Two-year evaluation of Intermittent Preventive Treatment for Children (IPTc) combined with timely home treatment for malaria control in Ghana

Background

Intermittent preventive treatment (IPT) has recently been accepted as an important component of the malaria control strategy. Intermittent preventive treatment for children (IPTc) combined with timely treatment of malaria related febrile illness at home to reduce parasite prevalence and malaria morbidity in children aged between six and 60 months in a coastal community in Ghana. This paper reports persistence of reduced parasitaemia two years into the intervention. The baseline and year-one-evaluation findings were published earlier.

Objective

The main objective in the second year was to demonstrate whether the two interventions would further reduce parasite prevalence and malaria-related febrile illness in the study population.

Methods

This was an intervention study designed to compare baseline and evaluation findings without a control group. The study combined home-based delivery of intermittent preventive treatment for children (IPTc) aged 6 - 60 months and home treatment of suspected febrile malaria-related illness within 24 hours. All children aged 6 - 60 months received home-based delivery of intermittent preventive treatment using amodiaquine + artesunate, delivered at home by community assistants every four months (6 times in 24 months). Malaria parasite prevalence surveys were conducted before the first and after the third and sixth IPTc to the children. The evaluation surveys were done four months after the third and sixth IPTc was given.

Results

Parasite prevalence which reduced from 25% to 3.0% at year-one evaluation had reduced further from 3% to 1% at year-two-evaluation. At baseline, 13.8% of the children were febrile (axilary temperature of ≥37.5°C) compared to 2.2% at year-one-evaluation while 2.1% were febrile at year-two-evaluation.

Conclusion

The year-two-evaluation result indicates that IPTc given three times in a year (every four months) combined with timely treatment of febrile malaria illness, is effective to reduce malaria parasite prevalence in children aged 6 to 60 months in the study community. This must give hope to malaria control programme managers in sub-Saharan Africa where the burden of the disease is most debilitating.

     

Rapid Antigen Detection Tests for Malaria Diagnosis in Severely Ill Papua New Guinean Children: A Comparative Study Using Bayesian Latent Class Models

Background

Although rapid diagnostic tests (RDTs) have practical advantages over light microscopy (LM) and good sensitivity in severe falciparum malaria in Africa, their utility where severe non-falciparum malaria occurs is unknown. LM, RDTs and polymerase chain reaction (PCR)-based methods have limitations, and thus conventional comparative malaria diagnostic studies employ imperfect gold standards. We assessed whether, using Bayesian latent class models (LCMs) which do not require a reference method, RDTs could safely direct initial anti-infective therapy in severe ill children from an area of hyperendemic transmission of both Plasmodium falciparum and P. vivax.

Methods and Findings

We studied 797 Papua New Guinean children hospitalized with well-characterized severe illness for whom LM, RDT and nested PCR (nPCR) results were available. For any severe malaria, the estimated prevalence was 47.5% with RDTs exhibiting similar sensitivity and negative predictive value (NPV) to nPCR (≥96.0%). LM was the least sensitive test (87.4%) and had the lowest NPV (89.7%), but had the highest specificity (99.1%) and positive predictive value (98.9%). For severe falciparum malaria (prevalence 42.9%), the findings were similar. For non-falciparum severe malaria (prevalence 6.9%), no test had the WHO-recommended sensitivity and specificity of >95% and >90%, respectively. RDTs were the least sensitive (69.6%) and had the lowest NPV (96.7%).

Conclusions

RDTs appear a valuable point-of-care test that is at least equivalent to LM in diagnosing severe falciparum malaria in this epidemiologic situation. None of the tests had the required sensitivity/specificity for severe non-falciparum malaria but the number of false-negative RDTs in this group was small.     

Elevated plasma von Willebrand factor and propeptide levels in Malawian children with malaria

Background

In spite of the significant mortality associated with Plasmodium falciparum infection, the mechanisms underlying severe disease remain poorly understood. We have previously shown evidence of endothelial activation in Ghanaian children with malaria, indicated by elevated plasma levels of both von Willebrand factor (VWF) and its propeptide. In the current prospective study of children in Malawi with retinopathy confirmed cerebral malaria, we compared these markers with uncomplicated malaria, non malarial febrile illness and controls.

