Complicated malaria and other severe febrile illness in a pediatric ward in Libreville, Gabon

ABSTRACT: BACKGROUND: Although a substantial decline of Plasmodium falciparum infection is observed in Africa following implementation of new control strategies, malaria is still considered as the major cause of febrile illness in hospitalized African children. The present study was designed to assess the management of febrile illness and to determine the proportion of children with febrile illness hospitalized for primary diagnosis of malaria who had confirmed complicated malaria after implementation of new malaria control strategies in Libreville, Gabon. METHODS: Demographic, clinical and biological data from hospitalized children with fever or a history of fever with a primary diagnosis of clinical malaria, aged less than 18 years old, who benefited from hematological measurements and microscopic malaria diagnosis were recorded and analyzed during a prospective and observational study conducted in 2008 in the Centre Hospitalier de Libreville. RESULTS: A total of 418 febrile children were admitted at hospital as malaria cases. Majority of them (79.4%) were aged below five years. After medical examination, 168 were diagnosed and treated as clinical malaria and, among them, only 56.7% (n = 95) had Plasmodium falciparum positive blood smears. Age above five years, pallor, Blantyre Coma Score <=2 and thrombocytopenia were predictive of malaria infection. Respiratory tract infections was the first leading cause of hospitalization (41.1%), followed by malaria (22.7%); co-morbidities were frequent (22%). Less than 5% of suspected bacterial infections were confirmed by culture. Global case fatality rate was 2.1% and 1% for malaria. Almost half (46%) of the children who received antimalarial therapy had negative blood smears. Likewise, antibiotics were frequently prescribed without bacteriological confirmation. CONCLUSIONS: The use of clinical symptoms for the management of children febrile illness is frequent in Gabon. Information, training of health workers and strengthening of diagnosis tools are necessary to improve febrile children care.     

Normal riboflavin status in malaria patients in Gabon

Previous publications reported commonly the occurrence of riboflavin deficiency and a positive correlation between riboflavin status and parasitemia in patients with Plasmodium falciparum malaria. In these studies, riboflavin status was determined by erythrocyte glutathione reductase activation coefficients (EGRACs). Inherited low erythrocyte glutathione reductase activity is highly prevalent in malarial regions, however. To rule out falsely diagnosed riboflavin deficiency in affected patients, we conducted an investigation using a high-performance liquid chromatography method (HPLC) instead of the EGRAC method. In 29 infants (age range, 1-5 years), 22 schoolchildren (age range, 6-12 years), and 33 adolescents and adults (age range, 13-74 years) from Lambaréné, Gabon, with acute P. falciparum malaria, plasma concentrations of riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) were measured by HPLC. Results were correlated with parasite densities. Profiles of plasma concentrations of all 3 flavin compounds were within the normal range in all patients. Concentrations of free riboflavin were not different between the 3 age groups. In adolescents and adults, FMN and FAD concentrations were higher than in infants (P = 0.002 and P = 0.001) and schoolchildren (P = 0.003 and P = 0.002). Comparing children with hyperparasitemic and uncomplicated malaria, no difference in the concentrations of either flavin compound was found. Neither the concentrations of free riboflavin nor the concentrations of one of the flavin nucleotides correlated with parasitemia within subgroups of age or of children with uncomplicated and hyperparasitemic malaria. Our data indicate that nutritional riboflavin deficiency might have been overestimated in previous malaria studies and do not support a relationship between flavin concentrations and parasitemia in P. falciparum malaria.     

Relationship between entomological inoculation rate,Plasmodium falciparum prevalence rate,and incidence of malaria attack in rural Gabon

To assess the relationships between variations of Plasmodium falciparum transmission and those of peripheral parasitaemia prevalence or malaria attack incidence rates in regions with limited fluctuations of transmission, we conducted a follow-up in two Gabonese populations. Entomological surveys were carried out from May 1995 to April 1996 in Dienga, and from May 1998 to April 1999 in Benguia. In Dienga, malaria transmission was seasonal, being not detected during two 3-month periods. Mean entomological inoculation rate (EIR) was 0.28 infective bite/person/night. In Benguia, malaria transmission was perennial with seasonal fluctuations, mean EIR being 0.76 infective bite/person/night. In Dienga, 301 schoolchildren were followed from October 1995 to March 1996. Clinical malaria attack was defined as fever associated with >5000 parasites/microl of blood. P. falciparum prevalence varied from 28 to 42%, and monthly malaria attack incidence from 30 to 169 per thousand. In Benguia, the entire population (122 persons) was followed from November 1998 to April 1999. Prevalence varied from 22 to 50%, and monthly malaria attack incidence from 52 to 179 per thousand. In each area, entomological variations were not related to parasite prevalence, but preceded malaria attack incidence with 1- or 2-month time lag, corresponding to the pre-patency period that differs in the two populations, possibly according to differences in immunity related to parasite transmission.     

