Plasmodium falciparum gametocytaemia in Nigerian children: Peripheral immature gametocytaemia as an indicator of a poor response to chloroquine treatment, and its relationship to molecular determinants of chloroquine resistance.

A group of 161 children who presented with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria in an endemic area of Nigeria was investigated. The aims of the study were to determine the clinical characteristics and responses to oral chloroquine (CQ) therapy of children who were gametocytaemic on presentation and those who were not [including those who were found to have developed peripheral immature gametocytaemias (PIG) when checked 72 h after commencing treatment], and to follow the development of PIG 72-336 h after the start of treatment. The 40 consecutive children who did have peripheral gametocytaemia on presentation and the 40 who did not were similar in their clinical characteristics and responses to oral CQ therapy. Nine of the 40 children who did not initially have gametocytaemias but who subsequently developed PIG (stages I-III) 72-336 h after commencing CQ treatment failed the treatment. In order to evaluate the presence of PIG as an indicator of response to CQ, the smears of blood from 81 children--66 classified as resistant to CQ (60, five and one considered RI, RII, RIII, respectively) and 15 who, though considered to have sensitive responses to CQ, cleared their peripheral parasitaemias > or =72 h after commencing CQ therapy--were examined for PIG. Most (42) of the 66 children with CQ-resistant (CQ-R) infections but none of the 15 with sensitive responses had PIG. Among the 66 children with CQ-R infections, the clinical features of those with PIG were generally similar to those without PIG, although those with PIG were more likely to have hepato-splenomegaly and less likely to have hepatomegaly alone. In the children with CQ-R infections, plasma concentrations of CQ on days 7 and 14 were generally above the level necessary to clear sensitive infections in the study area. The results of molecular analyses of isolates from children with both CQ-R infections and PIG revealed that all 14 checked for mutations in pfcrt had the T76 mutation associated with CQ resistance, and that four of the five also checked for mutations in pfmdr1 had the Y86 mutation associated with CQ resistance. The detection of PIG 72 h after the commencement of CQ treatment may be used as a microscopical indicator of a poor response to CQ in children from this endemic area.