Ilona Carneiro

Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study

Abstract Objective To study the diagnosis and outcomes in people admitted to hospital with a diagnosis of severe malaria in areas with differing intensities of malaria transmission. Design Prospective observational study of children and adults over the course a year. Setting 10 hospitals in north east Tanzania. Participants 17 313 patients were admitted to hospital; of these 4474 (2851 children aged under 5 years) fulfilled criteria for severe disease. Main outcome measure Details of the treatment given and outcome. Altitudes of residence (a proxy for transmission intensity) measured with a global positioning system. Results Blood film microscopy showed that 2062 (46.1%) of people treated for malaria had Plasmodium falciparum (slide positive). The proportion of slide positive cases fell with increasing age and increasing altitude of residence. Among 1086 patients aged ≥ 5 years who lived above 600 metres, only 338 (31.1%) were slide positive, while in children < 5 years living in areas of intense transmission (< 600 metres) most (958/1392, 68.8%) were slide positive. Among 2375 people who were slide negative, 1571 (66.1%) were not treated with antibiotics and of those, 120 (7.6%) died. The case fatality in slide negative patients was higher (292/2412, 12.1%) than for slide positive patients (142/2062, 6.9%) (P < 0.001). Respiratory distress and altered consciousness were the strongest predictors of mortality in slide positive and slide negative patients and in adults as well as children. Conclusions In Tanzania, malaria is commonly overdiagnosed in people presenting with severe febrile illness, especially in those living in areas with low to moderate transmission and in adults. This is associated with a failure to treat alternative causes of severe infection. Diagnosis needs to be improved and syndromic treatment considered. Routine hospital data may overestimate mortality from malaria by over twofold.

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

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

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

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

Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana.

Abstract Objective To evaluate the effects of intermittent preventive treatment for malaria in infants (IPTi) with sulfadoxine-pyrimethamine in an area of intense, seasonal transmission. Design Cluster randomised placebo controlled trial, with 96 clusters allocated randomly to sulfadoxine-pyrimethamine or placebo in blocks of eight. Interventions Children received sulfadoxine-pyrimethamine or placebo and one month of iron supplementation when they received DPT-2, DPT-3, or measles vaccinations and at 12 months of age. Main outcome measures Incidence of malaria and of anaemia determined through passive case detection. Results 89% (1103/1242) of children in the placebo group and 88% (1088/1243) in the IPTi group completed follow-up to 24 months of age. The protective efficacy of IPTi against all episodes of malaria was 24.8% (95% confidence interval 14.3% to 34.0%) up to 15 months of age. IPTi had no protective effect against malaria between 16 and 24 months of age (protective efficacy −4.9%, −21.3% to 9.3%). The incidence of high parasite density malaria (≥ 5000 parasites/μl) was higher in the IPTi group than in the placebo group between 16 and 24 months of age (protective efficacy −19.5%, −39.8% to −2.2%). IPTi reduced hospital admissions with anaemia by 35.1% (10.5% to 52.9%) up to 15 months of age. IPTi had no significant effect on anaemia between 16 and 24 months of age (protective efficacy −6.4%, −76.8% to 35.9%). The relative risk of death up to 15 months of age in the IPTi group was 1.26 (95% confidence interval 0.81 to 1.96; P =0.31), and from 16 to 24 months it was 1.28 (0.77 to 2.14; P =0.35). Conclusions Intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine can reduce malaria and anaemia in infants even in seasonal, high transmission areas, but concern exists about possible rebound in the incidence of malaria in the second year of life.

Effect of community-wide use of insecticide-treated nets for 3-4 years on malarial morbidity in Tanzania

Objectives  To investigate (1) benefits due to personal protection of individual net users vs. mass killing of mosquitoes within villages as a result of widespread net usage; (2) sustainability over several years of benefits against malarial morbidity of insecticide‐treated nets; (3) distribution of the benefits in different age groups of children and (4) whether, as a result of fading immunity, older age groups ‘paid for’ the benefits which they had enjoyed when younger.

