Human immunodeficiency virus seropositivity and malaria as risk factors for third-trimester anemia in asymptomatic pregnant women in western Kenya.

To assess risk factors for anemia in late pregnancy, we studied healthy pregnant women with a singleton uncomplicated pregnancy of > or = 32 weeks attending the prenatal clinic in the Provincial Hospital in Kisumu, Kenya. Between June 1996 and December 1998, 4,608 pregnant women had a blood sample collected for hemoglobin (Hb) measurement, malaria smear, and testing for human immunodeficiency virus (HIV). The mean +/- standard deviation of Hb was 9.58 +/- 1.8 g/dL; 21% had malaria in their blood; and 25% of the women were HIV seropositive. Plasmodium falciparum parasitemia was more common among HIV-seropositive women in all gravidities compared with HIV-seronegative women (risk ratio, 1.71; 95% confidence interval, 1.53-1.92). In a multivariate analysis, for primi- and secundigravidae women, the factors malaria, belonging to the Luo tribe, and HIV seropositivity were significantly associated with any anemia (Hb < 11 g/dL), and HIV seropositivity and documented fever were associated with severe anemia (Hb < 7 g/dL). In women of higher gravidities, HIV seropositivity was the only statistically significant factor associated with any anemia or with severe anemia. Asymptomatic HIV seropositivity is an important risk factor to be considered in the differential diagnosis of maternal anemia, independent of P. falciparum parasitemia.     

Association of Fcgamma receptor IIa (CD32) polymorphism with severe malaria in West Africa

Malaria continues to claim the lives of more children worldwide than any other infectious disease, and improved understanding of disease immunology is a priority for the development of new therapeutic and vaccination strategies. FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated with variability in susceptibility to both bacterial diseases and Plasmodium falciparum parasitemia. We investigated the role of this polymorphism in West Africans with mild and severe malarial disease. The HH131 genotype was significantly associated with susceptibility to severe malaria (P = 0.03, odds ratio = 1.40, 95% confidence interval = 1.02-1.91). In contrast to studies of parasitemia, the presence of the R131 allele, rather than the RR131 genotype, appeared to be the important factor in protection from disease. This is the first evidence for an association between CD32 polymorphism and severe malaria and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus.     

Relationship of hepcidin with parasitemia and anemia among patients with uncomplicated Plasmodium falciparum malaria in Ghana

The pathogenesis of malarial anemia is incompletely understood. Hepcidin, a recently discovered peptide hormone, is a major regulator of iron metabolism and is thought to play a central role in the anemia of chronic inflammation. The specific aim of the study was to characterize the association between urinary hepcidin, hemoglobin, and parasitemia in 199 patients presenting for evaluation of Plasmodium falciparum malaria in Ghana. Urinary hepcidin was semi-quantitatively assessed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Urinary hepcidin (intensity/mmol creatinine) was associated with log parasitemia in 86 children (beta = 0.086, standard error [SE] = 0.035, P < 0.017), 31 pregnant women (beta = 0.218, SE = 0.085, P < 0.016), and 82 adults (beta = 0.184, SE =0.043, P < 0.0001). Urinary hepcidin was not significantly associated with hemoglobin or anemia. Urinary hepcidin is more strongly associated with parasitemia than hemoglobin or anemia among patients with acute P. falciparum malaria in Ghana.     

Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.     

Interethnic differences in carriage of haemoglobin AS and Fcgamma receptor IIa (CD32) genotypes in children living in eastern Sudan

Fulani and Masaleit, two sympatric ethnic groups in eastern Sudan, are characterized by marked differences in susceptibility to Plasmodium falciparum malaria. It has been suggested that sickle cell trait carriage may protect from the most severe forms of malaria. Previously, we have shown that FcgammaRIIa polymorphism is associated with the outcome of malaria disease. The present study aimed at determining whether the two tribes differ in the frequency of FcgammaRIIa and Hb AS genotypes. For this, genotyping of FcgammaRIIa and Hb AS in 70 Fulani and 70 Masaleit age- and sex-matched subjects was conducted. The frequency of FcgammaRIIa H/H131 genotype was higher in the Fulani as compared to the Masaleit group (40.0% versus 14.3%; adjusted odd ratio [OR]=3.05, 95% confidence interval [CI]=1.19-7.82 and P=0.02), while the R/R131 genotype was significantly higher in the Masaleit group (14.3% for Fulani versus 45.0% for Masaleit; adjusted OR=0.26, 95% CI=0.11-0.64 and P<0.01). With regard to FcgammaRIIa allele frequencies, there were significant differences between the Fulani and Masaleit ethnic groups. Thus, the H131 allele was more frequent than the R131 among Fulani children (0.63 versus 0.37, OR=3.23, 95% CI=1.93-5.45 and P<0.001). The frequency of the Hb AS genotype was lower in the Fulani compared to the Masaleit group (15.7% versus 30.0%, respectively, adjusted OR=0.02, CI=0.01-0.18 and P<0.01). These data suggest that FcgammaRIIa and Hb AS polymorphisms may contribute to the clinical outcome of malaria. We conclude that the H/H131 genotype and H131 allele rather than Hb AS genotype (sickle cell trait patients) appear to associate with the Fulani ethnic group.     

