' observation to generate forecasts with this method gave lower errors than shorter or longer periods. Incidence during the rainy months of June-August was the most predictable with this method. Forecasts for the normally dry months, particularly December-February, were less accurate. The study shows the limitations of forecasting incidence from historical morbidity patterns alone, and indicates the need for improved epidemic early warning by incorporating external predictors such as meteorological factors

Application of Serological Tools and Spatial Analysis to Investigate Malaria Transmission Dynamics in Highland Areas of Southwest Uganda.

Serological markers, combined with spatial analysis, offer a comparatively more sensitive means by which to measure and detect foci of malaria transmission in highland areas than traditional malariometric indicators. Plasmodium falciparum parasite prevalence, seroprevalence, and seroconversion rate to P. falciparum merozoite surface protein-119 (MSP-119) were measured in a cross-sectional survey to determine differences in transmission between altitudinal strata. Clusters of P. falciparum parasite prevalence and high antibody responses to MSP-119 were detected and compared. Results show that P. falciparum prevalence and seroprevalence generally decreased with increasing altitude. However, transmission was heterogeneous with hotspots of prevalence and/or seroprevalence detected in both highland and highland fringe altitudes, including a serological hotspot at 2,200 m. Results demonstrate that seroprevalence can be used as an additional tool to identify hotspots of malaria transmission that might be difficult to detect using traditional cross-sectional parasite surveys or through vector studies. Our study findings identify ways in which malaria prevention and control can be more effectively targeted in highland or low transmission areas via serological measures. These tools will become increasingly important for countries with an elimination agenda and/or where malaria transmission is becoming patchy and focal, but receptivity to malaria transmission remains high

Variations in entomological indices in relation to weather patterns and malaria incidence in East African highlands: implications for epidemic prevention and control

<p>Abstract</p> <p>Background</p> <p>Malaria epidemics remain a significant public health issue in the East African highlands. The aim of this study was to monitor temporal variations in vector densities in relation to changes in meteorological factors and malaria incidence at four highland sites in Kenya and Uganda and to evaluate the implications of these relationships for epidemic prediction and control.</p> <p>Methods</p> <p>Mosquitoes were collected weekly over a period of 47 months while meteorological variables and morbidity data were monitored concurrently. Mixed-effects Poisson regression was used to study the temporal associations of meteorological variables to vector densities and of the latter to incidence rates of <it>Plasmodium falciparum</it>.</p> <p>Results</p> <p><it>Anopheles gambiae </it>s.s. was the predominant vector followed by <it>Anopheles arabiensis</it>. <it>Anopheles funestus </it>was also found in low densities. Vector densities remained low even during periods of malaria outbreaks. Average temperature in previous month and rainfall in previous two months had a quadratic and linear relationship with <it>An. gambiae </it>s.s. density, respectively. A significant statistical interaction was also observed between average temperature and rainfall in the previous month. Increases in densities of this vector in previous two months showed a linear relationship with increased malaria incidence.</p> <p>Conclusion</p> <p>Although epidemics in highlands often appear to follow abnormal weather patterns, interactions between meteorological, entomological and morbidity variables are complex and need to be modelled mathematically to better elucidate the system. This study showed that routine entomological surveillance is not feasible for epidemic monitoring or prediction in areas with low endemicity. However, information on unusual increases in temperature and rainfall should be used to initiate rapid vector surveys to assess transmission risk.</p

Costs of early detection systems for epidemic malaria in highland areas of Kenya and Uganda

BACKGROUND: Malaria epidemics cause substantial morbidity and mortality in highland areas of Africa. The costs of detecting and controlling these epidemics have not been explored adequately in the past. This study presents the costs of establishing and running an early detection system (EDS) for epidemic malaria in four districts in the highlands of Kenya and Uganda. METHODS: An economic costing was carried out from the health service provider's perspective in both countries. Staff time for data entry and processing, as well as supervising and coordinating EDS activities at district and national levels was recorded and associated opportunity costs estimated. A threshold analysis was carried out to determine the number of DALYs or deaths that would need to be averted in order for the EDS to be considered cost-effective. RESULTS: The total costs of the EDS per district per year ranged between US$ 14,439 and 15,512. Salaries were identified as major cost-drivers, although their relative contribution to overall costs varied by country. Costs of relaying surveillance data between facilities and district offices (typically by hand) were also substantial. Data from Uganda indicated that 4% or more of overall costs could potentially be saved by switching to data transfer via mobile phones. Based on commonly used thresholds, 96 DALYs in Uganda and 103 DALYs in Kenya would need to be averted annually in each district for the EDS to be considered cost-effective. CONCLUSION: Results from this analysis suggest that EDS are likely to be cost-effective. Further studies that include the costs and effects of the health systems' reaction prompted by EDS will need to be undertaken in order to obtain comprehensive cost-effectiveness estimates

