Dose- and time-dependent relations between infective Anopheles inoculation and outcomes of Plasmodium falciparum parasitemia among children in western Kenya

Abstract

Blood-stage level Plasmodium falciparum infection (parasitemia density) is generally elevated prior to, or at the time of, clinical presentation of severe pediatric malaria episodes. Intensity of exposure to infective Anopheles mosquito bites is a suspected determinant of higher density parasitemia. Analyses of entomologic and parasitologic data collected in 1986-1987 were conducted to investigate whether the dose of infective bites predicted the incidence or degree of P. falciparum parasitemia in Kenyan children < 6 years old. At 21 consecutive 30-day intervals, a new cohort (n approximately 50 each) was enrolled, cured of malaria parasites, and monitored over 84 days for recurrent parasitemia. Outcomes included time to parasitemia, time to parasitemia > or = 5,000/microliter, and parasitemia density. Ecologic and individual-level analyses were conducted. The mean infective bite exposure experienced by each cohort was significantly associated with the incidence of parasitemia (age-adjusted r2 = 0.38, p = 0.022) and more strongly associated with the incidence of parasitemia > or = 5,000/microliter (age-adjusted r2 = 0.72, p < 0.001). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia > or = 5,000/microliter among children exposed to > or = 1 infective bite per day as compared with the referent (rate ratio (RR) = 2.82, 95% confidence interval (CI) 2.24-3.56). Cumulative infective bite exposure, exposure duration, and age were significant predictors of recurrent parasitemia density in multiple linear regression analyses. The results support the contention that reductions in P. falciparum transmission intensity, in the absence of complete elimination, will reduce higher level parasitemia among African children.

PIP: Elevated numbers of asexual erythrocytic-stage Plasmodium falciparum parasites in the peripheral blood circulation is a known risk factor of the clinical severity of malaria episodes. The interrelationships among a continuum of sporozoite dose, duration of exposure, age, level of parasitemia at enrollment, village of residence, sex, and recurrent P. falciparum parasitemia were investigated in a 2-year (1986-87) study of 862 children 6 months to 6 years of age from six contiguous villages in Western Kenya. At 21 consecutive 30-day intervals, a new cohort was enrolled, cured, and monitored over 84 days for recurrent parasitemia. The mean cumulative dose was 23 inoculations, and there was a significant linear correlation between this variable and the incidence rate of first recurrent parasitemia, with even stronger associations for the incidence of higher density parasitemia. The overall 70-day cumulative incidence of first recurrent parasitemia was 88.5% (22.5% for high-density P. falciparum). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia equal to or above 5000/mcl among children exposed to one or more bites per day compared to the referent. Each one unit increase in the mean dose was associated with a 24% higher rate of recurrent parasitemia and a 26% higher rate of recurrent high-density parasitemia after adjustment for covariates. Multiple linear regression analyses indicated that parasitemia density was significantly positively associated with cumulative dose and inversely associated with duration of exposure and age. Approximately 36% of the variance in malaria incidence rates was explained by the mean cumulative dose of infective bites.