Fmi016 288.294

Plasmodium falciparum Malaria in Nigerian Children DuringHigh and Low Transmission Seasons: Gametocyte Carriageand Response to Oral Chloroquine by A. A. Adedeji,b F. A. Fehintola,a B. A. Fateye,a T. C. Happi,a A. O. J. Amoo,c G. O. Gbotosho,a and A. SowunmiaaDepartment of Pharmacology & Therapeutics and Institute for Medical Research and Training, University of Ibadan,Ibadan, Nigeria Departments of bPharmacology and cMedical Microbiology and Parasitology, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University, Sagamu, Nigeria Plasmodium falciparum malaria during high and low transmission seasons was evaluated in1031 children treated with different antimalarial drug in a hyperendemic area of southwesternNigeria. Seventy-three (10.5%) of 693 and forty (11.8%) of 338 children were gametocyte carriers inthe high transmission seasons (HTS) and low transmission seasons (LTS), respectively. In a multipleregression model, two factors were found to be independent risk factors for the presence ofgametocytemia at enrolment in the HTS: duration of illness `3 d, and asexual parasite densities lessthan 10000/kl. Similarly male gender, duration of illness `4 d and parasite density less than 5000/klwere found independent risk factors for presence of gametocytemia during LTS. The presentingparasitemia, parasite clearance times, intensity of gametocytemia and proportion carrying gametocytespost treatment differ significantly in the 333 (32.3%) of these children that were treated withchloroquine in the two seasons. These findings may be important in our understanding of P. falciparumtransmission sustenance, response to chloroquine therapy and contribution of chloroquine to gametocytecarriage as seasonal changes occur.
Although some studies have reported seasonal Incidence of Plasmodium falciparum malaria often influence on vectorial capacity, gametocyte carriage has seasonal pattern. Gametocyte generation, car- and trophozoite densities at the onset of dry or riage and infectivity to mosquitoes are crucial to during rainy season in endemic area in Africa and Thailand,14–17 little is known about the effect of infection, particularly in endemic areas. Carter and seasonal variations on gametocyte carriage and Miller1 demonstrated that the rate at which sexual response to chloroquine treatment in endemic areaof southwest Nigeria. Such information is crucial to our understanding of the potential contribution of erythrocytic stages depends on certain environmental seasonal changes to malaria transmission. Thus, in factors. Several other studies have reported immu- the present study, we evaluated the effect of low and nological stress2,3 impact of host response to high transmission seasons on gametocyte carriage parasite4–6 and chemotherapy7–13 as important fac- and response of children to chloroquine during tors involved in the induction of gametocytogenesis.
P. falciparum malaria infection in hyperendemicsouthwest Nigeria.
The study received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. AS was supported by a The study took place between July 1996 and University College Hospital in Ibadan, a hyperen- Correspondence: Dr A. A. Adedeji, Department of demic area for malaria in south-western Nigeria.18 Pharmacology, Obafemi Awolowo College of HealthSciences, Olabisi Onabanjo University, Sagamu, Nigeria.
Ethical clearance was provided by the local ethics committee. During the period, a series of antimalarial ß The Author [2005]. Published by Oxford University Press. All rights reserved. For Permissions, please email: drug studies were conducted to evaluate the efficacy for Windows version 10.01.28 Proportions were and safety of different treatment regimens spanning compared by calculating 2 with Yates’ correction the two periods of high (April–October) and low or by Fisher exact or by Mantel Haenszel tests.
