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Increased Levels of Inflammatory Mediators in Children with Severe Plasmodium falciparum Malaria with Respiratory Distress

  1. Gordon A. Awandare1,3,
  2. Bamenla Goka2,
  3. Philippe Boeuf4,
  4. John K. A. Tetteh1,
  5. Jorgen A. L. Kurtzhals5,
  6. Charlotte Behr4 and
  7. Bartholomew D. Akanmori1
  1. 1Immunology Department, Noguchi Memorial Institute for Medical Research, and
  2. 2Department of Child Health, University of Ghana Medical School, College of Health Sciences, and
  3. 3Department of Biochemistry, University of Ghana, Legon, Accra;
  4. 4Unité d’Immunologie Moléculaire des Parasites, Institut Pasteur, Paris, France;
  5. 5Centre for Medical Parasitology, Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark
  1. Reprints or correspondence: Prof. Bartholomew Dicky Akanmori, Immunology Dept., Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, PO Box LG 581, Legon, Accra, Ghana (BAkanmori{at}noguchi.mimcom.net)
 
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Abstract

BackgroundRespiratory distress (RD), a symptom of underlying metabolic acidosis, has been identified as a major risk factor for mortality in children with severe malaria in Africa, yet the molecular mediators involved in the pathogenesis of RD have not been identified

MethodsWe studied circulating levels of mediators of inflammation—including the cytokines tumor necrosis factor (TNF)–α and interleukin (IL)–10; the chemokines macrophage inflammatory protein (MIP)–1α, MIP-1β, and IL-8; and the immune activation marker neopterin—in children with RD, severe malarial anemia (SMA), cerebral malaria (CM), and uncomplicated malaria (UM)

ResultsChildren with RD had significantly higher plasma levels of TNF-α, IL-10, and neopterin and a significantly higher TNF-α:IL-10 ratio than those without RD. In addition, the results demonstrated that, relative to UM, CM was associated with increased levels of TNF-α and decreased levels of MIP-1α, whereas SMA was associated with decreased levels of IL-10. Circulating levels of neopterin were inversely correlated with hemoglobin, whereas levels of MIP-1β were positively correlated with parasitemia

ConclusionsWe conclude that distinct clinical presentations of severe malaria are associated with specific patterns of inflammatory mediators. In particular, we show, to our knowledge for the first time, that patients with malaria and RD have a strong and unbalanced proinflammatory response that may be involved in the pathogenesis of the underlying metabolic acidosis

More than 80% of all malaria-related mortality occurs in sub-Saharan Africa, and most cases of malaria are due to Plasmodium falciparum infection [1]. In semi-immune children, classical presentations of severe, life-threatening falciparum malaria are cerebral malaria (CM) and severe malarial anemia (SMA) [2]. In addition, recent studies have identified respiratory distress (RD) as an important clinical indicator of severe life-threatening malaria [3–5]. RD during malaria is usually a symptom of underlying metabolic acidosis, and it often occurs in children concomitantly with CM or SMA. RD increases mortality several-fold in children with SMA or CM, compared with those with SMA or CM alone [3, 4, 6]. However, the pathophysiologic mechanisms responsible for inducing the metabolic abnormalities that cause RD are not known

Mediators of inflammation are important in explaining the pathogenesis of many infectious diseases, including malaria. Various studies have shown that plasma levels of the proinflammatory cytokine tumor necrosis factor (TNF)–α are higher during severe malaria [7–12], which suggests that this mediator plays a role in the pathogenesis of the disease. Although TNF-α may contribute to the protective immune response to malaria by inducing fever, which is detrimental to parasite development, and/or by stimulating effector cells [8], adequate production of anti-inflammatory cytokines such as interleukin (IL)–10 is required to regulate TNF-α production and prevent pathologic consequences. Our previous studies and those of others demonstrated that the clinical course of severe malaria is influenced by the relative imbalance between TNF-α and IL-10 levels [9, 10, 12, 13]. Another important marker of inflammation and immune activation is neopterin, which is a pyrazino-pyrimidino derivative that is released by activated macrophages [14]. Increased circulating neopterin levels are associated with increased severity of anemia during malaria and the persistence of anemia after treatment [15–18]. Although a hypothesis has been proposed to explain the role that immune activation and inflammation play in the development of RD during severe malaria [5, 19], this hypothesis has not been directly investigated

