Letter to the editor Can therapeutically-rational exchange (T-REX) of type-O red blood cells (RBCs) benefit Plasmodium falciparum malaria patients?

New therapies are needed to reduce the morbidity and mortality caused by Plasmodium falciparum malaria. Recently, we proposed using therapeutically-rational exchange (T-REX) of red blood cells (RBCs) to treat P. falciparum malaria patients because studies of malaria-resistant and malaria-susceptible RBCs suggest T-REX may be substantially more effective – and prudent – than conventional exchange of nondescript RBCs that could, randomly, promote disease progression [ 1 2 3 4 5 ]. T-REX is a modified RBC exchange transfusion in which the patient’s parasitized RBCs are removed and – by definition – are only replaced with special RBCs known to be malaria-resistant (ex. sickle-cell-trait RBCs). The T-REX options we described previously take advantage of malaria-resistant RBC genetic variants, but the testing of blood units or donors needed to identify these malaria-resistant RBCs is not always routinely performed in blood banks (ex. hemoglobin electrophoresis). So, if a clinician specifically requests adjunctive T-REX of a malaria-resistant RBC variant previously described (ex. hemoglobin E trait RBCs) for a seriously ill P. falciparum malaria patient, T-REX might be delayed while the extra testing is conducted. Thus, here we also urge evaluating T-REX of type-O RBCs which are not only malaria-resistant but are (1) universally compatible, (2) already identified as type O, and (3) highly prevalent in most blood banks worldwide.

As adjunctive therapy for malaria, type-O T-REX seems like a therapeutic opportunity “hiding in plain sight” – a recent review noted that “Studies have definitively shown that individuals with blood type O are less susceptible to severe malaria and non-type O individuals are at increased risk” [ 6 ]. In one study of 567 Malian children with P. falciparum malaria, “group O was associated with a 66% reduction in the odds of developing severe malaria, compared with the non-O blood groups” [ 7 ]. Other studies also describe how type-O RBCs are malaria-resistant [ 8 9 10 11 12 13 14 ]. Protection is likely due to reduced “rosetting” (attachment of parasitized RBCs to healthy RBCs which, in turn, obstructs blood flow) of type-O RBCs compared to non-type-O blood groups [ 7 ].

Regarding its feasibility, T-REX of type-O RBCs is especially attractive because it can be performed immediately anywhere in the world. Consistent with known patterns of human evolution, it seems “biologically plausible” type-O T-REX would promote survival: Malaria-resistant type-O blood is very common in Africa, Asia, and South America where malaria is endemic [ 15 ]. For example, in Southeast Nigeria, the prevalence of type O is 87% [ 15 ]. “In contrast, group A is the predominant blood group in the colder regions of the Earth, where malaria has not been endemic” [ 15 ]. That is, type-O RBCs should be available for T-REX where it is most needed: in those regions (“hot zones”) where P. falciparum malaria is prevalent. Since every RBC unit must be ABO-typed and labelled, type-O units can be used immediately: No additional testing is needed. Fortunately, type-O blood is also “universal donor” blood – meaning T-REX of type-O RBCs can be administered to any P. falciparum malaria patient.

Perhaps most important is simply the prudent avoidance of “worst-case scenarios.” By transfusing only RBCs known to be malaria-resistant (like type-O RBCs), T-REX prevents jeopardizing patients by unknowingly transfusing those (known and unknown) malaria-susceptible RBCs that can promote disease progression. Historically, risk-avoidance has been the key rationale for donor-cell screening (“First, do no harm”) – not optimizing cell selection to optimize therapeutic efficacy (the goal of T-REX). For example, exchange transfusions of variant-specific RBCs were studied in 1981 to determine if these RBC variants harmed patients (with hyperbilirubinemia) and should be avoided [ 16 ]. Regarding malaria, some RBCs are considered malaria-susceptible [ 9, 17 ].

After reviewing laboratory and epidemiologic data, we urge clinicians to evaluate the use of malaria-resistant type-O RBCs (or other malaria-resistant RBCs) for simple or exchange transfusions (manual or automated) as adjunctive therapy for seriously ill P. falciparum malaria patients. Because type-O RBCs are (1) universally compatible, (2) already identified as type O, and (3) highly prevalent in most blood banks worldwide, T-REX of type O RBCs is the most convenient form of malaria T-REX. We feel T-REX of type-O RBCs warrants clinical evaluation because type-O T-REX is not just prudent (by avoiding transfusion of malaria-promoting RBCs) but is potentially life-saving by administering RBCs known to have potent anti-malaria properties that seem to have helped prevent human extinction. By evaluating different variant-specific malaria T-REX options, it may be determined that some malaria-resistant RBC variants are markedly more potent than others or that some are more appropriate for cerebral malaria or for organ failure.