Factors associated with hemoglobin concentrations in pre-school children in Western Kenya: cross-sectional studies

In sub-Saharan Africa, the etiology of anemia in early childhood is complex and multifactorial. Three community-based cross-sectional surveys were used to determine the prevalence and severity of anemia. Regression methods were used to compare mean hemoglobin (Hb) concentrations across covariate levels to identify children at risk of low Hb levels in an area with intense malaria transmission. In a random sample of 2,774 children < 36 months old, the prevalence of anemia (Hb < 11g/dL) was 76.1% and 71%, respectively, in villages without and with insecticide-treated bed nets (ITNs); severe-moderate anemia (Hb < 7 g/dL) was observed in 11% (non-ITN) and 8.3% (ITN). The prevalence of anemia, high-density malaria parasitemia (21.7%), microcytosis (34.9%), underweight (21.9%), and diarrhea (54.8%) increased rapidly from age three months onwards and remained high until 35 months of age. Multivariate analyses showed that family size, history of fever, pale body, general body weakness, diarrhea, soil-eating, concurrent fever, stunting, and malaria parasitemia were associated with mean Hb levels. Prevention of severe anemia should start early in infancy and include a combination of micronutrient supplementation, malaria control, and possibly interventions against diarrheal illness.     

Polymorphic variability in the interleukin (IL)-1beta promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1beta production

Interleukin (IL)-1beta is a cytokine released as part of the innate immune response to Plasmodium falciparum. Because the role played by IL-1beta polymorphic variability in conditioning the immunopathogenesis of severe malarial anemia (SMA) remains undefined, relationships between IL-1beta promoter variants (-31C/T and -511A/G), SMA (hemoglobin [Hb] level <6.0 g/dL), and circulating IL-1beta levels were investigated in children with parasitemia (n= 566) from western Kenya. The IL-1beta promoter haplotype -31C/-511A (CA) was associated with increased risk of SMA (Hb level <6.0 g/dL; odds ratio [OR], 1.98 [95% confidence interval {CI}, 1.55-2.27]; P < .05) and reduced circulating IL-1beta levels (p <.05). The TA (-31T/-511A) haplotype was nonsignificantly associated with protection against SMA (OR, 0.52 [95% CI, 0.18-1.16]; p =.11) and elevated IL-1beta production ( p<.05). Compared with the non-SMA group, children with SMA had significantly lower IL-1beta levels and nonsignificant elevations in both IL-1 receptor antagonist (IL-1Ra) and the ratio of IL-1Ra to IL-1beta. The results presented demonstrate that variation in IL-1beta promoter conditions susceptibility to SMA and functional changes in circulating IL-1beta levels.     

Malaria and nutritional status among pre-school children: results from cross-sectional surveys in western Kenya

Protein-energy malnutrition (PEM) affects millions of children in the developing world. The relationship between malaria and PEM is controversial. The goal of this study was to evaluate whether undernutrition is associated with increased or decreased malaria attributable morbidity. Three cross-sectional surveys were conducted using insecticide-treated bed nets (ITNs) among children aged 0-36 months living in an area with intense malaria transmission. Data were collected on nutritional status, recent history of clinical illness, socioeconomic status, current malaria infection status, and hemoglobin. In multivariate models, stunted children had more malaria parasitemia (odds ratio [OR] 1.98, P < 0.0001), high-density parasitemia (OR 1.84; P < 0.0001), clinical malaria (OR 1.77; P < 0.06), and severe malarial anemia (OR 2.65; P < 0.0001) than nonstunted children. The association was evident in children with mild-to-moderate (-3 < height-for-age Z-score [HAZ] < -2) and severe stunting (HAZ < -3). The cross-sectional nature of the study limits the interpretation of causality, but the data provide further observational support that the presence of undernutrition, in particular chronic undernutrition, places children at higher, not lower risk of malaria-related morbidity.     

Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia

Severe anemia is one of the most lethal complications of Plasmodium falciparum malaria. Red blood cells (RBCs) from children with severe malarial anemia are deficient in complement regulatory proteins (CR1 and CD55). A case-control, age- and sex-matched study was carried out to determine whether these deficiencies are acquired or inherited and the relative contribution of these complement regulatory protein deficiencies, the immune complex level, and the parasite density to the development of severe malarial anemia. RBC CR1 and CD55 deficiencies resolved after treatment, suggesting that these changes were acquired. Using conditional logistic regression, a decline in CD55 (or CR1) (odds ratio [OR], 4.2; 95% confidence interval [CI], 2.1-8.1; P<.001) and an increase in immune complex level (OR, 2.6; 95% CI, 1.5-4.8; P=.001) were significantly associated with severe malarial anemia.     

Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria

OBJECTIVE: Since the primary hematological complication in both pediatric HIV-1 and malaria is anemia, co-infection with these pathogens may promote life-threatening severe malarial anemia (SMA). The primary objective of the study was to determine if HIV-1 exposure [HIV-1(exp)] and/or HIV-1 infection [HIV-1(+)] increased the prevalence of SMA in children with acute malaria. DESIGN: The effect of HIV-1 exposure and HIV-1 infection on the prevalence of SMA (hemoglobin < 6.0 g/dl), parasitemia (parasites/microl), and high-density parasitemia (HDP, >or= 10 000 parasites/mul) was investigated in children 相似文献   

The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes

We hypothesized that Fcgamma receptor IIIa (FcgammaRIIIa), a polymorphic receptor for the Fc portion of immunoglobulin G (IgG) other than FcgammaRIIa, was involved in heparin-induced thrombocytopenia (HIT). FcgammaRIIa-131 and FcgammaRIIIa-158 genotypes were determined in 102 patients with definite HIT and in 2 control groups of patients treated by heparin (86 subjects without detectable antibodies [Abs] to heparin-platelet factor 4 [H/PF4], Ab(-) group; 84 patients with Abs to H/PF4 without HIT, Ab(+) group). There were no significant differences in genotype distribution or allele frequencies between the 3 groups for FcgammaRIIa-131H/R polymorphism. In contrast, FcgammaRIIIa-158V homozygotes were more frequent in the HIT group than in the Ab(+) group (P = .02), a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01). Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets may be increased in patients homozygous for the FcgammaRIIIa-158V allotype, thus contributing to the development of thrombocytopenia.     

The effects of malaria and intermittent preventive treatment during pregnancy on fetal anemia in Malawi

Background.?Fetal anemia is common in malarious areas and is a risk factor for infant morbidity and mortality. Malaria during pregnancy may cause decreased cord hemoglobin (Hb) and fetal anemia among newborns. Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is protective against malaria but may also affect hematopoiesis and contribute to fetal anemia. Methods.?Peripheral, placental, and cord blood were examined for malaria parasitemia and Hb concentration in a cross-section of 3848 mothers and infants delivered at Queen Elizabeth Central Hospital in Blantyre, Malawi between 1997 and 2006. Unconditional linear and logistic regressions were performed with multiple imputation for missing covariates to assess the associations between malaria, IPTp with SP, and fetal anemia. Results.?The overall prevalence of fetal anemia was 7.9% (n?=?304). Malaria parasitemia at delivery was associated with an adjusted decrease in cord Hb of -0.24?g/dL (95% confidence interval [CI], -.42 to -.05). The adjusted prevalence odds ratio for the effect of malaria on fetal anemia was 1.41 (95% CI, 1.05-1.90). Primigravidae who did not take IPTp had infants at highest risk for fetal anemia, and density of parasitemia was correlated with the decrease in cord Hb. There was no significant association between SP use and cord Hb or fetal anemia. Conclusions.?Malaria during pregnancy, but not IPTp, decreases cord Hb and is a risk factor for fetal anemia in Malawi. Intermittent preventive treatment during pregnancy with SP may continue to be safe and effective in preventing malaria during pregnancy and fetal anemia despite development of SP resistance.     

Characteristics of severe anemia and its association with malaria in young children of the Kassena-Nankana District of northern Ghana

Severe anemia is thought to be the principal underlying cause of malaria death in areas of intense seasonal malaria transmission such as the Kassena-Nankana District of northern Ghana. Factors associated with severe anemia in young children, 6-24 months old, were elucidated by analyzing results of 2 malaria-associated anemia surveys (1996, 2000), separated by 4 years, but conducted in the same community and at the same seasonal time point. Age-adjusted comparison confirmed that the proportion of severely anemic children and overall mean hemoglobin (Hb) levels in the November 2000 sample were significantly improved over those of the 1996 sample (17.5 versus 26.4%, P = 0.03; Hb 7.5 versus 6.9 g/dL, P = 0.002). Weight-for-age Z-scores also indicated a significant improvement in the 2000 sample (-1.93 versus -2.20, P < 0.05). Independently, each survey identified statistically significant associations between severe anemia and age, parasite rate, fever, and sex. Relative to children with Hb > or = 6.0 g/dL, those with severe anemia (Hb < 6.0 g/dL) were older, more frequently parasitemic (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.08-2.35), more often febrile (OR, 2.44; 95% CI, 1.71-3.48), and predominantly male (OR, 1.50; 95% CI, 1.05-2.13). An association was identified in both surveys between severe anemia and residence in the northern part of the district, but no clear link was observed in relation to irrigation. Blood transfusions, a likely surrogate index of severe anemia in young children, followed a distinct seasonal pattern. Evidence suggests that dramatic peaks and troughs of severe anemia are regular and possibly predictable events that may be used to gauge the health and survival of young children in this area.     

Association of interferon-gamma responses to pre-erythrocytic stage vaccine candidate antigens of Plasmodium falciparum in young Kenyan children with improved hemoglobin levels: XV. Asembo Bay Cohort Project

Previous studies in animal models have revealed an association between interferon-gamma (IFN-gamma), produced by CD8+ T cells and irradiated sporozoite-induced sterile immunity. To determine whether IFN-gamma can serve as a marker of pre-erythrocytic protective immunity in individuals naturally exposed to malaria, we characterized IFN-gamma and lymphocyte proliferative responses to previously defined CD8+ cytotoxic T lymphocyte (CTL) epitopes from six pre-erythrocytic stage antigens in 107 children six months to two years old from a community-based birth cohort in western Kenya. We found that IFN-gamma positive responders had higher hemoglobin (Hb) levels and significantly reduced prevalence of severe malarial anemia one month after the test compared with IFN-gamma non-responders, suggesting that IFN-gamma immune responses to these pre-erythrocytic antigens were associated with protection against malarial anemia. Children who responded by lymphocyte proliferation had a significantly longer time to first documented malaria parasitemia after birth; however, there was no correlation between the presence of lymphocyte proliferative response and higher Hb levels. We propose that IFN-gamma production could be used as a potential marker of protective immunity against malaria associated anemia in young children living in malaria holoendemic areas.     

Red cell surface changes and erythrophagocytosis in children with severe plasmodium falciparum anemia

Severe anemia is one of the most lethal complications in children infected with Plasmodium falciparum. The pathogenesis of this anemia is not completely understood. Experimental data from malaria-infected humans and animal models suggest that uninfected red cells have a shortened life span. This study looked for changes in the red cell surfaces of children with severe malarial anemia that could explain this accelerated destruction. A prospective case-control study was conducted of children with severe P falciparum anemia (hemoglobin of 5 g/dL or lower) admitted to a large general hospital in western Kenya. Children with severe anemia were compared with children who had symptoms of uncomplicated malaria and with asymptomatic children. Cytofluorometry was used to quantify in vitro erythrophagocytosis and to measure red cell surface immunoglobulin G (IgG) and the complement regulatory proteins CR1, CD55, and CD59. Red cells from patients with severe anemia were more susceptible to phagocytosis and also showed increased surface IgG and deficiencies in CR1 and CD55 compared with controls. Red cell surface CD59 was elevated in cases of severe anemia compared with asymptomatic controls but not as compared with symptomatic controls. The surface of red cells of children with severe P falciparum anemia is modified by the deposition of IgG and alterations in the levels of complement regulatory proteins. These changes could contribute to the accelerated destruction of red cells in these patients by mechanisms such as phagocytosis or complement-mediated lysis. (Blood. 2000;95:1481-1486)     

