A household randomized, controlled trial of the efficacy of 0.03% transfluthrin coils alone and in combination with long-lasting insecticidal nets on the incidence of Plasmodium falciparum and Plasmodium vivax malaria in Western Yunnan Province, China.

BACKGROUND: Mosquito coils are the most commonly used household insecticidal product in the world with sales exceeding 50 billion coils, used by two billion people worldwide annually. Despite strong evidence that coils prevent mosquito bites a systematic review concluded that there is no evidence that burning mosquito coils prevents malaria acquisition. Therefore, the current trial was designed to measure and compare prevention of malaria infection by mosquito coils or long-lasting insecticidal net (LLIN) or a combination of the two in Yunnan, China in the Greater Mekong sub-region. METHODS: A four-arm single blind household-randomized design was chosen as coils emanate insecticide throughout the household. Households enrolled at baseline were randomly allocated by the lottery method to one of the four intervention arms: (i) nothing, (ii) 0.03% transfluthrin coils alone, (iii) deltamethrin long-lasting insecticide treated nets, (LLINs) alone or (iv) a combination of transfluthrin coils and deltamethrin LLINs. All household members were recruited to the study, with only those households excluded with pregnant or breastfeeding mothers, members with chest complaints or allergies or members that regularly slept away from home. The main outcome of interest was Plasmodium falciparum malaria prevalence detected by rapid diagnostic tests (RDTs) during six repeated monthly cross-sectional surveys. The secondary outcome of interest was the effect on Plasmodium vivax prevalence detected in the same way. RESULTS: A total of 2,052 households were recruited into the study, comprising 7,341 individuals The odds ratios of testing positive by RDT with P. falciparum or P. vivax were >75% lower for all intervention arms compared with the control arm. Coils alone provided 77% protection (95% CI: 50%-89%), LLINs provided 91% protection (95% CI: 72%-97%) and the combination of coils and LLINs provided 94% protection (95% CI: 77%-99%) against P. falciparum compared with the control arm. There was no statistically significant difference between the protective efficacies of the different interventions. CONCLUSIONS: This is the first robust clinical evaluation of transfluthrin mosquito coils as a means to reduce malaria and the high degree of infection prevented would indicate they represent a potentially highly effective tool, which could be integrated into larger vector control programmes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00442442, March 2007.

Identification of hot spots of malaria transmission for targeted malaria control.

BACKGROUND: Variation in the risk of malaria within populations is a frequently described but poorly understood phenomenon. This heterogeneity creates opportunities for targeted interventions but only if hot spots of malaria transmission can be easily identified. METHODS: We determined spatial patterns in malaria transmission in a district in northeastern Tanzania, using malaria incidence data from a cohort study involving infants and household-level mosquito sampling data. The parasite prevalence rates and age-specific seroconversion rates (SCRs) of antibodies against Plasmodium falciparum antigens were determined in samples obtained from people attending health care facilities. RESULTS: Five clusters of higher malaria incidence were detected and interpreted as hot spots of transmission. These hot spots partially overlapped with clusters of higher mosquito exposure but could not be satisfactorily predicted by a probability model based on environmental factors. Small-scale local variation in malaria exposure was detected by parasite prevalence rates and SCR estimates for samples of health care facility attendees. SCR estimates were strongly associated with local malaria incidence rates and predicted hot spots of malaria transmission with 95% sensitivity and 85% specificity. CONCLUSIONS: Serological markers were able to detect spatial variation in malaria transmission at the microepidemiological level, and they have the potential to form an effective method for spatial targeting of malaria control efforts.

Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Administration of sulfadoxine-pyrimethamine at times of vaccination-intermittent preventive treatment in infants (IPTi)-is a promising strategy to prevent malaria. However, rising resistance to this combination is a concern. We investigated a shortacting and longacting antimalarial drug as alternative regimens for IPTi. METHODS: We undertook a double-blind, placebo-controlled trial of IPTi in an area of high resistance to sulfadoxine-pyrimethamine at sites of moderate (n=1280 infants enrolled) and low (n=1139) intensity of malaria transmission in Tanzania. Infants aged 8-16 weeks were randomly assigned in blocks of 16 to sulfadoxine (250 mg) plus pyrimethamine (12.5 mg; n=319 in moderate-transmission and 283 in low-transmission sites), chlorproguanil (15 mg) plus dapsone (18.75 mg; n=317 and 285), mefloquine (125 mg; n=320 and 284), or placebo (n=320 and 284), given at the second and third immunisations for diphtheria, pertussis, and tetanus, and for measles. Research team and child were masked to treatment. Recruitment was stopped early at the low-transmission site because of low malaria incidence. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2-11 months of age. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00158574. FINDINGS: All randomly assigned infants were analysed. At the moderate-transmission site, mefloquine had a protective efficacy of 38.1% (95% CI 11.8-56.5, p=0.008) against clinical malaria in infants aged 2-11 months, but neither sulfadoxine-pyrimethamine (-6.7%, -45.9 to 22.0) nor chlorproguanil-dapsone (10.8%, -24.6 to 36.1) had a protective effect. No regimen had any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1731 (8%) doses given on day 1 (odds ratio vs placebo 5.50, 95% CI 3.56-8.46). More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, respectively) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths per group; p=0.05 for difference between chlorproguanil-dapsone and placebo). INTERPRETATION: IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug. FUNDING: IPTi Consortium and the Gates Malaria Partnership.

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials.

BACKGROUND: Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS: We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS: The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING: Bill & Melinda Gates Foundation.

Intermittent preventive treatment for malaria in infants: a decision-support tool for sub-Saharan Africa.

OBJECTIVE: To develop a decision-support tool to help policy-makers in sub-Saharan Africa assess whether intermittent preventive treatment in infants (IPTi) would be effective for local malaria control. METHODS: An algorithm for predicting the effect of IPTi was developed using two approaches. First, study data on the age patterns of clinical cases of Plasmodium falciparum malaria, hospital admissions for infection with malaria parasites and malaria-associated death for different levels of malaria transmission intensity and seasonality were used to estimate the percentage of cases of these outcomes that would occur in children aged <10 years targeted by IPTi. Second, a previously developed stochastic mathematical model of IPTi was used to predict the number of cases likely to be averted by implementing IPTi under different epidemiological conditions. The decision-support tool uses the data from these two approaches that are most relevant to the context specified by the user. FINDINGS: Findings from the two approaches indicated that the percentage of cases targeted by IPTi increases with the severity of the malaria outcome and with transmission intensity. The decision-support tool, available on the Internet, provides estimates of the percentage of malaria-associated deaths, hospitalizations and clinical cases that will be targeted by IPTi in a specified context and of the number of these outcomes that could be averted. CONCLUSION: The effectiveness of IPTi varies with malaria transmission intensity and seasonality. Deciding where to implement IPTi must take into account the local epidemiology of malaria. The Internet-based decision-support tool described here predicts the likely effectiveness of IPTi under a wide range of epidemiological conditions.

The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings.

BACKGROUND: A greater understanding of the relationship between transmission intensity, seasonality and the age-pattern of malaria is needed to guide appropriate targeting of malaria interventions in different epidemiological settings. METHODS: A systematic literature review identified studies which reported the age of paediatric hospital admissions with cerebral malaria (CM), severe malarial anaemia (SMA), or respiratory distress (RD). Study sites were categorized into a 3 × 2 matrix of Plasmodium falciparum transmission intensity and seasonality. Probability distributions were fitted by maximum likelihood methods, and best fitting models were used to estimate median ages and to represent graphically the age-pattern of each outcome for each transmission category in the matrix. RESULTS: A shift in the burden of CM towards younger age groups was seen with increasing intensity of transmission, but this was not the case for SMA or RD. Sites with 'no marked seasonality' showed more evidence of skewed age-patterns compared to areas of 'marked seasonality' for all three severe malaria syndromes. CONCLUSIONS: Although the peak age of CM will increase as transmission intensity decreases in Africa, more than 75% of all paediatric hospital admissions of severe malaria are likely to remain in under five year olds in most epidemiological settings.

A simple method for defining malaria seasonality.

