Juliana Anyanwu, MD MPH
Nominated From: University of Minnesota
Research Site: Uganda
Research Area: Hematology
Primary Mentor: Chandy John
Does Hydroxyurea Protect from Clinical Malaria Episodes in Children with Sickle Cell Disease through an Increase in Hemoglobin F Levels?
Malaria and its impact on the morbidity and mortality of patients with sickle cell anemia is well studied. Heterozygous sickle cell disease (SCD) is protective against clinical malaria and homozygous SCD increases susceptibility to malaria.
Hydroxyurea, an inhibitor of ribonucleotide reductase and a potent inducer of HbF production, has shown many clinical benefits in patients with SCD. Results of clinical trials have shown reduced frequency of hospitalizations, blood transfusions, pain episodes, acute chest syndromes (ACS). There is well established literature on the benefits of hydroxyurea in SCD, however there are no documented clinical studies on the consequences/outcomes of using this drug in malaria endemic regions. There are concerns of using hydroxyurea in malarious environments as some studies have shown upregulation of intracelluar adhesion molecule 1 (ICAM-1) in endothelial cells, which in turn could lead to increased sequestration and adverse malaria events. However, literature has been conflicting on the relationship between ICAM-1 levels and hydroxyurea.
Given the lack of documented clinical studies on the effects of hydroxyurea in malaria endemic regions, a prospective, randomized phase III double-blinded placebo-controlled trial, (NOHARM study) has been developed, using oral hydroxyurea for pediatric patients with sickle cell anemia in this region. It will become the first prospective study to examine hydroxyurea’s use in SCD in a malaria endemic region, and the results can be extrapolated to other Sub-Saharan African countries . As a subset of the NOHARM study, I aim to establish a clearer understanding of the relationship between HbF levels and the risk of malaria.
85% of malaria cases and 90% of malaria deaths occur in the continent of Africa. Malaria deaths disproportionately affect children under five years of age, making up 77% of deaths in this age group. Plasmodium falciparum infection is considered to contribute significantly to this morbidity and mortality. The ability of P.falciparum to sequester in microvascular capillaries of organs (i.e. the brain) is a contributing factor, and is mediated by the binding of P.falciparum erythrocyte membrane protein 1 (PfEMP-1, the parasite’s cytoadherence antigen) to varying host receptors such as CD36, ICAM-1, VCAM-1. Sequestration contributes to endothelial dysfunction and microvascular inflammation. It is these cytoadherence interactions that are said to highly contribute to the development of malaria symptoms and development of high parasite densities. In newborns and infants under six months of age, there is a very low incidence of severe disease and low parasitemias. Passive maternal immunity, nutrition (breast milk does not contain p-aminobenzoic acid, a nutrient known to increase parasite growth) and elevated levels of fetal hemoglobin (HbF) are some explanations provided for infant resistance to malaria, with more than one factor potentially being involved.
After six months of age, susceptibility to severe malarial infection increases in endemic areas. It has been proposed that HbF confers malaria protection by imparing cytoadherence of P.falciparum infected red blood cells to microvascular endothelial cells (MVECs). Hb variants- HbS and HbC, are also found to be protective against severe P.falciparum infection, and studies have shown they display compromised adherence of PfRBC to MVECs in addition to disrupting rosetting. Further research is warranted in regards to assessing how HbF levels correlate to the risk of malaria.
Dr. Anyanwu in the News
The Fogarty International Center at the NIH which funds the Global Health Fellows published an interview with Juliana, a trainee in Uganda. Learn more about her research on sickle cell anemia.