Clinical case definitions for malaria: clinical malaria associated with very low parasite densities in African infants

In areas endemic for Plasmodium falciparum, clinical malaria is believed to be less common in infants than in older children, but specific case definitions have rarely been determined for this age group, As malaria case definitions are known to be both age- and site-specific, assessment of the risk of disease in infancy requires the development of appropriate diagnostic criteria. In southern Ghana, 154 children were recruited at birth and monitored for fever and malaria infection until 2 years of age. Logistic regression was used to model fever risk as a continuous function of parasite density to determine case definitions for the diagnosis of clinical malaria, and to determine age- and season-specific estimates of the fraction of fevers attributable to malaria (AF); 2360 observations were made on 154 children. For fevers defined by a measured temperature greater than or equal to 37.5 degrees C, the estimated population AF was 44% (95% confidence interval 34-53). Estimates of AF varied with age and season. For infants, AF was 51% during the wet season and 22% during the dry season; for children over one year of age, AF was 89% during the wet season and 36% during the dry season. The estimated parasite density threshold for initiation of a febrile episode was 100 parasites per mu L of blood in infants, compared with 3500 parasites per mu L for children over one year of age. Using these case definitions, the incidence of clinical malaria was estimated at 0.09 cases per child-year at risk for children less than 6 months of age, 0.40 for children aged 6-11 months, and 0.69 for children aged 12-23 months. Of 66 cases of clinical malaria, only 3 were observed in children under 5 months of age. We concluded that, although most fevers in infants are not due to malaria, infant clinical malaria may occur at extremely low parasite densities. This may be indicative of a lack of anti-disease immunity in this age group. In southern Ghana, an infant with axillary temperature greater than or equal to 37.5 degrees C and parasitaemia greater than or equal to 100/mu L should be considered to have clinical malaria. Nevertheless, the incidence of clinical malaria is very low in children under 6 months of age, confirming that they are significantly protected from clinical malaria compared to older children.