BACKGROUND: There is currently no standard way of defining malaria seasonality, resulting in a wide range of definitions reported in the literature. Malaria cases show seasonal peaks in most endemic settings, and the choice and timing for optimal malaria control may vary by seasonality. A simple approach is presented to describe the seasonality of malaria, to aid localized policymaking and targeting of interventions. METHODS: A series of systematic literature reviews were undertaken to identify studies reporting on monthly data for full calendar years on clinical malaria, hospital admission with malaria and entomological inoculation rates (EIR). Sites were defined as having 'marked seasonality' if 75% or more of all episodes occurred in six or less months of the year. A 'concentrated period of malaria' was defined as the six consecutive months with the highest cumulative proportion of cases. A sensitivity analysis was performed based on a variety of cut-offs. RESULTS: Monthly data for full calendar years on clinical malaria, all hospital admissions with malaria, and entomological inoculation rates were available for 13, 18, and 11 sites respectively. Most sites showed year-round transmission with seasonal peaks for both clinical malaria and hospital admissions with malaria, with a few sites fitting the definition of 'marked seasonality'. For these sites, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. The use of monthly EIR data was found to be of limited value when looking at seasonal variations of malaria transmission, particularly at low and medium intensity levels. CONCLUSION: The proposed definition discriminated well between studies with 'marked seasonality' and those with less seasonality. However, a poor fit was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this definition on a wide-scale, using routine health information system data where possible, to aid appropriate targeting of interventions.

Estimates of the burden of malaria morbidity in Africa in children under the age of 5 years.

OBJECTIVE: To estimate the direct burden of malaria among children younger than 5 years in sub-Saharan Africa (SSA) for the year 2000, as part of a wider initiative on burden estimates. METHODS: A systematic literature review was undertaken in June 2003. Severe malaria outcomes (cerebral malaria, severe malarial anaemia and respiratory distress) and non-severe malaria data were abstracted separately, together with information on the characteristics of each study and its population. Population characteristics were also collated at a national level. A meta-regression model was used to predict the incidence of malaria fevers at a national level. For severe outcomes, results were presented as median rates as data were too sparse for modelling. RESULTS: For the year 2000, an estimated 545,000 (uncertainty interval: 105,000-1,750,000) children under the age of 5 in SSA experienced an episode of severe malaria for which they were admitted to hospital. A total of 24,000 (interquartile range: 12,000-37,000) suffered from persistent neurological deficits as a result of cerebral malaria. The number of malaria fevers associated with high parasite density in under-5s in SSA in 2000 was estimated as 115,750,000 (uncertainty interval: 91,243,000-257,957,000). CONCLUSION: Our study predicts a lower burden than previous estimates of under-5 malaria morbidity in SSA. As there is a lack of suitable data to enable comprehensive estimates of annual malaria incidence, we describe the information needed to improve the validity of future estimates.

Setting priorities in global child health research investments: guidelines for implementation of CHNRI method.

This article provides detailed guidelines for the implementation of systematic method for setting priorities in health research investments that was recently developed by Child Health and Nutrition Research Initiative (CHNRI). The target audience for the proposed method are international agencies, large research funding donors, and national governments and policy-makers. The process has the following steps: (i) selecting the managers of the process; (ii) specifying the context and risk management preferences; (iii) discussing criteria for setting health research priorities; (iv) choosing a limited set of the most useful and important criteria; (v) developing means to assess the likelihood that proposed health research options will satisfy the selected criteria; (vi) systematic listing of a large number of proposed health research options; (vii) pre-scoring check of all competing health research options; (viii) scoring of health research options using the chosen set of criteria; (ix) calculating intermediate scores for each health research option; (x) obtaining further input from the stakeholders; (xi) adjusting intermediate scores taking into account the values of stakeholders; (xii) calculating overall priority scores and assigning ranks; (xiii) performing an analysis of agreement between the scorers; (xiv) linking computed research priority scores with investment decisions; (xv) feedback and revision. The CHNRI method is a flexible process that enables prioritizing health research investments at any level: institutional, regional, national, international, or global.

Haemoglobin and haematocrit: is the threefold conversion valid for assessing anaemia in malaria-endemic settings?

