Dataset Information

Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study.

ABSTRACT: BACKGROUND:Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. METHODS:Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A-(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes. RESULTS:In children, HbAS was associated, compared to wild type, with a lower incidence of malaria (IRR = 0.78, 95% CI 0.66-0.92, p = 0.003), lower parasite density upon infection (PR = 0.66, 95% CI 0.51-0.85, p = 0.001), and lower body temperature for any given parasite density (- 0.13 ℃, 95% CI - 0.21, - 0.05, p = 0.002). In children, HbSS was associated with a lower incidence of malaria (IRR = 0.17, 95% CI 0.04-0.71, p = 0.02) and lower parasite density upon infection (PR = 0.31, 95% CI 0.18-0.54, p < 0.001). α-/αα thalassaemia, was associated with higher parasite prevalence in both children and adults (RR = 1.23, 95% CI 1.06-1.43, p = 0.008 and RR = 1.52, 95% CI 1.04-2.23, p = 0.03, respectively). G6PD deficiency was associated with lower body temperature for any given parasite density only among male hemizygote children (- 0.19 ℃, 95% CI - 0.31, - 0.06, p = 0.003). CONCLUSION:RBC variants were associated with non-severe malaria outcomes. Elucidation of the mechanisms by which they confer protection will improve understanding of genetic protection against malaria.

SUBMITTER: Kakande E

PROVIDER: S-EPMC6964006 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study.

Kakande Elijah E Greenhouse Bryan B Bajunirwe Francis F Drakeley Chris C Nankabirwa Joaniter I JI Walakira Andrew A Nsobya Samuel L SL Katureebe Agaba A Rek John J Arinaitwe Emmanuel E Rosenthal Philip J PJ Kamya Moses R MR Dorsey Grant G Rodriguez-Barraquer Isabel I

Malaria journal 20200115 1

<h4>Background</h4>Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear.<h4>Methods</h4>Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A ...[more]

PMID: 31941490

Similar Datasets

Project description:BackgroundRed 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.MethodsThe 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.FindingsBetween 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.InterpretationThe 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.FundingIntramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Project description:BackgroundMalaria is a significant public health challenge in Uganda, with Plasmodium falciparum (P. falciparum) responsible for most of malaria infections. The high genetic diversity and multiplicity of infection (MOI) associated with P. falciparum complicate treatment and prevention efforts. This study investigated temporal changes in P. falciparum genetic diversity and MOI across three sites with varying malaria transmission intensities. Understanding these changes is essential for informing effective malaria control strategies for the different malaria transmission settings.MethodsA total of 220 P. falciparum-positive dried blood spot (DBS) filter paper samples from participants in a study conducted during 2011-2012 and 2015-2016 were analyzed. Genotyping utilized seven polymorphic markers: Poly-α, TA1, TA109, PfPK2, 2490, C2M34-313, and C3M69-383. Genetic diversity metrics, including the number of alleles and expected heterozygosity, were calculated using GENALEX and ARLEQUIN software. MOI was assessed by counting distinct genotypes. Multi-locus linkage disequilibrium (LD) and genetic differentiation were evaluated using the standardized index of association (IAS) and Wright's fixation index (FST), respectively. Statistical comparisons were made using the Kruskal-Wallis test, and temporal trends were analyzed using the Jonckheere-Terpstra test, with statistical significance set at p < 0.05.ResultsOf the 220 samples, 180 were successfully amplified. The majority of participants were males (50.6%) and children aged 5-11 years (46.7%). Genetic diversity remained high, with mean expected heterozygosity (He) showing a slight decrease over time (range: 0.73-0.82). Polyclonal infections exceeded 50% at all sites, and mean MOI ranged from 1.7 to 2.2, with a significant reduction in Tororo (from 2.2 to 2.0, p = 0.03). Linkage disequilibrium showed a slight increase, with Kanungu exhibiting the lowest IAS in 2011-2012 (0.0085) and Jinja the highest (0.0239) in 2015-2016. Overall genetic differentiation remained low, with slight increases in pairwise FST values over time, notably between Jinja and Tororo (from 0.0145 to 0.0353).ConclusionsThis study highlights the genetic diversity and MOI of P. falciparum in Uganda's malaria transmission settings, noting a slight decrease in both genetic diversity and MOI overtime. Continued surveillance and targeted control strategies are essential for monitoring the impact of malaria control efforts in Uganda.

