Child mortality and malaria transmission intensity in Africa

The desirability of controlling malaria transmission in the areas of highest endemicity of Plasmodium falciparum has long been debated. Most recently, it has been claimed that rates of malaria morbidity are no higher in areas of very high transmission in Africa than they are in places with lower inoculation rates. We now review the literature on the relationship of morbidity and mortality to malaria transmission intensity, and have linked published child mortality and malaria transmission rates to examine how age-specific mortality actually varies with the inoculation rate of P. falciparum.     

Malaria mortality rates in South Asia and in Africa: implications for malaria control

Malaria mortality in human populations varies greatly under different circumstances. The intense malaria transmission conditions found in many parts of tropical Africa, the much lower malaria inoculation rates currently sustained in areas of southern Asia, and the epidemic outbreaks of malaria occasionally seen on both continents, present highly contrasting patterns of malaria-related mortality. Here Harsha Alles, Kamini Mendis and Richard Carter examine malaria-related mortality under different circumstances and discuss implications for the management of malaria in these settings. They emphasize the power of rapid case treatment to save lives at risk under virtually all circumstances of malaria transmission.     

Urbanization, malaria transmission and disease burden in Africa

Many attempts have been made to quantify Africa's malaria burden but none has addressed how urbanization will affect disease transmission and outcome, and therefore mortality and morbidity estimates. In 2003, 39% of Africa's 850 million people lived in urban settings; by 2030, 54% of Africans are expected to do so. We present the results of a series of entomological, parasitological and behavioural meta-analyses of studies that have investigated the effect of urbanization on malaria in Africa. We describe the effect of urbanization on both the impact of malaria transmission and the concomitant improvements in access to preventative and curative measures. Using these data, we have recalculated estimates of populations at risk of malaria and the resulting mortality. We find there were 1,068,505 malaria deaths in Africa in 2000 - a modest 6.7% reduction over previous iterations. The public-health implications of these findings and revised estimates are discussed.     

Will reducing Plasmodium falciparum transmission alter malaria mortality among African children?

There have been few attempts to examine the relationship between the intensity of transmission and the ensuing burden of disease or mortality from Plasmodium falciparum in Africa. Bob Snow and Kevin Marsh here present the available data on malaria-specific mortality and severe morbidity among African children in relation to estimates of annual rates of falciparum inoculation. These data suggest that cohort mortality from malaria may remain similar between areas experiencing over 100-fold differences in transmission pressure. The authors raise doubts about the possible long-term benefits to children living in areas of high transmission of control strategies aimed at sustained reduction in human-vector contact, for example insecticide-treated bednets.     

What can the residents of malaria endemic countries do to protect themselves against malaria?

The incidence of malaria may vary substantially between adjacent communities and within an individual community, even in areas of high malaria transmission. Analysis of the factors responsible for these local variations in the incidence of malaria may identify potential control measures. Factors shown to be associated with local protection against malaria in some situations include house position, house design, the use of insect repellents and mechanical barriers such as bednets and curtains. The efficacy of insecticide treated nets and curtains in preventing mortality and morbidity from malaria, at least in the short-term, has been demonstrated convincingly. However, other measures of personal protection have not been evaluated in large trials which have clinical malaria as their endpoint. Such trials are needed to see if new malaria control tools can be identified that will assist current international efforts to improve malaria control, especially in Africa. The millions of non-immune travellers who visit malaria endemic areas each year need to protect themselves against malaria and the ways in which they can do this most effectively have been studied extensively. However, less attention has been paid to the local population of malaria endemic areas. What steps can they adopt to provide personal protection against malaria and how effective are these measures? Clues to which measures might be effective can come from study of the reasons for local variations in the incidence of malaria.     