BACKGROUND: Anaemic status is determined by haemoglobin using the HemoCue system or haematocrit measurements, and a threefold conversion is commonly used to equate the two measures (haemoglobin = haematocrit/3). The validity of this conversion in malaria endemic settings was assessed. METHODS: Concurrent measures of haemoglobin and centrifuged haematocrit in children aged 6-59 months were compared by modelling the difference between the two measures against their average. A random effects linear regression of the difference of the measures on their average was used to describe the line of best agreement and 95% limits of agreement for these two measures over a range of values after adjusting for statistically significant covariates. RESULTS: There was a consistent bias between the two measures, with haemoglobin less than haematocrit/3 in 87% (899/1,030) of observations. This difference was non-uniform, decreasing with the average measure, i.e. less difference at higher haemoglobin and haematocrit values. In these studies, use of haematocrit would have underestimated the prevalence of anaemia by misclassifying 10% (89/920) of individuals with haemoglobin < 11 g/dl, 66% (252/380) of individuals with haemoglobin < 8 g/dl and 100% (23/23) of individuals with haemoglobin < 5 g/dl. The mean difference between the measures was greater in males than females, increased with age between 6-59 months, and was greater in the wet than dry season suggesting that the relationship between haemoglobin and haematocrit may be modified by exposure to malaria. CONCLUSION: The regression model indicated that the standard threefold conversion from haematocrit to haemoglobin underestimates the prevalence of haemoglobin < 11 g/dl in children under five years of age in malaria endemic settings. This bias was more acute for more severe anaemia defined by haemoglobin < 8 g/dl and haemoglobin < 5 g/dl. This has important implications for the comparability of studies using these different measures. Direct determination of haemoglobin should be the measurement of choice for assessing anaemia outcomes in malaria intervention trials and surveys.

Setting priorities in global child health research investments: assessment of principles and practice.

This article reviews theoretical and practical approaches for setting priorities in global child health research investments. It also provides an overview of previous attempts to develop appropriate tools and methodologies to define priorities in health research investments. A brief review of the most important theoretical concepts that should govern priority setting processes is undertaken, showing how different perspectives, such as medical, economical, legal, ethical, social, political, rational, philosophical, stakeholder driven, and others will necessarily conflict each other in determining priorities. We specially address present research agenda in global child health today and how it relates to United Nation's (UN) Millennium Development Goal 4, which is to reduce child mortality by two-thirds between 1990 and 2015. The outcomes of these former approaches are evaluated and their benefits and shortcomings presented. The case for a new methodology for setting priorities in health research investments is presented, as proposed by Child Health and Nutrition Research Initiative, and a need for its implementation in global child health is outlined. A transdisciplinary approach is needed to address all the perspectives from which investments into health research can be seen as priorities. This prioritization requires a process that is transparent, systematic, and that would take into account many perspectives and build on advantages of previous approaches.

Gaps in policy-relevant information on burden of disease in children: a systematic review.

BACKGROUND: Valid information about cause-specific child mortality and morbidity is an essential foundation for national and international health policy. We undertook a systematic review to investigate the geographical dispersion of and time trends in publication for policy-relevant information about children's health and to assess associations between the availability of reliable data and poverty. METHODS: We identified data available on Jan 1, 2001, and published since 1980, for the major causes of morbidity and mortality in young children. Studies with relevant data were assessed against a set of inclusion criteria to identify those likely to provide unbiased estimates of the burden of childhood disease in the community. FINDINGS: Only 308 information units from more than 17,000 papers identified were regarded as possible unbiased sources for estimates of childhood disease burden. The geographical distribution of these information units revealed a pattern of small well-researched populations surrounded by large areas with little available information. No reliable population-based data were identified from many of the world's poorest countries, which account for about a third of all deaths of children worldwide. The number of new studies diminished over the last 10 years investigated. INTERPRETATION: The number of population-based studies yielding estimates of burden of childhood disease from less developed countries was low. The decreasing trend over time suggests reductions in research investment in this sphere. Data are especially sparse from the world's least developed countries with the highest child mortality. Guidelines are needed for the conduct of burden-of-disease studies together with an international research policy that gives increased emphasis to global equity and coverage so that knowledge can be generated from all regions of the world.

