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Background Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods and Findings This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. Conclusions A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. Trial registration Pan African Clinical Trials Registry PACTR201102000277177, In a randomized trial, Sanjeev Krishna and colleagues test for non-inferiority of a simplified artemisinin regimen as treatment for malaria in a low-resource setting., Editors' Summary Background Globally, about 200 million cases of malaria—a mosquito-borne parasitic disease—occur every year. Malaria infections, which can be caused by several parasites, can be “uncomplicated” or “severe.” Prompt treatment of uncomplicated malaria, which presents with flu-like symptoms, is essential to prevent the development of severe malaria. The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the first-line treatment of uncomplicated malaria in countries where the disease is always present. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are cleared rapidly from the body) are combined with a slower-acting, more slowly eliminated partner drug to prevent the original infection recurring and to reduce the risk of the malaria parasites becoming resistant to either drug. Severe malaria, which is usually caused by Plasmodium falciparum, is characterized by anemia and by damage to the brain and other organs. Severe malaria kills more than 400,000 people (mainly young children living in sub-Saharan Africa) every year. Why Was This Study Done? WHO recommends that severe malaria be treated with intravenous or intramuscular injections of artesunate, a parenteral (injectable) form of artemisinin; patients with severe malaria cannot take pills reliably or safely. Specifically, WHO recommends that patients be given 2.4 mg of artesunate per kilogram of body weight intravenously or intramuscularly at the time of admission (0 hours) and at 12, 24, 48, and 72 hours (followed by ACT to ensure full parasite clearance). But this five-dose regimen is complex. A simpler regimen would be easier to administer in resource-limited settings, where giving the correct doses on time to small, sick children can be challenging. In this open-label, non-inferiority randomized controlled trial (RCT), the researchers investigate the efficacy of a three-dose artesunate regimen for the treatment of severe malaria in African children. RCTs compare outcomes in people randomly chosen to receive different interventions; in an open-label RCT, both the researchers and the participants know which treatment is being given; a non-inferiority trial investigates whether one treatment is not worse than another treatment. What Did the Researchers Do and Find? The researchers randomly allocated 1,047 children aged six months to ten years with severe malaria attending seven clinical centers in five African countries to receive a total dose of 12 mg of artesunate per kilogram of body weight as five intramuscular injections of 2.4 mg/kg given at 0, 12, 24, 48, and 72 hours (the control regimen) or as three intramuscular or intravenous injections of 4 mg/kg given at 0, 12, and 24 hours (three-dose intramuscular and intravenous regimens, respectively). The trial’s primary endpoint was the proportion of children whose parasitemia (parasite count in the blood) at 24 hours was ≤1% of that at admission (in other words, ≥99% parasite clearance). Among the 1,002 children who received the planned drug doses (the per-protocol population), 78% in the three-dose intramuscular group had ≥99% parasite clearance compared to 79% in the five-dose intramuscular group, a result that met a preset criterion for non-inferiority at 24 hours of the three-dose intramuscular regimen to the control regimen. However, because only 74% of the children in the three-dose intravenous group had ≥99% parasite clearance, this regimen was not shown to be non-inferior to the conventional five-dose regimen. What Do These Findings Mean? These findings when combined with the findings of several secondary analyses suggest that, in African children, a three-dose intramuscular artesunate regimen is non-inferior to the WHO-recommended regimen for the treatment of severe malaria. The study’s open-label design may limit the accuracy of its findings, as may its use of a primary endpoint midway through drug treatment rather than at the end (the researchers note that 60% of deaths from severe malaria occur during the first 24 hours of illness and that parasitemia is harder to measure later during treatment) and its use of parasite clearance rather than death as the primary endpoint (case fatality rates in severe malaria treatment trials are very low, so a much larger study would be needed if death were used as the primary endpoint). Overall, these findings support the use of the three-dose intramuscular artesunate regimen for the treatment of severe malaria. Importantly, however, 22% of the children in the study developed delayed anemia, irrespective of treatment regimen. Thus, although further studies are needed to clarify whether treatment with artesunate or the malaria infection itself was responsible for the delayed anemia, patients treated with artesunate for severe malaria should be routinely monitored for this complication. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001938. Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2014 provides details of the current global malaria situation, including information on malaria in individual African countries; WHO’s Guidelines for the Treatment of Malaria and its Management of Severe Malaria: A Practical Handbook are available The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria The UK National Health Service Choices website also provides information about malaria, including a personal story Information is available from the Roll Back Malaria Partnership on the global control of malaria The Scientists Against Malaria collaboration applies modern drug design and modeling techniques to develop new treatments against malaria; its website includes information about many aspects of malaria Public Health England provides a collection of guidance and research and analysis on malaria MedlinePlus provides links to additional information on malaria (in English and Spanish) More information about this trial is available