Methods and Findings

Children with cerebral malaria, mild malaria and controls without malaria were recruited into the study. All comatose patients were examined by direct and indirect ophthalmoscopy. Plasma VWF and propeptide levels were measured by ELISA. Median VWF and propeptide levels were significantly higher in patients with uncomplicated malaria than in children with non-malarial febrile illness of comparable severity, in whom levels were higher than in non-febrile controls. Median concentrations of both markers were higher in cerebral malaria than in uncomplicated malaria, and were similar in patients with and without retinopathy. Levels of both VWF and propeptide fell significantly 48 hours after commencing therapy and were normal one month later.

Conclusions

In children with malaria plasma VWF and propeptide levels are markedly elevated in both cerebral and mild paediatric malaria, with levels matching disease severity, and these normalize upon recovery. High levels of both markers also occur in retinopathy-negative ‘cerebral malaria’ cases, many of whom are thought to be suffering from diseases other than malaria, indicating that further studies of these markers will be required to determine their sensitivity and specificity.     

Epidemiological, clinical and biological features of malaria among children in Niamey, Niger

Background

Malaria takes a heavy toll in Niger, one of the world's poorest countries. Previous evaluations conducted in the context of the strategy for the Integrated Management of Childhood Illness, showed that 84% of severe malaria cases and 64 % of ordinary cases are not correctly managed. The aim of this survey was to describe epidemiological, clinical and biological features of malaria among <5 year-old children in the paediatric department of the National Hospital of Niamey, Niger's main referral hospital.

Methods

The study was performed in 2003 during the rainy season from July 25^th to October 25^th. Microscopic diagnosis of malaria, complete blood cell counts and measurement of glycaemia were performed in compliance with the routine procedure of the laboratory. Epidemiological data was collected through interviews with mothers.

Results

256 children aged 3–60 months were included in the study. Anthropometrics and epidemiological data were typical of a very underprivileged population: 58% of the children were suffering from malnutrition and all were from poor families. Diagnosis of malaria was confirmed by microscopy in 52% of the cases. Clinical symptoms upon admission were non-specific, but there was a significant combination between a positive thick blood smear and neurological symptoms, and between a positive thick blood smear and splenomegaly. Thrombopaenia was also statistically more frequent among confirmed cases of malaria. The prevalence of severe malaria was 86%, including cases of severe anaemia among < 2 year-old children and neurological forms after 2 years of age. Overall mortality was 20% among confirmed cases and 21% among severe cases.

Conclusions

The study confirmed that malaria was a major burden for the National Hospital of Niamey. Children hospitalized for malaria had an underprivileged background. Two distinctive features were the prevalence of severe malaria and a high mortality rate. Medical and non-medical underlying factors which may explain such a situation are discussed.     

Recognising and Treatment Seeking for Acute Bacterial Meningitis in Adults and Children in Resource-Poor Settings: A Qualitative Study

Objective

High mortality burden from Acute Bacterial Meningitis (ABM) in resource-poor settings has been frequently blamed on delays in treatment seeking. We explored treatment-seeking pathways from household to primary health care and referral for ABM in Malawi.

Design

A cross-sectional qualitative study using narrative in-depth interviews, semi-structured interviews and focus group discussions.

Participants

Adults and children with proven and probable acute bacterial meningitis and/or their carers; adults from urban and peri-urban communities; and primary health care workers (HCW).

Setting

Queen Elizabeth Central Hospital (QECH), urban and peri-urban private and government primary health centres and communities in Blantyre District, Malawi.

Results

Whilst communities associated meningitis with a stiff neck, in practice responses focused on ability to recognise severe illness. Misdiagnosis of meningitis as malaria was common. Subsequent action by families depended on the extent to which normal social life was disrupted by the illness and depended on the age and social position of the sufferer. Seizures and convulsions were considered severe symptoms but were often thought to be malaria. Presumptive malaria treatment at home often delayed formal treatment seeking. Further delays in treatment seeking were caused by economic barriers and perceptions of inefficient or inadequate primary health services.

