| Malnutrition, Plasmodium falciparum malaria, and multiple helminths converge in coastal East Africa, resulting in a severe, multifactorial anemia that disproportionately afflicts young children. Using observational and experimental approaches, we investigated the pathophysiology of severe anemia [hemoglobin (Hb) ≤ 70 g/L] in young Zanzibari children. First, we applied a hematological model to two community-based samples: (1) 344 children, 6--59 mo with Hb 36--124; and (2) 225 children, 4--43 mo with Hb ≤ 70. This model uses Hb, erythropoietin (EPO), and transferrin receptor to classify anemia into three groups: hyperdestruction (Group 1), marrow hypoproliferation (Group 2), and defective EPO production (Group 3). Second, we investigated the 72-h effects of vitamin A (VA) and sulphadoxine-pyramethamine (SP, an antimalarial) on these indicators. In the first sample, the majority (51%) of children <30 mo were classified into Group 2, while the majority (62%) of children ≥30 mo were classified into Group 3. Increasing malaria parasite density predicted classification into Group 2, although children >30 mo had a higher threshold at which marrow was impaired. In children <30 mo, Trichuris predicted membership in Group 2, and Ascaris predicted membership in Group 3. In the second sample, 84% of children were classified into Group 2. These children had the lowest Hb (p = 0.053) and the highest proportion of malaria (p = 0.028). Although all children in this sample received VA, SP, iron, and B vitamins, for the first 72h they were randomized to either SP or VA (100,000 or 200,000 IU, based on age). In 72h, SP significantly reduced the proportion of children with malaria (mean change: -32.4%, p < 0.001), malaria parasite density (-5029 parasites/mul, p < 0.001), and CRP (-10.6 mg/L, p = 0.001). VA significantly reduced CRP (-9.6 mg/L, p = 0.011), serum ferritin (-18.1 mug/L, p = 0.042), and EPO (-194.7, p = 0.011) and increased reticulocyte production index (+0.40, p = 0.041). In summary, we found that marrow hypoproliferation due to malaria-induced inflammation was the predominant mechanism of anemia in children <30 mo, and especially in severely anemic children. In 72h, SP and VA rapidly reduced inflammation in severely anemic children. VA additionally mobilized iron from stores and decreased EPO secretion. |