(November–March) transmission seasons known Normally distributed, continuous data were com- in the area. The details of the studies have been pared by Student’s t-tests and analysis of variance described before.19,20,21 Briefly, children with symp- toms compatible with acute falciparum malaria distribution were compared by the Mann–Whitney who fulfilled the following criteria were enlisted in U-test and the Kruskal–Wallis test (or by Wilcoxon the study: age 13 years or below, pure P. falciparum rank sum test). A multiple logistic regression model parasitemia greater than 2000 asexual forms/ml was used to test the association between gameto- blood, negative urine tests for antimalarial drugs cytemia (Yes or No at presentation) and factors (Dill-Glazko and lignin tests), absence of concomi- that were significant at univariate analysis: male tant illness, no evidence of severe malaria22 and gender, presence of fever, duration of illness before written informed consent given by parents or presentation and asexual parasitemia at presentation.
guardians. After enrolment and start of treatment The values presented below are generally means (day 0), follow-up with clinical and parasitological and standard deviations (sd) or standard error (se).
evaluation was at days 1–7, and then on days 14, p-values of 50.05 were taken to indicate significant and when necessary, on days 21 and 28. Clinical evaluation consisted of a general clinical examinationincluding measurement of weight, core temperature Assessment of parasitemia and gametocytemia Clinical and parasitological features at enrolment Thick and thin blood films prepared from a finger The demographic parameters and other character- prick were Giemsa-stained and were examined by istics of the children enrolled in the study are light microscopy under an oil-immersion objective, summarised in Table 1. Of 1031 children enrolled at Â1000 magnification, by two independent asses- into the studies, 693 and 338 children were recruited sors. Parasitemia in thick films was estimated during the high and low transmission seasons by counting asexual parasites relative to 1000 respectively between 1996–2003. Patent gameto- leukocytes, or 500 asexual forms, whichever occurred cytemia (geometric mean 27, range 6–1344/ml) was first. From this figure, the parasite density was present in 73 (10.5%) of 693 and 40 (11.8%) of 338 calculated assuming a leukocyte count of 6000/ml of children at enrolment in both high and low transmis- blood. Gametocytes were also counted in thick blood sion seasons, respectively. These proportions were films against 1000 leukocytes assuming an average not significantly different (2 ¼ 0.27, p ¼ 0.6). The leukocyte count of 6000/ml of blood.23,24,25 parasite densities at enrolment in these childrenwere 36 748 (Geometric mean, range 209–150 000) and 27 961 (Geometric mean, range 1116–565 333) in In order to evaluate the response of children to both high and low transmission seasons respectively chloroquine treatment during the HTS and LTS, 25 mg/kg body weight of the drug over three days The responses of the asexual parasitemia to drug (10 mg/kg on day 1, 10 mg/kg on day 2 and 5 mg/kg treatments have been reported elsewhere. Factors on day 3) was administered to children. Response associated with gametocytemia at enrolment during the high transmission seasons (HTS) are presented Health Organization (WHO) criteria26 as follows: in Table 2. Duration of illness 43 d, and asexual S ¼ sensitive, clearance of parasitemia without recur- parasite densities less than 10 000/ml were related to rence; RI (mild resistance) ¼ parasitemia disappears the presence of gametocytemia at enrolment. None but reappears within 7–14 days; RII (moderate of age, gender or fever at presentation was indepen- resistance) ¼ decrease of parasitemia but no complete dent risk factor for gametocyte carriage (Table 2).
clearance from peripheral blood; RIII (severe resis- However, during low transmission seasons, gender, tance) ¼ no pronounced decrease or increase in duration of illness 44 d, and asexual parasite parasitemia at 48 h after treatment. In those with densities less than 5000/ml were the independent sensitive or RI response, parasite clearance time factors associated with gametocytemia at enrolment (PCT) was defined as the time elapsing from drug administration until there was no patent parasitemiafor at least 72 h.
