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Plasma Concentrations of Soluble Urokinase-Type Plasminogen Activator Receptor Are Increased in Patients with Malaria and Are Associated with a Poor Clinical or a Fatal Outcome

  1. Sisse R. Ostrowski1,
  2. Henrik Ullum1,2,
  3. Bamenla Q. Goka7,
  4. Gunilla Høyer-Hansen4,
  5. George Obeng-Adjei7,
  6. Bente K. Pedersen1,5,
  7. Bartholomew D. Akanmori8 and
  8. Jørgen A. L. Kurtzhals3,6
  1. Departments of
  2. 1Infectious Diseases,
  3. 2Clinical Immunology, and
  4. 3Clinical Microbiology,
  5. 4Finsen Laboratory,
  6. 5Copenhagen Muscle Research Centre, and
  7. 6Centre for Medical Parasitology, Rigshospitalet, Copenhagen, Denmark;
  8. 7Department of Child Health, Korle-Bu Teaching Hospital, Accra, and
  9. 8Immunology Unit, Noguchi Memorial Institute for Medical Research, Legon, Ghana
  1. Reprints or correspondence: Dr. Sisse R. Ostrowski, Rigshospitalet, Dept. of Infectious Diseases M7641, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (sro{at}dadlnet.dk)
 
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Abstract

BackgroundBlood concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) are increased in conditions with immune activation, and high concentrations of suPAR often predict a poor clinical outcome. This study explored the hypothesis that high plasma concentrations of suPAR are associated with disease severity in malaria

MethodsAt admission to the hospital, plasma concentrations of suPAR were measured by ELISA in samples from 645 African children with clinical symptoms of malaria: 478 had malaria, and 167 had a blood film negative for Plasmodium parasites. Fourteen healthy children were included for comparison

ResultsPlasma concentrations of suPAR were higher in patients with malaria (median, 7.90 ng/mL [interquartile range {IQR}, 6.56–9.15 ng/mL]), compared with those in plasmodium-negative patients (median, 5.59 ng/mL [IQR, 4.54–8.16 ng/mL]; P<.001) and those in healthy children (3.94 ng/mL [IQR, 3.46–4.82 ng/mL]; P<.001). The highest concentrations were found in patients with malaria who died (P=.008) or had complicated malaria (P<.001). In univariate logistic regression analysis, a 1 ng/mL increase in plasma concentration of suPAR was associated with increased risk of mortality (odds ratio, 1.42 [95% confidence interval, 1.09–1.86]; P=.009). In multivariate linear regression analysis, lower platelet count, lower hemoglobin level, and higher neutrophil count were independently associated with a higher plasma concentration of suPAR

ConclusionsIf the plasma concentration of suPAR reflects the extent of parasite-induced immune activation, this may explain why a high concentration of suPAR is associated with a poor clinical outcome in patients with malaria

Blood concentrations of soluble urokinase-type plasminogen activator receptor (suPAR; CD87) are increased in several diseases with profound immune activation, such as sepsis [1 –3], HIV-1 infection [4], Mycobacterium tuberculosis infection [5], rheumatoid arthritis [6], and various neoplastic diseases [7]. Furthermore, high blood concentrations of suPAR independently predict high mortality in patients with sepsis [3], patients with M. tuberculosis infection [5], patients with HIV-1 [8], and patients with any of many neoplastic diseases [7]

Urokinase-type plasminogen activator receptor (uPAR) is a central component (the cellular receptor for the serine protease urokinase-type plasminogen activator [uPA]) of the plasminogen activation system [9]. uPAR is expressed by various immune cells (neutrophils, eosinophils, monocytes, macrophages, activated T lymphocytes, and NK cells) [10 –12], endothelial cells [13], megakaryocytes [14], and certain tumor cells [7, 9]. uPAR is not expressed by platelets, erythrocytes, or resting T and B lymphocytes [12]. Since uPAR can be shed from the cell surface [9, 15, 16], suPAR is present in most human body fluids [7, 9]. uPAR is involved in recruitment of leukocytes from the circulation to extravascular sites of inflammation through its regulatory effects on pericellular proteolysis, cell adhesion, migration, chemotaxis, mitogenesis, and signal transduction [7, 9, 17 –19]

