Climent Casals-Pascual

Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis

Summary Background Malaria is a major cause of morbidity and mortality in Africa. International effort and funding for control has been stepped up, with substantial increases from 2003 in the delivery of malaria interventions to pregnant women and children younger than 5 years in The Gambia. We investigated the changes in malaria indices in this country, and the causes and public-health significance of these changes. Methods We undertook a retrospective analysis of original records to establish numbers and proportions of malaria inpatients, deaths, and blood-slide examinations at one hospital over 9 years (January, 1999–December, 2007), and at four health facilities in three different administrative regions over 7 years (January, 2001–December, 2007). We obtained additional data from single sites for haemoglobin concentrations in paediatric admissions and for age distribution of malaria admissions. Findings From 2003 to 2007, at four sites with complete slide examination records, the proportions of malaria-positive slides decreased by 82% (3397/10861 in 2003 to 337/6142 in 2007), 85% (137/1259 to 6/368), 73% (3664/16932 to 666/11333), and 50% (1206/3304 to 336/1853). At three sites with complete admission records, the proportions of malaria admissions fell by 74% (435/2530 to 69/1531), 69% (797/2824 to 89/1032), and 27% (2204/4056 to 496/1251). Proportions of deaths attributed to malaria in two hospitals decreased by 100% (seven of 115 in 2003 to none of 117 in 2007) and 90% (22/122 in 2003 to one of 58 in 2007). Since 2004, mean haemoglobin concentrations for all-cause admissions increased by 12 g/L (85 g/L in 2000–04 to 97 g/L in 2005–07), and mean age of paediatric malaria admissions increased from 3·9 years (95% CI 3·7–4·0) to 5·6 years (5·0–6·2). Interpretation A large proportion of the malaria burden has been alleviated in The Gambia. Our results encourage consideration of a policy to eliminate malaria as a public-health problem, while emphasising the importance of accurate and continuous surveillance. Funding UK Medical Research Council.

A non-sense mutation in Cd36 gene is associated with protection from severe malaria

We sought genetic evidence for the importance of host-parasite interactions involving CD36 in severe malaria. We identified a non-sense mutation in Cd36 gene and looked at the influence of this mutation on the outcome of malaria infection in 693 African children with severe malaria and a similar number of ethnically matched controls. We showed that heterozygosity for this mutation is associated with protection from severe disease (OR 0.74, 95% CI 0.55-0.99; p=0.036). These findings suggest that this Cd36 mutation might have a complex effect on malaria infection by decreasing parasite sequestration, and also by decreasing host immune responses.

Continued decline of malaria in The Gambia with implications for elimination.

Background A substantial decline in malaria was reported to have occurred over several years until 2007 in the western part of The Gambia, encouraging consideration of future elimination in this previously highly endemic region. Scale up of interventions has since increased with support from the Global Fund and other donors. Methodology/Principal Findings We continued to examine laboratory records at four health facilities previously studied and investigated six additional facilities for a 7 year period, adding data from 243,707 slide examinations, to determine trends throughout the country until the end of 2009. We actively detected infections in a community cohort of 800 children living in rural villages throughout the 2008 malaria season, and assayed serological changes in another rural population between 2006 and 2009. Proportions of malaria positive slides declined significantly at all of the 10 health facilities between 2003 (annual mean across all sites, 38.7%) and 2009 (annual mean, 7.9%). Statistical modelling of trends confirmed significant seasonality and decline over time at each facility. Slide positivity was lowest in 2009 at all sites, except two where lowest levels were observed in 2006. Mapping households of cases presenting at the latter sites in 2007–2009 indicated that these were not restricted to a few residual foci. Only 2.8% (22/800) of a rural cohort of children had a malaria episode in the 2008 season, and there was substantial serological decline between 2006 and 2009 in a separate rural area. Conclusions Malaria has continued to decline in The Gambia, as indicated by a downward trend in slide positivity at health facilities, and unprecedented low incidence and seroprevalence in community surveys. We recommend intensification of control interventions for several years to further reduce incidence, prior to considering an elimination programme.

Can erythropoietin be used to prevent brain damage in cerebral malaria

Erythropoietin (Epo) modulates the survival of developing erythroid cells and the production of new erythrocytes in the bone marrow and is a key molecule in the adaptation to hypoxia and anaemia. Epo receptors have been found to be widely expressed on non-haematopoietic cells, and Epo has been shown to have diverse actions (in particular, preventing ischaemic damage to tissues of the central nervous system). Recently, Epo has been shown to improve the outcome in a murine model of malaria, and high plasma levels of Epo in children with cerebral malaria were associated with a better outcome. Here, we review the biological importance of Epo, its mechanisms of action and the rationale for the proposed use of Epo as an adjunct treatment in cerebral malaria.

Severe malarial anaemia.

This review describes the importance of severe malarial anaemia as a public health problem, and the clinical and pathophysiological aspects of this syndrome. The review also highlights the recent advances in our understanding of the epidemiological, clinical, cellular and molecular aspects of severe malarial anaemia.

The clinical and pathophysiological features of malarial anaemia

This review will focus on the principal clinical and pathophysiological features of the anaemia of falciparum malaria, including the problems of treating malarial anaemia, and also will suggest how recent advances in genomics may help our understanding of cellular and molecular mechanisms underlying this syndrome.

Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria.

Hepcidin levels are high and iron absorption is limited in acute malaria. The mechanism(s) that regulate hepcidin secretion remain undefined. We have measured hepcidin concentration and cytokines in 100 Kenyan children with acute falciparum malaria and different degrees of anemia. Hepcidin was increased on admission and fell significantly one week and one month after treatment. The association of hepcidin with hemoglobin was not linear and hepcidin was very low in severe malarial anemia. Parasite density, IL-10 and IL-6 were significantly associated with hepcidin concentration. Hepcidin response to acute malaria supports the notion of iron sequestration during acute malaria infection and suggests that iron administration during acute malaria is futile. These data suggest iron supplementation policies should take into account the high hepcidin levels and probable poor utilization of iron for up to one week after treatment for the majority of patients with acute malaria.

Clinical Features of Severe Malaria Associated with Death: A 13-Year Observational Study in The Gambia

Background Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management. Methods A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in The Gambia to identify sensitive and specific predictors of poor outcome in Gambian children with severe malaria between the ages 4 months to 14 years. We have measured the sensitivity and specificity of clinical features that predict death or development of neurological sequelae. Findings Impaired consciousness (odds ratio {OR} 4.4 [95% confidence interval {CI}, 2.7–7.3]), respiratory distress (OR 2.4 [95%CI, 1.7–3.2]), hypoglycemia (OR 1.7 [95%CI, 1.2–2.3]), jaundice (OR 1.9 [95%CI, 1.2–2.9]) and renal failure (OR 11.1 [95%CI, 3.3–36.5]) were independently associated with death in children with SM. The clinical features that showed the highest sensitivity and specificity to predict death were respiratory distress (area under the curve 0.63 [95%CI, 0.60–0.65]) and impaired consciousness (AUC 0.61[95%CI, 0.59–0.63]), which were comparable to the ability of hyperlactatemia (blood lactate>5 mM) to predict death (AUC 0.64 [95%CI, 0.55–0.72]). A Blantyre coma score (BCS) of 2 or less had a sensitivity of 74% and specificity of 67% to predict death (AUC 0.70 [95% C.I. 0.68–0.72]), and sensitivity and specificity of 74% and 69%, respectively to predict development of neurological sequelae (AUC 0.72 [95% CI, 0.67–0.76]).The specificity of this BCS threshold to identify children at risk of dying improved in children less than 3 years of age (AUC 0.74, [95% C.I 0.71–0.76]). Conclusion The BCS is a quantitative predictor of death. A BCS of 2 or less is the most sensitive and specific clinical feature to predict death or development of neurological sequelae in children with SM.

Discovery and Validation of Biomarkers to Guide Clinical Management of Pneumonia in African Children

Lipocalin 2 distinguishes severe and bacterial pneumonia from nonsevere and nonbacterial pneumonia with a high level of precision. The clinical impact of this biomarker requires large-scale clinical evaluation.

PfHPRT: A New Biomarker Candidate of Acute Plasmodium falciparum Infection

Plasmodium falciparum is a protozoan parasite that causes human malaria. This parasitic infection accounts for approximately 655,000 deaths each year worldwide. Most deaths could be prevented by diagnosing and treating malaria promptly. To date, few parasite proteins have been developed into rapid diagnostic tools. We have combined a shotgun and a targeted proteomic strategy to characterize the plasma proteome of Gambian children with severe malaria (SM), mild malaria, and convalescent controls in search of new candidate biomarkers. Here we report four P. falciparum proteins with a high level of confidence in SM patients, namely, PF10_0121 (hypoxanthine phosphoribosyltransferase, pHPRT), PF11_0208 (phosphoglycerate mutase, pPGM), PF13_0141 (lactate dehydrogenase, pLDH), and PF14_0425 (fructose bisphosphate aldolase, pFBPA). We have optimized selected reaction monitoring (SRM) assays to quantify these proteins in individual patients. All P. falciparum proteins were higher in SM compared with mild cases or control subjects. SRM-based measurements correlated markedly with clinical anemia (low blood hemoglobin concentration), and pLDH and pFBPA were significantly correlated with higher P. falciparum parasitemia. These findings suggest that pHPRT is a promising biomarker to diagnose P. falciparum malaria infection. The diagnostic performance of this marker should be validated prospectively.