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Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; alpha-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions.

Severe anaemia in children is a leading cause of hospital admission and a major cause of mortality in sub-Saharan Africa, yet there are limited published data on blood transfusion in this vulnerable group. We present data from a large controlled trial of fluid resuscitation (Fluid Expansion As Supportive Therapy (FEAST) trial) on the prevalence, clinical features, and transfusion management of anaemia in children presenting to hospitals in three East African countries with serious febrile illness (predominantly malaria and/or sepsis) and impaired peripheral perfusion. Of 3,170 children in the FEAST trial, 3,082 (97%) had baseline haemoglobin (Hb) measurement, 2,346/3,082 (76%) were anaemic (Hb

Previous analyses have suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly. We fitted a mathematical model for the acquisition and loss of immunity to severe disease to the age distribution of severe malaria cases stratified by symptoms from a range of transmission settings in Tanzania, combined with data from several African countries on the age distribution and overall incidence of severe malaria. We found that immunity to severe disease was acquired more gradually with exposure than previously thought. The model also suggests that physiological changes, rather than exposure, may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure. This has consequences for the expected pattern of severe disease as transmission changes. Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided.

Malaria clinical trials need precise endpoints to measure efficacy. In endemic areas where asymptomatic parasitaemia is common, 'fever plus parasitaemia' may not differentiate between malaria cases and non-cases. Case definitions based on parasite cut-off densities may be more appropriate but may vary with age and transmission intensity. This study examines appropriate case definitions from parasitological surveys conducted over a broad range of transmission intensities, using altitude as a proxy for transmission intensity.Cross-sectional data collected from 24 villages at different altitudes in an endemic area of northeastern Tanzania were used to calculate malaria-attributable fractions using a modified Poisson regression method. We modelled fever as a function of parasite density and determined the optimum cut-off densities of parasites to cause fever using sensitivity and specificity analyses.The optimum cut-off density varied by altitude in children aged under 5 years: a case definition of 4,000 parasites per mul at altitudes600 m (high transmission intensity) was most appropriate, compared with 1,000 parasites per mul at altitudes600 m (low transmission intensity). In children aged over 5 years and adults, there was little variation by altitude and a case definition of any parasites plus fever was the most appropriate.Locally appropriate case definitions of malaria should be used for research purposes. In our setting, these varied independently with age and transmission intensity.

The isotype/subclass of immunoglobulin determines antibody function, but rather little is known about factors that direct class switching in vivo. To evaluate factors that might influence the maturation of the antibody response during infection, we conducted a seroepidemiological study of the immunoglobulin G (IgG) subclass response to four merozoite-associated antigens ofPlasmodium falciparumin a mountainous region of northeastern Tanzania, where malaria endemicity declines with increasing altitudes. We found that IgG1/IgG3 class switching is independently affected by the nature of the antigen, cumulative exposure to the antigen, and the maturity of the immune system (i.e., the age of the individual). These observations provide insights into the effects of immune system maturity, the duration and intensity of antigen exposure, and inherent characteristics of individual antigens on the process of class switching in human B cells. Our data also throw light on the consequences of class switch decisions on the gradual acquisition of antimalarial immunity.

In developed countries much progress has been made in reducing vertical transmission of HIV using antiretroviral therapies. To achieve similar gains in Africa the acceptability of routine HIV testing of pregnant women is becoming increasingly important. Evidence of reluctance of pregnant women to undergo HIV testing has led to suggestions to offer antiretroviral therapy to pregnant women without prior HIV testing. In this study we set out to identify risk factors for preferring to avoid HIV testing among women attending an antenatal clinic in northern Tanzania in the context of a hypothetical offer of Nevirapine and to explore the issues raised in more detail in focus group discussions. Two hundred and fifty women attending an antenatal clinic in late pregnancy were interviewed. Almost half of the women preferred to be offered Nevirapine without HIV testing. In a multiple logistic model having a partner with a history of a sexually transmitted disease (OR 2.72, 95% CI 1.14-6.47, p = 0.02) and having a partner who had another sexual partner in the last year (OR 1.89, 95% CI 1.04-3.45, p = 0.04) were positively associated with a preference to avoid HIV testing; while the presence of a partner living at home or feeling able to ask their partner to go for an HIV test were negatively associated with a preference to avoid HIV testing (OR 0.46, 95% CI 0.24-0.89, p = 0.02 and OR 0.56, 95% CI 0.3-1.05, p = 0.07 respectively). FGDs (focus group discussions) suggested that the major concern of women was for the reaction of their male partners to the possibility of a positive HIV test and low confidence in the confidentiality of HIV testing. This fear may lead to low uptake of antiretroviral programmes and treatment without prior testing should be considered.

The implementation and evaluation of malaria control programs would be greatly facilitated by new tools for the rapid assessment of malaria transmission intensity. Because acquisition and maintenance of antimalarial antibodies depend on exposure to malaria infection, such antibodies might be used as proxy measures of transmission intensity. We have compared the prevalence of IgG antibodies with threePlasmodium falciparumasexual stage antigens in individuals of all ages living at varying altitudes encompassing a range of transmission intensities from hyper- to hypoendemic in northeastern Tanzania, with alternative measures of transmission intensity. The prevalence of antibodies to merozoite surface protein-119was significantly more closely correlated with altitude than either point-prevalence malaria parasitemia or single measures of hemoglobin concentration. Analysis of age-specific seroprevalence rates enabled differentiation of recent (seasonal) changes in transmission intensity from longer-term transmission trends and, using a mathematical model of the annual rate of seroconversion, estimation of the longevity of the antibody response. Thus, serological tools allow us to detect variations in malaria transmission over time. Such tools will be invaluable for monitoring trends in malaria endemicity and the effectiveness of malaria control programs.

Hospital-acquired infections (HAI) are a major and largely preventable cause of morbidity and morbidity worldwide. Very few reports on the prevalence of HAI in sub-Saharan Africa have been published and most of those that have appeared in the press have focused on surgical-wound infection. In the present, questionnaire-based, point-prevalence study, in which the doctor on the ward round was used as the primary informant, the prevalences of all HAI among all the inpatients at a tertiary referral hospital in northern Tanzania were estimated. On the day of the study, there were 412 inpatients (in 15 ward areas) and 61 cases of HAI were identified, giving an overall HAI prevalence of 14.8%. The prevalences of HAI were particularly high in the medical intensive-care unit (40%), the surgical (orthopaedic and general surgery) wards (36.7%), and one of the general medical wards (22.2%). Factors associated with a patient having a HAI were hospitalization for >30 days [odds ratio (OR) = 4.07; 95% confidence interval (CI) = 2.07-7.99]; being a patient on the orthopaedic and general surgical ward known as 'Surgical 2' (OR = 2.14; CI = 1.02-4.46); and being referred from another health facility (OR = 1.90; CI = 1.02-3.42). The most commonly identified HAI in the hospital were urinary-tract infections (14 cases), followed by surgical-wound infections (10 cases) and then lower respiratory-tract infections (six cases). Twenty HAI were 'unspecified'. The study was rapid and cheap to carry out. The results not only gave a baseline estimate of HAI in the study setting but also identified key areas for interventions to reduce HAI.