Infection with Plasmodium falciparum is associated with profound immune activation [20], and excess production of tumor necrosis factor (TNF)–α contributes significantly to the pathogenesis of severe malaria [21 –24]. It was recently demonstrated that serum concentrations of suPAR are increased in children with acute malaria [25]. However, it is not known whether circulating concentrations of suPAR are associated with disease severity or clinical outcome in patients with acute malaria. To study this, we investigated plasma concentrations of suPAR in children with acute malaria (n=478), children with clinical symptoms compatible with acute malaria but with a blood film negative for Plasmodium parasites (n=167), and healthy children (n=14)

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Patients, Materials, and Methods

Patients Children with reported or observed fever and clinical symptoms compatible with acute malaria who were admitted to the emergency room at the Department of Child Health, Korle-Bu Teaching Hospital, Accra, Ghana, during the malaria transmission season (June–August) of 2000 and 2001 were enrolled in the study (n=645). All parents gave signed, informed consent for the participation of their children. The study was approved by the Ethical and Protocol Review Committee of the University of Ghana Medical School. The children were divided into 2 groups according to the presence or absence of asexual Plasmodium parasites in their blood: 478 children had a blood film positive for Plasmodium parasites (patients with malaria), and 167 children had a blood film negative for Plasmodium parasites (plasmodium-negative patients) (table 1). Common differential diagnoses in the plasmodium-negative group were otitis media, upper respiratory tract infection, urinary tract infection, gastrointestinal infection, septicemia, and febrile convulsions due to viral or bacterial infection

Figure 1
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Figure 1

Plasma concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) in children with malaria, children with acute febrile illness without malaria, and healthy age- and sex-matched children. Median (interquartile range) plasma concentrations of suPAR are shown for children with detectable Plasmodium parasites in thick or thin Giemsa-stained blood films (patients with malaria [•]; n=478), children with clinical symptoms compatible with acute malaria but without detectable Plasmodium parasites (plasmodium-negative patients [▴]; n=167), and healthy age- and sex-matched children (healthy children [▪]; n=14) (A) and for 478 children with malaria stratified into clinical groups according to fatal outcome (B) respiratory distress (C) coma (Blantyre coma score ⩽3 and coma lasting ⩾1 h) (D) hypoglycemia (blood glucose concentration ⩽2.2 mmol/L) (E) severe anemia (hemoglobin level ⩽5 g/dL) (F) or sickling phenotype (G). Please refer to the text for details about statistical analyses

Figure 2
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Figure 2

Correlations between plasma concentration of soluble urokinase-type plasminogen activator receptor (suPAR) and paraclinical variables in patients with malaria. Shown are correlations between plasma concentration of suPAR and asexual Plasmodium parasitemia (A) neutrophil count (B) platelet count (C) hemoglobin level (D) platelet distribution width (E) and red cell distribution width (F). Linear correlations with 95% confidence intervals are shown. Some variables were log transformed—parasitemia (log10), neutrophil count (log2), and platelet count (log2)—to provide a better linear fit, as determined by Pearson’s correlation coefficient (R)

Table 1
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Table 1

Clinical and paraclinical characteristics of patients with malaria and patients with a blood film negative for Plasmodium parasites (plasmodium negative)

In accordance with our previously described definitions of patients [26], plasma concentrations of suPAR were compared between children stratified according to the following diagnoses: respiratory distress (presence of alar flare, chest recession, abnormally deep breathing, and use of accessory muscles), coma (Blantyre coma score ⩽3 and coma lasting ⩾1 h), severe anemia (hemoglobin level ⩽5 g/dL), and severe hypoglycemia (blood glucose concentration ⩽2.2 mmol/L). The following information was obtained from the clinical history/examination: age (years), sex, duration of symptoms before admission (days), axillary body temperature at the time of collection of blood samples, liver and spleen sizes (centimeters below the curvature), and death. Fourteen healthy age-matched (median, 4 years old [interquartile range {IQR}, 4–6 years old]) and sex-matched (63% boys) children randomly selected from a school in the suburban community of Madina were included for comparison. The healthy children did not have microscopically detectable parasites

