Bill & Melinda Gates Foundation.

The symptoms of severe malaria and their contribution to mortality were assessed in 290 children in northern Ghana. Common symptoms were severe anemia (55%), prostration (33%), respiratory distress (23%), convulsions (20%), and impaired consciousness (19%). Age influenced this pattern. The fatality rate was 11.2%. In multivariate analysis, circulatory collapse, impaired consciousness, hypoglycemia, and malnutrition independently predicted death. Children with severe malaria by the current World Health Organization (WHO) classification, but not by the previous one (1990), showed relatively mild clinical manifestations and a low case fatality rate (3.2%). In hospitalized children with severe malaria in northern Ghana, severe anemia is the leading manifestation, but itself does not contribute to mortality. In this region, malnutrition and circulatory collapse were important predictors of fatal malaria. The current WHO criteria serve well in identifying life-threatening disease, but also include rather mild cases that may complicate the allocation of immediate care in settings with limited resources.

The high frequency of ␣ ؉ -thalassemia in malaria-endemic regions may reflect natural selection due to protection from potentially fatal severe malaria. In Africa, bearing 90% of global malaria morbidity and mortality, this has not yet been observed. We tested this hypothesis in an unmatched case-control study among 301 Ghanaian children with severe malaria and 2107 controls (62% parasitemic). In control children, ␣ ؉ -thalassemia affected neither prevalence nor density of Plasmodium falciparum. However, heterozygous ␣ ؉ -thalassemia was observed in 32.6% of controls but in only 26.2% of cases (odds ratio [ IntroductionSevere Plasmodium falciparum malaria is a major cause of death in sub-Saharan Africa, particularly in children younger than 5 years of age. 1 Interindividual variation in susceptibility and manifestation can be attributed partially to innate host factors such as the sickle cell trait. [2][3][4] According to Haldane's "malaria hypothesis," 5 these factors are subject to selection in endemic regions because of the resistance they confer against malaria. Another hemoglobin disorder, ␣ ϩ -thalassemia, reaches a prevalence of more than 80% in parts of Southeast Asia and Melanesia. [6][7][8] Heterozygosity is characterized by the commonly deletional loss of one of the duplicated ␣-globin genes (Ϫ␣/␣␣) and slight hematologic changes. Homozygous individuals (Ϫ␣/Ϫ␣) have mild microcytic anemia. 9 In Melanesia, the geographic correlation between the prevalence of ␣ ϩ -thalassemia and malarial endemicity suggests natural selection. 6 In one case-control study in Papua New Guinea, the risk of severe malaria was reduced by 60% and 34% in homozygous and heterozygous children, respectively. 7 In sub-Saharan Africa, ␣ ϩ -thalassemia affects up to 50% of the population, but protection against uncomplicated or severe malaria could not be demonstrated so far. 3,9,10 We examined whether ␣ ϩ -thalassemia confers protection from severe falciparum malaria in Ghana. Study design Patients and controlsWe conducted an unmatched case-control study in the city of Tamale and its vicinity, northern Ghana, during the rainy season 2002 (August to November). In the study area, malaria is hyperendemic (F.P.M., unpublished observations, December 1, 2003). Ethical clearance was obtained from the Ethics Committee, University for Development Studies, Tamale, and informed consent, from the participants' parents. We recruited 290 children with severe malaria according to WHO definition at Tamale Teaching Hospital. 1,11 An additional 11 children with severe malaria were detected during the survey mentioned later in this paragraph and classified as cases. In the 301 index patients, symptoms defining severe malaria were as follows: severe anemia, 57%; prostration, 32%; respiratory distress, 22%; multiple convulsions, 20%; impaired consciousness, 19%; jaundice, 11%; circulatory collapse, 3%; and hemoglobinuria, 3%. Controls were 2107 children from Tamale and the surrounding districts who were recruited following a 2-stage cluster sampling st...