Background: There is increasing recognition among trialists of the challenges in understanding how particular 'real-life' contexts influence the delivery and receipt of complex health interventions. Evaluations of interventions to change health worker and/or patient behaviours in health service settings exemplify these challenges. When interpreting evaluation data, deviation from intended intervention implementation is accounted for through process evaluations of fidelity, reach, and intensity. However, no such systematic approach has been proposed to account for the way evaluation activities may deviate in practice from assumptions made when data are interpreted.Methods: A collective case study was conducted to explore experiences of undertaking evaluation activities in the real-life contexts of nine complex intervention trials seeking to improve appropriate diagnosis and treatment of malaria in varied health service settings. Multiple sources of data were used, including in-depth interviews with investigators, participant-observation of studies, and rounds of discussion and reflection.Results and discussion: From our experiences of the realities of conducting these evaluations, we identified six key 'lessons learned' about ways to become aware of and manage aspects of the fabric of trials involving the interface of researchers, fieldworkers, participants and data collection tools that may affect the intended production of data and interpretation of findings. These lessons included: foster a shared understanding across the study team of how individual practices contribute to the study goals; promote and facilitate within-team communications for ongoing reflection on the progress of the evaluation; establish processes for ongoing collaboration and dialogue between sub-study teams; the importance of a field research coordinator bridging everyday project management with scientific oversight; collect and review reflective field notes on the progress of the evaluation to aid interpretation of outcomes; and these approaches should help the identification of and reflection on possible overlaps between the evaluation and intervention.Conclusion: The lessons we have drawn point to the principle of reflexivity that, we argue, needs to become part of standard practice in the conduct of evaluations of complex interventions to promote more meaningful interpretations of the effects of an intervention and to better inform future implementation and decision-making. © 2014 Reynolds et al.; licensee BioMed Central Ltd.

Background In 2006, the first-line anti-malarial drug treatment in Tanzania was changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu), an artemisinin-based combination (ACT), since when the use of SP has been restricted for intermittent preventive treatment in pregnancy (IPTp). A number of Plasmodium falciparum mutations are known to be associated with resistance to SP, but it is not known if the prevalence of these mutations is increasing or decreasing under the conditions of reduced levels of SP use. This study reports on the current SP resistant quintuple Pfdhfr-Pfdhps mutations in six regions of Tanzania. Methods Finger-prick blood on filter paper and rapid diagnostic test strips from P. falciparum-positive individuals of all age groups attending health facilities in six regions of Tanzania between June 2010 and August 2011 were obtained. Using chelex-100 extracted DNA, genotyping was done for mutations on codons 51, 59 and 108 of Pfdhfr and 437 and 540 of Pfdhps genes using PCR-RFLP technique. Results A total of 802 malaria-positive samples were screened and genotyped. The prevalence of Pfdhfr 51I, Pfdhps 437G and 540E varied between the regions (p

Southall made several points about our recent article.1 2 He suggests that “lethal hyperchloraemia” secondary to use of normal saline in FEAST (for boluses or maintenance) resulted in excess mortality. However, he did not comment on the key finding of the trial—that the increased 48 hour mortality was identical in both normal saline bolus (10.6%) and albumin bolus (10.6%) arms compared with the no bolus control group (7.3%).3 Harm was shown for every age group, in every condition, at each …

Cutaneous leishmaniasis (CL) due to Leishmania tropica appears to be an emerging disease in parts of north-east Afghanistan and north-west Pakistan. Timargara, an Afghan refugee camp of 17 years' standing, in the district of Dir, North West Frontier Province of Pakistan, experienced a major outbreak of CL in 1997 for the first time. As part of the investigation, each section of the camp was surveyed for CL. Around 38% of the 9200 inhabitants bore active lesions and a further 13% had scars from earlier attacks. According to interview statements, 99% of earlier infections had healed within the previous 2 years. To confirm the diagnosis, a sample of current CL lesions was examined parasitologically. Amastigotes were detectable by microscopy in only 36% of lesions. However, 48% of slide-negative cases produced positive cultures and some cases negative to both microscopy and culture were positive by PCR. Overall detection rate was about 80%. The sandfly Phlebotomus sergenti, a known vector of L. tropica, was captured within the camp, indicating local transmission. CL has not been reported from this area of Pakistan before. Although the majority of refugees left Afghanistan 2 decades ago, cross-border movement of men is common. The Afghanistan capital, Kabul, is currently experiencing a major epidemic of CL; infected migrant carriers from Kabul are probably the source of the outbreak in Timargara.

A nested PCR was developed to amplify the variable region of the kinetoplast minicircles of all Leishmania species which infect mammals. Each Leishmania parasite contains approximately 10,000 kinetoplast DNA minicircles, which are unequally distributed among approximately 10 minicircle classes. The PCR primers were designed to bind within the 120-bp conserved region which is common to all minicircle classes; the remaining approximately 600 bp of each minicircle is highly conserved within each minicircle class but highly divergent between classes. The nested PCR generated a strong signal from a minimum of 0.1 fg of Leishmania DNA. Restriction digests of the amplicons from the highest dilutions suggested that minicircles from only a limited number of minicircle classes had acted as template in the reaction. One PCR product was directly sequenced and found to be derived from only one minicircle class. Since the primers amplify all minicircle classes, this indicated that as little as 1/10 of one Leishmania parasite was present in the PCR template. This demonstrated that the nested PCR achieved very nearly the maximum theoretically possible sensitivity and is therefore a potentially useful method for diagnosis. The nested PCR was tested for sensitivity on 20 samples from patients from the Timargara refugee camp, Pakistan. Samples were collected by scraping out a small amount of tissue with a scalpel from an incision at the edge of the lesion; the tissue was smeared on one microscope slide and placed in a tube of 4 M guanidine thiocyanate, in which the sample was stable for at least 1 month. DNA for PCR was prepared by being bound to silica in the presence of 6 M guanidine thiocyanate; washed in guanidine thiocyanate, ethanol, and acetone; and eluted with 10 mM Tris-HCl. PCR products of the size expected for Leishmania tropica were obtained from 15 of the 20 samples in at least one of three replicate reactions. The negative samples were from lesions that had been treated with glucantime or were over 6 months old, in which parasites are frequently scanty. This test is now in routine use for the detection and identification of Leishmania parasites in our clinical laboratory. Fingerprints produced by restriction digests of the PCR products were defined as complex or simple. There were no reproducible differences between the complex restriction patterns of the kinetoplast DNA of any of the parasites from Timargara camp with Hae III and Hpa II. The simple fingerprints were very variable and were interpreted as being the product of PCR on a limited subset of minicircle classes, and consequently, it was thought that the variation was determined by the particular minicircle classes that had been represented in the template. The homogeneity of the complex fingerprints suggests that the present epidemic of cutaneous leishmaniasis in Timargara camp may be due to the spread of a single clone of L. tropica .

