Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases

Abstract

Background: The gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait [HbAS]) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete.

Methods: We studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya.

Results: The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes.

Conclusions: The present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases.

Figure 1

Geometric mean parasite densities, by clinical status and hemoglobin genotype (bars show 95% confidence intervals). The data on symptomless parasitemia derive from 4 cross-sectional surveys conducted in children participating in the mild-disease cohort study (n = 13 children with sickle cell trait [HbAS]; n = 95 children with HbAA). The data on mild clinical malaria derive from episodes of malaria detected during the same study (with mild clinical malaria defined as fever [axillary temperature of >37.50 °C] in association with a slide positive for blood-stage asexual Plasmodium falciparum at any density [definition 2 as given in Participants, Materials, and Methods]); the data on HbAA reflect 872 episodes of malaria in 283 children, and the data on HbAS reflect 79 episodes of malaria in 40 children. The data on hospital admissions derive from participants in the birth cohort study who were admitted to the hospital with a primary diagnosis of malaria. The data on HbAA reflect 538 episodes of malaria in 424 children, and the data on HbAS reflect 25 episodes of malaria in 23 children. Comparisons were made by linear regression, with adjustment for the effects of age, season, and clustering of events within individual study children. In addition, the data on hospital admission were adjusted for bed-net usage (by randomization arm), proximity to the nearest health center, and access to the hospital by bus. *P = .009; **P < .0001.