A central part of the inflammatory response to disease is the recruitment of immune cells such as monocytes and neutrophils to sites of infection; this recruitment is elicited by a group of structurally and functionally related proteins called chemokines, which are produced by several types of cell, including lymphocytes and monocytes [20, 21]. Besides their chemotactic properties, chemokines also play a central role in the modulation of immune responses: they influence both the quality and magnitude of the responses. Malaria infection is associated with increased production of some proinflammatory chemokines, including macrophage inflammatory protein (MIP)–1α, MIP-1β, and IL-8 [22–25]. MIP-1α and MIP-1β are potent chemoattractants for monocytes, and they activate monocytes/macrophages to produce TNF-α, IL-6, and IL-1α [26]. IL-8 preferentially recruits neutrophils and plays an important role in inflammatory diseases such as sepsis [27]. The role that chemokines play in the inflammatory response that determines the clinical course and severity of malaria, especially the development of RD in children, remains undefined

A critical factor in understanding the pathogenesis of malaria is an appropriate clinical definition of disease. Clinical characterization has often not been distinct enough, which has led to comparisons between heterogeneous groups with obvious overlaps and has made findings difficult to interpret [28]. To clarify the role that inflammatory mediators play in the pathogenesis of CM, SMA, and RD, we examined circulating levels of TNF-α, IL-10, IL-8, neopterin, MIP-1α, and MIP-1β in children with strictly defined categories of severe malaria. In addition, interrelationships among the different inflammatory mediators and correlations between each mediator with clinical characteristics were also examined

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Materials and Methods

Study area and participantsChildren (1–10 years old) with acute malaria were recruited at the Department of Child Health, Korle-Bu Teaching Hospital, Accra, Ghana, during the peak malaria transmission seasons (July–August) of 2 consecutive years, 2000 and 2001. In addition, apparently healthy children from a nearby community, Dodowa, were enrolled as asymptomatic control subjects (ACs). The study area is situated on the coastal savannah of Ghana, where malaria transmission is low to moderate, seasonal, and hyperendemic [29]. P. falciparum accounts for >90% of asymptomatic infections and >95% of clinical cases of malaria in this area [29]. The study was approved by the ethics and protocol review committee of the University of Ghana Medical School and by the Ghanaian Ministry of Health. All patients and control subjects were enrolled in the study only after signed, informed, parental consent was obtained

Inclusion criteriaGeneral inclusion criteria for acute malaria were asexual P. falciparum parasitemia >10,000 parasites/μL and axillary temperature >37.5°C. Children with any clinical presentation other than malaria or with a positive sickling test (metabisulfite method) were excluded from the study. Children with acute malaria were categorized as having uncomplicated malaria (UM; n=24) or severe malaria (SM; n=57). SM was defined as the presence of ⩾1 of SMA, CM, and RD. Categorization criteria were as follows: UM, full consciousness (Blantyre coma score, 5), hemoglobin (Hb) level ⩾8 g/dL, and no complications of malaria; SMA, Hb level <5 g/dL, no other cause of anemia, and full consciousness; CM, unrousable coma with a Blantyre score of ⩽3 for >60 min and no sign of meningitis or encephalitis on assessment of cerebrospinal fluid or other possible causes of coma, Hb level >5 g/dL; RD, rapid breathing plus ⩾1 of alar flare, chest recessions, use of accessory muscles for respiration, or abnormally deep breathing. Children with convulsions were excluded from the SMA and UM groups because febrile convulsions occur more frequently in malaria than in other febrile illnesses, which makes a degree of cerebral involvement difficult to exclude [30]

Blood collectionVenous blood was collected, at admission and before treatment, in sterile Vacutainer tubes that contained heparin as an anticoagulant. Plasma was obtained by centrifugation at 450 g for 10 min within 30 min of blood collection, and it was stored at −80°C until use

Laboratory analysesHb levels and complete blood cell counts were determined using an 18-parameter automated hematology analyzer (KX-21; Sysmex). Giemsa-stained thick and thin blood films were used for microscopic detection and the identification of Plasmodium parasites. Parasites were counted against 300 white blood cells (WBCs), and the value was converted into parasites per microliter of blood, on the basis of each individual’s WBC count. Creatinine levels in plasma were determined on a Microlab 200 device (Vital Scientific), using the kinetic rate method (Randox Laboratories) to reduce the effects of interference by other substances. Briefly, 0.1 mL of standard creatinine or sample was added to 1.0 mL of working reagent (0.5 mL of picric acid [35 mmol/L] with 0.5 mL of sodium hydroxide [0.32 mol/L]), mixed in a cuvette, and the absorbance read at 492 nm at 37°C. The minimum detectable level was 14 μmol/L