Conclusions

Given the difficulties in diagnosis of meningitis where malaria is common, any intervention for ABM at primary level must focus on recognising severe illness, and encouraging action at the household, community and primary health levels. Overcoming barriers to recognition and social constraints at community level require broad community-based strategies and may provide a route to addressing poor clinical outcomes.     

A new method for detection of pfmdr1 mutations in Plasmodium falciparum DNA using real-time PCR

Background

The erythrocyte binding antigen-175 (EBA-175) on Plasmodium falciparum merozoites mediates sialic acid dependent binding to glycophorin A on host erythrocytes and, therefore, plays a crucial role in cell invasion. Dimorphic allele segments have been found in its encoding gene with a 342 bp segment present in FCR-3 strains (F-segment) and a 423 bp segment in CAMP strains (C-segment). Possible associations of the dimorphism with severe malaria have been analysed in a case-control study in northern Ghana.

Methods

Blood samples of 289 children with severe malaria and 289 matched parasitaemic but asymptomatic controls were screened for eba- 175 F- and C-segments by nested polymerase chain reaction.

Results

In children with severe malaria, prevalences of F-, C- and mixed F-/C-segments were 70%, 19%, and 11%, respectively. The C-segment was found more frequently in severe malaria cases whereas mixed infections were more common in controls. Infection with strains harbouring the C-segment significantly increased the risk of fatal outcome.

Conclusion

The results show that the C-segment is associated with fatal outcome in children with severe malaria in northern Ghana, suggesting that it may contribute to the virulence of the parasite.     

Diagnosis of Bacterial Bloodstream Infections: A 16S Metagenomics Approach

Background

Bacterial bloodstream infection (bBSI) is one of the leading causes of death in critically ill patients and accurate diagnosis is therefore crucial. We here report a 16S metagenomics approach for diagnosing and understanding bBSI.

Methodology/Principal Findings

The proof-of-concept was delivered in 75 children (median age 15 months) with severe febrile illness in Burkina Faso. Standard blood culture and malaria testing were conducted at the time of hospital admission. 16S metagenomics testing was done retrospectively and in duplicate on the blood of all patients. Total DNA was extracted from the blood and the V3–V4 regions of the bacterial 16S rRNA genes were amplified by PCR and deep sequenced on an Illumina MiSeq sequencer. Paired reads were curated, taxonomically labeled, and filtered. Blood culture diagnosed bBSI in 12 patients, but this number increased to 22 patients when combining blood culture and 16S metagenomics results. In addition to superior sensitivity compared to standard blood culture, 16S metagenomics revealed important novel insights into the nature of bBSI. Patients with acute malaria or recovering from malaria had a 7-fold higher risk of presenting polymicrobial bloodstream infections compared to patients with no recent malaria diagnosis (p-value = 0.046). Malaria is known to affect epithelial gut function and may thus facilitate bacterial translocation from the intestinal lumen to the blood. Importantly, patients with such polymicrobial blood infections showed a 9-fold higher risk factor for not surviving their febrile illness (p-value = 0.030).

Conclusions/Significance

Our data demonstrate that 16S metagenomics is a powerful approach for the diagnosis and understanding of bBSI. This proof-of-concept study also showed that appropriate control samples are crucial to detect background signals due to environmental contamination.     

The Association between Cognition and Academic Performance in Ugandan Children Surviving Malaria with Neurological Involvement

Background

The contribution of different cognitive abilities to academic performance in children surviving cerebral insult can guide the choice of interventions to improve cognitive and academic outcomes. This study''s objective was to identify which cognitive abilities are associated with academic performance in children after malaria with neurological involvement.

