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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The patients received either chloroquine phosphate (Thai Government Pharmaceutical Organization, Bangkok, Thailand), 10 mg of base/kg, followed by 5 mg of base/kg every 6, 24, and 36 hours (n = 1,018), artesunate (Guilin No. 1 Factory, Guanxi, People’s Republic of China), 3.3 mg/kg on the first day followed by 1.65 mg/kg/day for four days (n = 586), artesunate, 1.65 mg/kg/day for seven days (n = 474); Fansidar® (500 mg of sulfadoxine plus 25 mg of pyrimethamine per tablet) (F. Hoffmann La Roche, Basel, Switzerland), 25/1.25 mg/kg (adult dose = three tablets) as a single dose, or primaquine alone (Thai Government Pharmaceutical Organization), 0.25 mg of base/kg/day (adult dose = 15 mg of base/ day) for 14 days. Patients received oral paracetamol if they had a temperature > 38°C. The effect of treatment on gametocytes will be reported elsewhere (Nacher M and others, unpublished data). This paper focuses on other factors influencing gametocyte carriage.
Ethical considerations. All patients provided informed consent before admission into the study. The study was reviewed and approved by the Ethical Committee of Mahidol University (Bangkok, Thailand).
Statistical analysis. The proportion of gametocyte carriers on admission, the peak gametocyte count, and the gametocyte carriage duration were outcome variables studied in relation to a number of clinical and paraclinical covariates. Since most variables had a non-normal distribution, the Mann-Whitney test was used to compare medians. Spearman’s correlations between variables were also used. To reduce the number of relevant covariates and to control for potential confounding between covariates, backward stepwise logistic or linear regression was used. The full model included the variables that were related to gametocyte carriage in simple analysis and variables that were biologically relevant. Given the number of observations and variables used, some of the variables on admission were missing. Therefore, the total number of observations used was lower than the initial number of case records used. The variables were assumed to be missing completely at random (i.e., when height had not been measured it was impossible to calculate the body mass index, and some laboratory results were lost). Since levels of serum bicarbonates were only measured systematically in the last five years of patient care, the number of available observations was much lower than for other variables. The stepwise regression results were verified with robust regression because of the non-normal distribution of a number of variables.
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RESULTS |
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Factors influencing the presence of gametocytes.
Table 1
shows that the comparisons of variables between patients with and without P. vivax gametocytes yielded a number of significant differences. Bivariate analysis showed that there were no significant differences between gametocyte carriers and gametocyte-free patients regarding age (22 years, inter-quartile range [IQR] = 19–28 versus 22 years [18–29]; P = 0.27), duration of symptoms before admission (4 hours [3–6] versus 4 hours [3–5]; P = 0.22), leukocytes (6,200 x 106/L [4,900–7,900] versus 6,100 x 106/L [4,900–7,600]; P = 0.28), lymphocytes (25% [16–36] versus 25% [18–36]; P = 0.5), neutrophils (64% [52–72] versus 63% [52–72]; P = 0.7), aspartate aminotransferase (29 IU [22–40] versus 28 IU [21–40]; P = 0.24), alkaline phosphatase (48.2 units/L [30–84] versus 52.1 units/L [30.6–87]; P = 0.13), sodium (138 mmol/L [136–140] versus 138 mmol/L [136–140]; P = 0.16), and the anion gap (11 mmol/L [9–13] versus 11 mmol/L [9–13]; P = 0.15).
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(excluding bicarbonates) and the presence or absence of splenomegaly were included in a stepwise logistic regression model retaining variables with a P value < 0.2. The only variables that remained significant after this procedure were the highest observed temperature (adjusted odds ratio [AOR] per °C increase = 0.82, 95% CI = 0.71–0.94, P = 0.006); asexual parasitemia > 9,200/µL (AOR = 2.8, 95% CI = 1.9–4.2, P < 0.0001); erythrocyte counts (AOR = 0.8/million/µL increase, 95% CI = 0.67–0.95, P = 0.01); monocyte percentage (AOR = 0.93 per % increase, 95% CI = 0.89–0.96, P < 0.0001); lymphocyte percentage (AOR = 0.98 per % increase, 95% CI = 0.97–0.99, P = 0.006); and albumin (AOR = 0.67 per 10 g/mL increase, 95% CI = 0.5–0.9, P = 0.007). A separate model including the same variables plus bicarbonates (only the patients admitted in the last five years benefited from this measurement) and the anion gap (Na+, Cl–, HCO3–) confirmed our results, and showed that the anion gap was positively associated with gametocyte carriage (AOR = 1.1 per unit increase, 95% CI = 1.02–1.14, P = 0.009).