Management of patientsIn accordance with institutional guidelines at the time, patients were treated with chloroquine at a total dose of 25 mg/kg body weight, administered as single daily doses over the course of 3 days; or with artesunate, 2.4 mg/kg initially, then 1.2 mg/kg at 12 and 24 h, then daily to complete a 7-day course. In the case of treatment failure, treatment was changed to amodiaquine (10 mg/kg body weight per day, as single daily doses for 3 days). Patients who were not fully conscious were treated with either amodiaquine syrup via nasogastric tube at the same dosage as those listed above or with intramuscular (im) quinine sulfate (10 mg/kg body weight every 8 h). This regimen of im quinine was changed to syrup at the same dosage when patients regained full consciousness or after 72 h (whichever was earlier), to complete a 7-day course. Patients with SMA or RD were given humidified oxygen, and children with Hb levels <5 g/dL received blood transfusions

Cytokine assaysPlasma concentrations of all inflammatory mediators were measured using commercial ELISA kits. IL-10, TNF-α, IL-8, MIP-1α, and MIP-1β levels were determined using Quantikine ELISA assays (D1000, DTA50, D8050, DMA00, and DMB00; R & D Systems). Limits of detection were >4 pg/mL for IL-10 and TNF-α and >10 pg/mL for IL-8, MIP-1α, and MIP-1β. Neopterin levels were determined using an ELISA kit from IBL (RE 59321), with a detection limit of >0.7 nmol/L. The Quantikine TNF-α assay detects both free and soluble receptor-bound TNF-α (R & D Systems). All assays were conducted in accordance with the manufacturer’s recommendations

Statistical analysesPlasma levels of inflammatory mediators were compared across ⩾3 groups by 1-way analysis of variance on&amp;ranks; where significant differences were observed, pairwise comparisons were conducted using Dunn’s test and the Mann-Whitney U test. Associations between different variables were analyzed by Spearman’s&amp;rank correlation, and coefficients ρ>0.25 and P<.05 were considered to be statistically significant

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Results

Characteristics of study participantsEighty-one children with acute P. falciparum malaria and 19 ACs were enrolled in the study. Patients with malaria were categorized as having UM (n=24) or SM (n=57), according to the criteria outlined in Materials and Methods. Children with SM were further divided into 2 major groups: SM with RD (SM+RD; n=18) and SM without RD (SM no RD; n=38), the latter group consisted of children with SMA (n=21), CM (n=15), or a combination of SMA and deep coma (n=2) (figure 1). There were no significant differences in age (P=.349), sex distribution (P=.137), and parasitemia levels (P=.513) across the UM, SM no RD, and SM+RD groups (table 1). Hb levels were markedly lower in patients with SM, compared with those with UM (P<.001 across groups) (table 1), but there was no significant difference in Hb levels between the SM+RD and SM no RD groups (P=.344). Because renal malfunction could affect the excretion of mediators such as neopterin, creatinine levels were measured and compared across groups. There were no significant differences in creatinine levels among children in the 3 groups (P=.803) (table 1), which suggests that renal function was not impaired in children with SM+RD, compared with those with SM no RD or UM. Most of the children in each group were treated with chloroquine or artesunate (table 1); however, a larger proportion of children in the SM no RD group received amodiaquine and quinine than children in the other groups, because this group included more children who were not fully conscious. The overall case-fatality rate (CFR) was 5.6%, and CFRs by disease category were 0% for UM, 4% for SMA, 27% for CM, and 44% for SM+RD

Figure 1
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Figure 1

Clinical presentations of children with severe malaria (SM). Children admitted to the pediatric ward of the Korle Bu teaching hospital, Accra, with ⩾1 symptom of SM were recruited. Symptoms of SM included coma (score ⩽3 on the Blantyre scale), severe anemia (hemoglobin [Hb] level, <5.0 g/dL), and respiratory distress (RD; rapid breathing involving abdominal muscles with alar flare). The no. of children showing the various symptoms, as well as the levels of Hb (in grams per deciliter) and parasitemia (Para, in parasites per microliter) are shown. The severe malarial anemia (SMA) and cerebral malaria (CM) categories were reserved for children with nonoverlapping symptoms as shown. Hb and para are presented as mean (SE) level