Collection of blood samples and hematological analysis  Five-milliliter blood samples were collected in EDTA at admission to the hospital, and plasma was separated by centrifugation and stored at −18°C. Thick and thin Giemsa-stained blood films were prepared from each sample. Parasites were counted relative to 300 white blood cells (WBCs), and parasitemia was calculated from the measured WBC count. One thousand WBCs were counted before a slide was declared to be negative. Hematological analysis was performed by use of an 18-parameter automatic hematological analyzer (Sysmex KX-21; Norderstedt); hemoglobin level, red blood cell (RBC) count, red cell distribution width (RDW), platelet count, platelet distribution width (PDW), total WBC count, neutrophil count, mixed cell (monocytes, eosinophils, and basophils) count, and lymphocyte count were determined. The blood glucose concentration was measured by the glucose oxidase method. Presence of a sickling phenotype was investigated by microscopy of EDTA-blood after incubation with metabisulphate

Plasma concentrations of suPAR suPAR was measured in thawed EDTA-plasma by use of a double-sandwich ELISA [27, 28]. Briefly, immunoassay plates (Nunc) coated with murine monoclonal antibody R2 (against uPAR domain 3) (0.3 μg/well) were incubated with 1:10 dilutions of plasma (sample dilution buffer containing 50×103 U/L heparin). Bound suPAR was detected by use of rabbit polyclonal anti-suPAR antibody (0.1 μg/well), and the color reaction between alkaline-phosphatase–conjugated anti–rabbit IgG (Clone RG-96; Sigma-Aldrich) and p-nitrophenyl phosphate was analyzed by end-point measurements. The lower limit of detection of the assay was 0.008 ng/mL. The intra- and interassay coefficients of variation were 6.6% (EDTA-plasma pool: mean concentration of suPAR, 2.31 ng/mL) and 13.2%, respectively

Statistics The plasma concentrations of suPAR in patients with malaria, plasmodium-negative patients, and healthy children were compared by analysis of variance. The plasma concentrations of suPAR in healthy children were compared with those in patients with malaria and those in plasmodium-negative patients by use of the Bonferroni adjusted post hoc 2-sample t test. The plasma concentrations of suPAR in patients with malaria were compared with those in plasmodium-negative patients by use of post hoc analysis of covariance (ANCOVA), with adjustment for age, sex, duration of symptoms before admission, temperature at the time of collection of blood samples, coma, and respiratory distress. Continuous and categorical variables for patients with malaria were compared with those for plasmodium-negative patients by use of a 2-sample t test and χ2/Fisher’s exact test, respectively. The plasma concentrations of suPAR in the clinical groups were compared by ANCOVA, with adjustment for age and sex. Results of the ANCOVA are presented as mean differences in plasma concentration of suPAR after adjustment for covariates. Goodness-of-fit of the linear models was assessed by investigating the residuals. Only covariates with parallel regression lines within the groups were included in the ANCOVA

Simple linear correlations were analyzed by Pearson’s correlations; results are shown with R and P values. By linear regression analysis, the contribution of parasitemia, platelet count, PDW, hemoglobin level, RDW, neutrophil count, and blood glucose concentration to the variation in plasma concentrations of suPAR in patients with malaria was investigated. Parasitemia, platelet count, and neutrophil count were log transformed in the linear regression analysis, to ensure a normal distribution of the residuals. Results are presented as regression coefficients (β) with 95% confidence intervals (CIs), t values, and P values

By logistic regression analysis, it was investigated whether changes in paraclinical (plasma concentration of suPAR, blood glucose concentration, WBC count, parasitemia, hemoglobin level, and platelet count) and clinical (respiratory distress and coma) variables could predict increased risk of mortality in patients with malaria. Significant univariate paraclinical variables were included in a multivariate logistic regression model that predicted increased risk of mortality. Some paraclinical variables in the logistic regression model were log transformed, to provide the best fit, as determined by the Wald χ2 value (parasitemia [log10] and platelet counts [log2]). Results from the logistic regression analysis are presented as odds ratios (ORs) with 95% CIs and Wald χ2 and P values. Data are presented as medians with IQRs. Two-sided P<.05 was considered to be significant. Statistical calculations were performed by use of SAS (version 8.2; SAS Institute)

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Results

Patient Characteristics

Patients with malaria and plasmodium-negative patients had comparable ages, sex distribution, durations of symptoms before admission, and temperatures at the time of collection of blood samples (table 1). Patients with malaria had a higher prevalence of coma and respiratory distress but a lower prevalence of sickling phenotype, whereas the prevalences of hypoglycemia, severe anemia, and death were comparable between groups (table 1). Patients with malaria had lower hemoglobin levels, RBC counts, RDW, platelet counts, and WBC counts but higher PDW, compared with plasmodium-negative patients (table 1). The 2 groups had comparable blood glucose concentrations (table 1), whereas patients with malaria had lower neutrophil counts (P<.001) and mixed cell counts (P<.001) and a tendency toward lower lymphocyte counts (P=.074) (data not shown)