Different response to Plasmodium falciparum in west African sympatric ethnic groups: possible implications for malaria control strategies

The comparison of malaria indicators among populations with different genetic backgrounds and uniformly exposed to the same parasite strains, is one of the approaches to the study of human heterogeneities in the response to the infection. The results of our comparative studies conducted in Burkina Faso, West Africa, showed consistent interethnic differences in Plasmodium falciparum infection rates, malaria morbidity, prevalence and levels of antibodies to various P. falciparum antigens, and genetic background. The differences in the immune response were not explained by the entomological observations which indicated substantially uniform exposure to infective bites. The presence in the same epidemiological context of individuals characterized by different immune reactivity to malaria represents an ideal opportunity to study the possible relationships between the baseline level of anti-malaria immunity of a population and the protective efficacy of control measures based on the reduction of transmission. In spite of similar reduction of entomological inoculation rates obtained by permethrin-impregnated curtains, ethnic- and age-dependent efficacy was observed. These studies demonstrate the existence of marked interethnic differences in the susceptibility to P. falciparum malaria, probably involving the genetic regulation of humoral immune responses. These differences should be considered in the development of anti-malaria vaccines and in the evaluation and application of malaria control strategies.     

Transmission of Plasmodium vivax in south-western Uganda: report of three cases in pregnant women

Plasmodium vivax is considered to be rare in the predominantly Duffy negative populations of Sub-Saharan Africa, as this red blood cell surface antigen is essential for invasion by the parasite. However, despite only very few reports of molecularly confirmed P. vivax from tropical Africa, serological evidence indicated that 13% of the persons sampled in Congo had been exposed to P. vivax. We identified P. vivax by microscopy in 8 smears from Ugandan pregnant women who had been enrolled in a longitudinal study of malaria in pregnancy. A nested polymerase chain reaction (PCR) protocol was used to detect and identify the Plasmodium parasites present. PCR analysis confirmed the presence of P. vivax for three of the women and analysis of all available samples from these women revealed clinically silent chronic low-grade vivax infections for two of them. The parasites in one woman carried pyrimethamine resistance-associated double non-synonymous mutations in the P. vivax dihydrofolate reductase gene. The three women found infected with P. vivax were Duffy positive as were nine of 68 women randomly selected from the cohort. The data presented from these three case reports is consistent with stable transmission of malaria in a predominantly Duffy negative African population. Given the substantial morbidity associated with vivax infection in non-African endemic areas, it will be important to investigate whether the distribution and prevalence of P. vivax have been underestimated in Sub-Saharan Africa. This is particularly important in the context of the drive to eliminate malaria and its morbidity.     

Virulence in malaria: an evolutionary viewpoint

Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.     

Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next?

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine-sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: II: effects of placental malaria on perinatal outcome; malaria and HIV

Placental malaria is recognized as a common complication of malaria in pregnancy in areas of stable transmission, and, as a consequence, serious health problems arise for the mother and especially her baby [1]. Although malaria in pregnancy is a major factor associated with adverse perinatal outcome, the link between malaria and perinatal morbidity/mortality is less clear in areas with stable endemic malaria where pregnant women have acquired immunity [2]. Histological examination of the placenta is a predictor of fetal morbidity, as well as being the most sensitive detector of maternal infection [3]. Adverse perinatal outcome has been described as an important indicator of poor quality of obstetric care and social development [4]. A variety of adverse perinatal outcomes associated with placental malaria have been described, including low birth weight, preterm delivery, intrauterine growth retardation, fetal anemia, congenital malaria, and fetal mortality. The most common clinical features in 80 percent of perinatal cases are fever, anemia, and splenomegaly [5]. Other signs and symptoms include hepatomegaly, jaundice, regurgitation, loose stools, poor feeding, and, occasionally, drowsiness, restlessness, and cyanosis also can be seen [5,6].A review of studies that investigated these poor fetal outcomes associated with placental malaria in sub-Saharan Africa is presented here.     