Levels of inflammatory mediators in children in the SM+RD groupIn our study cohort, 32% of children with severe malarial presentations (i.e., coma or severe anemia) had concomitant RD (figure 1), and this group had the highest CFR. To assess the contribution of inflammatory mediators to the development of RD, levels of the cytokines TNF-α and IL-10; the chemokines IL-8, MIP-1α, and MIP-1β; and the macrophage activation marker neopterin were determined in children with UM or with SM and RD or no RD. Preliminary analysis conducted that compared children with SMA with those with RD and Hb levels <5 g/dL and children with CM with those with RD and a coma score of ⩽3 revealed a pattern of increased levels of inflammatory mediators associated with RD (data not shown). Therefore, children with SM were stratified into 2 major groups—SM+RD and SM no RD—and levels of mediators were compared between the 2 groups and with children with UM. Circulating levels of TNF-α were higher in children with SM+RD than in those with UM (P<.05) and SM no RD (P=.05) (figure 2A). IL-10 levels were significantly higher in the SM+RD group relative to those in the SM no RD group (P<.05) (figure 2B). There were no significant differences in IL-10 levels between the UM and SM+RD or SM no RD groups (figure 2B). Furthermore, the TNF-α:IL-10 ratio was higher in children with SM+RD, compared with those with UM (P<.05) and SM no RD (P<.05) (figure 2C). However, there was no significant difference in TNF-α:IL-10 ratios between the UM and SM no RD groups, which suggests that the presence of RD may be related to a dysregulation in the balance between pro- and anti-inflammatory signals

Figure 2
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Figure 2

Increased circulating levels of inflammatory mediators in children with severe malaria (SM) with respiratory distress (RD). Plasma levels of inflammatory mediators in children with uncomplicated malaria (UM; n=24) and SM (hemoglobin [Hb] level, <5 g/dL, coma score ⩽3, or both) without RD (SM no RD; n=38), or with RD (SM+RD; n=18) were determined using ELISA. Data show plasma levels of the cytokines tumor necrosis factor (TNF)–α (A) and interleukin (IL)–10 (B) TNF-α:IL-10 ratio (C) and the marker of immune activation neopterin (D). Levels of mediators are presented as box plots: the box shows the interquartile range, the line through the box is the median, whiskers indicate the 10th and 90th percentiles, and individual symbols are data outside the 10th to 90th percentile range. *P<.05, #P=.05, **P<.005, Mann-Whitney U test

Plasma levels of the immune activation marker neopterin were significantly higher in children with SM+RD, compared with those with UM (P<.05) and SM no RD (P<.005) (figure 2D). Neopterin levels were not significantly different between the UM and SM no RD groups (figure 2D), which suggests that increased immune activation may be specifically associated with RD. There were no statistically significant differences in levels of the chemokines IL-8, MIP-1α, and MIP-1β among children in the UM, SM no RD, and SM+RD groups (data not shown)

Plasma levels of inflammatory mediators in children with distinct clinical presentations without RDTo investigate the role of inflammatory mediators in the pathogenesis of distinct forms of severe malaria, plasma levels of TNF-α, IL-10, neopterin, IL-8, MIP-1α, and MIP-1β were compared between groups of children with strictly defined clinical categories of acute malaria (UM, SMA, and CM) and age-matched ACs. As shown in table 2, levels of all mediators except MIP-1α were significantly higher in all categories of children with acute malaria than in ACs (P<.05 for all mediators). Among categories of children with acute malaria, TNF-α levels were significantly higher in children with CM than in those with UM (P<.05), whereas children with SMA had lower IL-10 levels than in those with UM (P<.05). There were no significant differences in levels of neopterin, IL-8, and MIP-1β among the 3 clinically distinct groups of children with malaria (table 2). However, children with CM had significantly lower levels of MIP-1α than those with UM (P<.05), and a similar trend was seen for children with SMA (P=.06)

