Hemoglobin variants and disease manifestations in severe falciparum malaria.
BACKGROUND
The geographical distributions of hemoglobin S (HbS), hemoglobin C (HbC), and alpha+-thalassemia (-alpha) 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 -alpha, 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 -alpha.


METHODS
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.


METHODS
Frequencies of HbS, HbC, and -alpha 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 -alpha 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 -alpha carrier state showed a negative association selectively with severe anemia (OR, 0.82; 95% CI, 0.69-0.96).


CONCLUSIONS
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 -alpha appeared to be limited to cerebral malaria and severe anemia, respectively.
May
Jürgen
J
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Evans
Jennifer A
JA
Timmann
Christian
C
Ehmen
Christa
C
Busch
Wibke
W
Thye
Thorsten
T
Agbenyega
Tsiri
T
Horstmann
Rolf D
RD
D000740:Anemia / Q000097:blood / Q000209:etiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005869:Ghana; D005914:Globins / Q000032:analysis; D006444:Hemoglobin C / Q000032:analysis; D006447:Hemoglobin H / Q000032:analysis; D006451:Hemoglobin, Sickle / Q000032:analysis; D006455:Hemoglobins, Abnormal / Q000032:analysis*; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000097:blood; D016778:Malaria, Falciparum / Q000097:blood* / Q000503:physiopathology*; D008297:Male; D017085:alpha-Thalassemia
D006451:Hemoglobin, Sickle; D006455:Hemoglobins, Abnormal; D005914:Globins; D006444:Hemoglobin C; D006447:Hemoglobin H