Background Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however, continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based on the prevalence of wild types at codon 76 of the Pfcrt gene in indigenous P. falciparum populations. The current prevalence of this Pfcrt- 76 CQ resistance marker from six regions of Tanzania mainland is hereby reported. Methods DNA extracted from filter-paper dried blood spots and rapid diagnostics kit strips collected from finger-prick blood were used to genotype the Pfcrt-76 resistance marker using PCR-RFLP. Data from previously published studies were used to generate CQ susceptibility recovery trends using logistic regression model. Results Seven hundred and forty one (741) samples were genotyped. The current frequency of the CQ-susceptible Pfcrt-K76 was above 92% and did not differ between regions in Tanzania (χ 2 = 2.37; p = 0.795). The K76 allelic prevalence was between 85.7 and 93% in regions (χ 2 = 7.88, p = 0.163). The CQ resistance recovery trends showed regional variability that may be caused by differences in malaria transmission intensity, but overall the trends converge as the susceptibility levels in all regions approach >90%. Conclusions CQ withdrawal in Tanzania has resulted into >90% recovery of susceptibility in ten years of withdrawal. These findings are in support of the search for CQ-based combination drugs as a possible future alternative to SP for IPTp in places where full recovery of CQ-susceptibility will be evident.

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.)

Data from a prospective study of 3,319 children ages 2 months to 5 years admitted with febrile illness to a Tanzanian district hospital were analyzed to determine the relationship of blood glucose and mortality. Hypoglycemia (blood sugar < 2.5 mmol/L and < 45 mg/dL) was found in 105 of 3,319 (3.2%) children at admission, and low-normal blood glucose (2.5-5 mmol/L and 45-90 mg/dL) was found in 773 of 3,319 (23.3%) children. Mortality was inversely related to admission blood sugar; compared with children with an admission blood glucose of > 5 mmol/L, the adjusted odds of dying were 3.3 (95% confidence interval = 2.1-5.2) and 9.8 (95% confidence interval = 5.1-19.0) among children with admission blood glucose 2.5-5 and < 2.5 mmol/L, respectively. Receiver operating characteristic (ROC) analysis suggested an optimal cutoff for admission blood sugar of < 5 mmol/L in predicting mortality (sensitivity = 57.7%, specificity = 75.2%). A cutoff for admission blood glucose of < 5 mmol/L represents a simple and clinically useful predictor of mortality in children admitted with severe febrile illness to hospital in resource-poor settings.

Background: In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. Methods: Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6−60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. Results:The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%–100%), with a sensitivity of 74% (95% CI, 72%–77%), whereas a concentration of 10% (95% CI, 3%–27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. Conclusions: The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

Excluding HIV infection among infants and young children in resource-poor settings where nucleic acid amplification tests (NAAT) are not routinely available remains a considerable challenge.To assess the performance of two rapid HIV antibody tests (RT) used alone and in parallel for excluding HIV infection among acutely ill infants and children18 months in comparison to NAAT in a region where maternal HIV prevalence was approximately 7%.Infants and children ≥218 months admitted to hospital with an acute febrile illness had two rapid antibody tests in parallel, with single and parallel results subsequently compared against NAAT.HIV prevalence among 1602 enrolled infants was 3.4%. All 1526 infants with 2 negative RT were HIV negative by NAAT. All 46 infants with 2 positive RT were HIV positive by NAAT. The overall specificity of two rapid tests for excluding HIV infection was 99.5%. Sensitivity and specificity were ≥99% and98%, respectively, across all age brackets ≥218 months. Overall sensitivity and specificity for a single RT was 98.2% and 99%, respectively, for Determine, and 85.5% and 99.6%, respectively, for Capillus.In a setting with a maternal HIV prevalence rate of10%, a single negative RT had excellent specificity and two negative RT performed in parallel had a perfect negative predictive value for HIV infection among acutely ill patients18 months of age. In this and similar settings, RT could assist with excluding HIV infection with much lower complexity and cost than NAAT.

Background While child mortality is declining in Africa there has been no evidence of a comparable reduction in neonatal mortality. The quality of inpatient neonatal care is likely a contributing factor but data from resource limited settings are few. The objective of this study was to assess the quality of neonatal care in the district hospitals of the Kilimanjaro region of Tanzania. Methods Clinical records were reviewed for ill or premature neonates admitted to 13 inpatient health facilities in the Kilimanjaro region; staffing and equipment levels were also assessed. Results Among the 82 neonates reviewed, key health information was missing from a substantial proportion of records: on maternal antenatal cards, blood group was recorded for 52 (63.4%) mothers, Rhesus (Rh) factor for 39 (47.6%), VDRL for 59 (71.9%) and HIV status for 77 (93.1%). From neonatal clinical records, heart rate was recorded for3 (3.7%) neonates, respiratory rate in 14, (17.1%) and temperature in 33 (40.2%). None of 13 facilities had a functioning premature unit despite calculated gestational age Conclusion Key aspects of neonatal care were found to be poorly documented or incorrectly implemented in this appraisal of neonatal care in Kilimanjaro. Efforts towards quality assurance and enhanced motivation of staff may improve outcomes for this vulnerable group.

The distribution of T cells using the V beta 2 gene was studied in a group of 99 humans. The distribution of V beta 2+CD4+ levels was bimodal. Twelve individuals had levels of V beta 2+CD4+ less than 2% and 86 others had values greater than 5%. Only one individual had a value between 2% and 5%. The V beta 2 low (mean 1.3 +/- 0.49) and V beta 2 high (mean 8.2 +/- 1.65) phenotypes were stable. The V beta 2 low phenotype is inherited and not limited to HLA or T cell receptor V beta gene complexes. The CD8V beta 2 levels of CD4V beta 2 low individuals are also low. The residual V beta 2+ T cells in V beta 2 low individuals were not anergic to V beta 2-specific stimulation. These data are compatible with the effects of an endogenous superantigen.

Background In malaria endemic areas, individuals are frequently asymptomatic and may be undetected by conventional microscopy or newer, rapid diagnostic tests. Molecular techniques allow a more accurate assessment of this asymptomatic parasite burden, the extent of which is important for malaria control. This study examines the relative prevalence of sub-microscopic level parasite carriage and clonal complexity of infections (multiplicity of infection) over a range of endemicities in a region of north-eastern Tanzania where altitude is an established proxy of malaria transmission. The PCR prevalence was then compared against other measures of transmission intensity collected in the same area. Methods This study used 1,121 blood samples collected from a previously conducted cross-sectional malario-metric survey during the short rainy season in 2001 from 13 villages (three at < 600 m, four at 600-1,200 m and six at > 1,200 m in altitude above sea level). Samples were analysed by PCR for carriage of parasites and multiplicity of infection. These data were compared with other measures of transmission intensity collected from the same area. Results Parasite prevalence was 34.7% by PCR and 13.6% by microscopy; a 2.5-fold difference in line with other recent observations. This fold difference was relatively consistent at the different altitude bands despite a marked decrease in parasite prevalence with altitude: < 600 m 70.9 vs 28.6, 600-1,200 m 35.5 vs 9.9, > 1,200 m 15.8 vs 5.9. The difference between parasite prevalence by PCR was 3.2 in individuals aged between 15 and 45 years (34.5 vs 10.9) compared with 2.5 in those aged 1-5 (34.0 vs 13.5) though this was not statistically significant. Multiplicity of infection (MOI) ranged from 1.2 to 3.7 and was positively associated with parasite prevalence assessed by both PCR and microscopy. There was no association of MOI and age. Village level PCR parasite prevalence was strongly correlated with altitude, sero-conversion rate and predicted entomological inoculation rate. Conclusions Asymptomatic, low density, multi-clone malaria infection was common in this study area. These infections are important as potential contributors to the infectious reservoir of parasites and need to be identified by control programmes especially in this era where malaria elimination is a focus. High throughput standardized PCR approaches are needed to identify individuals who are malaria carriers.