Figure 3
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Figure 3

Relationships of inflammatory mediators with parasitemia and hemoglobin (Hb) levels in children with acute malaria. Associations between circulating levels of the chemokine macrophage inflammatory protein (MIP)–1β and parasitemia (A) and neopterin and Hb level (B) in children with acute malaria are shown by scatter plots with regression lines. The association between neopterin and Hb was presented separately for the uncomplicated malaria (UM; mean Hb level, 9.5 g/dL) and severe malaria (SM; mean Hb level, 5.8 g/dL) groups, to illustrate the differences in the strengths of associations between the 2 groups. Statistical correlation was determined using Spearman’s&amp;rank correlation test. Correlation coefficients ρ>0.25 and P<.05 were considered to be statistically significant

Table 1
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Table 1

Demographic, clinical, and laboratory characteristics of children with malaria

Table 2
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Table 2

Circulating levels of inflammatory mediators in children with acute malaria and asymptomatic control subjects (ACs)

Association of levels of inflammatory mediators with parasitemia and Hb levelsThe relationships of individual inflammatory mediators with each other and with parasitemia and Hb levels were examined using Spearman’s&amp;rank correlational analyses. With the exception of neopterin, there was a high degree of correlation among all inflammatory mediators in children with acute malaria (ρ>0.25; P<.05 for all correlations except IL-10 vs. MIP-1α) (table 3). In addition, MIP-1β was positively correlated with parasitemia in children with acute malaria (ρ=0.257; P<.05) (figure 3A). There was no significant association between parasitemia and any of the other inflammatory mediators (data not shown). Finally, neopterin was inversely associated with Hb levels in the combined group of children with acute malaria (ρ=-0.210; P=.08) (figure 3B); this association was markedly stronger in children with UM (mean Hb level, 9.5 g/dL; ρ=-0.530; P<.05) than in those with SM (mean Hb level, 5.8 g/dL; ρ=-0.241; P=.08) (figure 3B)

Table 3
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Table 3

Correlations between inflammatory mediators in children with acute malaria

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Discussion

The present study examined a broad range of inflammatory mediators—including the cytokines TNF-α and IL-10; the chemokines IL-8, MIP-1α, and MIP-1β; and a marker of cellular immune activation, neopterin—in children with UM or with ⩾1 symptom of SM. The study was conducted in an area of moderate P. falciparum transmission where all the life-threatening complications of malaria occur—namely, coma, severe anemia, and RD. This allowed an unprecedented investigation of the molecular mediators of different clinical presentations of severe disease, including RD. The finding that levels of all inflammatory mediators were significantly higher in children presenting with acute malaria, compared with ACs, some of whom harbored low levels of parasitemia (<1000 parasites/μL), supports previous studies that described acute malaria as mainly a disease of immune activation and inflammation [19]. Moreover, the strong positive correlation between levels of the majority of the immune mediators examined suggests a generalized inflammation with cross-talk between cytokines and chemokines

The highest CFR was observed in children presenting with SM+RD, and RD emerged as the most important predictor of mortality, which supports similar observations in Kenyan cohorts [3, 4]. Malaria-related RD is usually a manifestation of metabolic acidosis [4, 5], which is significantly distinct from the hypoglycemia and hyperlactatemia that also occur during acute malaria [19]. The mechanisms responsible for malaria-induced metabolic acidosis have not been established; therefore, we investigated the production of proinflammatory mediators as a potential cause of RD in children with malaria. Because there was only 1 patient with RD as the single severe malarial presentation, we compared levels of mediators in children with SM with and without RD. Although neopterin levels were not significantly higher in children with either SMA or CM than in those with UM, the presence of RD in children with SM was particularly associated with higher circulating neopterin levels. This pattern suggests that the mechanisms of the pathogenesis of RD may be quite different from those responsible for SMA and CM and that RD may not simply be an end stage of either condition. In addition to neopterin levels, TNF-α levels were also substantially higher in children with RD relative to those without RD, which suggests that a stronger proinflammatory response is associated with RD. Because circulating TNF-α levels during malaria correlate with mortality [7] and RD is the best predictor of mortality, increased TNF-α levels in persons with RD may be a potential causal link between RD and mortality

An integral part of a protective immune response to malaria infection is the induction of interferon (IFN)–γ by IL-12; IFN-γ mediates control of parasitemia by activating monocytes and macrophages to undertake phagocytosis and secrete antiplasmodial mediators, including TNF-α and nitric oxide (NO) [31]. IFN-γ–activated monocytes and macrophages also secrete neopterin, which serves as a useful marker of cellular immune activation and phagocytosis [14, 32]. Despite their important role in parasite clearance, the immune activation and production of proinflammatory cytokines can be deleterious if it is not well regulated. The increased levels of the anti-inflammatory cytokine IL-10 observed in children with RD indicate an attempt to regulate an excessive inflammatory response. However, the TNF-α:IL-10 ratio in children with SM+RD was 2-fold higher than that in children with SM no RD, and it was 3-fold higher than that in children with UM, which suggests a profound imbalance in favor of proinflammatory mediators in children with RD

