Risk factors for gametocyte carriage in uncomplicated falciparum malaria.

RIC PRICE 0 FRANC OIS NOSTEN 0 JULIE A. SIMPSON 0 CHRISTINE LUXEMBURGER 0 LUCY PHAIPUN 0 FEIKO TER KUILE 0 MICHELE VAN VUGT 0 TAN CHONGSUPHAJAISIDDHI 0 NICHOLAS J. WHITE 0 0 Shoklo Malaria Research Unit, Mae Sod, Tak Province, Thailand; Faculty of Tropical Medicine, Mahidol University , Bangkok , Thailand; Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centers, University of Amsterdam , Amsterdam , The Netherlands ; Centre for Tropical Medicine Nuffield Department of Clinical Medicine, John Radcliffe Hospital , Headington, Oxford , United Kingdom The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] 5 7.8, 95% confidence interval [CI] 5 3.7-16, P , 0.001), anemia (hematocrit ,30%) (AOR 5 3.9, 95% CI 5 2.3-6.5, P , 0.001), no coincident P. vivax malaria (AOR 5 3.5, 95% CI 5 1.04-11.5, P , 0.04), presentation with a recrudescent infection (AOR 5 2.3, 95% CI 5 1.3-4.1, P , 0.004), and a history of illness longer than two days (AOR 5 3.3, 95% CI 5 1.7-6.6, P , 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks 5 1.9, 95% CI 5 1.3-2.7 and 2.8, 95% CI 5 2.0-4.0, respectively; P , 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential. - Study site. The study took place between 1990 and 1995 in patients living in a camp for displaced person of the Karen ethnic minority situated in an area of malarious hill forest on the western border of Thailand. During the five-year period, a series of 18 antimalarial drug studies were conducted to determine the optimum treatment of falciparum malaria in the face of a continuing decrease in mefloquine sensitivity. The epidemiology of malaria at this site has recently been described in detail.2 Transmission of malaria is low (each person experiencing approximately one vivax and one falciparum malaria infection every two years) and seasonal in this area. Nearly all falciparum malaria infections are symptomatic, and the treatments of every episode have been documented. Patients. Patients of all ages were recruited into these studies provided that they or their accompanying relatives gave fully informed consent. Each of the studies was approved by the Ethics Committee of the Faculty of Tropical Medicine of Mahidol University. All patients had slide-confirmed falciparum malaria. Pregnant women, children weighing , 5 kg, and patients with signs of severity or concomitant disease requiring hospital admission were all excluded. On admission, a questionnaire was completed recording details of symptoms and their duration, and the history of previous antimalarial medication (since health structures in the camp are the only source of antimalarial drugs in this area, the history is generally a reliable guide to pretreatment). A full clinical examination was also completed and blood was taken for routine hematology and quantitative parasite counts. Drug treatment significantly affects the subsequent development of gametocytemia3 at this study site, and for this reason patients in this study were categorized into four antimalarial treatment groups for the purposes of this analysis: mefloquine (single or split dose without artemisinin derivatives), halofantrine (high or low dose), artemisinin derivatives (artesunate or artemether with and without mefloquine), and quinine (Table 1). Drug administration was observed in all cases. All patients were examined daily until they became asymptomatic and aparasitemic, and were then seen weekly during the follow-up period. Before 1993, this was for was four weeks, and since then for nine weeks. A blood smear was taken at each weekly visit or if symptoms returned between follow-up appointments. Recrudescent infections were treated with a seven-day regimen of quinine sulfate (30 mg of salt/kg/day) in combination with tetracycline (16 mg/kg/ day) if more than eight years old, or more recently with a seven-day regimen of artesunate or artemether (12 mg/kg given over a seven-day period). 24 mg/kg in 1 day 72 mg/kg over 3 days As 10 mg/kg (3 doses in 1 day) 1 M15 As 4 mg/kg (1 dose) 1 M25 As 4 mg/kg daily for 3 days 1 M25 As 12 mg/kg (over 5 days) 1 M25 As 12 mg/kg (over 7 days) 1 M25 12 mg/kg over 5 days 12 mg/kg over 7 days Parasite counting. Parasite counts were made on Giemsastained thick and thin blood films and parasitemia was expressed as the number of parasitized erythrocytes per 1,000 red blood cells or the number of parasites seen on the thick film per 500 white blood cells. Thin films were counted if the thick film exceeded 1,000 parasites per 500 white blood cells. Parasite counts on thick films were calculated assuming a total white blood count of 8,000/ml. Gametocyte counts were made only on thick blood films. Those instances where parasite counts were recorded per 1,000 red blood cells (i.e., parasitemias .0.5%) were therefore regarded as missing data when assessing gametocytemia in these series. Data analysis. Data were analyzed using the statistical programs SPSS for Windows (SPSS Institute, Chicago, IL) and Epi-Info 6 (Centers for Disease Control and Prevention [Atlanta, GA] Public Domain Software). Normally distributed continuous data were compared by Students t-test and analysis of variance. Data not conforming to a normal distribution were compared by the Mann-Whitney U test and Kruskal-Wallis analysis of variance. The association between two continuous variables was assessed using Spearmans rank correlation coefficient. Following antimalarial treatment, gametocyte carriage was assessed on days 7 and 14, and expressed as the proportion of patients with patent gametocytemia (gametocyte positivity rate [GPR]). A multiple logistic regression model was used to determine adjusted odds ratios (AORs) for risk factors for gametocyte carriage on admission and the variables associated with the GPR. Any variables found to be associated significantly with the dependent variable in a univariate analysis were entered into the equation and the model was constructed using a forward stepwise analysis using the Wald statistic. In this area, there a (...truncated)