Severe febrile illness is a major cause of adult hospital admission in Africa. Studies of non-malarial fever come largely from children or from high HIV prevalence settings. This prospective study of adult admissions with severe febrile illness in a malaria-endemic area with moderate/low HIV prevalence investigated admission diagnosis as well as final diagnosis based on results of investigations. Severe malaria was the admission diagnosis in 148/198 (74.7%) cases. Plasmodium falciparum was identified in 38/188 (20.2%) admissions and 26/198 (13.1%) were bacteraemic, with 13/25 (52%) prescribed empirical antibiotics. HIV was equally common among those with (16/37; 43.2%) and without P. falciparum (50/138; 36.2%) (p=0.44). In 6/22 (27.3%) deaths, blood cultures were positive for a pathogen, with Streptococcus pneumoniae, Escherichia coli and non-Typhi Salmonella predominating. Chest radiography was suspicious for bacterial/mycobacterial disease in 5/22 additional deaths. Systemic inflammatory response syndrome criteria were more sensitive but less specific than WHO severe malaria criteria for predicting mortality. Malaria is overdiagnosed in adults with severe febrile illness and was not associated with mortality in the absence of co-infection in this high-incidence setting. Adults with severe febrile illness should be tested for malaria and HIV using rapid, sensitive tests. Early antibiotic use should be promoted. Improved diagnostics for invasive bacterial disease are needed.

Background The annual incidence and temporal trend of severe malaria and community-acquired bacteraemia during a four-year period in Muheza, Tanzania was assessed. Methods Data on severely ill febrile children aged 2 months to 14 years from three prospective studies conducted at Muheza District Hospital from 2006 to 2010 was pooled and analysed. On admission, each enrolled child had a thin and thick blood film and at least one rapid diagnostic test for falciparum malaria, as well as a blood culture. The annual incidence of bacteraemia and severe malaria among children coming from Muheza was calculated and their temporal trend was assessed. Results Overall, 1, 898 severe falciparum malaria and 684 bacteraemia cases were included. Of these, 1, 356 (71%) and 482 (71%), respectively, were from the referral population of Muheza. The incidence of falciparum malaria and all-cause bacteraemia in Muheza decreased five-fold and three-fold, respectively, from the first to the fourth year of surveillance (p < 0.0001). During this period, the median ages of children from Muheza admitted with severe malaria increased from 1.7 to 2.5 years (p < 0.0001). The reduction in all-cause bacteraemia was mainly driven by the 11-fold decline in the incidence of non-typhoidal salmonellosis. The annual incidences of Haemophilus influenzae and pneumococcal invasive bacterial infections decreased as well but were much fewer in number. Conclusions These results add to the growing evidence of the decline in malaria associated with a decrease in non-typhoidal salmonellosis and possibly other bacteraemias. Malarial prevention and control strategies may provide a greater benefit than the mere reduction of malaria alone.

Methods We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. Results The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P = 0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P = 0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P = 0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P = 0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P = 0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P = 0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albuminbolus group and 56% (9 of 16) in the saline-bolus group died (P = 0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. Conclusions Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.)

Background WHO guidelines for the treatment of young children with suspected malaria have recently changed from presumptive treatment to anti-malarial treatment guided by a blood slide or malaria rapid diagnostic test (RDT). However, there is limited evidence of the safety of this policy in routine outpatient settings in Africa. Methods Children 3-59 months of age with a non-severe febrile illness and no obvious cause were enrolled over a period of one year in a malaria endemic area of Tanzania. Treatment was determined by the results of a clinical examination and RDT result, and blood culture and serum lactate were also collected. RDT-negative children were followed up over 14 days. Results Over the course of one year, 965 children were enrolled; 158 (16.4%) were RDT-positive and treated with artemether-lumefantrine and 807 (83.4%) were RDT-negative and treated with non-anti-malarial medicines. Compared with RDT-positives, RDT-negative children were on average younger with a lower axillary temperature and more likely to have a history of cough or difficulty in breathing. Six (0.6%) children became RDT-positive after enrolment, all of whom were PCR-negative for Plasmodium falciparum DNA at enrolment. In addition, 12 (1.2%) children were admitted to hospital, one with possible malaria, none of whom died. A bacterial pathogen was identified in 9/965 (0.9%) children, eight of whom were RDT-negative and one was RDT-positive, but slide-negative. Excluding three children with Salmonella typhi, all of the children with bacteraemia were ≤12 months of age. Compared to double-read research slide results RDTs had a sensitivity of 97.8% (95%CI 96.9-98.7) and specificity of 96.3% (95%CI 96.3-98.4). Conclusions Use of RDTs to direct the use of anti-malarial drugs in young children did not result in any missed diagnoses of malaria although new infections soon after a consultation with a negative RDT result may undermine confidence in results. Invasive bacterial disease is uncommon in children with non-severe illness and most cases occurred in infants with a current fever.

Summary objective To compare the performance of the Paracheck rapid diagnostic test (RDT) withmicroscopy for diagnosing malaria in hospitalised children.methods Children aged between 2 months and 13 years with fever were enrolled in the study over1 year. A standard clinical history and examination were recorded and blood drawn for culture,complete blood count, Paracheck RDT and double-read blood slide.results Of 3639 children enrolled, 2195 (60.3%) were slide positive. The sensitivity and specificityof Paracheck were 97.5% (95% CI 96.9–98.0) and 65.3% (95% CI 63.8–66.9), respectively. There wasan inverse relationship between age-specific prevalence of parasitaemia and Paracheck specificity. Inlogistic regression model, false-positive Paracheck results were significantly associated with pre-admission use of antimalarial drug (OR 1.44, 95% CI 1.16–1.78), absence of current fever (OR 0.64,95% CI 0.52–0.79) and non-typhi Salmonella bacteraemia (OR 3.89. 95% CI 2.27–6.63). In spite ofhigh sensitivity, 56⁄2195 (2.6%) of true infections were Paracheck negative and 8⁄56 (14.3%) were inpatients with >50 000 parasites⁄ll.conclusions Paracheck had poor specificity in diagnosing malaria in severely ill children; this waslikely to be due to HRP2 persistence following recent parasite clearance. The combination of positiveParacheck and negative blood slide results identified a group of children at high risk of non-typhiSalmonella infection. While Paracheck was highly sensitive, some high-density infections were missed.For children with severe febrile illness, at least two reliable negative parasitological test results should beavailable to justify withholding antimalarial treatment; the optimal choice of these has yet to beidentified.keywords malaria, severe, rapid diagnostic test, hospitalIntroductionThe use of rapid immunochromatographic tests for malaria(RDTs) in primary care facilities has been studied over anumber of years, and these tests are now being rolled outon a large scale in Africa as a means to restrict antimalarialdrug use to parasitologically confirmed cases, a policy nowsupported by WHO (WHO 2010). However, the WHOcriteria for malaria diagnosis apply irrespective of severity,and it is therefore surprising that as far as we are aware,only one small study has so far been published on the use ofRDTs in patients admitted to hospital (Birku et al. 1999).The wider use of RDTs in patients hospitalised withsevere febrile illness seems inevitable given the increasingavailability of RDTs. Given current evidence of the lowaccuracy of routinely read slide results, this may representan improvement over current practice (Reyburn et al.2004; Zurovac et al. 2006). However, the performance ofHRP2-based RDTs may differ when used for severely illchildren compared to use in non-severe illness. First,specificity may be reduced by the persistence of HRP2 forup to 5 weeks following clearance of parasites and this