Plasma Concentrations of suPAR in Patients with Malaria

Plasma concentrations of suPAR and disease severity After adjustment for relevant covariates, plasma concentrations of suPAR were higher in patients with malaria, compared with those in plasmodium-negative patients (1.15 ng/mL [95% CI, 0.74–1.56 ng/mL] higher) (figure 1A ). Plasma concentrations of suPAR were also higher in patients with malaria, compared with those in healthy children (figure 1A ). After adjustment for age and sex, plasma concentrations of suPAR were higher in patients with malaria who died (1.6 ng/mL [95% CI, 0.43–2.92 ng/mL] higher) or had respiratory distress (1.09 ng/mL [95% CI, 0.61–1.56 ng/mL] higher), coma (0.94 ng/mL [95% CI, 0.48–1.40 ng/mL] higher), or hypoglycemia (1.47 ng/mL [95% CI, 0.73–2.21 ng/mL] higher) (figure 1B–E ). In patients with malaria, plasma concentrations of suPAR were comparable between those with and those without severe anemia (0.16 ng/mL [95% CI, −0.27 to 0.58 ng/mL] higher) (figure 1F ) but were lower in patients with malaria with a sickling phenotype (−1.48 ng/mL [95% CI, −2.28 to −0.67 ng/mL] lower) (figure 1G ). Plasma concentration of suPAR correlated negatively with duration of symptoms before admission (R=-0.10; P=.031) and positively with temperature at the time of collection of blood samples (R=0.16; P < .001) and liver size (R=0.23; P<.001) but did not correlate with spleen size (R=0.02; P=.633)

Plasma concentrations of suPAR and paraclinical surrogate markers for disease severity in malaria Plasma concentration of suPAR correlated positively with parasitemia (figure 2A ), neutrophil count (figure 2B ), and PDW (figure 2E ) and negatively with platelet count (figure 2C ) and RDW (figure 2F ). In patients with malaria, plasma concentration of suPAR did not correlate with hemoglobin level (figure 2D ) or RBC count (R=-0.07; P=.170)

Plasma concentration of suPAR correlated positively with WBC count (R=0.14; P=.005) but did not correlate with mixed cell count (R=-0.01; P=.855) or lymphocyte count (R=0.07; P=.171). Plasma concentration of suPAR correlated negatively with blood glucose concentration (R = −0.13; P=.006)

In univariate linear regression analysis with plasma concentration of suPAR as a dependent variable, higher parasite level, PDW, and neutrophil count and lower platelet count, hemoglobin level, and RDW were associated with a higher plasma concentration of suPAR (table 2). In multivariate linear regression analysis, a 2-fold lower platelet count, a 1 g/dL lower hemoglobin level, and a 2-fold higher neutrophil count were independently associated with a 0.12–0.82 ng/mL higher plasma concentration of suPAR, which explains 26% of the variation in plasma concentrations of suPAR (table 2)

Table 2
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Table 2

Contribution of paraclinical variables to the plasma concentration of soluble urokinase-type plasminogen activator receptor (suPAR) in patients with malaria

Plasma concentration of suPAR and mortality In univariate logistic regression analysis, a 1 ng/mL higher plasma concentration of suPAR predicted increased risk of mortality (table 3). Other paraclinical variables that predicted increased risk of mortality were lower blood glucose concentration and higher WBC count, whereas parasitemia, hemoglobin level, and platelet count did not predict increased risk of mortality (table 3). In multivariate logistic regression analysis with adjustment for significant univariate paraclinical variables, only blood glucose concentration predicted increased risk of mortality (table 3)

Table 3
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Table 3

Paraclinical variables that predicted increased risk of mortality in patients with malaria

In univariate logistic regression analysis, respiratory distress and coma both predicted increased risk of mortality (OR, 8.86 [95% CI, 2.50–31.46] [χ2=11.4; P=.001] and OR, 7.86 [95% CI, 2.22–27.82] [χ2=10.2; P=.001], respectively). Overall, plasma concentration of suPAR was a univariate predictor of increased risk of mortality and increased with disease severity, a shorter duration of symptoms before admission, and a higher degree of parasitemia, thrombocytopenia, neutrophilia, anemia, and hypoglycemia

Plasma Concentrations of suPAR in Plasmodium-Negative Patients

Plasma concentrations of suPAR were higher in plasmodium-negative patients, compared with those in healthy children (figure 1A ). Several clinical and paraclinical variables correlated with plasma concentration of suPAR in a way similar to that seen in patients with malaria. Thus, plasma concentrations of suPAR were highest (ANCOVA, with adjustment for age and sex) in patients who died (2.53 ng/mL [95% CI, 0.05–5.02 ng/mL] higher; P=.047), had respiratory distress (1.57 ng/mL [95% CI, 0.21–2.92 ng/mL] higher; P=.024), or had hypoglycemia (1.76 ng/mL [95% CI, 0.06–3.45 ng/mL] higher; P = .043, with adjustment for age only, because of a significant interaction between sex and hypoglycemia). Plasma concentration of suPAR correlated positively with liver size (R=0.40; P < .001), temperature at the time of collection of blood samples (R=0.15; P=.049), and PDW (R=0.46; P<.001) and negatively with platelet count (R=-0.37; P<.001). In plasmodium-negative patients, plasma concentration of suPAR tended to correlate with WBC count (R=0.15; P=.076) and lymphocyte count (R=0.16; P=.056) but did not correlate with RDW (R=0.02; P=.832)

In contrast to the findings for patients with malaria, plasma concentrations of suPAR were highest in plasmodium-negative patients with severe anemia (ANCOVA; 2.11 ng/mL [95% CI, 1.23–2.99 ng/mL] higher; P<.001) and correlated negatively with hemoglobin level (R=-0.39; P<.001) and RBC count (R=-0.35; P<.001). Plasma concentrations of suPAR were comparable between patients with or without coma or a sickling phenotype (data not shown); plasma concentration of suPAR correlated positively with spleen size (R=0.38; P<.001) and duration of symptoms before admission (R=0.23; P=.002) but did not correlate with blood glucose concentration (R=-0.02; P=.759) or neutrophil count (R=0.10; P=.299). Because of the low number of fatal cases in this group, it was not investigated whether plasma concentration of suPAR could predict increased risk of mortality in plasmodium-negative patients

Overall, in plasmodium-negative patients, plasma concentrations of suPAR increased with disease severity and with longer duration of symptoms before admission. They were strongly associated with a higher degree of thrombocytopenia and anemia but not of neutrophil count

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Discussion

The main finding of the present study was that plasma concentrations of suPAR were increased in children with acute malaria, with the highest concentrations in children who died or had complicated malaria (i.e., with respiratory distress, coma, hypoglycemia, or a combination of these). Only a few studies have investigated uPA and its receptor, uPAR, in malaria [25, 29 –32]. A recent study found increased serum concentrations of suPAR in children with acute P. falciparum infection, with decreasing concentrations of suPAR after initiation of antimalarial treatment [25]. In a postmortem study of human cerebral malaria, expression of uPAR was increased on macrophages, microglial cells, astrocytes, and endothelial cells in histologically altered regions, and it was suggested that expression of uPAR on activated endothelial cells could serve as an additional adhesion molecule for parasitized erythrocytes [29]. Furthermore, experiments with cell cultures have demonstrated that uPA can bind to human erythrocytes infected with mature forms of P. falciparum and that uPA is required for erythrocyte rupture and merozoite release [30]. The uPA-binding molecule on parasitized erythrocytes, however, has not been identified [30], since normal erythrocytes lack expression of uPAR [12]. Finally, P. berghei–infected uPAR-deficient mice have reduced mortality, attenuated thrombocytopenia, absent platelet trapping [31], augmented leukocytosis, and reduced apoptosis in lymphoid organs [32], compared with wild-type mice, suggesting an influence of uPAR on platelet kinetics [31] and leukocyte migration and survival [32]. Since, in humans, platelets lack expression of uPAR [12, 14, 33], it is unknown whether the uPA-uPAR system exerts specific effects on platelets in human malaria