Project description:Asymptomatic malaria infections may affect red blood cell (RBC) homeostasis. Reports indicate a role for chronic hemolysis and splenomegaly, however, the underlying processes are incompletely understood. New hematology analysers provide parameters for a more comprehensive analysis of RBC hemostasis. Complete blood counts were analysed in subjects from all age groups (n = 1118) living in a malaria hyperendemic area and cytokines and iron biomarkers were also measured. Subjects were divided into age groups (<2 years, 2-4, 5-14 and ≥15 years old) and clinical categories (smear-negative healthy subjects, asymptomatic malaria and clinical malaria). We found that hemoglobin levels were similar in smear-negative healthy children and asymptomatic malaria children but significantly lower in clinical malaria with a maximum difference of 2.2 g/dl in children <2 years decreasing to 0.1 g/dl in those aged ≥15 years. Delta-He, presenting different hemoglobinization of reticulocytes and RBC, levels were lower in asymptomatic and clinial malaria, indicating a recent effect of malaria on erythropoiesis. Reticulocyte counts and reticulocyte production index (RPI), indicating the erythropoietic capacity of the bone marrow, were higher in young children with malaria compared to smear-negative subjects. A negative correlation between reticulocyte counts and Hb levels was found in asymptomatic malaria (ρ = -0.32, p<0.001) unlike in clinical malaria (ρ = -0.008, p = 0.92). Free-Hb levels, indicating hemolysis, were only higher in clinical malaria. Phagocytozing monocytes, indicating erythophagocytosis, were highest in clinical malaria, followed by asymptomatic malaria and smear-negative subjects. Circulating cytokines and iron biomarkers (hepcidin, ferritin) showed similar patterns. Pro/anti-inflammatory (IL-6/IL-10) ratio was higher in clinical than asymptomatic malaria. Cytokine production capacity of ex-vivo whole blood stimulation with LPS was lower in children with asymptomatic malaria compared to smear-negative healthy children. Bone marrow response can compensate the increased red blood cell loss in asymptomatic malaria, unlike in clinical malaria, possibly because of limited level and length of inflammation. Trial registration: Prospective diagnostic study: ClinicalTrials.gov identifier: NCT02669823. Explorative cross-sectional field study: ClinicalTrials.gov identifier: NCT03176719.

Project description:Pediatric severe malaria is a significant contributor of morbidity and mortality in Uganda. Most information is derived from tertiary referral centers and urban centers. Little is known about routine care or post-discharge outcomes in rural areas. We conducted a longitudinal cohort study of pediatric severe malaria at St. Paul's Level IV Health Center (SPHC) in Kasese, Uganda. We collected demographic, clinical, and laboratory results, and conducted follow-up 14 days post-discharge to assess patient outcomes in the immediate post-discharge period. The initial cohort included 187 children aged 0 to 17 years enrolled between July 9th, 2023 and January 9th, 2024. Almost all (94.7%) participants had a parasitological confirmed malaria diagnosis by rapid diagnostic tests or blood smear. While at SPHC, 95.7% of patients received 3+ doses of intravenous Artesunate, and 92.0% also received oral antimalarials. 62.0% had at least one symptom of severe malaria, with altered consciousness (40.6%) and convulsions (29.9%) the most frequently reported. 26.1% had evidence of severe malarial anemia (Hb <5 g/dl), of whom 93.5% received a blood transfusion. Most (82.2%) patients received care that we assessed as consistent with key elements of WHO management guidelines. We were able to contact 183 of the 187 patient caregivers post-discharge. Caregivers reported that 25.6% of patients were experiencing symptoms related to their hospitalization, with fever (18.5%) and nausea/ not feeding well (10.3%) reported most frequently. Children who experienced altered consciousness during their acute illness had 1.69 times the adjusted risk of reporting symptoms 14-days post-discharge compared to those who did not have altered consciousness (aRR: 1.69, 95% CI: 1.01-2.82). Six deaths were recorded, including three at SPHC and three post-transfer or discharge. Findings suggest that at private health facilities in rural areas, treatment appears to be consistent with guidelines. Future research should investigate high morbidity in the immediate post-discharge period.

Dataset Information

Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study.

Publications

Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets