HbAA Children Research Articles

Only a small proportion of anemia in northeast Thai schoolchildren is associated with iron deficiency

Iron deficiency is assumed to be the major cause of anemia in northeast Thailand, but other factors may be involved. We determined the prevalence of anemia among schoolchildren in northeast Thailand and the role of hemoglobinopathies, selected micronutrient deficiencies, and other factors in hemoglobin status. Blood samples were collected from 567 children aged 6-12.9 y attending 10 primary schools for the determination of a complete blood count and hemoglobin type [Hb AA (normal hemoglobin), Hb AE (heterozygous for Hb type E), and Hb EE (homozygous for Hb type E)] and the measurement of serum ferritin, transferrin receptor, retinol, vitamin B-12, and plasma and erythrocyte folate concentrations. Children with a C-reactive protein concentration > or = 10 mg/L (n = 12), which indicated infection, were excluded. The prevalence of anemia was 31%. Age, hemoglobin type, and serum retinol were the major predictors of hemoglobin concentration. Hb AA and Hb AE children with anemia had lower (P < 0.01) hematocrit, mean cell volume, and serum retinol values than did their nonanemic counterparts; no significant differences in serum ferritin were found by hemoglobin type. Only 16% (n = 22) of the anemic Hb AA and Hb AE children were iron deficient. Hb AA and Hb AE children with a serum retinol concentration <0.70 micromol/L (n = 14) had a significantly higher geometric mean serum ferritin concentration than did those with a retinol concentration > or = 0.70 micromol/L (P = 0.009); no significant difference in transferrin receptor concentrations was found between these 2 groups. Hemoglobinopathies, suboptimal vitamin A status, and age were the major predictors of hemoglobin concentration. The contribution of iron deficiency to anemia was low, and its detection was complicated by coexisting suboptimal vitamin A status.

Relation between the response to iron supplementation and sickle cell hemoglobin phenotype in preschool children in western Kenya

Iron supplementation has been associated with greater susceptibility to malaria and lower hematologic responses in pregnant Gambian women with sickle cell trait (HbAS) than in similar women with the normal (HbAA) phenotype. It is not known whether a similar interaction exists in children. Our aim was to determine the influence of the HbAS phenotype on hematologic responses and malaria after iron supplementation in anemic (hemoglobin: 70-109 g/L) children aged 2-35 mo. We conducted a double-blind, randomized, placebo-controlled trial (HbAS, n = 115; HbAA, n = 408) of intermittent preventive treatment with sulfadoxine pyrimethamine (IPT-SP) at 4 and 8 wk and daily supervised iron for 12 wk. The mean difference in hemoglobin concentrations at 12 wk between children assigned iron and placebo iron, after adjustment for the effect of IPT-SP, was 9.1 g/L (95% CI: 6.4, 11.8) and 8.2 g/L (4.0, 12.4) in HbAA and HbAS children, respectively (P for interaction = 0.68). Although malaria parasitemia and clinical malaria occurred more often in HbAS children in the iron group than in those in the placebo iron group, this difference was not significant; incidence rate ratios were 1.23 (95% CI: 0.64, 2.34) and 1.41 (0.39, 5.00), respectively. The corresponding incidence rate ratios in HbAA children in the same groups were 1.07 (95% CI: 0.77, 1.48) and 0.59 (0.35, 1.01), respectively. The corresponding interactions between the effects of iron and hemoglobin phenotype were not significant. There was no evidence for a clinically relevant modification by the hemoglobin S phenotype of the effects of iron supplementation in the treatment of mild anemia. The benefits of iron supplementation are likely to outweigh possible risks associated with malaria in children with the HbAA or HbAS phenotype.

Increased efficacy of sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria among children with sickle cell trait in Western Kenya.

The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2-3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36-0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome.