Methods

62 Ugandan children with a history of malaria with neurological involvement were assessed for cognitive ability (working memory, reasoning, learning, visual spatial skills, attention) and academic performance (reading, spelling, arithmetic) three months after the illness. Linear regressions were fit for each academic score with the five cognitive outcomes entered as predictors. Adjusters in the analysis were age, sex, education, nutrition, and home environment. Exploratory factor analysis (EFA) and structural equation models (SEM) were used to determine the nature of the association between cognition and academic performance. Predictive residual sum of squares was used to determine which combination of cognitive scores was needed to predict academic performance.

Results

In regressions of a single academic score on all five cognitive outcomes and adjusters, only Working Memory was associated with Reading (coefficient estimate = 0.36, 95% confidence interval = 0.10 to 0.63, p<0.01) and Spelling (0.46, 0.13 to 0.78, p<0.01), Visual Spatial Skills was associated with Arithmetic (0.15, 0.03 to 0.26, p<0.05), and Learning was associated with Reading (0.06, 0.00 to 0.11, p<0.05). One latent cognitive factor was identified using EFA. The SEM found a strong association between this latent cognitive ability and each academic performance measure (P<0.0001). Working memory, visual spatial ability and learning were the best predictors of academic performance.

Conclusion

Academic performance is strongly associated with the latent variable labelled “cognitive ability” which captures most of the variation in the individual specific cognitive outcome measures. Working memory, visual spatial skills, and learning together stood out as the best combination to predict academic performance.     

Features and prognosis of severe malaria caused by Plasmodium falciparum, Plasmodium vivax and mixed Plasmodium species in Papua New Guinean children

Background

Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking.

Methods and Findings

We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%). The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P = 0.001); one child died (3.7%). The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P = 0.003 vs falciparum malaria). Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO).

Conclusions

The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis.     

Socio-economic inequity in demand for insecticide-treated nets, in-door residual house spraying, larviciding and fogging in Sudan

Background

Malaria continues to claim one to two million lives a year, mainly those of children in sub-Saharan Africa. Reduction in mortality depends, in part, on improving the quality of hospital care, the training of healthcare workers and improvements in public health. This study examined the prognostic indicators of severe falciparum malaria in Gabonese children.

Methods

An observational study examining the clinical presentations and laboratory features of severe malaria was conducted at the Centre Hospitalier de Libreville, Gabon over two years. Febrile children aged from 0 to 10 years with Plasmodium falciparum infection and one or more features of severe malaria were enrolled.

Results

Most children presenting with severe falciparum malaria were less than 5 years (92.3% of 583 cases). Anaemia was the most frequent feature of severe malaria (67.8% of cases), followed by respiratory distress (31%), cerebral malaria (24%) hyperlactataemia (16%) and then hypoglycaemia (10%). Anaemia was more common in children under 18 months old, while cerebral malaria usually occurred in those over 18 months. The overall case fatality rate was 9%. The prognostic indicators with the highest case fatality rates were coma/seizures, hyperlactataemia and hypoglycaemia, and the highest case fatality rate was in children with all three of these features.

Conclusions

Prompt and appropriate, classification and treatment of malaria helps identify the most severely ill children and aids early and appropriate management of the severely ill child.     

Cost Implications of Improving Malaria Diagnosis: Findings from North-Eastern Tanzania

Background

Over diagnosis of malaria contributes to improper treatment, wastage of drugs and resistance to the few available drugs. This paper attempts to estimate the rates of over diagnosis of malaria among children attending dispensaries in rural Tanzania and examines the potential cost implications of improving the quality of diagnosis.