The epidemiology of malaria in Papua New Guinea

Papua New Guinea (PNG) is a patchwork of different ecological zones, inhabited by human populations of exceptional cultural and linguistic diversity. This results in complex variations in vector ecology and malaria epidemiology. Malaria is the main cause of morbidity in many health facilities in lowland areas, but it is absent in much of the highlands. All four human malaria species occur, but endemicity varies widely, with Plasmodium falciparum locally reaching holo-endemic levels that are rarely found outside sub-Saharan Africa. The high frequency of Plasmodium vivax is an important difference to most African situations. PNG is therefore a prime location for studies of interactions between different parasite species, and of the biology of local human genetic adaptation and its implications for malaria morbidity and mortality.     

Combating malaria morbidity and mortality by reducing transmission

Jean-Fran?ois Trape and Christophe Rogier present epidemiological data and an analysis of the relationship between transmission, morbidity and mortality from malaria which suggest that any intervention aiming to reduce transmission will not, on a long-term basis, reduce the burden of malaria in the majority of epidemiological contexts observed in tropical Africa.     

Seasonally Dependent Relationships between Indicators of Malaria Transmission and Disease Provided by Mathematical Model Simulations

Evaluating the effectiveness of malaria control interventions on the basis of their impact on transmission as well as impact on morbidity and mortality is becoming increasingly important as countries consider pre-elimination and elimination as well as disease control. Data on prevalence and transmission are traditionally obtained through resource-intensive epidemiological and entomological surveys that become difficult as transmission decreases. This work employs mathematical modeling to examine the relationships between malaria indicators allowing more easily measured data, such as routine health systems data on case incidence, to be translated into measures of transmission and other malaria indicators. Simulations of scenarios with different levels of malaria transmission, patterns of seasonality and access to treatment were run with an ensemble of models of malaria epidemiology and within-host dynamics, as part of the OpenMalaria modeling platform. For a given seasonality profile, regression analysis mapped simulation results of malaria indicators, such as annual average entomological inoculation rate, prevalence, incidence of uncomplicated and severe episodes, and mortality, to an expected range of values of any of the other indicators. Results were validated by comparing simulated relationships between indicators with previously published data on these same indicators as observed in malaria endemic areas. These results allow for direct comparisons of malaria transmission intensity estimates made using data collected with different methods on different indicators. They also address key concerns with traditional methods of quantifying transmission in areas of differing transmission intensity and sparse data. Although seasonality of transmission is often ignored in data compilations, the models suggest it can be critically important in determining the relationship between transmission and disease. Application of these models could help public health officials detect changes of disease dynamics in a population and plan and assess the impact of malaria control interventions.     

The origin and dispersion of human parasitic diseases in the old world (Africa,Europe and Madagascar)

The ancestors of present-day man (Homo sapiens sapiens) appeared in East Africa some three and a half million years ago (Australopithecs), and then migrated to Europe, Asia, and later to the Americas, thus beginning the differentiation process. The passage from nomadic to sedentary life took place in the Middle East in around 8000 BC. Wars, spontaneous migrations and forced migrations (slave trade) led to enormous mixtures of populations in Europe and Africa and favoured the spread of numerous parasitic diseases with specific strains according to geographic area. The three human plasmodia (Plasmodium falciparum, P. vivax, and P. malariae) were imported from Africa into the Mediterranean region with the first human migrations, but it was the Neolithic revolution (sedentarisation, irrigation, population increase) which brought about actual foci for malaria. The reservoir for Leishmania infantum and L. donovani--the dog--has been domesticated for thousands of years. Wild rodents as reservoirs of L. major have also long been in contact with man and probably were imported from tropical Africa across the Sahara. L. tropica, by contrast, followed the migrations of man, its only reservoir. L. infantum and L. donovani spread with man and his dogs from West Africa. Likewise, for thousands of years, the dog has played an important role in the spread and the endemic character of hydatidosis through sheep (in Europe and North Africa) and dromadary (in the Sahara and North Africa). Schistosoma haematobium and S. mansoni have existed since prehistoric times in populations living in or passing through the Sahara. These populations then transported them to countries of Northern Africa where the specific, intermediary hosts were already present. Madagascar was inhabited by populations of Indonesian origin who imported lymphatic filariosis across the Indian Ocean (possibly of African origin since the Indonesian sailors had spent time on the African coast before reaching Madagascar). Migrants coming from Africa and Arabia brought with them the two African forms of bilharziosis: S. haematobium and S. mansoni.     

