Can Exchange Transfusions Using Red Blood Cells from Donors with Hemoglobin E Trait Prevent or Ameliorate Severe Malaria in Patients with Multi-drug Resistant Plasmodium falciparum?

Dear Editor,

Malaria continues to be a devastating parasitic disease. In 2015, an estimated 212 million new infections caused 429,000 deaths across the world—about 70% of these deaths were children less than 5-years-old [1]. The Plasmodium falciparum parasite was responsible for 99% of all deaths [1]. Unfortunately, in 2017, multi-drug resistant strains of P. falciparum are spreading throughout the Greater Mekong subregion. Because of multi-drug resistance, new therapeutic options are needed. We recently proposed that a selective or “therapeutically-rational red blood cell exchange” (T-REX) strategy using Southeast Asian ovalocytosis (SAO) RBCs may reduce the morbidity and mortality of patients infected with multi-drug resistant P. falciparum malaria [2]. Here we propose an alternative strategy using RBCs with hemoglobin E trait (HbAE), which may be feasible in regions where SAO is not prevalent.

Hemoglobin E (HbE) is a hemoglobin variant caused by a point mutation in codon 26 of the β-globin gene which substitutes lysine for glutamic acid. HbAE is most common in Southeast Asia, especially northeast and eastern India and eastern Thailand [3] where more than 50% of some populations have HbAE [4]. In addition, HbAE is also prevalent in Myanmar, Indonesia, and Malaysia [3]. Fortunately, HbAE protects against severe P. falciparum malaria [5] and explains why this variant is common in malaria-endemic regions. HbAE is characterized by microcytosis without anemia and has no clinical significance for carriers. HbAE can be screened-for/diagnosed using high-pressure liquid chromatography (HPLC), acid/alkaline hemoglobin electrophoresis, isoelectric focusing, or DNA-based tests.

Instead of using routine, “standard-issue” RBC units for exchange transfusion to ameliorate severe malaria (by removing infected, cytoadherent RBCs and replacing them with “standard-issue” RBCs), we suggest evaluating the efficacy of selective HbAE-RBC T-REX. In hospitals without an automated RBC-exchange machine, manual RBC exchange can be performed. Fortunately, HbAE RBCs are already commonly and safely used to treat blood loss. Because clinical studies have shown that HbAE-RBCs are protective against severe P. falciparum malaria, HbAE-RBC T-REX could prove to be life-saving. Fortunately, HbAE-RBC T-REX is feasible because (1) individuals with HbAE are generally asymptomatic, not anemic, and qualify as blood donors, (2) up to 50% of individuals in regions of India and Thailand have HbAE, and (3) blood banks can identify units as HbAE by testing the donors or a blood-tubing segment for low mean corpuscular hemoglobin (MCV), followed by confirmatory testing. Of course, severely anemic patients could receive HbAE-RBC blood transfusions before undergoing HbAE-RBC T-REX.

Because more than 400,000 P. falciparum malaria patients still die each year due to delayed drug administration or multi-drug resistance, non-drug cell therapies warrant serious consideration. Fortunately, compelling clinical data and modern public health infrastructures mean that selective HbAE-RBC T-REX can—and should—be evaluated for the prevention or amelioration of severe malaria in high-risk patients in regions where HbAE donor blood is available.

Compliance with ethical standards

Conflict of interest

Ryan Jajosky is the CEO and part-owner of Biconcavity Inc. Philip Jajosky is CFO and part-owner of Biconcavity Inc, a biotechnology research and development company exploring drug-linked-erythrocytes. This company does not have any interest in Hemoglobin E or malaria.