Sickle cell trait carriage: imbalanced distribution of IgG subclass antibodies reactive to Plasmodium falciparum family-specific MSP2 peptides in serum samples from Gabonese children

Several mechanisms have been proposed for explaining the protection of young children with hemoglobin AS from severe Plasmodium falciparum malaria. In a previous study carried out in Gabon, we have shown an association between hemoglobin AS carriage and a greater P. falciparum infection complexity. In the present study, we have investigated the presence and fine specificity of merozoite surface protein 2 (MSP2) reactive antibodies using different peptides covering conserved and polymorphic regions (Blocks 1–3) of P. falciparum MSP2 molecules. A cross-sectional study was conducted in the city of Bakoumba (Gabon), where malaria is hyperendemic with perennial P. falciparum transmission. Among the 641 children included, 135 were heterozygous for the sickle cell trait (HbAS). There was no significant difference in age distribution (mean age: 5 years, 0.5–11 years) and sex ratio in both hemoglobin groups (HbAA vs. HbAS). Blood group O was, however, associated with the sickle cell trait ( P=0.02). P. falciparum isolates obtained from children with HbAS had a trend to higher infection complexity before the age of 5 years. Plasma samples were tested for the presence of antibodies to the different MSP2 peptides. Total IgG antibodies with a predominant reactivity against the FC27 type (the predominant P. falciparum MSP2 genotype) were found in serum samples from both groups. The profile of the IgG subclasses varied according to the hemoglobin phenotype. IgG3 and IgG2 were predominantly detected in plasma samples from HbAS children, whereas mainly IgG3 was found in children with HbAA. The role of the high multiclonal carriage associated with high family-specific antibodies reactive to MSP2 in HbAS children with asymptomatic P. falciparum parasitism is discussed.

The clinical manifestations of cerebral malaria among Nigerian children with the sickle cell trait.

In order to describe the interaction between haemoglobin type and the clinical manifestations of cerebral malaria, we studied 60 children aged between 6 and 60 months at University College Hospital, Ibadan, Nigeria. Haemoglobin AS individuals with cerebral malaria did not exhibit major differences in clinical and laboratory characteristics when compared with their haemoglobin AA counterparts. There were no deaths among the Hb AS children compared with an 18% mortality in the Hb AA group. Blood transfusion rates were higher in the AS than in the AA children (86% vs 44%). The higher transfusion rates in the AS group is consistent with in-vitro observations of sickling of parasitized red cells containing Hb S which in vivo would be cleared by the reticuloendothelial system. It is concluded that the clinical manifestations of cerebral malaria are essentially similar in children with haemoglobins AS and AA but the former have higher transfusion needs and are less likely to die.

Morbidity from malaria and immune responses to defined Plasmodium falciparum antigens in children with sickle cell trait in The Gambia

Morbidity from Plasmodium falciparum malaria and humoral and in vitro cellular immune responses to defined malaria antigens were measured in rural Gambian children with haemoglobin phenotype AS (HbAS) and in those with a normal haemoglobin (HbAA). In a survey undertaken during the dry season, HbAS children had a higher parasite rate than HbAA children but a lower prevalence of parasitaemia at a level of 500/μl or greater. Malariometric indices measured during a rainy season survey were similar in the 2 groups of children. During the rainy season, the incidence of infection with P. falciparum did not vary with haemoglobin phenotype. However, in children aged 6 years or less, a significantly smaller proportion of HbAS children who acquired infection developed clinical symptoms than did HbAA children. During both the dry season and rainy season surveys, humoral and in vitro cellular immune responses to defined antigens from the sporozoite and merozoite stages of P. falciparum were similar in the 2 groups of children. Thus, despite the differences in parasite indices and morbidity from malaria between the 2 groups of children, we found no evidence of an enhanced immune response to malaria infection amongst HbAS children compared with normal children.

Seasonal changes in cell mediated immune responses to soluble Plasmodium falciparum antigens in children with haemoglobin AA and haemoglobin AS

In this longitudinal study peripheral blood mononuclear cells (PBMC) were obtained before and during the malaria season from healthy HbAA and HbAS children. Cells were compared for proliferation in response to stimulation by soluble Plasmodium falciparum antigens (SPAg) or purified derivative of tuberculin (PPD). The lymphoproliferative responses to SPAg of the paired PBMC samples showed 2 distinct seasonal changes in relation to the haemoglobin phenotype. In HbAA children, the lymphoproliferative responses to SPAg were suppressed during the malaria season. In contrast, they were enhanced in HbAS children during the malaria season. No distinct seasonal change in the response to PPD was found in relation to the haemoglobin phenotype. The study points to the role of the sickle cell trait in modulating the cellular immune responses to falciparum malaria.

