Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia.

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged <5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a 2-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10; interquartile range [IQR]: 0.03-0.19) than those with CM (0.24; IQR: 0.14-0.69; P=0.006) or asymptomatic malaria (0.19; IQR: 0.09-0.46; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL; IQR: 4.7-49.8) and hepcidin/ferritin ratios (0.03; IQR: 0.01-0.22) than those with NTS alone (105.8 ng/mL; IQR: 17.3-233.3; P=0.02 and 0.31; IQR: 0.06-0.66; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole, we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

Malaria and Age Variably but Critically Control Hepcidin Throughout Childhood in Kenya.

Both iron deficiency (ID) and malaria are common among African children. Studies show that the iron-regulatory hormone hepcidin is induced by malaria, but few studies have investigated this relationship longitudinally. We measured hepcidin concentrations, markers of iron status, and antibodies to malaria antigens during two cross-sectional surveys within a cohort of 324 Kenyan children ≤ 8 years old who were under intensive surveillance for malaria and other febrile illnesses. Hepcidin concentrations were the highest in the youngest, and female infants, declined rapidly in infancy and more gradually thereafter. Asymptomatic malaria and malaria antibody titres were positively associated with hepcidin concentrations. Recent episodes of febrile malaria were associated with high hepcidin concentrations that fell over time. Hepcidin concentrations were not associated with the subsequent risk of either malaria or other febrile illnesses. Given that iron absorption is impaired by hepcidin, our data suggest that asymptomatic and febrile malaria contribute to the high burden of ID seen in African children. Further, the effectiveness of iron supplementation may be sub-optimal in the presence of asymptomatic malaria. Thus, strategies to prevent and eliminate malaria may have the added benefit of addressing an important cause of ID for African children.

Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children.

Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and α(+)thalassemia. Hb S heterozygotes and α(+)thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta-analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and α(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous α(+)thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but α(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of α(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies.

The haptoglobin 2-2 genotype is associated with a reduced incidence of Plasmodium falciparum malaria in children on the coast of Kenya.

BACKGROUND: Haptoglobin (Hp) genotype determines the efficiency of hemoglobin clearance after malaria-induced hemolysis and alters antioxidant and immune functions. The Hp2 allele is thought to have spread under strong selection pressure, but it is unclear whether this is due to protection from malaria or other diseases. METHODS: We monitored the incidence of febrile malaria and other childhood illnesses with regard to Hp genotype in a prospective cohort of 312 Kenyan children during 558.3 child-years of follow-up. We also conducted 7 cross-sectional surveys to determine the prevalence of Plasmodium falciparum parasitemia. RESULTS: The Hp2/2 genotype was associated with a 30% reduction in clinical malarial episodes (adjusted incidence rate ratio, 0.67; P=.008 for Hp2/2 vs. Hp1/1 and Hp2/1 combined). Protection increased with age; there was no protection in the first 2 years of life, 30% protection at > or = 2 years of age, and 50% protection from 4-10 years of age. Children with the Hp1/1 genotype had a significantly lower rate of nonmalarial fever (P=.001). CONCLUSIONS: Balancing selection pressures may have influenced the spread of the Hp gene. Our observations suggest that the Hp2 allele may have spread as a result of protection from malaria, and the Hp1 allele may be sustained by protection from other infections.

The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya.

BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.