Showing papers by "Feiko O. ter Kuile published in 2012"

Profile: The KEMRI/CDC Health and Demographic Surveillance System—Western Kenya

Abstract: The KEMRI/Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS) is located in Rarieda, Siaya and Gem Districts (Siaya County), lying northeast of Lake Victoria in Nyanza Province, western Kenya. The KEMRI/CDC HDSS, with approximately 220 000 inhabitants, has been the foundation for a variety of studies, including evaluations of insecticide-treated bed nets, burden of diarrhoeal disease and tuberculosis, malaria parasitaemia and anaemia, treatment strategies and immunological correlates of malaria infection, and numerous HIV, tuberculosis, malaria and diarrhoeal disease treatment and vaccine efficacy and effectiveness trials for more than a decade. Current studies include operations research to measure the uptake and effectiveness of the programmatic implementation of integrated malaria control strategies, HIV services, newly introduced vaccines and clinical trials. The HDSS provides general demographic and health information (such as population age structure and density, fertility rates, birth and death rates, in- and out-migrations, patterns of health care access and utilization and the local economics of health care) as well as disease- or intervention-specific information. The HDSS also collects verbal autopsy information on all deaths. Studies take advantage of the sampling frame inherent in the HDSS, whether at individual, household/compound or neighbourhood level.

Neonatal mortality risk associated with preterm birth in East Africa, adjusted by weight for gestational age: individual participant level meta-analysis.

Abstract: Background Low birth weight and prematurity are amongst the strongest predictors of neonatal death. However, the extent to which they act independently is poorly understood. Our objective was to estimate the neonatal mortality risk associated with preterm birth when stratified by weight for gestational age in the high mortality setting of East Africa. Methods and Findings Members and collaborators of the Malaria and the MARCH Centers, at the London School of Hygiene & Tropical Medicine, were contacted and protocols reviewed for East African studies that measured (1) birth weight, (2) gestational age at birth using antenatal ultrasound or neonatal assessment, and (3) neonatal mortality. Ten datasets were identified and four met the inclusion criteria. The four datasets (from Uganda, Kenya, and two from Tanzania) contained 5,727 births recorded between 1999–2010. 4,843 births had complete outcome data and were included in an individual participant level meta-analysis. 99% of 445 low birth weight (<2,500 g) babies were either preterm (<37 weeks gestation) or small for gestational age (below tenth percentile of weight for gestational age). 52% of 87 neonatal deaths occurred in preterm or small for gestational age babies. Babies born <34 weeks gestation had the highest odds of death compared to term babies (odds ratio [OR] 58.7 [95% CI 28.4–121.4]), with little difference when stratified by weight for gestational age. Babies born 34–36 weeks gestation with appropriate weight for gestational age had just three times the likelihood of neonatal death compared to babies born term, (OR 3.2 [95% CI 1.0–10.7]), but the likelihood for babies born 34–36 weeks who were also small for gestational age was 20 times higher (OR 19.8 [95% CI 8.3–47.4]). Only 1% of babies were born moderately premature and small for gestational age, but this group suffered 8% of deaths. Individual level data on newborns are scarce in East Africa; potential biases arising due to the non-systematic selection of the individual studies, or due to the methods applied for estimating gestational age, are discussed. Conclusions Moderately preterm babies who are also small for gestational age experience a considerably increased likelihood of neonatal death in East Africa. Please see later in the article for the Editors' Summary.