Age-Patterns of Malaria Vary with Severity, Transmission Intensity and Seasonality in Sub-Saharan Africa: A Systematic Review and Pooled Analysis

Background There is evidence that the age-pattern of Plasmodium falciparum malaria varies with transmission intensity. A better understanding of how this varies with the severity of outcome and across a range of transmission settings could enable locally appropriate targeting of interventions to those most at risk. We have, therefore, undertaken a pooled analysis of existing data from multiple sites to enable a comprehensive overview of the age-patterns of malaria outcomes under different epidemiological conditions in sub-Saharan Africa. Methodology/Principal Findings A systematic review using PubMed and CAB Abstracts (1980–2005), contacts with experts and searching bibliographies identified epidemiological studies with data on the age distribution of children with P. falciparum clinical malaria, hospital admissions with malaria and malaria-diagnosed mortality. Studies were allocated to a 3×2 matrix of intensity and seasonality of malaria transmission. Maximum likelihood methods were used to fit five continuous probability distributions to the percentage of each outcome by age for each of the six transmission scenarios. The best-fitting distributions are presented graphically, together with the estimated median age for each outcome. Clinical malaria incidence was relatively evenly distributed across the first 10 years of life for all transmission scenarios. Hospital admissions with malaria were more concentrated in younger children, with this effect being even more pronounced for malaria-diagnosed deaths. For all outcomes, the burden of malaria shifted towards younger ages with increasing transmission intensity, although marked seasonality moderated this effect. Conclusions The most severe consequences of P. falciparum malaria were concentrated in the youngest age groups across all settings. Despite recently observed declines in malaria transmission in several countries, which will shift the burden of malaria cases towards older children, it is still appropriate to target strategies for preventing malaria mortality and severe morbidity at very young children who will continue to bear the brunt of malaria deaths in Sub-Saharan Africa.

Altitude-Dependent and -Independent Variations in Plasmodium falciparum Prevalence in Northeastern Tanzania

BACKGROUND 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. METHODS 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. RESULTS 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). DISCUSSION 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.

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

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

Plant based insect repellent and insecticide treated bed nets to protect against malaria in areas of early evening biting vectors: double blind randomised placebo controlled clinical trial in the Bolivian Amazon.

Objective To determine the effectiveness in reducing malaria of combining an insect repellent with insecticide treated bed nets compared with the nets alone in an area where vector mosquitoes feed in the early evening. Design A double blind, placebo controlled cluster-randomised clinical study. Setting Rural villages and peri-urban districts in the Bolivian Amazon. Participants 4008 individuals in 860 households. Interventions All individuals slept under treated nets; one group also used a plant based insect repellent each evening, a second group used placebo. Main outcome measure Episodes of Plasmodium falciparum or P vivax malaria confirmed by rapid diagnostic test or blood slide, respectively. Results We analysed 15 174 person months at risk and found a highly significant 80% reduction in episodes of P vivax in the group that used treated nets and repellent (incidence rate ratio 0.20, 95% confidence interval 0.11 to 0.38, P<0.001). Numbers of P falciparum cases during the study were small and, after adjustment for age, an 82% protective effect was observed, although this was not significant (0.18, 0.02 to 1.40, P=0.10). Reported episodes of fever with any cause were reduced by 58% in the group that used repellent (0.42, 0.31 to 0.56, P<0.001). Conclusions Insect repellents can provide protection against malaria. In areas where vectors feed in the early evening, effectiveness of treated nets can be significantly increased by using repellent between dusk and bedtime. This has important implications in malaria vector control programmes outside Africa and shows that the combined use of treated nets and insect repellents, as advocated for most tourists travelling to high risk areas, is fully justified. Registration NCT 00144716.

Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies.

Insecticide-treated mosquito nets (ITN) provide excellent protection against malaria; however, they have a number of shortcomings that are particularly evident in politically unstable countries or countries at war: not everyone at risk can necessarily afford a net, nets may be difficult to obtain or import, nets may not be suitable for migrants or refugees sleeping under tents or plastic shelter. There is a need to develop cheaper, locally appropriate alternatives for the most impoverished and for victims of complex emergencies. Afghan women, in common with many Muslim peoples of Asia, wear a veil or wrap known as a chaddar to cover the head and upper body. This cloth doubles as a sheet at night, when they are used by both sexes. A randomized controlled trial was undertaken in which 10% of the families of an Afghan refugee camp (population 3950) in north-western Pakistan had their chaddars and top-sheets treated with permethrin insecticide at a dosage of 1 g/m2 while a further 10% had their chaddars treated with placebo formulation. Malaria episodes were recorded by passive case detection at the camps health centre. From August to November the odds of having a falciparum or vivax malaria episode were reduced by 64% in children aged 0-10 years and by 38% in refugees aged < 20 years in the group using permethrin-treated chaddars and top-sheets. Incidence in refugees over 20 years of age was not significantly reduced. The cost of the permethrin treatment per person protected (US