Methodology/Principal Findings

The magnitude of over diagnosis of malaria was estimated by comparing the proportion of outpatient attendees of all ages clinically diagnosed as malaria to the proportion of attendees having a positive malaria rapid diagnostic test over a two month period. Pattern of causes of illness observed in a <2 year old cohort of children over one year was compared to the pattern of causes of illness in <5 year old children recorded in the routine health care system during the same period. Drug and diagnostic costs were modelled using local and international prices. Over diagnosis of malaria by the routine outpatient care system compared to RDT confirmed cases of malaria was highest among <5 year old children in the low transmission site (RR 17.9, 95% CI 5.8–55.3) followed by the ≥5 year age group in the lower transmission site (RR 14.0 95%CI 8.2–24.2). In the low transmission site the proportion of morbidity attributable to malaria was substantially lower in <2 year old cohort compared to children seen at routine care system. (0.08% vs 28.2%; p<0.001). A higher proportion of children were diagnosed with ARI in the <2 year old cohort compared to children seen at the routine care system ( 42% vs 26%; p<0.001). Using a RDT reduced overall drug and diagnostic costs by 10% in the high transmission site and by 15% in the low transmission site compared to total diagnostic and drug costs of treatment based on clinical judgment in routine health care system.

Implications

The introduction of RDTs is likely to lead to financial savings. However, improving diagnosis to one disease may lead to over diagnosis of another illness. Quality improvement is complex but introducing RDTs for the diagnosis of malaria is a good start.     

Association of severe malaria outcomes with platelet-mediated clumping and adhesion to a novel host receptor

Introduction

Severe malaria has been attributed partly to the sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature of vital host organs. Identification of P. falciparum cytoadherence phenotypes that are associated with severe malaria may lead to the development of novel strategies against life-threatening malaria.

Methods and Findings

Forty-six P. falciparum isolates from Mozambican children under 5 years of age with severe malaria (cases) were examined and compared to 46 isolates from sex and age matched Mozambican children with uncomplicated malaria (controls). Cytoadherence properties such as platelet-mediated clumping, rosetting and adhesion to purified receptors (CD36, ICAM1 and gC1qR), were compared between these matched pairs by non-parametric tests. The most common clinical presentation associated with severe malaria was prostration. Compared to matched controls, prevalence of platelet-mediated clumping was higher in cases (P = .019), in children presenting with prostration (P = .049) and in children with severe anaemia (P = .025). Prevalence of rosetting and gC1qR adhesion were also higher in isolates from cases with severe anemia and multiple seizures, respectively (P = .045 in both cases), than in controls.

Conclusions

These data indicate a role for platelet-mediated clumping, rosetting and adhesion to gC1qR in the pathogenesis of severe malaria. Inhibition of these cytoadherence phenotypes may reduce the occurrence or improve the prognosis of severe malaria outcomes.     

The plant-based immunomodulator curcumin as a potential candidate for the development of an adjunctive therapy for cerebral malaria

Background

Considering the natural history of malaria of continued susceptibility to infection and episodes of illness that decline in frequency and severity over time, studies which attempt to relate immune response to protection must be longitudinal and have clearly specified definitions of immune status. Putative vaccines are expected to protect against infection, mild or severe disease or reduce transmission, but so far it has not been easy to clearly establish what constitutes protective immunity or how this develops naturally, especially among the affected target groups. The present study was done in under six year old children to identify malaria antigens which induce antibodies that correlate with protection from Plasmodium falciparum malaria.

Methods

In this longitudinal study, the multiplex assay was used to measure IgG antibody levels to 10 malaria antigens (GLURP R0, GLURP R2, MSP3 FVO, AMA1 FVO, AMA1 LR32, AMA1 3D7, MSP1 3D7, MSP1 FVO, LSA-1and EBA175RII) in 325 children aged 1 to 6 years in the Kassena Nankana district of northern Ghana. The antigen specific antibody levels were then related to the risk of clinical malaria over the ensuing year using a negative binomial regression model.

Results

IgG levels generally increased with age. The risk of clinical malaria decreased with increasing antibody levels. Except for FMPOII-LSA, (p = 0.05), higher IgG levels were associated with reduced risk of clinical malaria (defined as axillary temperature ≥37.5°C and parasitaemia of ≥5000 parasites/ul blood) in a univariate analysis, upon correcting for the confounding effect of age. However, in a combined multiple regression analysis, only IgG levels to MSP1-3D7 (Incidence rate ratio = 0.84, [95% C.I.= 0.73, 0.97, P = 0.02]) and AMA1 3D7 (IRR = 0.84 [95% C.I.= 0.74, 0.96, P = 0.01]) were associated with a reduced risk of clinical malaria over one year of morbidity surveillance.