Lymphoproliferative Responses to Plasmodium falciparum Antigens in Children With and Without the Sickle Cell Trait

Blood mononuclear cells (BMNC) were isolated from sickle cell trait (HbAS) healthy donors and normal haemoglobin (HbAA) healthy donors resident in a P. falciparum endemic area of eastern Sudan. Blood samples were collected during the malaria season. BMNC were tested for their proliferative responses to phytohaemagglutinin (PHA), purified protein derivative of tuberculin (PPD) and to soluble P. falciparum antigens (SPAg). Higher responses to SPAg and PPD were observed in the HbAS children compared with the HbAA children, whereas no differences were observed among adults of the two phenotypes. Proliferative responses to PHA were comparable in all individuals tested. The significance of these findings in relation to haemoglobin phenotype, age and the possible immunoregulatory mechanisms operating in HbAS and HbAA children during the malaria season is discussed.

Population studies in Cameroon: hemoglobin S, glucose-6-phosphate dehydrogenase deficiency and falciparum malaria.

Examination of blood samples from 1,183 individuals from Cameroon indicates that sickle cell trait frequencies and G6PD deficiency frequencies were heterogeneous among villages as well as within geographic areas and ethnic groups. Mean parasite counts were significantly correlated with Hb AS frequencies for children 6 years of age and under, although no correlation was found for mean parasite counts and G6PD deficiency frequencies. The mean age of sickle cell trait individuals was found to be significantly greater than the mean age of Hb AA individuals. The mean age of G6PD-deficient males did not differ from the mean age of G6PD-normal males. Hb AA and Hb AS children did not differ significantly in mean positive parasite counts. Falciparum malaria appears to be a selective pressure keeping Hb S frequencies high; yet it may not be the major selective force maintaining the G6PD polymorphism.

Luetic Deafness

Red blood cell variants protect African children from severe falciparum malaria. However, their individual and interactive effects on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood. In this study, we address these knowledge gaps in a prospective cohort study of malaria risk and Plasmodium falciparum densities in Malian children.The Kenieroba Innate Defense Study for Malaria (KIDS-Malaria) was a 4-year prospective cohort study of children aged 6 months to 17 years undertaken in Mali between 2008 and 2011. Red blood cell variants were haemoglobin S (HbS), haemoglobin C (HbC), α thalassaemia, ABO blood groups, and glucose-6-phosphate dehydrogenase (G6PD) deficiency encoded by the X-linked A– allele. The primary outcome was malaria incidence, measured as the number of uncomplicated or severe malaria episodes over time. The secondary outcome was parasite density at the time of a malaria episode. We modelled incidence rate ratios with quasi-Poisson regression and we analysed parasite densities using generalised estimating equations. This study is registered with ClinicalTrials.gov, number NCT00669084.Between May 1, 2008, and Dec 29, 2011, we enrolled 1586 children into the study. We successfully typed all five red blood cell variants for 1543 of these children, who therefore constituted the evaluable population and in whom we diagnosed 4091 malaria episodes over 2656 child-years of follow-up. In these 1543 children, red blood cell variants were common, and occurred at the following frequencies: sickle cell trait (HbAS) 220 (14%), HbC heterozygosity (HbAC) 103 (7%), α thalassaemia 438 (28%), type O blood group 621 (40%), and G6PD deficiency 72 (9%) in 767 boys and 158 (20%) in 776 girls. The overall incidence of malaria was 1·54 episodes per child-year of follow-up, ranging from 2·78 episodes per child-year at age 3 years to 0·40 episodes per child-year at age 17 years. The malaria incidence was lower in HbAS children than in HbAA children with normal haemoglobin (adjusted incidence rate ratio [aIRR] 0·66 [95% CI 0·59–0·75], p<0·0001) and lower in G6PD A–/A– homozygous girls than in G6PD A+/A+ girls (0·51 [0·29–0·90], p=0·020), but was higher in HbAC children than in HbAA children (1·15 [1·01–1·32], p=0·039). Parasite density was lower in HbAS children (median 10 550 parasites per μL [IQR 1350–26 250]) than in HbAA children (15 150 parasites per μL [4250–31 050]; p=0·0004). The HbAS-associated reductions in malaria risk and parasite density were greatest in early childhood.The individual and interactive effects of HbAS, HbAC, and G6PD A–/A– genotypes on malaria risk and parasite density define clinical and cellular correlates of protection. Further identification of the molecular mechanisms of these protective effects might uncover new targets for intervention.Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health.