ABO In Morbidity and Mortality of Plasmodium Falciparum malaria

Plasmodium falciparum malaria has been called the greatest force in human evolution as a result of its disproportionate lethality among children and its longstanding presence in human history. Malaria's complex pathogenesis is based in part on cytoadhesion, which is mediated by a parasite-derived surface protein (PfEMP1) expressed on infected erythrocytes. PfEMP1 binds with ligands on red cells, platelets, and endothelium, and through the lectin-like DBL1α domain, binds preferentially to blood Group A. This contributes to the obstruction of microvascular perfusion and to cerebral malaria, lactic acidosis, and death. Initial studies demonstrated increased cytoadhesion to Group A RBC in vitro, suggesting that Group A hosts may be at risk of greater morbidity with P falciparum. Subsequently, retrospective clinical studies demonstrated a higher proportion of Group A individuals among those with severe disease. Recently, attention has focused on malaria pathogenesis and von Willebrand factor, which is elevated in Group A individuals. While the cumulative evidence suggests a central role for ABO in malaria, proof for a driving effect on the evolutionary distribution of ABO blood groups has awaited definitive study of the relationship between ABO and P falciparum malaria mortality. We report here initial findings from the Cytoadherence in Pediatric Malaria (CPM) Study (clinicaltrials.gov, NCT 00707200) which was designed to examine associations between malaria outcomes and host blood groups implicated in erythrocyte cytoadhesion.

We performed a 2 year prospective observational study of children with acute malaria (age 6 mo – 12 yr) presenting for care at Mulago Hospital, Uganda. HIV positive patients were excluded from analysis. We enrolled children who met pre-study WHO criteria for either Uncomplicated Malaria (UM) or Severe Malaria (SM). Patients were followed from the time of presentation to discharge or death. ABO blood groups were determined by standard hemagglutination. The study was approved by the Uganda National Council on Science and Technology and all participating institutions.

At the study's conclusion (October 2009), 2092 children were enrolled. Children with HIV (n=45), those whose blood smears lacked species-confirmed P falciparum parasitemia on review by an external, blinded reference parasitology laboratory (n=35), and one child outside of the pre-defined study age range were excluded, leaving 2011 for analysis. Of these, 1078 had UM and 855 had SM, with 48 of the SM (5.6%) being fatal cases. Among those with SM, 850 had either cerebral malaria (CM, n=174), severe malaria anemia (SMA, hemoglobin < 5g/dL, n=558), or lactic acidosis (LA, lactate >5mM, n=482) in an overlapping distribution.

The proportion of individuals with Group A or AB increased with categories of increasing disease severity (UM = 28%, SM = 37.1%; fatal = 47.9%). Group O correspondingly decreased (UM = 49.9%, SM = 40.6%, fatal = 37.5%). There was a highly statistically significant difference in the distribution of A, B, AB and O between UM and SM, χ2 =29.57, p=0.000002. Importantly, we observed a significant difference between UM and fatal cases for the distribution of all four ABO groups (χ2 = 4.624, p=0.0315) which was especially significant for Group A or AB versus O (χ2 = 5.946, p=0.0147). A significant difference in ABO distribution was also observed for specific severe malaria syndromes, with Group O enriched for UM and Group A or AB enriched among those with CM (χ2= 12.18, p=0.006791) and SMA (χ2 = 34.24, p<10⁻⁵).

This is the largest prospective study on the relationship between ABO blood groups and P falciparum malaria and the first report sufficiently powered to demonstrate the effect of ABO on survival in P falciparum malaria. We report a statistically significant and clinically important advantage among group O hosts and a corresponding disadvantage for group A or AB hosts. Our results confirm clinically the findings of in vitro studies on ABO and cytoadhesion as well as prior retrospective studies on ABO and disease severity. Because our study was conducted in children, the results have direct bearing on the effect of malaria on genetic selection. The results have implications for the pathogenesis of P falciparum malaria, for new treatment strategies aimed at interrupting cytoadhesion, and for our understanding of the worldwide distribution of ABO blood groups.

No relevant conflicts of interest to declare.