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children due to lower acquired immunity, and this has implications for ongoing control strategies. Methods and Findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child’s age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval [CI] 0.54–0.58) in 1998 to 0.07 (95% CI 0.06–0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22–0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030–0.040] among young children compared to 0.22 [95% CI 0.21–0.23] in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to, Using observational data over 25 years, Polycarp Mogeni and colleagues examine the age, spatial, and temporal variations in malaria hospital admissions in Kilifi County, Kenya., Author Summary Why Was This Study Done? The past decade has seen a marked decline in malaria transmission in some parts of Africa alongside substantial investments to control malaria. However, malaria remains a public health emergency in sub-Saharan Africa. As malaria declines in some parts of Africa, older children may become more susceptible to clinical malaria because reduced exposure earlier in life decreases opportunities for acquired immunity. Insecticide-treated net (ITN) use in randomized controlled trials and observational studies of effectiveness has been associated with reduced malaria morbidity and mortality. Given the ongoing global campaign to increase coverage, there is need for continuous assessment of ITN effectiveness in field conditions. What Did the Researchers Do and Find? We analyzed 25 y of longitudinal surveillance data of hospital admissions to Kilifi County Hospital in the Kenyan Coast between 1990 and 2014. We included 69,104 children between 3 mo and 13 y of age in the analysis. We observed a decline in the proportion of admitted children with malaria parasites on blood testing from 1998 to 2009. However, there was a steady and marked increase in the proportion of admitted children with malaria parasites in their blood from 2009 to 2014. This coincided with a shift of malaria burden from younger to older children. Fortunately, there was no increase in malaria-related mortality. The proportion of children with malaria parasites was consistently higher in the southern region of Kilifi County compared to the north, thereby providing an opportunity for targeted interventions. However, within the northern and southern regions there was substantial geographical variability from year to year, which would complicate targeted control. Community ITN use around the admitted child’s residence was highly effective—i.e., children presenting for admission surrounded by high ITN usage at the community level were less likely to present with malaria parasites compared with those surrounded by low ITN usage. What Do These Findings Mean? These findings suggest that further reductions of malaria transmission are needed to mitigate the increasing burden among older children and that universal ITN coverage is a promising strategy to achieve this goal.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition., The accepted definition of severe malaria is appropriate for clinical purposes, but Philip Bejon and colleagues show its specificity in clinical trials may be improved by a parasite density threshold and by excluding children with certain conditions., Editors' Summary Background. Malaria is responsible for over a million deaths every year, and most of those who die are children in Africa. Until a few years ago, not enough research was being done on malaria, but now many researchers are active in this field. Doctors describe some cases of malaria as being “severe.” Severe malaria in children is very hard to diagnose precisely. Current protocols for diagnosing severe malaria are very sensitive: that is, virtually all children who do have severe malaria will be correctly diagnosed as such. However, the protocols are not very specific: many children who do not have severe malaria, but whose symptoms are instead caused by other diseases, will be defined as suffering from severe malaria. This definition is acceptable for the clinical care of sick children, because it ensures that antimalarial drugs are given to all who might benefit from them, plus some additional children for whom those drugs are not required. However, this definition is not particularly useful for research purposes. When conducting a clinical trial aimed at preventing cases of malaria, it is important to evaluate whether the intervention being tested actually works. Therefore, a more specific method of calculating the number of malaria cases within a population is needed for this type of research. Why Was This Study Done? The current definition for diagnosing severe malaria includes a set of signs and symptoms that may be observed at the bedside or as a result of laboratory investigation, along with the detection of malaria parasites in the patient's blood. However, in many malarious areas, a large proportion of the population carries malaria parasites without signs of disease; at the same time, the signs and symptoms of malaria are shared with other diseases. The investigators here wanted to find out whether they could develop an accurate “case definition” of severe malaria that can be used in research. What Did the Researchers Do and Find? In this study, two groups of children were studied: first, 1,422 children admitted to the children's wards of the Kilifi District Hospital in Kenya, and second, 4,583 children from the surrounding community. Blood samples were taken in order to find out how common malaria parasites were in the children's blood, and standard clinical and laboratory data were also collected from the children admitted to the hospital. The researchers then compared these data using a computer and tried to find out whether, by excluding certain children who had particular signs, symptoms, or observations, from the diagnosis of severe malaria, they were able to improve the accuracy of their definition. Essentially, for each patient group, the authors calculated “malaria-attributable fractions,” i.e., the proportion of individuals studied whose disease was likely caused by malaria. The researchers found that in areas with low and moderate transmission of malaria, the proportion of individuals whose disease could be attributed to malaria was high—nearly 85%. In areas with a high transmission rate of malaria, this fraction was much lower, but could be improved by including only children with a high proportion of parasites in their blood. Importantly, the researchers were also able to increase the recognition of children with disease likely caused by malaria by excluding individuals who had also been diagnosed with gastroenteritis, lower respiratory tract infections, meningitis, and bacterial infection in the blood. If all of these individuals were excluded—so only individuals with more than 2,500 parasites per microliter in their blood were regarded as having severe malaria—the “malaria-attributable fraction” rose to 95%. What Do These Findings Mean? These findings should not be directly used to change the clinical care of children with the signs and symptoms of severe malaria, but rather can be used within a clinical trial to create a “case definition” of malaria particular to that trial. This ability will help researchers more accurately find out whether the intervention being tested in their trial really does help to prevent cases of malaria or not. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040251. The World Health Organization Global Malaria Programme details the organization's activities in fighting malaria, and provides a number of helpful resources; a factsheet on children and malaria is also available The US Centers for Disease Control and Prevention provides many malaria resources General information about malaria, including illustrations, is available from the“Medline Plus” encyclopedia