High Iron Stores in the Low Malaria Season Increase Malaria Risk in the High Transmission Season in a Prospective Cohort of Rural Zambian Children

Abstract

Higher iron stores, defined by serum ferritin (SF) concentration, may increase malaria risk. We evaluated the association between SF assessed during low malaria season and the risk of malaria during high malaria season, controlling for inflammation. Data for this prospective study were collected from children aged 4-8 y ( = 745) participating in a biofortified maize efficacy trial in rural Zambia. All malaria cases were treated at baseline (September 2012). We used baseline SF and malaria status indicated by positive microscopy at endline (March 2013) to define exposure and outcome, respectively. Iron status was defined as deficient (corrected or uncorrected SF <12 or <15 μg/L, depending on age <5 or ≥5 y, respectively), moderate (<75 μg/L, excluding deficient), or high (≥75 μg/L). We used a modified Poisson regression to model the risk of malaria in the high transmission seasons (endline) as a function of iron status assessed in the low malaria seasons (baseline). We observed an age-dependent, positive dose-response association between ferritin in the low malaria season and malaria incidence during the high malaria season in younger children. In children aged <6 y (but not older children), we observed a relative increase in malaria risk in the moderate iron status [incidence rate ratio (IRR) with SF: 1.56; 95% CI: 0.64, 3.86; IRR with inflammation-corrected SF: 1.92; 95% CI: 0.75, 4.93] and high iron status (IRR with SF: 2.66; 95% CI: 1.10, 6.43; or IRR with corrected SF: 2.93; 95% CI: 1.17, 7.33) categories compared with the deficient iron status category. The relative increase in malaria risk for children with high iron status was statistically significant only among those with a concurrently normal serum soluble transferrin receptor concentration (<8.3 mg/L; IRR: 1.97; 95% CI: 1.20, 7.37). Iron adequacy in 4- to 8-y-old children in rural Zambia was associated with increased malaria risk. Our findings underscore the need to integrate iron interventions with malaria control programs. This trial was registered at clinicaltrials.gov as NCT01695148.

Iron Status and Associated Malaria Risk Among African Children

“…Similarly, studies in Malawi (aged 6–60 months with 1 year of follow-up) [12] and Tanzania (birth to 3 years follow-up) [13] reported reduced malaria risk of 45% and 23%, respectively. Recently, a study in Zambian children aged 4–8 years followed for 6 months reported an increased risk of malaria in children with high ferritin concentrations [14]. These estimates are similar to our finding of a 30% reduction in malaria risk in iron-deficient children (0–7 years).…”

“…Study-specific estimates and their relative contribution (percentage weight and sample size) to overall estimates are shown. Definitions of ID varied by study: Nyakeriga et al 2004 [11], ferritin <12 µg/L plus transferrin saturation <10%; Jonker et al 2012 [12], ferritin <30 µg/L; Gwamaka et al 2012 [13], ferritin <30 µg/L if C-reactive protein (CRP) <8.2 mg/L or ferritin <70 µg/L if CRP >8.2 mg/L; Barffour et al 2017 [14], ferritin <12 µg/L in children aged <5 years or <15 µg/L in children aged ≥5 years; and current study, ferritin <12 µg/L or <30 µg/L if CRP >5 mg/L in children aged <5 years or <15 µg/L in children aged ≥5 years. Abbreviations: CI, confidence interval; IRR, incidence rate ratio.…”

Malaria causes long-term effects on markers of iron status in children: a critical assessment of existing clinical and epidemiological tools

“…This finding challenges the interpretation of previous epidemiological studies of iron deficiency in malaria-exposed populations, which have used various approaches to control for inflammation. Some studies have employed an upward adjustment of the cut-off for ferritin in case of raised CRP to levels > 8.2–10 mg/L [7, 8], while others have used arithmetic correction factors based on CRP and AGP levels [10, 28, 29]. In the recent BRINDA study, it is advocated to use internal linear regression to correct ferritin concentrations based on CRP and AGP levels [27].…”

“…Iron deficiency has a negative impact on child development [1–4], but may also be associated with reduced susceptibility to infections because iron is essential for the growth of micro-organisms [5]. In line with this, an increasing number of epidemiological studies suggest that iron deficiency has a protective effect against malaria [6–10]. However, these studies have used conventional inflammation-dependant biomarkers, such as ferritin, as indicators of iron status, although they are known to be modified (usually increased) by malaria [11, 12].…”

Risk of malaria in young children after periconceptional iron supplementation

“…Cohort studies from Benin (Moya‐Alvarez et al, 2017), Malawi (Jonker et al, 2012), Tanzania (Gwamaka et al, 2012), Zambia (Barffour et al, 2017), Kenya and Uganda (Muriuki et al, 2019) have reported that better iron status in young children predicted increased future malaria risk, with iron deficiency significantly decreasing odds of subsequent parasitaemia. A twofold increased risk in young children of malaria parasitaemia and clinical malaria was also seen in mothers experiencing P. falciparum infections during pregnancy (Park et al, 2020), with several studies identifying an association of increased child malaria with placental malaria in their mothers (Agbota, Accrombessi, et al, 2019; Asante et al, 2013; Awine et al, 2016; Bardají et al, 2011; Le Port et al, 2011; Schwarz et al, 2008; Sylvester et al, 2018; Sylvester et al, 2016).…”