Differences between preschoolers with asthma and allergies in urban and rural environments

Objective: Previous studies have provided conflicting results about how living in a rural or urban environment influences schoolchildren with asthma and allergic diseases in different ways. The aim of the present study was to evaluate if recurrent wheezing preschoolers from rural or urban areas differ in asthma, allergic diseases, and atopy. Methods: A cross-sectional-study in Rafaela, Argentina, on 143 preschoolers with recurrent wheezing from rural and urban settings was performed (2010–2012). Diagnosis of asthma (by positive asthma predictive index [API]), allergic diseases (rhinitis, dermatitis), and atopy (by skin prick test [SPT], peripheral blood eosinophils, and serum total IgE) were assessed. Results: Preschoolers from rural settings had significantly higher prevalence of vaginal delivery, longer breastfeeding, earlier onset of wheezing, more parental smoking, siblings, shared a bedroom, and more exposure to chemicals used in plant fumigation or farm animals, and unpasteurized milk consumption, in comparison to preschoolers living in urban setting. In contrast, preschoolers from urban areas had significantly higher prevalence of parental history of allergy, positive skin prick test, and positive API. After multivariate analysis adjusting for covariates, maternal smoking [odds ratio (OR) = 3.44] and positive SPT (OR = 5.57) significantly increase the risk of asthma diagnosis (positive API); in contrast, living in rural setting (OR = 0.04), and having more siblings (OR = 0.51) decrease their risk. Conclusions: Recurrent wheezing preschoolers from rural areas had a significant inverse odds of being diagnosed with asthma (type-2 inflammation) when compared to those from urban areas. Exposure to farm animals and consumption of unpasteurized milk might have a role.     

Family analysis of malaria infection in Dienga,Gabon

Fifty children from 9 families were enrolled in a longitudinal study of 8 months to evaluate individual levels of Plasmodium falciparum density in blood during asymptomatic infections. Individual parasite densities were adjusted for age and date of blood intake. The arithmetic means of these adjusted parasite densities (MAPD) were not influenced by sickle cell trait nor by G6PD enzyme activity. On the contrary, family analysis revealed the presence of similar MAPD values according to the sibships. Moreover, sibships frequently infected with P. malariae exhibited the highest P. falciparum MAPDs. The difference in aggressiveness of malaria vectors between the northern and southern halves of the village did not explain the distribution of MAPD, nor did it explain the differences in mean frequency of P. malariae infection among the sibships. We conclude that the familial characteristic of susceptibility to both P. falciparum and P. malariae infections is more likely influenced by the host's genetic background than by differences in the levels of malaria transmission.     

Prevalence of hypoglycemia among severe malaria children in a rural African population

ObjectiveTo determine the prevalence of hypoglycemia in severe malaria children in a rural African community.MethodsThirty two children who fulfilled the inclusion criteria were recruited for the study from two hospitals with intensive care facilities. Blood sugar levels of the patients were monitored serially at admission and then every 4 hours (after admission) for 24 hours using a glucometer; taking values <2.2 mmol/L as hypoglycemia. The children received intensive care according to WHO guidelines for severe malaria.ResultsFifteen out of 32 children recruited (representing 46.9%) had hypoglycemia with about 60% under 5 years of age. The mean age of the children was (4.49±2.89) years. The pre-correction and average post correction blood glucose levels were (2.04±0.13) mmol/L and (3.18±0.23) mmol/L, respectively.ConclusionsThe result has demonstrated that about 1 in 2 children with severe malaria may suffer from hypoglycemia in an African rural environment hence there is a need for at least three-point glucose estimation (at recruitment, 4 hours following correction and the end of the 24 hours).     

Epidemiology and population structure of Staphylococcus aureus in various population groups from a rural and semi urban area in Gabon, Central Africa

Little data is available on the epidemiology of Staphylococcus aureus in Africa. In the present study we aim at characterizing the population structure of S. aureus in healthy subjects from a rural and a semi-urban area in Lambaréné, Gabon as well as in hospital staff and inpatients. In total, 500 subjects were screened for S. aureus colonization of the nares, axillae and inguinal region. Overall, 146 (29%) were positive. We found 46 different spa types. The most frequent spa types were t084 (35%) and the agr II was the most prevalent subtype of the accessory gene regulator (56%, n=82). Five isolates (3%) were methicillin resistant S. aureus (MRSA). Carriage rates of S. aureus in Gabon are comparable to developed countries. MRSA is for the first time described and could pose a significant health threat in this region with limited access to microbiological laboratory facilities and to adequate antimicrobial agents.     

Antigen presentation and dendritic cell biology in malaria

Dendritic cells (DCs) are important both in amplifying the innate immune response and in initiating adaptive immunity and shaping the type of T helper (Th) response. Although the role of DCs in immune responses to many intracellular pathogens has been delineated and research is underway to identify the mechanisms involved, relatively little is known concerning the role of DCs in immunity to malaria. In this review, we provide an overview and summary of previous and current studies aimed to investigate the role of DCs as antigen presenting cells (APCs). In addition, the role of DCs in inducing innate and adaptive immunity to blood-stage malaria is discussed and, where information is available, the mechanisms involved are presented. Data from studies in humans infected with Plasmodium falciparum, the major human parasite responsible for the high morbidity and mortality associated with malaria throughout many regions of the developing world, as well as data from experimental mouse models are presented. Overall, the data from these studies are conflicting. The possible reasons for these differences, including the use of different parasite species and parasite strains in the mouse studies, are discussed. Nevertheless, together the data have important implications for development of an effective malaria vaccine since the selection of appropriate Plasmodium antigens and/or adjuvants, targeting innate immune responses involving DCs, may provide optimal protection against malaria. It is hoped that this review promotes more investigation among malariologists and immunologists alike on DCs and malaria.     

Liver cell dysplasia accompanying hepatocellular carcinoma in southern Africa. Differences between urban and rural populations

Liver cell dysplasia (LCD) has been recognised for many years in association with hepatocellular carcinoma (HCC). The presence of LCD relates to cirrhosis, particularly macronodular, as well as HBsAg positivity in many countries. These relationships have not previously been recognised in southern Africa. This study of LCD in 160 rural and urban black patients with proven HCC records a significant difference between the prevalence of dysplasia in rural HBsAg-positive and -negative cases: 75.6% in HBsAg+ individuals vs. 29.4% of those negative for HBsAg (P less than 0.01). Furthermore a significant relationship is reported between dysplasia and macronodular cirrhosis, LCD being observed in 62.9% of those with macronodular cirrhosis vs. 29.5% of non-cirrhotics (P less than 0.001). In addition there was evidence for a relationship between severity of dysplasia and domicile (rural greater than urban), age (being more extensive in younger patients), and ongoing viral replication (82.3% of patients showing the highest grade of dysplasia were found to be serum HBeAg+ and/or tissue HBcAg+ cf. 3.7% with absent or low-grade dysplasia). It is apparent that in southern Africa the presence of dysplasia in HBsAg+ individuals implies that HCC should be actively excluded in these patients and that they should thereafter be carefully monitored for the development of a tumour.     

The microcirculation in severe malaria

Severe malaria in humans and animals is initiated by interactions between malaria-infected cells, host blood cells (including monocytes, T cells and platelets) and endothelial cells of the microcirculation. Adhesion to vascular cells, and possible vascular obstruction in severe human disease, involves interaction between host receptors and parasite-derived proteins, such as the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Our understanding of how different PfEMP1 variants may target infected erythrocytes to specific sites, such as the placenta, is rapidly increasing. However, in most instances downstream immune-mediated inflammatory processes appear more central than parasite accumulation to development of severe malaria. Using genetically-manipulated animal models of severe malaria, key roles for CD8 T cells and mediators such as lymphotoxin in the pathogenesis of murine disease have been established. Experimental and human studies suggest vascular deposition of activated platelets may have a central role. Here, we review some recent advances in the understanding of severe malaria pathogenesis from human and animal studies, focusing on events at the level of the microcirculation, and highlight the role for activated host cells in initiating the pathology of the disease.     

Observations on malaria patients seeking treatment in hospitals in a rural and an urban area of Sri Lanka.

Malaria in Sri Lanka is endemic in the dry zone and occurs during epidemics in the wet zone. A survey was carried out on malaria patients presenting at a hospital located in a predominantly rural area in the dry zone (Polonnaruwa) and an urban area in the wet zone (Ragama). Higher incidence of Plasmodium falciparum infections than reported nationally were observed in both locations. Of particular interest is the rapidity with which patients gained access to hospital treatment after the onset of malaria symptoms. The observed mode is 3-6 days. It is postulated that early treatment may impair the development of clinical immunity to malaria in the Sri Lankan population.     

Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon

BACKGROUND: The development of novel artemisinin-combination therapies suitable for the treatment of pediatric patients suffering from malaria is a research priority. The aim of this study was to investigate a novel fixed-dose pyronaridine-artesunate combination for the treatment of uncomplicated falciparum malaria in Gabonese patients 2-14 years old. METHODS: The study was designed as an open-label dose-escalation study recruiting 60 pediatric patients sequentially in 4 treatment cohorts: study drugs were administered once daily for 3 days, as tablet coformulations (pyronaridine:artesunate ratios of 6:2, 9:3, and 12:4 mg/kg) and as a granule coformulation (pyronaridine:artesunate ratio of 9:3 mg/kg). The primary end points were tolerability, safety, and pharmacokinetics of pyronaridine-artesunate treatment. Efficacy was treated as a secondary outcome measure. RESULTS: The drugs had a good tolerability and safety profile, at all dose levels. Pharmacokinetic analysis revealed a dose-dependent increase in the maximum plasma/blood concentration and the area under the curve, as well as comparable relative bioavailability for the granule coformulation. Polymerase chain reaction-corrected cure rates at day 28 were 100% in per-protocol analysis, at all dose levels. CONCLUSIONS: Pyronaridine-artesunate is a promising novel artemisinin-combination therapy for pediatric patients with uncomplicated Plasmodium falciparum malaria, and the development of both the tablet and the granule coformulations is warranted.     

Pathophysiology of severe malaria in children

Over the past decade there has been a growing recognition that the rationalization of severe malaria in children into the two major syndromes of cerebral malaria and severe malaria anaemia is much too simplistic. Indeed, it has become apparent that death from severe malaria may arise from a wider spectrum of pathophysiological disorders with many features in common with the derangements seen in sepsis syndromes. Amongst these derangements acidosis has emerged as a central feature of severe malaria and the major predictor of a fatal outcome. We review the improved understanding of the pathophysiology of severe malaria through a series of clinical scenarios that reflect more accurately the clinical diversity of severe malaria in African children. Current therapeutic challenges are discussed and research priorities are highlighted.     

Plasma and in vitro levels of cytokines during and after a Plasmodium falciparum malaria attack in Gabon

Fifty subjects living in a malaria endemic area were studied at diagnosis of a Plasmodium falciparum attack and 3 weeks later. Absolute numbers of CD3(+), CD4(+) and CD8(+) lymphocytes as well as plasma cytokines and secreted cytokines after in vitro mitogenic stimulation were measured. At enrollment, lymphopenia was observed, lending support to the reallocation hypothesis during the acute phase. A significant elevation of the number of CD8(+) cells was present in the peripheral blood during the recovery phase. During the acute phase, plasma IL-6 levels peaked while in vitro production capacity was high at both phases. Plasma IL-6 concentrations were positively related to blood parasite density at D0, as IL-4 and IFN-gamma, suggesting an early intervention of these cytokines. Plasma IL-2 levels were low at diagnosis although cells retained their ability to produce IL-2, which was found more frequently in plasma after cure. Acquisition of immunity with age was in relation with greater secretion abilities of cells for type 1 and type 2 cytokines during the parasite clearance phase. We conclude to an early implication of type 2 cytokines and IFN-gamma, with particularly high levels of IL-6.