Determinants of the accuracy of rapid diagnostic tests in malaria case management: evidence from low and moderate transmission settings in the East African highlands

BACKGROUND: The accuracy of malaria diagnosis has received renewed interest in recent years due to changes in treatment policies in favour of relatively high-cost artemisinin-based combination therapies. The use of rapid diagnostic tests (RDTs) based on histidine-rich protein 2 (HRP2) synthesized by Plasmodium falciparum has been widely advocated to save costs and to minimize inappropriate treatment of non-malarial febrile illnesses. HRP2-based RDTs are highly sensitive and stable; however, their specificity is a cause for concern, particularly in areas of intense malaria transmission due to persistence of HRP2 antigens from previous infections. METHODS: In this study, 78,454 clinically diagnosed malaria patients were tested using HRP2-based RDTs over a period of approximately four years in four highland sites in Kenya and Uganda representing hypoendemic to mesoendemic settings. In addition, the utility of the tests was evaluated in comparison with expert microscopy for disease management in 2,241 subjects in two sites with different endemicity levels over four months. RESULTS: RDT positivity rates varied by season and year, indicating temporal changes in accuracy of clinical diagnosis. Compared to expert microscopy, the sensitivity, specificity, positive predictive value and negative predictive value of the RDTs in a hypoendemic site were 90.0%, 99.9%, 90.0% and 99.9%, respectively. Corresponding measures at a mesoendemic site were 91.0%, 65.0%, 71.6% and 88.1%. Although sensitivities at the two sites were broadly comparable, levels of specificity varied considerably between the sites as well as according to month of test, age of patient, and presence or absence of fever during consultation. Specificity was relatively high in older age groups and increased towards the end of the transmission season, indicating the role played by anti-HRP2 antibodies. Patients with high parasite densities were more likely to test positive with RDTs than those with low density infections. CONCLUSION: RDTs may be effective when used in low endemicity situations, but high false positive error rates may occur in areas with moderately high transmission. Reports on specificity of RDTs and cost-effectiveness analyses on their use should be interpreted with caution as there may be wide variations in these measurements depending upon endemicity, season and the age group of patients studied

Dried blood spots as a source of anti-malarial antibodies for epidemiological studies

BACKGROUND: Blood spots collected onto filter paper are an established and convenient source of antibodies for serological diagnosis and epidemiological surveys. Although recommendations for the storage and analysis of small molecule analytes in blood spots exist, there are no published systematic studies of the stability of antibodies under different storage conditions. METHODS: Blood spots, on filter paper or glass fibre mats and containing malaria-endemic plasma, were desiccated and stored at various temperatures for different times. Eluates of these spots were assayed for antibodies against two Plasmodium falciparum antigens, MSP-119 and MSP2, and calculated titres used to fit an exponential (first order kinetic) decay model. The first order rate constants (k) for each spot storage temperature were used to fit an Arrhenius equation, in order to estimate the thermal and temporal stability of antibodies in dried blood spots. The utility of blood spots for serological assays was confirmed by comparing antibodies eluted from blood spots with the equivalent plasma values in a series of samples from North Eastern Tanzania and by using blood spot-derived antibodies to estimate malaria transmission intensity in this site and for two localities in Uganda. RESULTS: Antibodies in spots on filter paper and glass fibre paper had similar stabilities but blood was more easily absorbed onto filter papers than glass fibre, spots were more regular and spot size was more closely correlated with blood volume for filter paper spots. Desiccated spots could be stored at or below 4 degrees C for extended periods, but were stable for only very limited periods at ambient temperature. When desiccated, recoveries of antibodies that are predominantly of IgG1 or IgG3 subclasses were similar. Recoveries of antibodies from paired samples of serum and of blood spots from Tanzania which had been suitably stored showed similar recoveries of antibodies, but spots which had been stored for extended periods at ambient humidity and temperature showed severe loss of recoveries. Estimates of malaria transmission intensity obtained from serum and from blood spots were similar, and values obtained using blood spots agreed well with entomologically determined values. CONCLUSION: This study has demonstrated the suitability of filter paper blood spots paper for collection of serum antibodies, and provided clear guidelines for the treatment and storage of filter papers which emphasize the importance of desiccation and minimisation of time spent at ambient temperatures. A recommended protocol for collecting, storing and assaying blood spots is provided