BACKGROUND: Lactic acidosis is a consistent predictor of mortality owing to severe infectious disease, but its detection in low-income settings is limited to the clinical sign of "deep breathing" because of the lack of accessible technology for its measurement. We evaluated the use of a point-of-care (POC) diagnostic device for blood lactate measurement to assess the severity of illness in children admitted to a district hospital in Tanzania. METHODS: Children between the ages of 2 months and 13 years with a history of fever were enrolled in the study during a period of 1 year. A full clinical history and examination were undertaken, and blood was collected for culture, microscopy, complete blood cell count, and POC measurement of blood lactate and glucose. RESULTS: The study included 3248 children, of whom 164 (5.0%) died; 45 (27.4%) of these had raised levels of blood lactate (>5 mmol/L) but no deep breathing. Compared with mortality in children with lactate levels of ≤ 3 mmol/L, the unadjusted odds of dying were 1.6 (95% confidence interval [CI].8-3.0), 3.4 (95% CI, 1.5-7.5), and 8.9 (95% CI, 4.7-16.8) in children with blood lactate levels of 3.1-5.0, 5.1-8.0, or >8.0 mmol/L, respectively. The prevalence of raised lactate levels (>5 mmol/L) was greater in children with malaria than in children with nonmalarial febrile illness (P < .001) although the associated mortality was greater in slide-negative children. CONCLUSIONS: POC lactate measurement can contribute to the assessment of children admitted to hospital with febrile illness and can also create an opportunity for more hospitals in resource-poor settings to participate in clinical trials of interventions to reduce mortality associated with hyperlactatemia.

Background The diagnosis of typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi (S. typhi). However, a more rapid, simpler, and cheaper diagnostic method would be very useful especially in developing countries. The Widal test is widely used in Africa but little information exists about its reliability. Methods We assessed the performance of the Widal tube agglutination test among febrile hospitalized Tanzanian children. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various anti-TH and -TO titers using culture-confirmed typhoid fever cases as the "true positives" and all other febrile children with blood culture negative for S. typhi as the "true negatives." Results We found that 16 (1%) of 1,680 children had culture-proven typhoid fever. A single anti-TH titer of 1:80 and higher was the optimal indicator of typhoid fever. This had a sensitivity of 75%, specificity of 98%, NPV of 100%, but PPV was only 26%. We compared our main findings with those from previous studies. Conclusion Among febrile hospitalized Tanzanian children with a low prevalence of typhoid fever, a Widal titer of ≥ 1:80 performed well in terms of sensitivity, specificity, and NPV. However a test with improved PPV that is similarly easy to apply and cost-efficient is desirable.

OBJECTIVE: Tanzania has a policy of free provision of inpatient care for young children in order to promote timely access and thus reduce the current levels of mortality. However, little is known about out-of-pocket costs that may be incurred by families in seeking care for sick children. We conducted this study to identify the magnitude of these costs in relation to family income. METHODS: Five hundred and ten caretakers were interviewed on the day of discharge of their child from 11 hospitals in north-east Tanzania. Caretakers were asked to report expenditure related to hospitalization in various categories and family wealth was assessed through reported expenditure in the previous month. RESULTS: Food (mean US$2.2, median US$1.6), transport (mean US$1.7, median US$0) and medicines (mean US$1.0, median US$0.4) were the leading categories of expenditure, and overall the mean out-of-pocket expenditure was US$5.5 (median US$3.7) per admission. Mean out-of-pocket expenditure was more than 1.5 times higher for households in the highest monthly expenditure quintile compared with those in the lowest. However, this differential was reversed when expenditure was considered as a proportion of family expenditure in the previous month; for the lowest quintile, families spent more than three-quarters of their total monthly expenditure on a single paediatric admission. CONCLUSION: Out-of-pocket expenditure on child hospitalization places a considerable burden on poor families. Our findings justify a closer scrutiny of how this expenditure could be reduced, particularly through the provision of adequate food for both children and caretakers and through reducing stock-outs of essential medicines.

OBJECTIVES: To assess the performance of WHO's "Guidelines for care at the first-referral level in developing countries" in an area of intense malaria transmission and identify bacterial infections in children with and without malaria. DESIGN: Prospective study. SETTING: District hospital in Muheza, northeast Tanzania. PARTICIPANTS: Children aged 2 months to 13 years admitted to hospital for febrile illness. MAIN OUTCOME MEASURES: Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials. RESULTS: Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P

Background Blood transfusion (BT) can be lifesaving for children; however, monitoring the quality of BT is important. The current study describes the quality of paediatric BT delivered in two district hospitals in north-east Tanzania in order to identify areas for quality assurance and improvement in the administration of BT. Methods All 166 children admitted in the paediatric wards and receiving BT through April to June 2007 were prospectively observed. Medical records, request forms and registers in the laboratories were reviewed to identify blood source, blood screening and indications for BT. BT was observation before, during and after transfusion process. Results Malaria related anaemia accounted for 98% of the BTs. Ninety-two percent of the children were assessed for paleness. Clinical signs such as difficult breathing and symptoms of cardiac failure were only assessed in 67% and 15% of the children respectively, prior to the BT decision. Pre-transfusion haemoglobin and body temperature were recorded in 2/3 of the patients, but respiratory rate and pulse rate were not routinely recorded. In 40% of BTs, the transfusion time exceeded the recommended 4 hours. The zonal blood bank (ZBB) and local donors accounted for 10% and 90% of the blood, respectively. ABO and RhD typing and screening for HIV and syphilis were undertaken in all transfused blood. Evidence for hepatitis B or C infection was not checked except in the ZBB. Conclusion Criteria for BT are not always fulfilled; time to initiate and complete the transfusion is often unacceptable long and monitoring of vital signs during BT is poor. Blood from the ZBB was often not available and BT often depended on local donors which implied lack of screening for hepatitis B and C. It is recommended that an external supervision system be established to monitor and evaluate the quality of BT performance in the laboratories as well as in wards.