Conclusion

The data from this study support the view that a multivalent vaccine involving different antigens is most likely to be more effective than a monovalent one. Functional assays, like the parasite growth inhibition assay will be necessary to confirm if these associations reflect functional roles of antibodies to MSP1-3D7 and AMA1-3D7 in this population.     

Burden of Complicated Malaria in a Densely Forested Bastar Region of Chhattisgarh State (Central India)

Background

A prospective study on severe and complicated malaria was undertaken in the tribal dominated area of Bastar division, Chhattisgarh (CG), Central India, with an objective to understand the clinical epidemiology of complicated malaria in patients attending at a referral hospital.

Methods

Blood smears, collected from the general medicine and pediatric wards of a government tertiary health care facility located in Jagdalpur, CG, were microscopically examined for malaria parasite from July 2010 to December 2013. The Plasmodium falciparum positive malaria cases who met enrollment criteria and provided written informed consent were enrolled under different malaria categories following WHO guidelines. PCR was performed to reconfirm the presence of P.falciparum mono infection among enrolled cases. Univariate and multivariate logistic regression analysis was done to identify different risk factors using STATA 11.0.

Results

A total of 40,924 cases were screened for malaria. The prevalence of malaria and P.falciparum associated complicated malaria (severe and cerebral both) in the hospital was 6% and 0.81%, respectively. P.falciparum malaria prevalence, severity and associated mortality in this region peaked at the age of>4–5 years and declined with increasing age. P.falciparum malaria was significantly more prevalent in children than adults (P<0.00001). Among adults, males had significantly more P.falciparum malaria than females (P<0.00001). Case fatality rate due to cerebral malaria and severe malaria was, respectively, 32% and 9% among PCR confirmed mono P.falciparum cases. Coma was the only independent predictor of mortality in multivariate regression analysis. Mortality was significantly associated with multi-organ complication score (P = 0.0003).

Conclusion

This study has revealed that the pattern of morbidity and mortality in this part of India is very different from earlier reported studies from India. We find that the peak morbidity and mortality in younger children regardless of seasonality. This suggests that this age group needs special care for control and clinical management.     

Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study

Background

Differentiating cerebral malaria (CM) from other causes of serious illness in African children is problematic, owing to the non-specific nature of the clinical presentation and the high prevalence of incidental parasitaemia. CM is associated with endothelial activation. In this study we tested the hypothesis that endothelium-derived biomarkers are associated with the pathophysiology of severe malaria and may help identify children with CM.

Methods and Findings

Plasma samples were tested from children recruited with uncomplicated malaria (UM; n = 32), cerebral malaria with retinopathy (CM-R; n = 38), clinically defined CM without retinopathy (CM-N; n = 29), or non-malaria febrile illness with decreased consciousness (CNS; n = 24). Admission levels of angiopoietin-2 (Ang-2), Ang-1, soluble Tie-2 (sTie-2), von Willebrand factor (VWF), its propeptide (VWFpp), vascular endothelial growth factor (VEGF), soluble ICAM-1 (sICAM-1) and interferon-inducible protein 10 (IP-10) were measured by ELISA. Children with CM-R had significantly higher median levels of Ang-2, Ang-2:Ang-1, sTie-2, VWFpp and sICAM-1 compared to children with CM-N. Children with CM-R had significantly lower median levels of Ang-1 and higher median concentrations of Ang-2:Ang-1, sTie-2, VWF, VWFpp, VEGF and sICAM-1 compared to UM, and significantly lower median levels of Ang-1 and higher median levels of Ang-2, Ang-2:Ang-1, VWF and VWFpp compared to children with fever and altered consciousness due to other causes. Ang-1 was the best discriminator between UM and CM-R and between CNS and CM-R (areas under the ROC curve of 0.96 and 0.93, respectively). A comparison of biomarker levels in CM-R between admission and recovery showed uniform increases in Ang-1 levels, suggesting this biomarker may have utility in monitoring clinical response.

