Sources and pathways by which low-grade inflammation contributes to anaemia in rural African children from 6 months to 3 years of age: study protocol for observational studies IDeA 1 and IDeA 2

Background: Recent work suggests that persistent inflammation, even at low levels, could be more important than low dietary iron intake in the aetiology of iron deficiency and iron deficiency anaemia (IDA) in young children living in poor environments. Methods: We will conduct 2 parallel observational studies in well and unwell rural Gambian children to identify the origins of chronic low-grade inflammation and characterise its relationship to iron handling and iron deficiency anaemia. IDeA Study 1 will enrol 120 well children attending our regular paediatric well-child clinics at 6, 12 and 18 months of age. IDeA Study 2 will enrol 200 sick children suffering from upper-respiratory tract infection, lower respiratory tract infection, gastroenteritis or urinary tract infection and study them on Days 0, 3, 7 and 14 after initial presentation. At each visit, children will be assessed for signs of inflammation. Full blood count and iron-related biomarkers (serum ferritin, serum iron, unsaturated iron-binding capacity, soluble transferrin receptor, transferrin) will be measured before and after an oral dose of ferrous iron to assess status and acute iron absorption. Inflammatory markers (C-reactive protein and α1-acid glycoprotein), hepcidin, erythroferrone and erythropoietin will be measured to characterize the anaemia of inflammation in these children. Conclusion: We will assess the impact of acute and chronic low-grade inflammation on iron absorption and investigate the hypothesis that chronic inflammation, juxtaposed on a poor diet, causes a complex anaemia of inflammation which exacerbates iron deficiency by blocking both non-haem iron absorption and iron utilization by the bone marrow. KEYWORDS: Anaemia, anaemia of inflammation, low-grade inflammation, iron, The Gambia, children, hepcidin, erythroferrone, erythropoietin, C-reactive protein Clinical trial registry: ClinicalTrials.gov NCT04097639 and NCT04095884 Author approval: All authors have read and approved this manuscript.