*2.3.1.3 Severe* P. falciparum *malaria*

Compared to healthy children, HbC appears to protect against severe malaria to a lesser degree than HbS and in proportion to allele frequency [31, 33, 44, 73, 89]. Protection from specific severe malaria syndromes has not been fully investigated in HbCC; in one study [90] HbAC showed mild protection from cerebral malaria (CM) and severe malarial anemia (SMA). When compared to children with uncomplicated malaria, protection from severe malaria is inconsistent: non-significant protection is reported from severe malaria in some studies [30, 33, 44, 69] of HbCC and HbAC, and from SMA in other studies [30, 33, 69] that combined homozygotes and heterozygotes. Significant protection from CM was reported in one study of Malian children that combined homo- and heterozygotes [30, 33] Prospective studies have not reported the incidence of severe syndromes in HbC children. Thus, convincing evidence for protection from severe malaria owing to HbC derives largely from few case–control studies. Also, a further strong evidence for overall protection comes from a recent GWAS, which concluded that for each copy of the HbC allele, the risk for severe *P. falciparum* malaria was reduced by 29% [56, 70].

• Uncomplicated *P. falciparum* malaria

Few studies have reported the risk of uncomplicated malaria associated with HbC. However some comparative studies [44, 72] and prospective studies have yielded conflicting results [26, 33, 74, 91]. Further studies are still needed to show the evidence of protection from uncomplicated malaria afforded by HbCC and HbAC.

• *P. falciparum* parasitaemia

In most studies cross-sectional surveys with adults and children, HbC has not been associated with a reduced prevalence of *P. falciparum* parasitaemia