Effect of Early Detection and Treatment on Malaria Related Maternal Mortality on the North-Western Border of Thailand 1986–2010

Abstract: Introduction Maternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand Methods and Findings All medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12th May 1986 to 31st December 2010 were reviewed, and maternal death records were analyzed for causality There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once Three were suicide and excluded from the analysis as incidental deaths The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150–230) per 100,000 live births In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200–780) in 1986–90 to 79 (40–170) in 2006–10, p<005 In migrants from adjacent Myanmar the decline in MMR was less significant: 588 (100–3260) to 252 (150–430) from 1996–2000 to 2006–2010 Mortality from Pfalciparum malaria in pregnancy dropped sharply with the introduction of systematic screening and treatment and continued to decline with the reduction in the incidence of malaria in the communities Pvivax was not a cause of maternal death in this population Infection (non-puerperal sepsis and Pfalciparum malaria) accounted for 397 (27/68) % of all deaths Conclusions Frequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from Pfalciparum malaria No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai–Myanmar border

Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya

Abstract: Background Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp) and information on population prevalence of the SP resistance molecular markers in pregnant women is limited.

Intermittent preventive therapy for malaria with monthly artemether–lumefantrine for the post-discharge management of severe anaemia in children aged 4–59 months in southern Malawi: a multicentre, randomised, placebo-controlled trial

Abstract: Summary Background Young children with severe malarial anaemia in Africa are at high risk of readmittance to hospital or death within 6 months of discharge. We aimed to assess whether 3 months of chemoprevention with artemether–lumefantrine reduced this risk. Methods We did a randomised, placebo-controlled, multicentre trial in four hospitals in Malawi testing the efficacy and safety of intermittent preventive therapy post-discharge (IPTpd) in children aged 4–59 months admitted for severe malarial anaemia. All convalescent children who had completed a blood transfusion received artemether–lumefantrine at discharge and were randomly assigned by a computer-generated sequence to receive placebo or artemether–lumefantrine at 1 month and 2 months after discharge, providing about 1 month and 3 months of protection, respectively. Patients and study staff were masked throughout the study. The primary endpoint was a composite of all-cause mortality or hospital readmittance because of all-cause severe anaemia or severe malaria between 1 and 6 months after enrolment. This trial is registered, number ISRCTN89727873. Results Of 1414 children enrolled, 708 were assigned to receive placebo and 706 the intervention. By 6 months, 192 children (14%) had died or were readmitted with severe malaria or severe anaemia. 1–6 months after randomisation, 109 primary events occurred in 85 children in the placebo group and 86 in 74 children in the intervention group (adjusted protective efficacy [PE] 31%, 95% CI 5–50; absolute rate reduction 11·7 per 100 children years, 95% CI 1·8–18·9; p=0·024). The protective effect was greatest during the IPTpd period (1–3 months), when 58 primary events occurred in 49 children in the placebo group and 37 in 34 children in the intervention group (PE 41%, 10–62; p=0·01), but was not sustained after the third month (4–6 months, PE 17%, −27 to 45; p=0·395). When episodes in the first month were included—ie, before the first dose of IPTpd, when both groups benefited from the post-treatment prophylactic effect of artemether–lumefantrine provided at discharge—the overall cumulative PE by 6 months was 26% (−2 to 46; p=0·06). Interpretation In areas with intense malaria transmission, chemoprevention with IPTpd given to children with severe malarial anaemia might reduce rates of readmittance to hospital for severe anaemia or malaria. Studies to confirm these findings and to investigate different delivery mechanisms and cost-effectiveness are needed. Funding The Netherlands African Partnership for Capacity Development and Clinical Interventions Against Poverty Related Diseases, the UBS-Optimus Foundation, and the Gates Malaria Partnership.

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study

Abstract: Pregnancy-associated malaria (PAM) is an important, preventable cause of poor birth outcomes in malaria-endemic areas in sub-Saharan Africa [1]. Intermittent preventive therapy with antimalarials during pregnancy (IPTp) is a critical tool for reducing the incidence of PAM-attributable adverse birth outcomes [2]. Sulfadoxine-pyrimethamine (SP) is the most commonly administered drug for IPTp owing to its long half-life, favorable side-effect profile, and safety during pregnancy. However, Plasmodium falciparum strains harboring mutations associated with SP resistance are increasingly prevalent throughout sub-Saharan Africa. The outcome of antimalarial therapy results from complex interactions between parasite pathogenicity, host immunity, drug characteristics, and parasite susceptibility to drug therapy. Recent in vitro studies have suggested that the removal of susceptible parasites from heterogeneous parasitemias by antimalarial therapy may facilitate the relative overgrowth of the remaining resistant parasites and therefore potentiate their pathogenicity [3]. A recent study in Tanzania documented increases in placental inflammation that were associated with SP receipt, suggesting that SP may potentiate placental pathology when applied to partially susceptible infections [4]. However, the effect of these placental findings upon birth outcomes was unclear. Given the prevalence of SP resistance and the current lack of appropriate, safe alternatives for use as IPTp, it is critical to explore the associations between IPTp-SP, SP resistance, and delivery outcomes in further contexts to inform malaria control policies. Malawi adopted a policy of IPTp with SP in 1993, and despite the subsequent development of widespread SP resistance [5], a sustained decline in the prevalence of PAM was observed from 1997 to 2005 [6]. In view of the evidence from Tanzania [4], we hypothesized that the emergence of SP-resistant parasites would modify the effect of IPTp-SP and thereby potentiate placental inflammation and parasite densities and worsen birth outcomes. The Queen Elizabeth Central Hospital Epidemiology of Resistance in Pregnancy-Associated Malaria (QuEERPAM) study [7] was a serial cross-sectional analysis in which we explored the relationships between IPTp-SP, the presence of resistant parasites at delivery, and multiple measures of adverse delivery outcome, including parasite densities, placental histology, maternal hemoglobin concentration, and birth weight.

The Malaria in Pregnancy Library: a bibliometric review

Abstract: The Malaria in Pregnancy (MiP) Library is a bibliographic database that was created by the MiP Consortium in 2005 and is updated every four months using a standardized search protocol. A bibliometric review was conducted of the contents of the Library to determine dynamics in the type, content and volume of literature on malaria in pregnancy over time. Data on year of publication, type, language, country of first-author affiliation and content (topic) were extracted from entries in the MiP Library and plotted over time. By January 2012, the MiP Library contained 5,346 entries, consisting of 3,721 journal articles (69.6%), 697 reports (13.0%), 219 academic theses (4.1%), 92 books or book chapters (1.7%), 487 conference proceedings (9.1%), 68 registered studies (1.3%) and 62 ‘other’ (1.2%). Most of the sources were in English language (87.3%), followed by French (7.5%) and Spanish (1.5%). Over 40% of source material was publicly available online (42.4%) and the remaining with restricted access (35.0%) or otherwise unavailable (22.7%). The number of journal articles related to malaria in pregnancy increased from 41 in the 1960s, to 708 in the 1990s, and 1,895 between 2000 and 2009, and the variety of themes has increased over time. English-language articles were sourced from 737 different journals. The top three journals were the American Journal of Tropical Medicine and Hygiene (184), Malaria Journal (158) and the Transactions of the Royal Society of Tropical Medicine and Hygiene (131). The last decade has seen a dramatic increase in publications related to malaria in pregnancy, and an increasing proportion of these are publically available online. The MiP Library is a useful, scholarly source for literature and systematic reviews related to malaria in pregnancy.

Differential association of gene content polymorphisms of killer cell immunoglobulin-like receptors with placental malaria in HIV- and HIV+ mothers.

