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Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.

© 2015 Gathara et al. Background: Regular assessment of quality of care allows monitoring of progress towards system goals and identifies gaps that need to be addressed to promote better outcomes.We report efforts to initiate routine assessments in a low-income country in partnership with government. Methods: A cross-sectional survey undertaken in 22 'internship training' hospitals across Kenya that examined availability of essential resources and process of care based on review of 60 case-records per site focusing on the common childhood illnesses (pneumonia, malaria, diarrhea/dehydration, malnutrition and meningitis). Results: Availability of essential resources was 75% (45/61 items) or more in 8/22 hospitals. A total of 1298 (range 54-61) case records were reviewed. HIV testing remained suboptimal at 12% (95% CI 7-19). A routinely introduced structured pediatric admission record form improved documentation of core admission symptoms and signs (median score for signs 22/ 22 and 8/22 when form used and not used respectively). Correctness of penicillin and gentamicin dosing was above 85% but correctness of prescribed intravenous fluid or oral feed volumes for severe dehydration and malnutrition were 54% and 25% respectively. Introduction of Zinc for diarrhea has been relatively successful (66% cases) but use of artesunate for malaria remained rare. Exploratory analysis suggests considerable variability of the quality of care across hospitals. Conclusion: Quality of pediatric care in Kenya has improved but can improve further. The approach to monitoring described in this survey seems feasible and provides an opportunity for routine assessments across a large number of hospitals as part of national efforts to sustain improvement. Understanding variability across hospitals may help target improvement efforts.

Includes bibliographical references, In addition to treating symptomatic patients, malaria prevention and elimination requires giving antimalarial drugs to asymptomatic or uninfected individuals. This shifts the harm-benefit balance and heightens the importance of accurately defining drug safety. Large data sets, including those pooled from multiple sources, are needed to understand uncommon adverse drug reactions. Interpreting individual studies , comparisons between studies and pooled datasets can be compromised, however, by inadequate or varied methods of safety data collection. Specifically, questioning methods may influence participants' reports of medical history, adverse events (AEs) and non-study medications. A Cochrane systematic review synthesised literature on research comparing methods for eliciting AEs from trial participants . A global online survey investigated how antimalarial researchers collect these data, and mixed-methods were used to identify barriers to accurate and complete reporting in South African and Tanzanian antimalarial-antiretroviral drug interaction trials. Focus group discussions were conducted in Ghana, Kenya and Uganda with women in a drugs exposure pregnancy registry to examine barriers to reporting at antenatal clinics, and how they might be overcome. The review included thirty-three studies in various therapeutic areas showing that more specific questioning increases the number of AEs reported by trial participants. Survey responses of 52 antimalarial researchers in 25 countries evidenced a range of methods to obtain AEs, medical histories and non-study drug reports. Qualitative data revealed that the trial context is influential and that detailed questioning facilitated participants' recognition and consideration of what to report. Non-reporting is due to forgetting, not knowing drug names, considering which information is relevant or significant to themselves or trial/healthcare workers, the potential consequences of reporting, and perceiving verbal responses inferior to what blood test results can show. Pregnant women's improved relationship with antenatal staff facilitated information-sharing and registry tools helped overcome problems with recall and naming of medicines. This project provides evidence of the substantial impact of different questioning methods on safety assessments . The results should contribute to developing a framework for researchers when planning globally-relevant, yet context-specific, antimalarial drug safety data collection strategies, and enhance efforts to pool data from multiple sources.