Conclusions

These results suggest that endothelial proteins are informative biomarkers of malarial disease severity. These results require validation in prospective studies to confirm that this group of biomarkers improves the diagnostic accuracy of CM from similar conditions causing fever and altered consciousness.     

Invasive Salmonellosis among Children Admitted to a Rural Tanzanian Hospital and a Comparison with Previous Studies

Background

The importance of invasive salmonellosis in African children is well recognized but there is inadequate information on these infections. We conducted a fever surveillance study in a Tanzanian rural hospital to estimate the case fraction of invasive salmonellosis among pediatric admissions, examine associations with common co-morbidities and describe its clinical features. We compared our main findings with those from previous studies among children in sub-Saharan Africa.

Methodology/Principal Findings

From 1 March 2008 to 28 Feb 2009, 1,502 children were enrolled into the study. We collected clinical information and blood for point of care tests, culture, and diagnosis of malaria and HIV. We analyzed the clinical features on admission and outcome by laboratory-confirmed diagnosis. Pathogenic bacteria were isolated from the blood of 156 (10%) children, of which 14 (9%) were S. typhi, 45 (29%) were NTS and 97 (62%) were other pathogenic bacteria. Invasive salmonellosis accounted for 59/156 (38%) bacteremic children. Children with typhoid fever were significantly older and presented with a longer duration of fever. NTS infections were significantly associated with prior antimalarial treatment, malarial complications and with a high risk for death.

Conclusions/Significance

Invasive salmonellosis, particularly NTS infection, is an important cause of febrile disease among hospitalized children in our rural Tanzanian setting. Previous studies showed considerable variation in the case fraction of S. typhi and NTS infections. Certain suggestive clinical features (such as older age and long duration of fever for typhoid whereas concomitant malaria, anemia, jaundice and hypoglycemia for NTS infection) may be used to distinguish invasive salmonellosis from other severe febrile illness.     

Cytokine Profiles at Birth Predict Malaria Severity during Infancy

Background

Severe malaria risk varies between individuals, and most of this variation remains unexplained. Here, we examined the hypothesis that cytokine profiles at birth reflect inter-individual differences that persist and influence malaria parasite density and disease severity throughout early childhood.

Methods and Findings

Cytokine levels (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6 and IL-10) were measured at birth (cord blood; N=783) and during subsequent routine follow-up visits (peripheral blood) for children enrolled between 2002 and 2006 into a birth cohort in Muheza, Tanzania. Children underwent blood smear and clinical assessments every 2-4 weeks, and at the time of any illness. Cord blood levels of all cytokines were positively correlated with each other (Spearman’s rank correlation). Cord levels of IL-1β and TNF-α (but not other cytokines) correlated with levels of the same cytokine measured at routine visits during early life (P < 0.05). Higher cord levels of IL-1β but not TNF-α were associated with lower parasite densities during infancy (P=0.003; Generalized Estimating Equation (GEE) method), with an average ~40% reduction versus children with low cord IL-1β levels, and with decreased risk of severe malaria during follow-up (Cox regression): adjusted hazard ratio (95% CI) 0.60 (0.39-0.92), P = 0.02.

Conclusion

IL-1β levels at birth are related to future IL-1β levels as well as the risk of severe malaria in early life. The effect on severe malaria risk may be due in part to the effect of inflammatory cytokines to control parasite density.     

High Prevalence of Malaria Parasitemia and Anemia among Hospitalized Children in Rakai,Uganda

Background

There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda.

Methods

Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities.

Results

2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18–4.24) and seizures (aPRR 1.12; CI 1.09–1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91–0.93), HIV infected children (aPRR 0.60 CI 0.52–0.71), and children with diarrhea (aPRR 0.76; CI 0.65–0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%.

Conclusion

There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population.     

Etiology of Severe Febrile Illness in Low- and Middle-Income Countries: A Systematic Review

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.