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Jürgen May, MD; Jennifer A. Evans, MD; Christian Timmann, MD; Christa Ehmen; Wibke Busch; Thorsten Thye, MD; Tsiri Agbenyega, MD, PhD; Rolf D. Horstmann, MD

JAMA. 2007;297(20):2220-2226.

Context  The geographical distributions of hemoglobin S (HbS), hemoglobin C (HbC), and ⁺-thalassemia (–) strongly suggest balancing selection with malaria. However, whereas several studies indicate that the HbS carrier state protects against all major forms of clinical malaria, malaria protection on clinical grounds has been more difficult to confirm for HbC and –, and questions remain as to whether it applies to all forms of the disease.

Objective  To assess the association between major clinical forms of severe falciparum malaria and HbS, HbC, and –.

Design, Setting, and Participants  Case-control study of 2591 children with severe falciparum malaria enrolled at a tertiary referral center in Ghana, West Africa, and 2048 age-, sex-, and ethnicity-matched control participants recruited by community surveys.

Main Outcome Measures  Frequencies of HbS, HbC, and – in patients and controls, including stratifications of patients for signs of disease.

Results  Patients presented with partly overlapping signs of disease, including severe anemia (64%), cerebral malaria (22%), respiratory distress (30%), hyperparasitemia (32%), prostration (52%), acidosis (59%), and hyperlactatemia (56%). Carrier states of HbS, HbC, and – were found in 1.4%, 9.4%, and 25.2% of the patients, respectively, and 14.8%, 8.7%, and 27.3% of controls. The HbS carrier state was negatively associated with all forms of the disease studied (overall odds ratio [OR], 0.08; 95% confidence interval [CI], 0.06-0.12). The HbC carrier state showed a negative association selectively with cerebral malaria (OR, 0.64; 95% CI, 0.45-0.91), and the – carrier state showed a negative association selectively with severe anemia (OR, 0.82; 95% CI, 0.69-0.96).

Conclusion  Whereas the HbS carrier state was found to be negatively associated with all major forms of severe falciparum malaria, the negative associations of the carrier states of HbC and – appeared to be limited to cerebral malaria and severe anemia, respectively.

Author Affiliations: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (Drs May, Evans, Timmann, Thye, and Horstmann and Mss Ehmen and Busch); Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana (Dr Evans); Institute of Medical Biometry and Statistics, University of Schleswig-Holstein, Campus Lübeck, Germany (Dr Timmann); School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi (Dr Agbenyega); and Department of Child Health, Komfo Anokye Teaching Hospital, Kumasi (Dr Agbenyega).

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