Is ineffective in outpatients and should be used only in rare cases Artemisinin combination therapy is the first line treatment for uncomplicated malaria in nearly all malaria endemic countries in sub-Saharan Africa. This treatment is relatively expensive, but it kills parasites faster than any other method and has few adverse effects.1 The combination artemether-lumefantrine (Coartem) is co-formulated, can be taken in a convenient schedule over three days, and is popular with patients and healthcare providers.2 The linked study by Achan and coworkers (doi:10.1136/bmj.b2763) confirms the excellent cure rate (all patients were cured after adjusting for reinfection) of this drug in children with uncomplicated malaria in Uganda.3 However, oral quinine is often used to treat uncomplicated malaria either because artemisinin combinations are not available,4 or on the assumption that it must be effective because it is still the drug of choice for severe malaria in African children (although it is now known to be inferior to artesunate in Asian adults …

Background Sero-epidemiological methods are being developed as a tool for rapid assessment of malaria transmission intensity. Simple blood collection methods for use in field settings will make this more feasible. This paper describes validation of such a method, by analysing immunoglobulins from blood retained within immunophoretic rapid diagnostic tests (RDTs) for Plasmodium falciparum. RDTs are now widely used for the diagnosis of malaria and estimation of parasite rates, and this method represents a further use for these devices in malaria control. Methods Immunoglobulins eluted from RDTs, designed to detect parasite histidine rich protein-2 (HRP-2), were analysed by indirect ELISA for IgG recognizing the P. falciparum blood stage antigens merozoite surface protein-119 (MSP-119) and apical membrane antigen-1 (AMA-1). Optimal storage conditions for RDTs were evaluated by comparing antibody responses from RDTs stored in dry or humid conditions at 4°C or at ambient temperature (with or without air-conditioning) for 7, 31 or 70 days. Antibody levels estimated using 3,700 RDT samples from attendees at health facilities in North-eastern Tanzania were compared with contemporaneously collected filter paper blood spots (FPBS) and used to estimate seroconversion rates. Results Storage of RDTs at 4°C was optimal for immunoglobulin recovery but short-term storage at ambient temperatures did not substantially affect anti-malarial IgG levels. Results from RDTs were comparable with those from FPBSs, for both antigens. RDT-generated titres tended to be slightly higher than those generated from FPBSs, possibly due to greater recovery of immunoglobulins from RDTs compared to filter paper. Importantly, however, RDT-based seroconversion rates, and hence serological estimates of malaria transmission intensity, agreed closely with those from FPBSs. Conclusion RDTs represent a practical option for collecting blood for sero-epidemiological surveys, with potential cost and logistical advantages over filter paper and other blood collection methods. RDT-based seroepidemiology can be incorporated into routine monitoring of malaria endemicity, providing information to supplement parasite prevalence rates and generating rapid, robust assessment of malaria transmission intensity at minimal extra cost.

Contains fulltext : 80249.pdf (Publisher’s version ) (Closed access) Disturbances in iron homeostasis are frequently observed in individuals with malaria. To study the effect of malaria and its treatment on iron homeostasis and to provide a mechanistic explanation for observed alterations in iron distribution, we studied the course of the iron regulatory hormone hepcidin in anemic Tanzanian children with febrile Plasmodium falciparum malaria. Before initiation of antimalarial treatment, urinary concentrations of hepcidin were strongly elevated and were associated with iron maldistribution, as was suggested by the presence of hypoferremia and high serum concentrations of ferritin. Antimalarial treatment resulted in a rapid decrease in urinary concentrations of hepcidin and reversal of the hypoferremia. Exploration of regulatory pathways of hepcidin production by analysis of iron, erythropoietic, and inflammatory indices suggested that reduced erythropoietic activity and inflammation stimulated hepcidin production. We conclude that high concentrations of hepcidin explain the observed disturbances in host iron homeostasis associated with malaria and may contribute to malarial anemia and an impaired erythropoietic response to iron supplementation.

Background Patient, or parent/guardian, satisfaction with health care provision is important to health outcomes. Poor relationships with health workers, particularly with nursing staff, have been reported to reduce satisfaction with care in Africa. Participatory research approaches such as the Health Workers for Change initiative have been successful in improving provider-client relationships in various developing country settings, but have not yet been reported in the complex environment of hospital wards. We evaluated the HWC approach for improving the relationship between nurses and parents on a paediatric ward in a busy regional hospital in Tanzania. Methods The intervention consisted of six workshops, attended by 29 of 31 trained nurses and nurse attendants working on the paediatric ward. Parental satisfaction with nursing care was measured with 288 parents before and six weeks after the workshops, by means of an adapted Picker questionnaire. Two focus-group discussions were held with the workshop participants six months after the intervention. Results During the workshops, nurses demonstrated awareness of poor relationships between themselves and mothers. To tackle this, they proposed measures including weekly meetings to solve problems, maintain respect and increase cooperation, and representation to administrative forces to request better working conditions such as equipment, salaries and staff numbers. The results of the parent satisfaction questionnaire showed some improvement in responsiveness of nurses to client needs, but overall the mean percentage of parents reporting each of 20 problems was not statistically significantly different after the intervention, compared to before it (38.9% versus 41.2%). Post-workshop focus-group discussions with nursing staff suggested that nurses felt more empathic towards mothers and perceived an improvement in the relationship, but that this was hindered by persisting problems in their working environment, including poor relationships with other staff and a lack of response from hospital administration to their needs. Conclusion The intended outcome of the intervention was not met. The priorities of the intervention – to improve nurse-parent relationships – did not match the priorities of the nursing staff. Development of awareness and empathy was not enough to provide care that was satisfactory to clients in the context of working conditions that were unsatisfactory to nurses.

Poor quality of care is a major concern in low-income countries, and is in part attributed to low motivation of healthcare workers. Non-physician clinicians (mid-level cadre healthworkers) are central to healthcare delivery in half of the countries in Africa, but while much is expected from these clinicians, little is known about their expectations and motivation to perform well. Understanding what motivates these healthworkers in their work is essential to provide an empirical base for policy decisions to improve quality of healthcare. In 2006-2007, we conducted a mixed-method study to evaluate factors affecting motivation, including reasons for varying levels of motivation, amongst these clinicians in Tanzania. Using a conceptual framework of 'internal' and 'environmental' domains known to influence healthworker motivation in low-income countries, developed from existing literature, we observed over 2000 hospital consultations, interviewed clinicians to evaluate job satisfaction and morale, then designed and implemented a survey instrument to measure work motivation in clinical settings. Thematic analysis (34 interviews, one focus group) identified social status expectations as fundamental to dissatisfaction with financial remuneration, working environments and relationships between different clinical cadres. The survey included all clinicians working in routine patient care at 13 hospitals in the area; 150 returned sufficiently complete data for psychometric analysis. In regression, higher salary was associated with 'internal' motivation; amongst higher earners, motivation was also associated with higher qualification and salary enhancements. Salary was thus a clear prerequisite for motivation. Our results are consistent with the hypothesis that non-salary motivators will only have an effect where salary requirements are satisfied. As well as improvements to organisational management, we put forward the case for the professionalization of non-physician clinicians.