Modeling the relationship between the population prevalence of Plasmodium falciparum malaria and anemia.

More than half of all young children and pregnant women are affected by anemia. Although its etiology is multi-factorial, malaria is likely to be a major contributor to chronic anemia in endemic areas. Recent reviews have examined the effect of community-based malaria control interventions on anemia. We analyze how the prevalence of anemia depends on that of Plasmodium falciparum malaria by developing models of the excess risk of anemia caused by malaria at a population level in 24 villages in northeastern Tanzania. In that setting, we estimated that the prevalence of a hemoglobin level < 8 g/dL attributable to malaria was 4.6% in infants, 4.1% in children one year of age, 2.7% in children two years of age, and 3.3% in women of childbearing age. Successful validation of our models in other malaria-endemic settings would enable their use for predicting the impact of malaria control interventions on anemia, and for long-term monitoring and surveillance of malaria.

Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria.

CONTEXT: There are concerns that malaria control measures such as use of insecticide-treated bed nets, by delaying acquisition of immunity, might result in an increase in the more severe manifestations of malaria. An understanding of the relationships among the level of exposure to Plasmodium falciparum, age, and severity of malaria can provide evidence of whether this is likely. OBJECTIVE: To describe the clinical manifestations and case fatality of severe P falciparum malaria at varying altitudes resulting in varying levels of transmission. DESIGN, SETTING, AND PATIENTS: A total of 1984 patients admitted for severe malaria to 10 hospitals serving populations living at levels of transmission varying from very low (altitude >1200 m) to very high (altitude <600 m) in a defined area of northeastern Tanzania, studied prospectively from February 2002 to February 2003. Data were analyzed in a logistic regression model and adjusted for potential clustering within hospitals. MAIN OUTCOME MEASURES: Specific syndromes of severe malaria; mortality. RESULTS: The median age of patients was 1 year in high transmission, 3 years in moderate transmission, and 5 years in low transmission areas. The odds of severe malarial anemia (hemoglobin <5 g/dL) peaked at 1 year of age at high transmission and at 2 years at moderate and low transmission intensities and then decreased with increasing age (P = .002). Odds were highest in infants (0-1 year: referent; 2-4 years: odds ratio [OR], 0.83; 95% confidence interval [CI], 0.72-0.96), 5 to <15 years: OR, 0.44; 95% CI, 0.27-0.72; > or =15 years: OR, 0.44; 95% CI, 0.27-0.73; P<.001) and high transmission intensity areas (altitude <600 m: referent; 600 m to 1200 m: OR, 0.55; 95% CI, 0.35-0.84; >1200 m: OR, 0.55; 95% CI, 0.26-1.15; P for trend = .03). The odds of cerebral malaria were significantly higher in low transmission intensity areas (altitude of residence <600 m: referent; 600 m to 1200 m: OR, 3.17; 95% CI, 1.32-7.60; >1200 m: OR, 3.76; 95% CI, 1.96-7.18; P for trend = .003) and with age 5 years and older (0-1 year: referent; 2-4 years: OR, 1.57; 95% CI, 0.82-2.99; 5 to <15 years: OR, 6.07; 95% CI, 2.98-12.38; > or =15 years: OR, 6.24; 95% CI, 3.47-11.21; P<.001). The overall case-fatality rate of 7% (139 deaths) was similar at high and moderate levels of transmission but increased to 13% in low transmission areas (P = .03), an increase explained by the increase in the proportion of cases with cerebral malaria. CONCLUSIONS: Age and level of exposure independently influence the clinical presentation of severe malaria. Our study suggests that an increase in the proportion of cases with more fatal manifestations of severe malaria is likely to occur only after transmission has been reduced to low levels where the overall incidence is likely to be low.

Risks of Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficient Infants Exposed to Chlorproguanil-Dapsone, Mefloquine and Sulfadoxine-Pyrimethamine as Part of Intermittent Presumptive Treatment of Malaria in Infants.

BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimalarial regimens. We sought to examine the joint effects of G6PD status and IPTi antimalarial treatment on incidence of hemolysis in asymptomatic children treated with CD, sulfadoxine-pyrimethamine (SP), and mefloquine (MQ). METHODS: A secondary analysis of data from a double-blind, placebo-controlled trial of IPTi was conducted. Hemoglobin (Hb) measurements were made at IPTi doses, regular follow-up and emergency visits. G6PD genotype was determined at 9 months looking for SNPs for the A- genotype at coding position 202. Multivariable linear and logistic regression models were used to examine hemolysis among children with valid G6PD genotyping results. Hemolysis was defined as the absolute change in Hb or as any post-dose Hb <8 g/dL. These outcomes were assessed using either a single follow-up Hb on day 7 after an IPTi dose or Hb obtained 1 to 14 or 28 days after each IPTi dose. FINDINGS: Relative to placebo, CD reduced Hb by approximately 0.5 g/dL at day 7 and within 14 days of an IPTi dose, and by 0.2 g/dL within 28 days. Adjusted declines in the CD group were larger than in the MQ and SP groups. At day 7, homo-/hemizygous genotype was associated with higher odds of Hb <8 g/dL (adjusted odds ratio = 6.7, 95% CI 1.7 to 27.0) and greater absolute reductions in Hb (-0.6 g/dL, 95% CI -1.1 to 0.003). There was no evidence to suggest increased reductions in Hb among homo-/hemizygous children treated with CD compared to placebo, SP or MQ. CONCLUSIONS: While treatment with CD demonstrated greater reductions in Hb at 7 and 14 days after an IPTi dose compared to both SP and MQ, there was no evidence that G6PD deficiency exacerbated the adverse effects of CD, despite evidence for higher hemolysis risk among G6PDd infants.

Variation of malaria transmission and morbidity with altitude in Tanzania and with introduction of alphacypermethrin treated nets.

BACKGROUND: Highland areas with naturally less intense malaria transmission may provide models of how lowland areas might become if transmission was permanently reduced by sustained vector control. It has been argued that vector control should not be attempted in areas of intense transmission. METHODS: Mosquitoes were sampled with light traps, pyrethrum spray and window exit traps. They were tested by ELISA for sporozoites. Incidence of malaria infection was measured by clearing existing infections from children with chlorproguanil-dapsone and then taking weekly blood samples. Prevalence of malaria infection and fever, anaemia and splenomegaly were measured in children of different age groups. All these measurements were made in highland and lowland areas of Tanzania before and after provision of bednets treated with alphacypermethrin. RESULTS: Entomological inoculation rates (EIR) were about 17 times greater in a lowland than a highland area, but incidence of infection only differed by about 2.5 times. Malaria morbidity was significantly less prevalent in the highlands than the lowlands. Treated nets in the highlands and lowlands led to 69-75% reduction in EIR. Malaria morbidity showed significant decline in younger children at both altitudes after introduction of treated nets. In children aged 6-12 the decline was only significant in the highlands CONCLUSIONS: There was no evidence that the health benefits to young children due to the nets in the lowlands were "paid for" by poorer health later in life. Our data support the idea of universal provision of treated nets, not a focus on areas of natural hypo-endemicity.

Can topical insect repellents reduce malaria? A cluster-randomised controlled trial of the insect repellent N,N-diethyl-m-toluamide (DEET) in Lao PDR.

