This is the first longitudinal study assessing the effect of malnutrition on the posttreatment prophylactic effect of ACTs; thus, no direct comparisons to previous studies can be made. We evaluated patients prospectively, taking advantage of a comprehensive clinic infrastructure which provided assurance that all episodes of malaria were captured and followed and that compliance with the treatment regimen was high. Compared to other studies which have evaluated this vulnerable patient population, our sample size of over 2,000 malarial episodes is one of the largest published. In addition, this study utilized the new 2006 WHO growth standards, which provide a more accurate tool for monitoring growth differences, as they evaluate growth patterns from healthy breastfed children from around the world (7
). Our results indicate that in a high-transmission setting, both AL and DP are efficacious antimalarial regimens for treatment of P. falciparum
malaria in children under 3 years of age, regardless of nutritional status. Parasite clearance overall was excellent, with more than 99% of study participants clearing all primary parasites by day 3. Recrudescence could not be directly evaluated as an outcome of this study, due to low numbers (less than 3%), though the lack of recrudescence is further support of the efficacy of these two drug regimens. Compared to children treated with DP, children treated with AL were at higher risk for recurrent parasitemia after 42 days of follow-up. Children with signs of mild to moderate chronic malnutrition not taking TS prophylaxis were at higher risk for recurrent parasitemia. However, this was significant only in the DP group.
Although there are no published studies evaluating the relationship of malnutrition and recurrent parasitemia, a few studies have assessed the association between malnutrition and malaria risk. In a cross-sectional study in Kenya of 1,862 children under 36 months of age, stunted children were more likely to have more parasitemia (odds ratio [OR] = 1.98) and clinical malaria (OR = 2.65) than nonstunted children (11
). Likewise, a prospective cohort study of 487 children under 5 years of age in the Gambia found that stunted children were at higher risk for malaria (RR = 1.35) than nonstunted children (5
). Contrary to our findings, a prospective cohort study of 136 children 4 months to 10 years of age in Papua New Guinea found that the incidence rate of malaria (of any type, as well as P. falciparum
alone) increased with increasing HAZ (12
), indicating that lower HAZ was protective against an attack of clinical malaria. Two longitudinal studies, one in Senegal with children 12 months to 5 years of age and the other in Burkina Faso with children 10 months to 10 years of age, found that stunting and being underweight were not associated with an increased risk of P. falciparum
). There may be several explanations for the conflicting findings. The study conducted in Kenya was conducted with children representing an age range similar to that of the children in the Tororo study, while the studies conducted in Papua New Guinea and Burkina Faso were conducted with older children. Moreover, the study in Kenya was conducted in an area of high transmission (60 to 300 infective bites per person per year), whereas the studies which found compromised nutritional status to be protective or to have no effect on malaria risk were conducted in areas where malaria transmission occurred seasonally with lower transmission rates than in Kenya as well as in the Tororo district in Uganda. Both the differences in age and the transmission intensity may lead to differences in acquired immunity and thus differences in malaria risk.
The mechanism behind the increased risk of recurrent parasitemia in children with signs of mild to moderate chronic malnutrition is unclear, but is likely due in part to the impact of chronic malnutrition on the immune system. Chronic malnutrition and accompanying micronutrient deficiencies (e.g., zinc, magnesium, iron, selenium, and vitamin A) can lead to immune dysfunction and increased infection in children by impairing both the innate and the adaptive immune systems, affecting thymic activity and cytokine production, by impairing T cell response and macrophage activation, and by disrupting IgA and IgG antibody response (4
). Results from the few studies evaluating the relationship between malnutrition and immune response in children with malaria have been conflicting. A cross-sectional study with preschool-aged children conducted in Senegal found that IgG antibody levels were significantly lower in stunted children than in controls, regardless of differences in parasite density (10
). In contrast, a study of children up to 10 years of age conducted in Papua New Guinea found an increase in cytokine production in response to stimulation by specific antimalarial antigens in undernourished (stunted and wasted) children and a decrease in antibody response in wasted children (12
). Future studies evaluating the effect of malnutrition on immune response are warranted. In addition to altering immune function, malnutrition may have an impact on the pharmacokinetics of antimalarial treatment. Total body water has been shown to be increased in malnourished children, leading to a greater volume of distribution of drugs, which in turn would result in lower blood concentrations of drug. In addition, malnutrition is associated with intestinal malabsorption and villous atrophy of the jejunal mucosa, which can impair drug absorption (22
). The few pharmacokinetic studies conducted with children have indicated that because of differences in drug metabolism and elimination, children may be receiving suboptimal doses of antimalarial drugs (23
). Additional analysis of data from a subset of this patient population, including complete pharmacokinetic profiles, is under way.
Interestingly, the association of increased risk of recurrent parasitemia with decreasing HAZ was evident only for children not taking TS prophylaxis. TS is an antifolate which has been associated with reduced morbidity and mortality in HIV-infected children and adults. TS also has antimalarial properties. Though TS has been used to treat P. falciparum
malaria in the past, its effectiveness as an antimalarial treatment is limited (8
), and it is no longer considered acceptable as a first-line therapy. However, TS has been shown to reduce the incidence of malaria even in areas of high parasite resistance to antifolates (15
). Perhaps the chronic use of TS, a moderately effective antimalarial when used alone, acts synergistically with the administration of a relatively more potent artemisinin-based treatment to override the deleterious effect of chronic malnutrition on the immune system. TS is easy to administer, with treatment once a day or thrice weekly for prophylaxis, is widely available, and is relatively inexpensive. The results from this study indicate that children with mild to moderate signs of chronic malnutrition at risk for malaria may benefit from TS prophylaxis.
The limitations of this study should be considered. First, we may have not controlled for all potential confounders that may be involved in the complex relationship between malnutrition and malaria. Second, we made multiple comparisons evaluating the relationship between malnutrition and the risk of recurrent parasitemia, which could potentially lead to spurious findings. Only by comparing the lowest levels of malnutrition to those for the baseline group was statistical significance achieved. Finally, the mechanisms underlying the differences in risk of recurrent parasitemia in children with mild to moderate chronic malnutrition could not be elucidated.
AL and DP are effective antimalarial therapies for clearing primary infection in chronically malnourished young children in a high-transmission setting. However, young children with signs of mild to moderate chronic malnutrition not taking TS prophylaxis are at increased risk for recurrent parasitemia. Further studies are warranted to evaluate if this risk is mediated by altered drug metabolism in chronically malnourished children or through differences in immune response. Children with chronic malnutrition should be targeted for malaria prevention strategies such as provision of bed nets or chemoprevention integrated with nutrition-based interventions.