Abstract: Pregnant women have abundant natural killer (NK) cells in their placenta, and NK cell function is regulated by polymorphisms of killer cell immunoglobulin-like receptors (KIRs). Previous studies report different roles of NK cells in the immune responses to placental malaria (PM) and human immunodeficiency virus (HIV-1) infections. Given these references, the aim of this study was to determine the association between KIR gene content polymorphism and PM infection in pregnant women of known HIV-1 status. Sixteen genes in the KIR family were analyzed in 688 pregnant Kenyan women. Gene content polymorphisms were assessed in relation to PM in HIV-1 negative and HIV-1 positive women, respectively. Results showed that in HIV-1 negative women, the presence of the individual genes KIR2DL1 and KIR2DL3 increased the odds of having PM, and the KIR2DL2/KIR2DL2 homozygotes were associated with protection from PM. However, the reverse relationship was observed in HIV-1 positive women, where the presence of individual KIR2DL3 was associated with protection from PM, and KIR2DL2/KIR2DL2 homozygotes increased the odds for susceptibility to PM. Further analysis of the HIV-1 positive women stratified by CD4 counts showed that this reverse association between KIR genes and PM remained only in the individuals with high CD4 cell counts but not in those with low CD4 cell counts. Collectively, these results suggest that inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus, play a role in the inverse effects on PM and PM/HIV co-infection and the effect of KIR genes on PM in HIV positive women is dependent on high CD4 cell counts. In addition, analysis of linkage disequilibrium (LD) of the PM relevant KIR genes showed strong LD in women without PM regardless of their HIV status while LD was broken in those with PM, indicating possible selection pressure by malaria infection on the KIR genes.

Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria.

Abstract: Aims To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria. Methods Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai–Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption. Key findings The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. Conclusions The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.

The Malaria in Pregnancy Library: a bibliometric

Abstract: Background: The Malaria in Pregnancy (MiP) Library is a bibliographic database that was created by the MiP Consortium in 2005 and is updated every four months using a standardized search protocol. A bibliometric review was conducted of the contents of the Library to determine dynamics in the type, content and volume of literature on malaria in pregnancy over time. Methods: Data on year of publication, type, language, country of first-author affiliation and content (topic) were extracted from entries in the MiP Library and plotted over time. Results: By January 2012, the MiP Library contained 5,346 entries, consisting of 3,721 journal articles (69.6%), 697 reports (13.0%), 219 academic theses (4.1%), 92 books or book chapters (1.7%), 487 conference proceedings (9.1%), 68 registered studies (1.3%) and 62 ‘other’ (1.2%). Most of the sources were in English language (87.3%), followed by French (7.5%) and Spanish (1.5%). Over 40% of source material was publicly available online (42.4%) and the remaining with restricted access (35.0%) or otherwise unavailable (22.7%). The number of journal articles related to malaria in pregnancy increased from 41 in the 1960s, to 708 in the 1990s, and 1,895 between 2000 and 2009, and the variety of themes has increased over time. English-language articles were sourced from 737 different journals. The top three journals were the American Journal of Tropical Medicine and Hygiene (184), Malaria Journal (158) and the Transactions of the Royal Society of Tropical Medicine and Hygiene (131). Conclusion: The last decade has seen a dramatic increase in publications related to malaria in pregnancy, and an increasing proportion of these are publically available online. The MiP Library is a useful, scholarly source for literature and systematic reviews related to malaria in pregnancy.

Effect of intermittent preventative therapy for secondary prevention of severe malarial anaemia – Authors' reply

Abstract: 1describe an innovative study of intermittent preventative therapy post-discharge (IPTpd) for children admitted to hospital with severe malarial anaemia needing blood transfusion. They postulated that prevention of recurrent malaria in these children would reduce the risk of death, recurrence of severe anaemia, and readmission with severe malaria. By combining these outcomes into a composite primary endpoint they showed protective effi cacy of 31% for IPTpd. In secondary endpoint analyses, IPTpd also prevented another composite endpoint of readmissions for severe anaemia or severe malaria (combined) as well as all-cause readmissions, but not mortality. These fi ndings suggest that reduced readmissions were the main factor in the protective effi cacy noted for the primary endpoint. However, the analysis did not diff erentiate severe anaemia from severe malaria. This distinction is relevant because IPTpd also signifi cantly reduced episodes of non-severe clinical malaria, in keeping with studies of intermittent preventative therapy in other populations; 2,3 thus IPTpd might