BACKGROUND: Mosquito vectors of malaria in Southeast Asia readily feed outdoors making malaria control through indoor insecticides such as long-lasting insecticidal nets (LLINs) and indoor residual spraying more difficult. Topical insect repellents may be able to protect users from outdoor biting, thereby providing additional protection above the current best practice of LLINs. METHODS AND FINDINGS: A double blind, household randomised, placebo-controlled trial of insect repellent to reduce malaria was carried out in southern Lao PDR to determine whether the use of repellent and long-lasting insecticidal nets (LLINs) could reduce malaria more than LLINs alone. A total of 1,597 households, including 7,979 participants, were recruited in June 2009 and April 2010. Equal group allocation, stratified by village, was used to randomise 795 households to a 15% DEET lotion and the remainder were given a placebo lotion. Participants, field staff and data analysts were blinded to the group assignment until data analysis had been completed. All households received new LLINs. Participants were asked to apply their lotion to exposed skin every evening and sleep under the LLINs each night. Plasmodium falciparum and P. vivax cases were actively identified by monthly rapid diagnostic tests. Intention to treat analysis found no effect from the use of repellent on malaria incidence (hazard ratio: 1.00, 95% CI: 0.99-1.01, p = 0.868). A higher socio-economic score was found to significantly decrease malaria risk (hazard ratio: 0.72, 95% CI: 0.58-0.90, p = 0.004). Women were also found to have a reduced risk of infection (hazard ratio: 0.59, 95% CI: 0.37-0.92, p = 0.020). According to protocol analysis which excluded participants using the lotions less than 90% of the time found similar results with no effect from the use of repellent. CONCLUSIONS: This randomised controlled trial suggests that topical repellents are not a suitable intervention in addition to LLINs against malaria amongst agricultural populations in southern Lao PDR. These results are also likely to be applicable to much of the Greater Mekong Sub-region. TRIAL REGISTRATION: This trial is registered with number NCT00938379.

Insecticide-treated plastic sheeting for emergency malaria prevention and shelter among displaced populations: an observational cohort study in a refugee setting in Sierra Leone.

A double-blind phase III malaria prevention trial was conducted in two refugee camps using pre-manufactured insecticide-treated plastic sheeting (ITPS) or untreated polyethylene sheeting (UPS) randomly deployed to defined sectors of each camp. In Largo camp the ITPS or UPS was attached to inner walls and ceilings of shelters, whereas in Tobanda the ITPS or UPS was used to line only the ceiling and roof. In Largo the Plasmodium falciparum incidence rate in children up to 3 years of age who were cleared of parasites and monitored for 8 months was 163/100 person-years under UPS and 63 under ITPS (adjusted odds ratio [AOR] = 0.40, 95% confidence interval [CI] = 0.33-0.47). In Tobanda incidence was 157/100 person-years under UPS and 134 under ITPS (AOR = 0.85, 95% CI = 0.75-0.95). Protective efficacy was 61% under fully lined ITPS and 15% under roof lined ITPS. Anemia rates improved under ITPS in both camps. This novel tool proved to be a convenient, safe, and long-lasting method of malaria control when used as a full shelter lining in an emergency setting.

IgG responses to Anopheles gambiae salivary antigen gSG6 detect variation in exposure to malaria vectors and disease risk.

Assessment of exposure to malaria vectors is important to our understanding of spatial and temporal variations in disease transmission and facilitates the targeting and evaluation of control efforts. Recently, an immunogenic Anopheles gambiae salivary protein (gSG6) was identified and proposed as the basis of an immuno-assay determining exposure to Afrotropical malaria vectors. In the present study, IgG responses to gSG6 and 6 malaria antigens (CSP, AMA-1, MSP-1, MSP-3, GLURP R1, and GLURP R2) were compared to Anopheles exposure and malaria incidence in a cohort of children from Korogwe district, Tanzania, an area of moderate and heterogeneous malaria transmission. Anti-gSG6 responses above the threshold for seropositivity were detected in 15% (96/636) of the children, and were positively associated with geographical variations in Anopheles exposure (OR 1.25, CI 1.01-1.54, p = 0.04). Additionally, IgG responses to gSG6 in individual children showed a strong positive association with household level mosquito exposure. IgG levels for all antigens except AMA-1 were associated with the frequency of malaria episodes following sampling. gSG6 seropositivity was strongly positively associated with subsequent malaria incidence (test for trend p = 0.004), comparable to malaria antigens MSP-1 and GLURP R2. Our results show that the gSG6 assay is sensitive to micro-epidemiological variations in exposure to Anopheles mosquitoes, and provides a correlate of malaria risk that is unrelated to immune protection. While the technique requires further evaluation in a range of malaria endemic settings, our findings suggest that the gSG6 assay may have a role in the evaluation and planning of targeted and preventative anti-malaria interventions.