Factors influencing magnitude and duration of carriage.
The median gametocyte count was 510/mm3 (IQR = 330–910) and the median duration of gametocyte carriage was 24 hours (IQR = 12–48). Among patient with gametocytes, the peak number of gametocytes was positively correlated with the initial parasitemia (Spearman’s 
= 0.26, P < 0.0001) and negatively correlated with the highest observed temperature (Spearman’s = –0.07, P = 0.045). No other variables other than treatment were significantly associated with the magnitude of gametocyte carriage. Because of the obvious influence of treatment, these associations were tested using multivariate methods, and remained significant after controlling for the same variables reported earlier and treatment using stepwise regression, and controlling the final models with robust regression models (P < 0.0001 and P = 0.01, respectively).
The duration of gametocyte carriage was proportional to gametocyte count (Spearman’s = 0.36, P < 0.0001) and asexual parasites count (Spearman’s = 0.10, P = 0.001). Conversely, there was a negative correlation between albuminemia and the duration of gametocyte carriage (Spearman’s = –0.09, P = 0.01). There was a negative correlation between the highest observed temperature and gametocyte carriage duration (Spearman’s = –0.05, P = 0.02). After controlling for their respective effects and the influence of treatment, the observed correlations between gametocyte carriage duration, gametocyte counts, and albuminemia were still significant (P < 0.0001, and P = 0.008, respectively), but no longer with the highest observed temperature (P = 0.27) or asexual parasite counts (P = 0.24).
Hemoglobinopathies and gametocytes. Among a subgroup of patients for which hemoglobin electrophoresis was available (n = 1,014), there were no significant differences between patients with normal hemoglobins and patients with the hemoglobin E trait for median gametocyte counts (495/ mm3 [IQR = 330–830] versus 445/mm3 [305–795]; P = 0.5) and for median durations of gametocyte carriage (24 hours [12–48] versus 24 hours [12–48]; P = 0.31).
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DISCUSSION |
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Finally, the increase in gametocyte carriage in patients with low albuminemia suggests that the host’s nutritional status has an important impact on plasmodial physiology, possibly interference with parasite multiplication, the attenuation of malaria symptoms, or hematologic consequences of malnutrition favor gametocytogenesis.
Although the results of this study show a variety of factors influencing patent gametocyte carriage, most of them could be grouped into two compatible unifying perspectives, one that does not seem to be well supported by the present data where most findings would be consequences of the duration of the infection, and another in which parasite multiplication and erythrocyte destruction would increase gametocytogenesis through the events surrounding tissue hypoxia.
Although the infectivity of P. vivax gametocytes is only weakly correlated with gametocyte densities, factors influencing the magnitude and duration of gametocyte carriage may translate into differences in mosquito infection. This would require prospective studies on the factors influencing transmission to the mosquito.
Received October 29, 2003. Accepted for publication January 8, 2004.
Acknowledgments: We thank the staff of the Hospital for Tropical Diseases for their help.
Financial support: This study was supported by grants from Mahidol University. Mathieu Nacher is supported by a Howard Grant from the Institut Pasteur (Paris, France).
Authors’ addresses: Mathieu Nacher, Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, 10400, Bangkok, Thailand, Shoklo Malaria Research Unit, Intrakiri Road, PO Box 46, Mae Sot, Tak 63110, Thailand and Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, 25/28 Rue du Dr. Roux, 75015 Paris, France, E-mail: m_nacher{at}lycos.com. Udomsak Silachamroon, Pratap Singhasivanon, Polrat Wilairatana, Weerapong Phumratanaprapin, and Sornchai Looareesuwan, Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, 10400, Bangkok, Thailand. Arnaud Fontanet, Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, 25/28 Rue du Dr. Roux, 75015 Paris, France.
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REFERENCES |
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This article has been cited by other articles:
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  S. Pukrittayakamee, M. Imwong, P. Singhasivanon, K. Stepniewska, N. J. Day, and N. J. White Effects of Different Antimalarial Drugs on Gametocyte Carriage in P. Vivax Malaria Am J Trop Med Hyg, September 1, 2008; 79(3): 378 - 384. [Abstract] [Full Text] [PDF]
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