ABSTRACT
Despite widespread resistance, chloroquine remains widely used in West Africa, particularly in home treatment. We examined chloroquine blood levels on admission to a referral hospital with respect to the manifestation of severe malaria in 290 Ghanaian children. Of the patients, 78% exhibited chloroquine concentrations (subtherapeutic, 35%; therapeutic, 37%; supratherapeutic, 6%) and 11% died. Most parasites (78%) carried the pfcrt-T76 chloroquine resistance mutation. High drug concentrations correlated with reduced parasitaemia but also with selection of resistant parasites, lower respiratory and heart rates, increased plasma lactate levels and impaired consciousness. Geometric mean chloroquine concentrations tended to be higher in children who died than in survivors (1.135 vs. 778nmol/l; P=0.09). Supratherapeutic drug levels (>5000nmol/l) were associated with fatal outcome (odds ratio 8.6; 95% CI 1.4-51.7). Residual chloroquine concentrations were found to be abundant in children with severe malaria and to be associated with alterations in the clinical manifestation of the disease and its case fatality. This may result from toxic effects of the drug and/or reflect preceding overtreatment in children with acute life-threatening disease. In areas of intense chloroquine resistance and frequent pre-treatment, additional administration of chloroquine at hospital admission is not only ineffective but may even further endanger patients.
Subject(s)
Antimalarials/blood , Chloroquine/blood , Malaria, Falciparum/blood , Plasmodium falciparum/genetics , Animals , Antimalarials/adverse effects , Child , Child, Preschool , Chloroquine/adverse effects , Dose-Response Relationship, Drug , Drug Resistance/genetics , Female , Ghana/epidemiology , Humans , Infant , Malaria, Falciparum/drug therapy , Malaria, Falciparum/epidemiology , Male , Membrane Transport Proteins/genetics , Plasmodium falciparum/drug effects , Protozoan Proteins/genetics , Treatment FailureABSTRACT
Hemoglobin (Hb) C has been reported to protect against severe malaria. It is unclear whether relative resistance affects infection, disease, or both. Its extent may vary between regions and with disease pattern. We conducted a case-control study of children with severe malaria, asymptomatic parasitemic children, and healthy children in Ghana. HbAC did not prevent infection but reduced the odds of developing severe malaria and severe anemia. Protection was stronger with HbAS. The frequencies of HbCC and HbSC decreased, from healthy children to asymptomatic parasitemic children to children with severe malaria. These data support the notion that natural selection of HbC occurs because of the relative resistance it confers against severe malaria but argue against the notion that HbC offers resistance to infection.
