By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: For young children in Africa who return home after hospitalization for severe anemia, monthly long-acting malaria prophylaxis can reduce the rates of readmission and death during the three months following hospitalization.

SOURCE: Kwambai TK, Dhabangi A, Idro R, et al. Malaria chemoprevention in the postdischarge management of severe anemia. N Engl J Med 2020;383:2242-2254.

Realizing that part of the morbidity and mortality associated with severe anemia occurs during the months following initial inpatient care, Kwambai and colleagues in Kenya and Uganda studied the effect of post-discharge monthly courses of dihydroartemisinin–piperaquine on hospital readmission rates and death rates during the six months after the initial admission.

Preschool-age children hospitalized for severe anemia (hemoglobin less than 5 gm/dL) without concurrent sickle cell disease or cancer were randomized to receive either placebo or dihydroartemisinin-piperaquine as a three-day treatment course two, six, and 10 weeks after the initial admission. (Each course of this treatment is known to provide four weeks of malaria prevention.) This was a double-blind, placebo-controlled trial. Iron supplements (2 mg/kg/day) also were given for the first four weeks. Bed net use was advised. Outcomes were followed for six months.

From May 2016 through May 2018, 1,049 children were included in the study. The anemia was thought to be caused by malaria in more than three-fourths of the study participants. Overall, 97% were compliant with the study treatment, and 7% of participants were lost to follow-up. There were no serious adverse events attributed to the intervention, but asymptomatic prolongation of the QT interval was noted in the medication-treated children.

Thirty percent of children were readmitted and/or died during the six months of follow-up: 26% of the chemoprophylaxis group and 34% of the placebo group. There were 31 deaths in the placebo group and 12 in the treatment group. The rate of readmission or death was 35% lower in the chemoprophylaxis group (P < 0.001) than in the placebo group. The difference in both readmissions and deaths was significant during the first three months but not during the second half of the six-month follow-up period.

The authors stated that it is not known if ongoing treatment beyond 10 weeks would have extended the benefit. Similarly, they do not know if further iron supplementation or more aggressive mosquito avoidance measures might have further reduced the risks of subsequent readmission and death.

COMMENTARY

Malaria still is a major killer, with more than 400,000 deaths globally per year.1 Children in sub-Saharan Africa are disproportionately affected.1 During the years I worked in a rural medical center in incompletely resourced central Africa, we frequently saw preschool-age children with severe anemia. Most days, at least one child would present with high fever, fatigue, tachycardia, tachypnea, and pallor. Hemoglobin levels were in the range of 3 gm/dL to 5 gm/dL. Malaria smears were strongly positive. We would treat the malaria and provide careful blood transfusions. For the short-term, the children did well. Unfortunately, though, some of these children returned with subsequent similar bouts of malaria with severe anemia.

Interestingly, these children were rarely jaundiced. Although the malaria-induced hemolysis was enough to tip the children into enough anemia to cause mild heart failure, there was not enough hemolysis to cause jaundice. We surveyed healthy children in the community and found that the mean hemoglobin level was about 8 gm/dL and that iron deficiency was common. It seemed that many seemingly asymptomatic children had chronic iron deficiency anemia and then got malaria with high fever and enough hemolysis to push them into cardiovascular decompensation. To prevent future episodes of severe decompensation and to treat the underlying nutritional deficiency, we gave iron supplements. Again, this seemed to work well — until malaria recurred.

Of course, there is an interaction between Plasmodium parasites and iron in children. Iron supplements seem to help foster parasite multiplication before they restore iron sufficiency.2 Thus, it is important to make sure that children in malaria-endemic areas who receive iron also are using bed nets and trying to avoid mosquito bites. And, as with severe acute malnutrition, new iron supplementation can be delayed until infections are managed and initial nutritional rehabilitation is established.3

Now, though, Kwambai and colleagues extend our two-pronged battle against both malaria and anemia a step further. They clearly showed that adding antimalarial chemoprophylaxis to the post-transfusion regimen in children with severe malarial anemia is effective in reducing hospitalizations and death during the subsequent three months.

For those working in or advising about the care of children in sub-Saharan Africa, attention must be given to managing both malaria and anemia. Children hospitalized with severe anemia should receive the benefit not only of iron supplementation but also of prophylactic malaria medication. Malaria chemoprophylaxis after acute malaria treatment and blood transfusion reduces the risks of death and readmission.

REFERENCES

  1. World Health Organization. Malaria. https://www.who.int/news-room/fact-sheets/detail/malaria
  2. Moya-Alvarez V, Bodeau-Livinec F, Cot M. Iron and malaria: A dangerous liaison? Nutr Rev 2016;74:612-623.
  3. Ashworth A, Khanum S, Jackson A, Schofield C. Guidelines for the inpatient treatment of severely malnourished children. World Health Organization 2013: 16. https://www.who.int/nutrition/publications/guide_inpatient_text.pdf