The cyclic destruction of parasitized erythrocytes in malaria represents an enormous stimulus for the monocyte-macrophage system, which responds with release of soluble factors toxic to the parasite (e.g., TNF-α [20, 34 –37]). TNF-α is a potent proinflammatory cytokine that, besides activation of various immune cells, induces adhesion of leukocytes, platelets, and parasitized erythrocytes to vascular endothelial cells through up-regulation of intercellular adhesion molecule (ICAM)–1 [23, 38 –40]

In the present study, plasma concentrations of suPAR increased with disease severity; low platelet count, low hemoglobin level, and high neutrophil count were independent markers of a high plasma concentration of suPAR. A low platelet count could contribute to a high plasma concentration of suPAR through enhanced differentiation of megakaryocytes, with a high level of expression of uPAR in the bone marrow [14], which is compatible with the association between plasma concentration of suPAR and PDW. A high neutrophil count could contribute directly to a high plasma concentration of suPAR, since release of uPAR is enhanced from neutrophils (and other leukocyte subpopulations) stimulated with TNF-α [41 –43] and various microbial products [43 –45]. Expression of uPAR is important for leukocyte adhesion, since removal of uPAR from the cell surface reduces β2-integrin–mediated leukocyte adhesion to ICAM-1 by 65%–80% [46]. A recent study demonstrated enhanced release of uPAR in cocultures of endothelial cells/peripheral blood mononuclear cells and endothelial cells/platelets, compared with the release of uPAR in single-cell cultures [33]. Given that interactions between blood cells and endothelial cells enhance the release of uPAR [33], excessive adhesion of parasitized erythrocytes (through P. falciparum erythrocyte membrane protein 1) [40], platelets, or leukocytes could be expected to contribute to high plasma concentrations of suPAR in malaria. If the circulating concentration of suPAR reflects parasite-induced turnover of platelets, cytoadhesion, and immune activation (various proinflammatory cytokines also enhance release of uPAR from endothelial cells [47]), it is not surprising that a high plasma concentration of suPAR is associated with a poor clinical outcome in acute malaria. However, due to the low number of fatal cases in the present study, the potential association between plasma concentration of suPAR and mortality in malaria should be confirmed in subsequent studies

Although plasma concentration of suPAR and anemia were weakly associated in the multivariate linear regression analysis (which included approximately half of the patients), when all patients with malaria were investigated, low hemoglobin level was not associated with high plasma concentration of suPAR. Severe malarial anemia is associated with a relatively modest increase in TNF-α levels that appears to be insufficient to control parasite growth [48, 49], and the imbalance between immune activation and regulation of feedback through interleukin-10 may be of pathogenic significance [49]. If the concentration of suPAR is related to the magnitude of the TNF-α response in malaria, the lower TNF-α levels in patients with malarial anemia may explain the weak association between plasma concentration of suPAR and anemia in patients with malaria. However, since we did not measure TNF-α levels, the present study cannot confirm this hypothesis

Patients with malaria with a sickling phenotype had reduced plasma concentrations of suPAR. In P. falciparum malaria, a sickling phenotype is associated with reduced parasitemia and less-severe disease [50]. If the concentration of suPAR is related to parasitemia, either directly or indirectly, the reduced concentrations of suPAR in patients with malaria with a sickling phenotype could be explained by low parasitemia. The lack of an association between plasma concentration of suPAR and a sickling phenotype in plasmodium-negative patients supports the notion that the Plasmodium parasite contributes to increases in plasma concentration of suPAR

The plasmodium-negative patients represent a heterogeneous patient group. The high prevalence of severe anemia and the high plasma concentrations of suPAR in plasmodium-negative patients with severe anemia could indicate that some plasmodium-negative patients had undiagnosed malaria. We have previously shown that the vast majority of children from areas in which malaria is endemic who present with severe anemia have soluble malaria antigens in their plasma despite microscopically undetectable parasitemia [51] (M. Helleberg, unpublished data). Thus, the use of antigen-detection tests in the present study would probably have identified some patients with malaria in the plasmodium-negative group, which would have tended to underestimate the difference in plasma concentrations of suPAR between the groups

Compared with the healthy children, the plasmodium-negative patients had higher plasma concentrations of suPAR. In healthy adults, the circulating concentration of suPAR is often between 1 and 2 ng/mL, depending on the sample material, the anticoagulant, and the assay used [27, 52]. The reference concentration for suPAR in children is unknown, but the serum concentration of uPA is comparable in children and adults [53, 54]. Although the median plasma concentration of suPAR was >2 ng/mL in the healthy children, such concentrations have previously been demonstrated in healthy adults [27]. Furthermore, it is also possible that the high plasma concentrations of suPAR in the healthy children could be attributed to constant low-grade immune activation due to intestinal helminths and other repeated infections [55]