Clinical features and response to chloroquineOf 333 children that were treated with chloroquine during the study, 168 were placed in the HTS and Data were analysed using version 6 of the Epi-Info 165 in the LTS. The clinical features at presentation and parasitological parameters of these children are summarized in Table 4. The clinical features were Gametocytemia during treatment with chloroquine were significantly younger ( p ¼ 0.03), had signifi- Gametocytemia was found in 27 out of 168 and 28 cantly lower presenting temperature ( p ¼ 0.03) and out of 165 during the HTS and LTS, respectively, at lower geometric mean parasite density ( p ¼ 0.001).
enrolment. There was no difference in the geometric Though, the fever clearance times were similar in mean gametocyte densities (24, range 12–1344/ml, the HTS and LTS, the parasite clearance times were vs. 26, range 6–150/ml; p ¼ 0.3). Gametocytemia significantly different ( p ¼ 0.003). The therapeutic increased significantly in densities by day 7 and 14 responses (Table 4) were similar in the two seasons.
in children treated in the HTS when compared to Analysis of the treatment failures showed that of the gametocyte densities obtained on these days in the 71 that had resistance response in the HTS, 60, those treated during LTS following chloroquine 6 and 5 children had RI, RII, and RIII respectively; treatment (Table 5). However, the cumulative gameto- similarly in the LTS, 52 had RI, 10 had RII and 11 cyte carriage by day 7 and 14 were significantly had RIII responses. RIII response occur more in the higher in the children treated with chloroquine LTS than HTS but the difference was not significant during the LTS ( p ¼ 0.015 and p ¼ 0.03) than those Summary of demographic and other characteristics of The primary purpose of the present study was toevaluate the effect of seasons in the low and high transmission period characteristic of malaria infec-tion in Nigerian children, on gametocyte carriage, the response to oral chloroquine and gametocyte carriage following treatment. Gametocyte carriage rates may vary widely and depend on several factors.
In this study, observed prevalence of malaria infec- tion was significantly higher in the high transmission season (67.2%) than in the LTS (32.8%), but the gametocyte carriage rate was slightly higher in the latter. Such seasonal effect had been observed earlier in the same area16. Prompt visit to clinic and early treatment of the infection during HTS compared to Risk factors for P. falciparum gametocytemia at enrolment during the high transmission seasons OR, odds ratio.
* Fever, axillary temperature 437.5C.
CI, confidence interval.
Risk factors for P. falciparum gametocytemia at enrolment during the low transmission seasons OR, odds ratio.
* Fever, axillary temperature 437.5C.
CI, confidence interval.
slow response of infected individuals during LTS virulence in the circulating asexual parasites during may be contributory. People in this setting appear to the LTS. Smalley, et al.32 had observed that longer suspect malaria infection more in the rainy season established P. falciparum infections are likely to once symptomatic or pyrexic. It is noteworthy that produce gametocytes. It is likely therefore that longer asexual parasitemia at enrolment was markedly duration of illness before presentation in the LTS higher in the HTS than in the LTS. The reason(s) may allow sufficient time for the progression of for this is not clear from the present study. A similar committed asexual parasites to gametocytes.
observation of low parasite rate during the low The effect of antimalarial drugs in sexual differ- transmission period had been earlier reported for the entiation in P. falciparum is still not fully understood.
area.18,29 It may be that the features of asexual Certain antimalarial drugs, for example chloroquine P. falciparum infectivity or clinical presentation vary and pyrimethamine – sulphadoxine, have been with season or respond to changes in the environ- reported contribute to gametocytogenesis in vitro33 ment in such a way to favour its parasitism and or gametocyte generation or release in vivo.12,13,34 It is remarkable to note that the children in the A critical evaluation of the risk factors for carriage cohorts treated with chloroquine in this study during of the sexual forms may provide some clues in respect LTS were significantly younger, had lower presenting of the above observation. In the present study, temperature and low parasite density compared to two and three independent factors were associated those treated with chloroquine during the HTS.
with gametocyte carriage in the HTS and LTS Although fever clearance times were similar, the respectively. Why would male gender be a risk parasite clearance times were significantly different factor for gametocyte carriage in LTS and not in in the two transmission seasons. The children treated the HTS remains unclear. Testosterone and cortico- during the LTS had delayed clearance of their steroids had been reported stimulate P. falciparum asexual forms suggesting differing parasite behaviour gametocytogenesis in vitro.30,31 Could there be sea- and dynamics during transmission seasons. Thus sonal variation in the levels of sex hormones in the use of chloroquine in children in the study area in prepubertal male and female? This finding would the HTS appeared more favourable and important require further investigation in African children.
