A. Menon

Mortality and morbidity from malaria after stopping malaria chemoprophylaxis.

Gambian children who had received malaria chemoprophylaxis for a variable period of time during their first 5 years of life were followed to determine whether they experienced a rebound in mortality or in morbidity from malaria during the period after chemoprophylaxis was stopped. The risk of dying between the ages of 5 years, when chemoprophylaxis was stopped, and 10 years was no higher among children who had received chemoprophylaxis with Maloprim (pyrimethamine plus dapsone) for some period during their first 5 years of life than among children who had received placebo (21 vs. 24 deaths) and the beneficial effect of chemoprophylaxis on mortality observed during the first 5 years of life was sustained. The incidence of clinical attacks of malaria during the year after medication was stopped was significantly higher among children who had previously received Maloprim for several years than among children who had previously received placebo. However, at the end of this year, there was no significant difference in spleen rate, parasite rate or packed cell volume between the 2 groups of children. Thus, stopping chemoprophylaxis after a period of several years increased the risk of clinical malaria but did not result in a rebound in mortality in Gambian children. However, the number of deaths recorded was small, so a modest effect on mortality cannot be excluded.

Sustained protection against mortality and morbidity from malaria in rural Gambian children by chemoprophylaxis given by village health workers

Mortality and morbidity from malaria were measured in children for a one-year period in a rural area of The Gambia 3-4 years after the introduction of a primary health care programme into some villages in the study area. Among children resident in primary health care villages who received treatment for febrile illnesses from a village health worker resident in their village there was no reduction in overall mortality or in morbidity from malaria compared with levels found in villages without a primary health care worker. However, among children aged 3-59 months who received malaria chemoprophylaxis from a village health worker in addition to treatment there was a 49% reduction in mortality and a 73% reduction in attacks of clinical malaria. The level of protection against malaria achieved by chemoprophylaxis given by village health workers 3-4 years after the chemoprophylaxis programme was started was as high as that obtained shortly after the introduction of the primary health care programme.

Cellular immune responses to Plasmodium falciparum antigens in children receiving long term anti-malarial chemoprophylaxis

Fifty-two Gambian children who had received fortnightly chemoprophylaxis with maloprim, (pyrimethamine and dapsone), and 45 receiving placebo, were studied. Cellular immune responses to malaria antigens, measured by lymphoproliferative responses and interferon production, were higher in children who had received prophylaxis than in controls, although the anti-malarial antibody levels were lower. During a one-year period after termination of prophylaxis, there was no increase in the frequency of clinical episodes of malaria in the children who had received Maloprim. These results suggest that chemoprophylaxis for 3 years may lower malaria antibody levels, but does not interfere with the development of protective immunity, perhaps by enhancing cell-mediated immune responses to malaria in protected children.

Immunity to malaria in young Gambian children after a two-year period of chemoprophylaxis

A cohort of 48 Gambian children was protected against malaria by fortnightly administration of Maloprim (pyrimethamine and dapsone) for 2 years between their 3 and 5 birthdays. A matched cohort of 47 children received placebo. During the year following the termination of prophylaxis there was no increase in the frequency of clinical attacks of malaria in the protected children compared with the control children. Antibody levels to circumsporozoite protein were measured by a radioimmunoassay and that to blood-stage antigens by a variety of techniques including an ELISA to whole blood-stage Plasmodium falciparum antigen, immunofluorescent assays (IFAT) to acetone fixed, glutaraldehyde fixed and unfixed parasites, a merozoite inhibition test and an opsonizing assay. Antibody levels were, in general, lower in protected than in control children and several differences between the two groups were statistically significant. When antibody levels were measured by ELISA and IFAT at the end of the following rainy season, when malaria transmission was intense, those in protected children had increased to comparable levels to those found in control children. Our findings suggest that chemoprophylaxis given for 2 years lowers malaria antibody levels but that it does not interfere with the development of protective immunity.

A comparative study of Lapudrine® (chlorproguanil) and Maloprim® (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children

A comparison has been made of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine +dapsone) as malaria chemoprophylactics when given every two weeks for 3 years to Gambian children under the age of 5 years. Both drugs produced falls in spleen and malaria parasite rates and an increase in packed cell volume. Maloprim, but not chlorproguanil, significantly reduced the incidence of episodes of fever accompanied by malaria parasitaemia. Children who received Maloprim, but not those who received chlorproguanil, grew better than children in the placebo group. This finding suggests that brief clinical episodes of malaria are more important in impairing growth than more prolonged periods of asymptomatic parasitaemia. No serious side-effect attributable to either drug was observed. After chemoprophylaxis had been given for 3 malaria transmission seasons the level of resistance of Plasmodium falciparum to pyrimethamine and to chlorproguanil was about 10%.

An ELISA test for detecting chloroquine in urine

Two ELISA tests for detecting chloroquine in urine have been developed using polyclonal and monoclonal antibodies which react with the 7-chloro-4-amino-quinoline part of the chloroquine molecule and thus recognize chloroquine, its metabolites, and amodiaquine. The ELISAs were sensitive and specific and did not cross-react with other commonly used antimalarials. In a field trial the chloroquine ELISA performed better than the Dill Glazko or Haskins colorimetric tests. A small proportion of urines gave an apparently false positive reaction when tested at a dilution of 1:10, but not when tested at higher dilution.

A national survey of the prevalence of chloroquine resistant Plasmodium falciparum malaria in The Gambia.

In The Gambia, 760 children less than 10 years of age with Plasmodium falciparum malaria were treated with chloroquine (25 mg/kg) and followed-up 2 and 9 d after the start of treatment. 700 children (92.1%) completed the study. The level of in vivo resistance to chloroquine varied by area from 0.4% to 16.4%. Of the 28 children found to have chloroquine resistant malaria, none was ill when seen at the 9 d follow-up and only 3 (10.3%) required further treatment with alternative antimalarials because of persistent high levels of parasitaemia. However, the fact that 30.4% of the children who completed the study had chloroquine in their urine at presentation may have masked the true level of resistance and led to underestimation of the clinical significance of these findings. The blood film at day 2 did not usefully predict resistance. 67 isolates were tested in vitro for chloroquine sensitivity. The mean EC50 was 15.5 nmol/litre, an eight-fold decrease in sensitivity from that of isolates tested in 1982. 8 (11%) of the isolates had EC50s above the WHO reference value for sensitive isolates of 18.3 nmol/litre, with values ranging from 22 to 65 nmol/litre of culture medium. Gambian isolates were sensitive to quinine (mean EC50 = 49.6 nmol/litre).