Background There is no clear consensus on the most sustainable and effective distribution strategy for insecticide treated bed nets (ITNs). Tanzania has been a leader in social marketing but it is still not clear if this can result in high and equitable levels of coverage. Methods A cluster-randomized survey of ITN and bed net ownership and use was conducted in a rural area exposed to intense Plasmodium falciparum transmission in NE Tanzania where ITN distribution had been subject to routine delivery of national strategies and episodic free distribution through local clinics. Data were collected on household assets to assess equity of ITN coverage and a rapid diagnostic test for malaria (RDT) was performed in all ages. Results Among 598 households in four villages the use of any or insecticidal bed nets in children less than five years of age was 71% and 54% respectively. However there was a 19.8% increase in the number of bed nets per person (p < 0.001) and a 13.4% increase in the number of insecticidal nets per person (p < 0.001) for each quintile increase in household asset score. The odds of being RDT-positive were reduced by more than half in the least poor compared to the poorest households (OR 0.49, 95% CI 0.35–0.70). Poorer households had paid less for their nets and acquired them more recently, particularly from non-commercial sources, and bed nets in the least poor households were less likely to be insecticidal compared to nets in the poorest households (OR 0.44, 95% CI 0.26–0.74). Conclusion Marked inequity persists with the poorest households still experiencing the highest risk of malaria and the lowest ITN coverage. Abolition of this inequity within the foreseeable future is likely to require mass or targeted free distribution, but risks damaging what is otherwise an effective commercial market.

Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries. © 2008 Macmillan Publishers Limited. All rights reserved.

After many years of development, rapid diagnostic tests (RDTs) for malaria are now being rolled out in many African countries to support the introduction of artemisinin-based combination therapies (ACT). RDTs create new opportunities both for improved care and as research tools, but it is important that the research agenda continues to address the many challenges, both operational and technical, that still need to be met. Here we review what is known and what new evidence is needed to maximise the utility of RDTs in Africa.

OBJECTIVE: To gain a better understanding of the decision-making context in the diagnosis of malaria in order to inform behaviour change strategies, using quantitative methods. METHODS: We observed hospital outpatient and inpatient consultations in northeast Tanzania where malaria testing was routinely available, recording potential influences on testing and prescribing decisions. We analysed the effects of variables at patient, clinical context and clinician levels on three key decisions in malaria diagnosis and treatment: decision to test for malaria, presumptive treatment and treatment of test-negative patients with antimalarials. RESULTS: Observation of 2082 consultations took place during 120 clinics (different shifts on different days and in different departments) with 34 clinicians. Malaria tests were requested for 16.9% of patients. This decision was driven primarily by clinical symptoms. Of patients not tested for malaria, 36.0% were prescribed antimalarials, this decision being associated with both clinical and non-clinical factors. In outpatients fever was a strong predictor of presumptive treatment [adjusted odds ratio (AOR): 45.9, 95% CI: 30-73], in inpatients this was less so (AOR: 2.7, 95% CI: 0.98-7.7). Outpatient clinicians who were working alone or who had attended

Background Intermittent preventive treatment (IPTp) is efficacious in reducing the adverse outcomes associated with pregnancy-associated malaria, however uptake of the recommended two doses is low in Tanzania, and little is known of the timepoint during pregnancy at which it is delivered. This study investigated the timing of delivery of IPTp to pregnant women attending antenatal clinics (ANC), and the potential determinants of timely uptake. Methods Structured interviews were conducted with staff and pregnant women at antenatal clinics in northeast Tanzania, and antenatal consultations were observed. Facility-based and individual factors were analysed for any correlation with timing of IPTp uptake. Results Almost half the women interviewed first attended ANC during or before the fourth month of gestation, however 86% of these early attendees did not receive IPTp on their first visit. The timing of IPTp delivery complied closely with the national guidelines which stipulate giving the first dose at 20–24 weeks gestation. Uptake of at least one dose of IPTp among women who had reached this gestation age was 67%, although this varied considerably between clinics. At one facility, IPTp was not delivered because SP was out of stock. Conclusion Early uptake of IPTp was found to be hampered by factors external to health worker performance or women's individual preferences. These include insufficient drug stocks and an apparent lack of information to health workers on the reasoning for continued use of SP for IPTp when it has been replaced as a first-line treatment. In addition, an unexpectedly high proportion of women attend antenatal clinics before 20 weeks of pregnancy. While current policy denies the use of IPTp at this time, there is emerging, but incomplete, evidence that malaria in early pregnancy may contribute considerably to the burden of pregnancy-related malaria. Current policy may thus result in a missed opportunity for maximising the benefit of this intervention, and efforts to encourage earlier attendance at ANC alone are unlikely to improve uptake of IPTp. More evidence is needed to weigh the benefits of early IPTp use against theoretical risks of antifolate drugs in early pregnancy.

Background Malaria over-diagnosis in Africa is widespread and costly both financially and in terms of morbidity and mortality from missed diagnoses. An understanding of the reasons behind malaria over-diagnosis is urgently needed to inform strategies for better targeting of antimalarials. Methods In an ethnographic study of clinical practice in two hospitals in Tanzania, 2,082 patient consultations with 34 clinicians were observed over a period of three months at each hospital. All clinicians were also interviewed individually as well as being observed during routine working activities with colleagues. Interviews with five tutors and 10 clinical officer students at a nearby clinical officer training college were subsequently conducted. Results Four, primarily social, spheres of influence on malaria over-diagnosis were identified. Firstly, the influence of initial training within a context where the importance of malaria is strongly promoted. Secondly, the influence of peers, conforming to perceived expectations from colleagues. Thirdly, pressure to conform with perceived patient preferences. Lastly, quality of diagnostic support, involving resource management, motivation and supervision. Rather than following national guidelines for the diagnosis of febrile illness, clinician behaviour appeared to follow 'mindlines': shared rationales constructed from these different spheres of influence. Three mindlines were identified in this setting: malaria is easier to diagnose than alternative diseases; malaria is a more acceptable diagnosis; and missing malaria is indefensible. These mindlines were apparent during the training stages as well as throughout clinical careers. Conclusion Clinicians were found to follow mindlines as well as or rather than guidelines, which incorporated multiple social influences operating in the immediate and the wider context of decision making. Interventions to move mindlines closer to guidelines need to take the variety of social influences into account.

OBJECTIVE: Rapid diagnostic tests for malaria seem cost effective in standard analyses, but these do not take account of clinicians' response to test results. This study tested the impact of clinicians' response to rapid diagnostic test or microscopy results on the costs and benefits of testing at different levels of malaria transmission and in different age groups. DESIGN: Cost-benefit analysis using a decision tree model and clinical data on the effectiveness of diagnostic tests for malaria, their costs, and clinicians' response to test results. SETTING: Tanzania. METHODS: Data were obtained from a clinical trial of 2425 patients carried out in three settings of varying transmission. RESULTS: At moderate and low levels of malaria transmission, rapid diagnostic tests were more cost beneficial than microscopy, and both more so than presumptive treatment, but only where response was consistent with test results. At the levels of prescription of antimalarial drugs to patients with negative tests that have been found in observational studies and trials, neither test methodis likely to be cost beneficial, incurring costs 10-250% higher, depending on transmission rate, than would have been the case with fully consistent responses to all test results. Microscopy becomes more cost beneficial than rapid diagnostic tests when its sensitivity under operational conditions approaches that of rapid diagnostic tests. CONCLUSIONS: Improving diagnostic methods, including rapid diagnostic tests, can reduce costs and enhance the benefits of effective antimalarial drugs, but only if the consistency of response to test results is also improved. Investing in methods to improve rational response to tests is essential. Economic evaluations of diagnostic tests should take into account whether clinicians' response is consistent with test results.