to reduce circulating parasite load. Despite similar The duration of illness longer than 4 days and therapeutic outcome and resistance rates in the reduced parasitemia found as risk factors for two transmission periods, early resistance of RII gametocyte carriage in the LTS contrary to the and RIII occur in more children during the LTS.
shorter duration of illness and two fold parasite Surprisingly, the post treatment gametocytemia density in the HTS suggest that there is delayed and gametocyte carriage differ significantly in the two presentation of symptoms or possibly low degree of seasons compared to pretreatment gametocytemia Comparison of clinical parameters of 333 children with Comparison of gametocyte intensity at presentation acute falciparum malaria at presentation and their and following treatment in 333 children with acute therapeutic response following treatment with chloro- falciparum malaria during high and low transmission quine during high and low transmission seasons GMPD, geometric mean parasite density.
The increase resistance to chloroquine, which still remained most common, readily available, cheap and first line antimalarial drug in the study area, may be contributory to differences in the post treatment gametocyte generation or release and carriage in children. Patients with slow response to treatment are likely to carry gametocytes than those that responded rapidly.38 Furthermore, high carriage rate in the LTS post treatment with chloroquine may also suggest a compensatory mechanism toensure furtherance of transmission at almost same GMPD, geometric mean parasite density; PRR, parasite potential as in HTS relative to available transmission reduction ratio; FCT, fever clearance time; PCT, parasite aids. This may find relevance in our understanding clearance time. RI ¼ parasitemia disappears but reap- of how the parasite ensures transmission despite pears within 7 to 14 days; RII ¼ decrease of parasitemiabut no complete clearance from peripheral blood; chemotherapy of the infection. More studies would RIII ¼ no pronounced decrease or increase in parasitemia be needed to elucidate parasite response and behaviour to other antimalarial drugs during lowand high transmission seasons.
Overall a strategy that avoids the identified risk and gameytocyte carriage that were similar. In the factors for gametocyte carriage in the two transmis- HTS, post treatment gametocyte intensity was sion seasons and controlled use of antimalarial high but significantly fewer children were carriers drugs may reduce gametocyte prevalence and con- compared with low gametocyte intensity and high tribute to a reduction in malaria transmission.
carriage rate in the LTS. This antimalarial drugchemotherapy may impose stress on the parasite, response to which could result in increased gameto- 1. Carter P, Miller LH. Evidence for environmental cyte production.33,35 The higher sexual parasite density in the HTS may in addition support increased falciparum in continuous culture. Bull WHO 1979; 57 parasite burden on mosquito and probability of 2. Smalley ME, Brown J. Plasmodium falciparum gameto- burden of malaria and high transmission in the area.
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Adaptive changes in Plasmodium transmission strategies with pyrimethamine-sulfadoxine in the treatment of following chloroquine chemotherapy. Proc Roy Soc malaria in children. Ann Trop Med Parasitol 2002; 8. Robert V, Molez J-F, Trape J-F. Short report: gametocytes, chloroquine pressure, and the relative 21. Sowunmi A. A randomized comparison of chloroquine parasite survival advantage of resistant strains of and chloroqunie plus ketotifen, in the treatment falciparum malaria in West Africa. Am J Trop Med malaria in children. Ann Trop Med Parasitol 2003; 9. Robert V, Awono-Ambene HP, Le Hesran J-Y, Trape J-F. Gametocytemia and infectivity to mosqui- malaria. Trans Roy Soc Trop Med Hyg 2000; 94 falciparum malaria attacks treated with chloroquine 23. Shaper AG, Lewis P. Genetic neutropenia in people of or sulfadoxine-pyrimethamine. Am J Trop Med Hyg African origin. Lancet 1971; ii1021–23.
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