Steroid treatment of an adult patient with malaria has been shown to resolve RD, coincident with a rapid decrease in plasma levels of proinflammatory cytokines, including TNF-α [33], which supports an association between increased proinflammatory cytokine levels and RD. Acidosis is caused by the accumulation of protons resulting from an overreliance on the anaerobic regeneration of ATP, which is usually due to disruptions in the oxidative phosphorylation pathways. Inflammatory mediators are capable of inhibiting enzymes of oxidative phosphorylation via downstream effector molecules, such as the free radical NO, which could be responsible for RD in children with malaria [19]. Moreover, studies in adults with malaria have shown that high TNF-α is associated with multiple organ dysfunction [34], which could result in metabolic acidosis. In addition, neopterin and its derivatives influence the redox balance by modulating the formation of free radicals [35], and it synergizes with IFN-γ to sustain TNF-α production [36]. Thus, in addition to being a marker of immune activation, neopterin has biological activities that may directly or indirectly be involved in causing metabolic acidosis in children with malaria-associated RD

Consistent with our previous observations in the same area, CM was associated with significantly higher TNF-α levels, whereas SMA was associated with decreased IL-10 levels, relative to children with UM [9, 10]. Parallels have been drawn between CM and sepsis, and the role that TNF-α plays in the pathogenesis of the 2 diseases is thought to be similar (i.e., the promotion of systemic inflammation) [19, 37]. The decreased IL-10 levels in children with SMA may allow dysregulated TNF-α production, which could promote the development of SMA by causing dyserythropoiesis and increasing erythrophagocytosis [38]. There was no association between levels of the chemokines MIP-1β and IL-8 with the development of SMA or CM. However, MIP-1α levels were significantly lower in children with CM than in those with UM. Because MIP-1α induces TNF-α [26], the high levels of TNF-α in CM may be suppressing MIP-1α via feedback regulation. In addition, there was a significant positive correlation between MIP-1β levels and parasitemia, which suggests that parasitic antigens may be directly involved in the induction of MIP-1β. One candidate is hemozoin, which has recently been shown to induce the production of β-chemokines in vitro [25]

Previous studies have observed associations between increased neopterin levels and malarial anemia [17, 18]. Although neopterin levels were not significantly higher in children with SMA than in those with CM and UM, we observed a significant inverse correlation between neopterin and Hb levels. Interestingly, this association was markedly stronger in the less-anemic UM children than in children with SM, most of whom had pronounced anemia, which suggests that the role neopterin plays may be more important during the process of decreasing Hb, rather than after the attainment of severe malaria. Alternatively, this may suggest that severe anemia is distinct from moderate reductions in Hb levels in children with malaria, as was suggested by our previous studies of IL-10 levels in persons with SMA [9]

Taken together, the present results illustrate that distinct clinical presentations of SM are associated with specific patterns of inflammatory cytokine and chemokine levels. More importantly, the data show that, although malaria-associated RD usually occurs in association with CM and SMA, RD is a separate severe malarial presentation, and it may have different mechanisms of pathogenesis. We have shown, to our knowledge for the first time, that RD in children with malaria is characterized by a strong and unbalanced proinflammatory response that may be involved in the pathogenesis of the underlying metabolic acidosis

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Acknowledgments

We thank Eric Kyei-Baffour, for technical assistance; the staff at the Department of Child Health, Korle-Bu Teaching Hospital, Accra, and at the Immunology Department of Noguchi Memorial Institute for Medical Research, Legon, for various contributions; and the study participants and their parents or guardians

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Footnotes

  • ↵Financial support: United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases (TDR) (Multilateral Initiative on Malaria/TDR grant 980037); International Cooperation Program of the European Commission with Developing Countries (project IC18CT980370); Programme for Enhancement of Research Capacity in Developing Countries, Danish International Development Assistance

    Potential conflicts of interest: none reported

  • Received May 23, 2006.
  • Accepted July 22, 2006.
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  1. J Infect Dis. (2006) 194 (10): 1438-1446. doi: 10.1086/508547
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