Discussion
anaemia, malaria, inflammation, infections, infection, atrophy, iron-deficiency anaemia
ANAEMIA, ADVERSE EVENTS, INFLAMMATION, MALARIA, INFECTIONS, INFECTION, IRON DEFICIENCY, IRON-DEFICIENCY ANAEMIA, ATROPHY, HAEMOGLOBINOPATHIES
Improved diets with better access to iron-rich foods, as well as environmental improvements aimed at reducing infections and inflammation in early childhood, remain the cornerstone of strategies to reduce the high prevalence of anaemia in many low-income settings. In regions where anaemia prevalence still exceeds 40%, WHO recommends provision of daily multiple micronutrient sachets containing 10·0–12·5 mg elemental iron with a target of at least 90 doses per 6 months in children aged 6–23 months and 2–12 years; however, there are concerns that iron supplementation could increase the risk of infection.Despite the fact that its efficacy is often low and that side-effects are common, iron is probably the most commonly used preventive and therapeutic agent worldwide. In low-income settings, health systems are forced to use low-cost iron salts. In children, these salts are generally poorly absorbed due to both villous atrophy (because the iron-absorbing divalent metal transporter is active at the tip of the villusIn the current study, we reasoned that we could achieve a similar efficacy at a lower daily dose of iron (hence reducing spillover to the large gut) using two hepcidin-guided screen-and-treat regimens to target periods when iron absorption would be most efficient. We used a previously derived hepcidin threshold to identify periods when children would be ready and safe to receive iron.We set a non-inferiority margin of –5 g/L as the clinically acceptable amount by which a lower efficacy would be tolerated if the regimen had counterbalancing advantages of fewer side-effects and a better safety profile. By use of the primary endpoint of haemoglobin value at day 84, the screen-and-treat regimens failed the formal non-inferiority test and were demonstrably worse than the WHO recommendation of daily iron supplementation. The screen-and-treat regimens were also less effective than daily supplementation at resolving anaemia, iron deficiency, and iron-deficiency anaemia. Several key measures of iron status (sTfR, transferrin, plasma iron, unsaturated iron-binding capacity, and transferrin saturation) were also indicative of significantly lower iron status in the two screen-and-treat groups than in the control group. Our analogous trial in pregnant women with anaemia passed the non-inferiority test, but also showed no advantages over the standard WHO recommendation of universal daily iron.Despite the daily supplements being administered by fieldworkers and a high compliance rate of 95%, the WHO standard of care still showed modest efficacy with an increase in haemoglobin of 7·7 g/L (from 97·0 g/L to 104·0 g/L) and a reduction in anaemia of 14 percentage points (from 91% to 77%) over 12 weeks. This finding is likely to be due to the relatively short intervention period of 12 weeks and the probable wide range of causes of anaemia (including haemoglobinopathies), which are only partly directly attributable to iron deficiency. Of note, there was a greater reduction in iron deficiency in the standard of care group and the haemoglobin response probably showed a lag. We estimate that only 1·6% of the total iron administered in the control group was accrued as haemoglobin. These results are typical of similar trials elsewhere in low-income and middle-income countries.We calculated that only 1·6% of the total 984 mg iron administered to children in the control group was accrued in haemoglobin. In a substudy of 15 children aged 17 months from the control group of the current study, we used a novel Our results indicate that the 6 mg screen-and-treat regimen would not be acceptable under any circumstances. The poorer performance of the 12 mg screen-and-treat regimen might be acceptable if it had a superior profile of side-effects and safety than the WHO standard of care, which would permit long-term supplementation and a gradual resolution of anaemia. However, this situation was not the case; there was no evidence of differences in childhood illnesses reported by the caregiver, adverse or serious adverse events, or in the proxy safety assays of malaria parasite growth in erythrocytes nor in sentinel bacteria growth in plasma between the screen-and-treat regimens and the WHO recommended regimen.This study has several strengths. First, the trial was conducted in children with anaemia living in the kind of rural, low-income environment representative of many areas where innovative approaches to anaemia prevention and treatment are needed. Second, the study adhered to strict clinical trial standards, the supplements were administered directly, and adherence to supplementation was high. Third, there was a large number of reported illnesses and adverse events, allowing for the detection of group differences if they existed. Fourth, the hepcidin-directed screening protocol achieved the desired reduction in iron dosing (halved in the 12 mg screen-and-treat group and halved again in the 6 mg screen-and-treat group). Finally, the study used innovative ex-vivo safety assays developed and validated in our laboratory.The study was arguably weakened by being conducted in an area of very low malaria prevalence, which precluded testing of altered susceptibility to clinical malaria. Additionally, the weak association between the amount of iron administered and the haematological response could be viewed as a limitation to the study, but is a consequence of the small amount of iron accrued.There are several reasons that could explain why the notion of targeting iron administration to children who were most likely to absorb more iron, and least likely to be adversely affected, did not work in practice. One explanation might be that the weekly measures of hepcidin concentration were not frequent enough to capture the daily (or even within-day) dynamics of enterocyte iron flux mediated by hepcidin. Nevertheless, studies of diurnal and between-day hepcidin responses to iron administration do not support this explanation.In conclusion, despite the conceptual elegance of a hepcidin-guided screen-and-treat approach, this approach is inferior to WHO's recommendation of universal iron distribution in practice. Of note, even in this context of high adherence to the regimen, the current WHO protocol still only had relatively low efficacy. The search for more effective strategies to combat anaemia in children across low-income settings with high exposure to pathogens must continue, and will probably require a combination of iron compounds with better absorption and fewer side-effects, together with parallel measures to reduce environmental contamination, infection, and persistent low-grade inflammation.