As in patients with malaria, in plasmodium-negative patients, the highest concentrations of suPAR were found in patients with severe clinical symptoms, which emphasizes that circulating concentrations of suPAR are increased in patients with acute systemic inflammation, which is in accordance with previous findings [1 –3]. Since the present study did not investigate plasma concentrations of suPAR in plasmodium-negative patients stratified according to differential diagnoses, it cannot be concluded that malaria is associated with concentrations of suPAR higher than those observed in, for instance, patients with sepsis

Plasma concentration of suPAR and duration of symptoms before admission correlated negatively in patients with malaria but positively in plasmodium-negative patients. One may hypothesize that the excessive inflammation in malaria could trigger biological processes rapidly leading to profound increases in the concentration of suPAR, whereas the more modest inflammation in nonmalaria diseases may require longer time to obtain significant increases in the concentration of suPAR

Severe infections activate the coagulation system through the extrinsic (tissue factor mediated by high levels of proinflammatory cytokines) and intrinsic (contact mediated by some microbial products) pathways [56, 57]. uPAR is also involved in fibrinolysis (as a high-affinity receptor for uPA) [9], and complex formation with suPAR enhances pro-uPA–mediated fibrinolysis in vitro [58]. Despite high plasma concentrations of suPAR in patients with malaria and sepsis [1 –3, 25], both diseases are mainly characterized by a hypercoagulable state (apart from an initial activation of fibrinolysis in sepsis) [56, 57, 59 –62]. Previous studies of hemostasis in malaria and sepsis found down-regulation of anticoagulant mechanisms (reduced levels of protein C, protein S, and antithrombin III), up-regulation of procoagulant mechanisms (increased levels of tissue factor and von Willebrand factor and increased activity of procoagulant monocytes), and inhibition of fibrinolysis (reduced levels of tissue-type plasminogen activator and increased levels of plasminogen activator inhibitor 1) [56, 57, 59 –62]. In contrast to sepsis (which is often associated with profound perturbations in hemostasis and disseminated intravascular coagulation [DIC]) [59], P. falciparum infection may be associated with varying perturbations, ranging from isolated thrombocytopenia to consumption of clotting factors, with high levels of fibrin degradation products and DIC [60, 61]

If high circulating concentrations of suPAR in malaria reflect excessive activation of immune cells, adhesion of blood cells at sites of inflammation, perturbations in hemostasis, or a combination of these, a high plasma concentration of suPAR may be a passive marker of immune activation. However, it may also reflect that suPAR plays a role as a cause of these phenomena through its biological activity in vivo [1], which may affect hemostasis [58] or cell migration through interaction with integrins [46, 63, 64], regulation of chemotaxis [65, 66], or competitive inhibition of binding of uPA to membrane-associated uPAR [67 –70]

In summary, the present study investigated plasma concentrations of suPAR in children with acute malaria, children with clinical symptoms compatible with acute malaria and a blood film negative for Plasmodium parasites, and healthy children. Plasma concentrations of suPAR were higher in children with malaria, compared with those in plasmodium-negative children and those in healthy children. The highest concentrations of suPAR were in children with complicated malaria, and, in univariate logistic regression analysis, a higher plasma concentration of suPAR predicted increased risk of mortality. In multivariate linear regression analysis, low platelet count and hemoglobin level and high neutrophil count were independent predictors of a high plasma concentration of suPAR. The latter finding suggests that a high plasma concentration of suPAR in malaria may be a marker of parasite-induced turnover of platelets, cytoadhesion, and immune activation

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Acknowledgments

We thank Benjamin Scheel Jørgensen, for his excellent technical assistance, and the children and their parents, for their participation in this study

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Footnotes

  • ↵Financial support: Enhancement of Research Capacity program of the Danish International Development Assistance; Danish Council for Development Research; Danish Medical Research Council; World Health Organization/Special Programme for Research and Training in Tropical Diseases/Multilateral Initiative on Malaria (project 980037); European Union International Cooperation–Developing Countries (project ERB 3514 PL973009)

  • Received August 17, 2004.
  • Accepted November 8, 2004.
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