Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal <i>Salmonella</i> bacteremia

Abstract Background Severe 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, within the Salmonella -containing vacuole. Methods We first investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged ≤5 years between August 1998 and October 2019 (n=75,015). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malaria anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA alone (n=33); (3) NTS alone (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. Results In hospitalized children SMA, but not other malaria phenotypes, was associated with an increased risk of NTS (adjusted OR 2.88 [95% CI 1.97, 4.23]; P<0.0001). Risk of NTS increased by 30% with each 1g/dl decrease in hemoglobin concentrations. In hospitalized children median hepcidin levels were lower in the SMA+NTS (9.3 ng/mL [interquartile range 4.7, 49.8]) and SMA (31.1 ng/mL [5.5, 61.2]) groups, compared to levels in those with CM (90.7 ng/mL [38.7, 176.1]) or NTS (105.8 ng/mL [17.3, 233.3]), despite similar ferritin and CRP levels. Soluble transferrin receptor levels were lower in the CM group compared to the other hospitalized groups. Conclusion SMA was associated with increased risk of NTS and with reduced hepcidin levels. We hypothesized that reduced hepcidin might allow increased movement of iron into the Salmonella -containing vacuole favoring bacterial growth.