Parasite multiplication potential and the severity of Falciparum malaria

The multiplication rates and invasiveness of Plasmodium falciparum parasites isolated from adult Thai patients hospitalized with uncomplicated malaria (n=34) were compared with those from persons with severe malaria (n=42). To simulate severe malaria and control for host effects, the in vitro cultures were adjusted to 1% parasitemia and used the same red blood cell donor. P. falciparum isolates from persons with severe malaria had initial cycle multiplication rates in vitro that were 3-fold higher than those from uncomplicated malaria (median [95% confidence interval], 8.3 [7. 1-10.5] vs. 2.8 [1.7-3.9]; P=.001). Parasites causing severe malaria exhibited unrestricted red blood cell invasion, whereas those from uncomplicated malaria were restricted to a geometric mean of 40 (31%-53%) of red blood cells. P. falciparum parasites causing severe malaria were less selective and multiplied more at high parasitemias than those causing uncomplicated malaria.     

Both heterozygous and homozygous alpha+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya

Although the alpha+ thalassemias almost certainly confer protection against death from malaria, this has not been formally documented. We have conducted a study involving 655 case patients with rigorously defined severe malaria and 648 controls, frequency matched on area of residence and ethnic group. The prevalence of both heterozygous and homozygous alpha+ thalassemia was reduced in both case patients with severe malaria (adjusted odds ratios [ORs], 0.73 and 0.57; 95% confidence intervals [95% CIs], 0.57-0.94 and 0.40-0.81; P = .013 and P = .002, respectively, compared with controls) and among the subgroup of children who died after admission with severe malaria (OR, 0.60 and 0.37; 95% CI, 0.37-1.00 and 0.16-0.87; P = .05 and P = .02, respectively, compared with surviving case patients). The lowest ORs were seen for the forms of malaria associated with the highest mortality-coma and severe anemia complicated by deep, acidotic breathing. Our study supports the conclusion that both heterozygotes and homozygotes enjoy a selective advantage against death from Plasmodium falciparum malaria.     

Severe anemia in young children after high and low malaria transmission seasons in the Kassena-Nankana district of northern Ghana

Malaria and anemia accounted for 41% and 18% respectively of hospital deaths in the Kassena-Nankana district of northern Ghana during 1996. We measured hemoglobin (Hb), malaria prevalence, and anthropometric indices of 6--24-month-old infants and young children randomly selected from this community at the end of the high (May-October, n = 347) and low (November-April, n = 286) malaria transmission seasons. High transmission season is characterized by rainfall (the equivalent of 800-900 mm/yr.), while the remaining months receive less than 50 mm/yr. Severe anemia, defined as Hb < 6.0 g/dL, was 22.1% at the end of the high transmission season compared to 1.4% at the end of the low transmission season (Odds Ratio [OR] = 20.1; 95% CI: 7.1-55.3). Parasitemia was 71% and 54.3% at these time points (OR = 2.1; 95% CI: 1.5-2.9). Nutritional anemia appeared to have little impact upon this seasonal difference since anthropometric indices were comparable. Although the relative contributions of other causes of severe anemia were not assessed, repeated malaria infections may be a primary determinant of severe anemia among infants and young children during the high transmission season.     

High titers of IgG antibodies against Plasmodium falciparum serine repeat antigen 5 (SERA5) are associated with protection against severe malaria in Ugandan children

Plasmodium falciparum serine repeat antigen (SERA5) is a promising asexual blood stage malaria candidate vaccine. However, there is a paucity of information about natural immune responses to SERA5 in children from malaria-endemic regions. We undertook a hospital-based case-control study of severe malaria in Apac District, Northern Uganda, in children 6-59 months of age. The commonest symptoms observed in children with severe malaria (SM) were respiratory distress (53.4%) and prostration (40.4%) followed by circulatory collapse (7.4%), severe anemia (Hb < 5 g/dL, 7.0%), and seizures (2.6%). None of the SM children had impaired consciousness, coma, or cerebral malaria. We measured serum IgG antibodies using a recombinant construct of SERA5 (SE36) in enzyme-linked immunosorbent assays. High titers of IgG anti-SE36 were associated with protection against severe malaria in children under 5 years old.