High levels of Plasmodium falciparum rosetting in all clinical forms of severe malaria in African children

Abstract

Plasmodium falciparum rosetting (the spontaneous binding of infected erythrocytes to uninfected erythrocytes) is a well-recognized parasite virulence factor. However, it is currently unclear whether rosetting is associated with all clinical forms of severe malaria, or only with specific syndromes such as cerebral malaria. We investigated the relationship between rosetting and clinical malaria in 209 Malian children enrolled in a case-control study of severe malaria. Rosetting was significantly higher in parasite isolates from severe malaria cases compared with non-severe hyperparasitemia and uncomplicated malaria controls (F(2,117) = 8.15, P < 0.001). Analysis of sub-categories of severe malaria (unrousable coma, severe anemia, non-comatose neurological impairment, repeated seizures or a small heterogeneous group with signs of renal failure or jaundice) showed high levels of rosetting in all sub-categories, and no statistically significant differences in rosetting between sub-categories (F(4,67) = 1.28, P = 0.28). Thus rosetting may contribute to the pathogenesis of all severe malaria syndromes in African children, and interventions to disrupt rosetting could be potential adjunctive therapies for all forms of severe malaria in Africa.

Figure 1

Distribution of P. falciparum field isolate rosette frequencies in relation to malaria severity. Box plots showing significantly higher rosette frequencies in parasite isolates collected from children with severe malaria (severe, N = 78) compared with isolates from children with non-severe hyperparasitemia (hyp, N = 40) or uncomplicated malaria (uncomp, N = 91), Kruskal-Wallis test, P < 0.0001. Boxes indicate the median (central line) and the interquartile range. The error bar indicates the 90th percentile, and points beyond the 90^th percentile are shown as circles.

Figure 2

Distribution of P. falciparum field isolate rosette frequencies in relation to severe malaria sub-categories. Box plots (as in Figure 1) showing no significant difference in rosette frequencies between various severe malaria sub-categories including severe malarial anemia (anemia, median 30.5%, interquartile range (IQR) 11–58%), cerebral malaria (coma, median 16.5%, IQR 4–28%), non-comatose neurological impairment (neuro, median 22.0%, IQR 13–45%), repeated seizures (seizures, median 22.0%, IQR 11–29%), and renal failure/jaundice (other, median 9.5%, IQR 0–71%), Kruskal-Wallis test, P = 0.63. A full definition of each sub-category is given in the methods. The number of isolates (N) in each subcategory is shown. For comparison, the non-severe hyperparasitemia patients had a median rosette frequency of 8.5%, IQR 2–20%, and the uncomplicated malaria patients had a median rosette frequency of 1%, IQR 0–12%.