Katherine Halliday and colleagues conducted a cluster randomized controlled trial in Kenyan school children in an area of low to moderate malaria transmission to investigate the effect of intermittent screening and treatment of malaria on health and education. Please see later in the article for the Editors' Summary, Background Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence of the benefits of alternative school-based malaria interventions or how the impacts of interventions vary according to intensity of malaria transmission. We investigated the effect of intermittent screening and treatment (IST) for malaria on the health and education of school children in an area of low to moderate malaria transmission. Methods and Findings A cluster randomised trial was implemented with 5,233 children in 101 government primary schools on the south coast of Kenya in 2010–2012. The intervention was delivered to children randomly selected from classes 1 and 5 who were followed up for 24 months. Once a school term, children were screened by public health workers using malaria rapid diagnostic tests (RDTs), and children (with or without malaria symptoms) found to be RDT-positive were treated with a six dose regimen of artemether-lumefantrine (AL). Given the nature of the intervention, the trial was not blinded. The primary outcomes were anaemia and sustained attention. Secondary outcomes were malaria parasitaemia and educational achievement. Data were analysed on an intention-to-treat basis. During the intervention period, an average of 88.3% children in intervention schools were screened at each round, of whom 17.5% were RDT-positive. 80.3% of children in the control and 80.2% in the intervention group were followed-up at 24 months. No impact of the malaria IST intervention was observed for prevalence of anaemia at either 12 or 24 months (adjusted risk ratio [Adj.RR]: 1.03, 95% CI 0.93–1.13, p = 0.621 and Adj.RR: 1.00, 95% CI 0.90–1.11, p = 0.953) respectively, or on prevalence of P. falciparum infection or scores of classroom attention. No effect of IST was observed on educational achievement in the older class, but an apparent negative effect was seen on spelling scores in the younger class at 9 and 24 months and on arithmetic scores at 24 months. Conclusion In this setting in Kenya, IST as implemented in this study is not effective in improving the health or education of school children. Possible reasons for the absence of an impact are the marked geographical heterogeneity in transmission, the rapid rate of reinfection following AL treatment, the variable reliability of RDTs, and the relative contribution of malaria to the aetiology of anaemia in this setting. Trial registration www.ClinicalTrials.gov NCT00878007 Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, more than 200 million cases of malaria occur worldwide and more than 600,000 people, mostly children living in sub-Saharan Africa, die from this mosquito-borne parasitic infection. Malaria can be prevented by controlling the night-biting mosquitoes that transmit Plasmodium parasites and by sleeping under insecticide-treated nets to avoid mosquito bites. Infection with malaria parasites causes recurring flu-like symptoms and needs to be treated promptly with antimalarial drugs to prevent the development of anaemia (a reduction in red blood cell numbers) and potentially fatal damage to the brain and other organs. Treatment also reduces malaria transmission. In 1998, the World Health Organization and several other international bodies established the Roll Back Malaria Partnership to provide a coordinated global approach to fighting malaria. In 2008, the Partnership launched its Global Malaria Action Plan, which aims to control malaria to reduce the current burden, to eliminate malaria over time country by country, and, ultimately, to eradicate malaria. Why Was This Study Done? In recent years, many malaria-endemic countries (countries where malaria is always present) have implemented successful malaria control programs and reduced malaria transmission levels. In these countries, immunity to malaria is now acquired more slowly than in the past, the burden of clinical malaria is shifting from very young children to older children, and infection rates with malaria parasites are now highest among school-aged children. Chronic untreated Plasmodium infection, even when it does not cause symptoms, can negatively affect children's health, cognitive development (the acquisition of thinking skills), and educational achievement. However, little is known about how school-based malaria interventions affect the health of children or their educational outcomes. In this cluster randomized trial, the researchers investigate the effect of intermittent screening and treatment (IST) of malaria on the health and education of school children in a rural area of southern Kenya with low-to-moderate malaria transmission. Cluster randomized trials compare the outcomes of groups (“clusters”) of people randomly assigned to receive alternative interventions. IST of malaria involves periodical screening of individuals for Plasmodium infection followed by treatment of everyone who is infected, including people without symptoms, with antimalarial drugs. What Did the Researchers Do and Find? The researchers enrolled more than 5,000 children aged between 5 and 20 years from 101 government primary schools in Kenya into their 24-month study. Half the schools were randomly selected to receive the IST intervention (screening once a school term for infection with a malaria parasite with a rapid diagnostic test [RDT] and treatment of all RDT-positive children, with or without malaria symptoms, with six doses of artemether-lumefantrine), which was delivered to randomly selected children from classes 1 and 5 (which contained younger and older children, respectively). During the study, 17.5% of the children in the intervention schools were RDT-positive at screening on average. The prevalences of anaemia and parasitemia (the proportion of children with anaemia and the proportion who were RDT-positive, respectively) were similar in the intervention and control groups at the 12-month and 24-month follow-up and there was no difference between the two groups in classroom attention scores at the 9-month and 24-month follow-up. The IST intervention also had no effect on educational achievement in the older class but, unexpectedly, appeared to have a negative effect on spelling and arithmetic scores in the younger class. What Do These Findings Mean? These findings indicate that, in this setting in Kenya, IST as implemented in this study provided no health or education benefits to school children. The finding that the educational achievement of younger children was lower in the intervention group than in the control group may be a chance finding or may indicate that apprehension about the finger prick needed to take blood for the RDT had a negative effect on the performance of younger children during educational tests. The researchers suggest that their failure to demonstrate that the school-based IST intervention they tested had any long-lasting health or education benefits may be because, in a low-to-moderate malaria transmission setting, most of the children screened did not require treatment and those who did lived in focal high transmission regions, where rapid re-infection occurred between screening rounds. Importantly, however, these findings suggest that school screening using RDT could be an efficient way to identify transmission hotspots in communities that should be targeted for malaria control interventions. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001594. This study is further discussed in a PLOS Medicine Perspective by Lorenz von Seidlein Information is available fro m the World Health Organization on malaria (in several languages); the 2012 World Malaria Report provides details of the current global malaria situation The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about children with malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Kenya MedlinePlus provides links to additional information on malaria (in English and Spanish) More information about this trial is available More information about malaria control in schools is provided in the toolkit

Background Between 1995 and 2000, KwaZulu–Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL) was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities. Methods and Findings We reviewed four years of malaria morbidity and mortality data at four sentinel health-care facilities within KwaZulu–Natal's malaria-endemic area. In the year following improved vector control and implementation of AL treatment, malaria-related admissions and deaths both declined by 89%, and outpatient visits decreased by 85% at the sentinel facilities. By 2003, malaria-related outpatient cases and admissions had fallen by 99%, and malaria-related deaths had decreased by 97%. There was a concomitant marked and sustained decline in notified malaria throughout the province. No serious adverse events were associated causally with AL treatment in an active sentinel pharmacovigilance survey. In a prospective study with 42 d follow up, AL cured 97/98 (99%) and prevented gametocyte developing in all patients. Consistent with the findings of focus group discussions, a household survey found self-reported adherence to the six-dose AL regimen was 96%. Conclusion Together with concurrent strengthening of vector control measures, the antimalarial treatment policy change to AL in KwaZulu–Natal contributed to a marked and sustained decrease in malaria cases, admissions, and deaths, by greatly improving clinical and parasitological cure rates and reducing gametocyte carriage., In KwaZulu-Natal strengthening of vector control and a change in antimalarial treatment policy to use of artemether-lumefantrine has been associated with a decrease in malaria cases, admissions, and deaths.

BACKGROUND: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). METHODS: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. RESULTS: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. CONCLUSIONS: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.