Modeling Future Conservation of Hawaiian Honeycreepers by Mosquito Management and Translocation of Disease-Tolerant Amakihi

Avian malaria is an important cause of the decline of endemic Hawaiian honeycreepers. Because of the complexity of this disease system we used a computer model of avian malaria in forest birds to evaluate how two proposed conservation strategies: 1) reduction of habitat for mosquito larvae and 2) establishment of a low-elevation, malaria-tolerant honeycreeper (Hawaii Amakihi) to mid-elevation forests would affect native Hawaiian honeycreeper populations. We evaluated these approaches in mid-elevation forests, where malaria transmission is seasonal and control strategies are more likely to work. Our model suggests the potential benefit of larval habitat reduction depends on the level of malaria transmission, abundance of larval cavities, and the ability to substantially reduce these cavities. Permanent reduction in larval habitat of >80% may be needed to control abundance of infectious mosquitoes and benefit bird populations. Establishment of malaria-tolerant Amakihi in mid-elevation forests increases Amakihi abundance, creates a larger disease reservoir, and increases the abundance of infectious mosquitoes which may negatively impact other honeycreepers. For mid-elevation sites where bird populations are severely affected by avian malaria, malaria-tolerant Amakihi had little impact on other honeycreepers. Both management strategies may benefit native Hawaiian honeycreepers, but benefits depend on specific forest characteristics, the amount of reduction in larval habitat that can be achieved, and how malaria transmission is affected by temperature.     

Pyrimethamine–sulfadoxine resistance in Plasmodium falciparum: what next?

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine–sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.     

Sickle cell disease and malaria morbidity: a tale with two tails

More than 230,000 children are born in Africa with sickle cell disease (SCD) each year: approximately 85% of all affected births worldwide. Although malaria is commonly viewed as a major problem for African patients with this condition, questions still remain about its relative importance as a cause of ill heath and death. In the absence of definitive studies investigating the contribution of malaria to morbidity and mortality in African children with SCD, policy makers will continue to lack the evidence on which to base appropriate management guidelines.     

Diagnosis of malaria: challenges for clinicians in endemic and non-endemic regions

Malaria is a leading cause of morbidity and mortality worldwide. Prompt diagnosis and treatment are critical factors in reducing morbidity and mortality, as delayed treatment of malaria increases the risk of death. Microscopy has long been the standard of malaria diagnosis, but newer diagnostic tests now offer advantages in certain settings. Malaria diagnosis is complicated by the fact that acquired immunity to malaria can result in asymptomatic infections. In a symptomatic (febrile) patient, no existing malaria diagnostic test can distinguish malarial illness from parasitemia with concomitant fever of another cause. In this review we discuss the available malaria diagnostic tests, appropriate applications for each, and the challenges of malaria diagnosis in both endemic and non-endemic settings.     

Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

Artemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the 'premier' combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.     

Genetic differentiation of Anopheles gambiae s.s. populations in Mali,West Africa,using microsatellite loci

Anopheles gambiae sensu stricto is a principal vector of malaria through much of sub-Saharan Africa, where this disease is a major cause of morbidity and mortality in human populations. Accordingly, population sizes and gene flow in this species have received special attention, as these parameters are important in attempts to control malaria by impacting its mosquito vector. Past measures of genetic differentiation have sometimes yielded conflicting results, in some cases suggesting that gene flow is extensive over vast distances (6000 km) and is disrupted only by major geological disturbances and/or barriers. Using microsatellite DNA loci from populations in Mali, West Africa, we measured genetic differentiation over uniform habitats favorable to the species across distances ranging from 62 to 536 km. Gene flow was strongly correlated with distance (r(2) = 0.77), with no major differences among chromosomes. We conclude that in this part of Africa, at least, genetic differentiation for microsatellite DNA loci is consistent with traditional models of isolation by distance.