User and provider perceptions of quality of care are likely to affect both use and provision of services. However, little is known about how health workers and mothers perceive the delivery of care in hospital paediatric wards in Africa. Paediatric staff and mothers of paediatric inpatients were interviewed to explore their opinions and experience of the admission process and conditions on the ward. Overcrowding, unsanitary conditions and lack of food were major concerns for mothers on the ward, who were deterred from seeking treatment earlier due to fears that hospital admission posed a significant risk of exposure to infection. While most staff were seen as being sympathetic and supportive to mothers, a minority were reported to be judgemental and authoritarian. Health workers identified lack of trained staff, overwork and low pay as major concerns. Staff shortages, lack of effective training and equipment are established problems but our findings also highlight a need for wards to become more parent-friendly, particularly with regard to food, hygiene and space. Training programmes focused on professional conduct and awareness of the problems that mothers face in seeking and receiving care may result in a more supportive and cooperative attitude between staff and mothers.

OBJECTIVE: To compare rapid diagnostic tests (RDTs) for malaria with routine microscopy in guiding treatment decisions for febrile patients. DESIGN: Randomised trial. SETTING: Outpatient departments in northeast Tanzania at varying levels of malaria transmission. PARTICIPANTS: 2416 patients for whom a malaria test was requested. INTERVENTION: Staff received training on rapid diagnostic tests; patients sent for malaria tests were randomised to rapid diagnostic test or routine microscopy MAIN OUTCOME MEASURE: Proportion of patients with a negative test prescribed an antimalarial drug. RESULTS: Of 7589 outpatient consultations, 2425 (32%) had a malaria test requested. Of 1204 patients randomised to microscopy, 1030 (86%) tested negative for malaria; 523 (51%) of these were treated with an antimalarial drug. Of 1193 patients randomised to rapid diagnostic test, 1005 (84%) tested negative; 540 (54%) of these were treated for malaria (odds ratio 1.13, 95% confidence interval 0.95 to 1.34; P=0.18). Children aged under 5 with negative rapid diagnostic tests were more likely to be prescribed an antimalarial drug than were those with negative slides (P=0.003). Patients with a negative test by any method were more likely to be prescribed an antibiotic (odds ratio 6.42, 4.72 to 8.75; P

Background With apparent declines in malaria worldwide during the last decade and more widespread use of malaria rapid diagnostic tests, healthcare workers in low-resource areas face a growing proportion of febrile patients without malaria. We sought to describe current knowledge and identify information gaps of the etiology severe febrile illness in low-and middle-income countries. Methods and Findings We conducted a systematic review of studies conducted in low-and-middle income countries 1980–2013 that prospectively assessed consecutive febrile patients admitted to hospital using rigorous laboratory-based case definitions. We found 45 eligible studies describing 54,578 patients; 9,771 (17.9%) had a positive result for ≥1 pathogen meeting diagnostic criteria. There were no eligible studies identified from Southern and Middle Africa, Eastern Asia, Oceania, Latin American and Caribbean regions, and the European region. The median (range) number of diagnostic tests meeting our confirmed laboratory case definitions was 2 (1 to 11) per study. Of diagnostic tests, 5,052 (10.3%) of 49,143 had confirmed bacterial or fungal bloodstream infection; 709 (3.8%) of 18,142 had bacterial zoonosis; 3,488 (28.5%) of 12,245 had malaria; and 1,804 (17.4%) of 10,389 had a viral infection. Conclusions We demonstrate a wide range of pathogens associated with severe febrile illness and highlight the substantial information gaps regarding the geographic distribution and role of common pathogens. High quality severe febrile illness etiology research that is comprehensive with respect to pathogens and geographically representative is needed.

Background There is a need for improved targeting of antimalarial treatment if artemisinin combination therapy is to be successfully introduced in Africa. This study aimed to explore why malaria slides are requested and how their results guide treatment decisions in an area of low transmission of P. falciparum. Methods Outpatients attending a district hospital in a highland area of Tanzania were studied over a 3-week period. Clinical and social data were collected from patients who had been prescribed an antimalarial or sent for a malaria slide. Hospital slides were re-read later by research methods. Results Of 1,273 consultations 132(10%) were treated presumptively for malaria and 214(17%) were sent for a malaria slide; only 13(6%) of these were reported positive for P. falciparum but 96(48%) of the 201 slide-negative cases were treated for malaria anyway. In a logistic regression model, adults (OR 3.86, P < 0.01), a history of fever (OR1.72, P = 0.03) and a longer travel time to the clinic (OR 1.77 per hour travelled, P < 0.01) independently predicted the request for a malaria slide. Only a history of a cough predicted (negatively) the prescription of an antimalarial with a negative slide result (OR 0.44, P < 0.01). The sensitivity and specificity of hospital slide results were 50% and 96% respectively. Conclusion Progress in targeting of antimalarials in low malaria transmission settings is likely to depend on consistent use of malaria microscopy and on the willingness of health workers to be guided by negative slide results. Further studies are needed to identify how this can be achieved.

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.To describe the clinical manifestations and case fatality of severe P falciparum malaria at varying altitudes resulting in varying levels of transmission.A total of 1984 patients admitted for severe malaria to 10 hospitals serving populations living at levels of transmission varying from very low (altitude1200 m) to very high (altitude600 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.Specific syndromes of severe malaria; mortality.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 (hemoglobin5 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 to15 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 (altitude600 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 residence600 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 to15 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.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.

Effective malaria control requires information about intensity of transmission across large areas and populations. Estimates based on entomological factors lack precision and are not cost-effective to obtain. We tested altitude and rainfall measurements as correlates of transmission intensity in different ecological settings. We conducted 2 cross-sectional surveys of approximately 12,000 people (1-45 years old) in 6 altitude transects (150-1800 m) in the Kilimanjaro and Tanga regions of Tanzania. Data were analyzed for associations with altitude and rainfall estimates by use of appropriate regression models. Plasmodium falciparum prevalence showed a negative relationship with altitude (19% and 21% decrease/100-m altitude increase, respectively, in children in Kilimanjaro and Tanga) and rainfall during the 3 months before the survey (46% decrease/100-mm rainfall increase in children in Kilimanjaro). Mean hemoglobin concentrations increased with altitude (0.05 and 0.09 g/dL/100-m altitude increase, respectively, in children in Kilimanjaro and Tanga) and rainfall (0.17 g/dL/100-mm rainfall increase in children and adults in Kilimanjaro). Altitude and rainfall were correlated with parasite prevalence and mean hemoglobin concentration; however, the relationship varied according to ecological setting. Climatological variables alone cannot predict malarial outcomes. Local variations in seasonality of malaria transmission--together with vector species composition, topography, host and parasite genetics, and socioeconomic factors--may influence malaria prevalence.