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Keywords:

  • malaria;
  • host response;
  • comparison;
  • parasitemia;
  • tumour necrosis factor
  • paludisme;
  • réponse de l'hôte;
  • comparaison;
  • parasitémie;
  • facteur nécrosant des tumeurs
  • paludismo;
  • respuesta del hospedero;
  • comparación;
  • parasitemia;
  • Factor de Necrosis Tumoral

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

Objective and methods  Fever tends to start at a lower level of parasitemia in Plasmodium vivax or ovale than in P. falciparum malaria, but hyperparasitemia and complications are more likely to occur in P. falciparum malaria. Therefore, we compared the relationship between parasitemia and host response parameters before therapy in 97 patients with P. faciparum malaria (18 with complications), and 28 with P. vivax or ovale malaria.

Results  In both types of malaria, parasitemia correlated with blood levels of tumour necrosis factor alpha (TNF-alpha), lactate dehydrogenase (LDH), Thrombin–antithrombin III (TAT) and elastase, and these parameters were higher in P. falciparum malaria than in P. vivax or ovale malaria. In contrast, the ratios of TNF-alpha, TAT, elastase, and LDH per parasitized erythrocyte were higher in P. vivax or ovale malaria than in uncomplicated P. falciparum malaria. They were lowest in complicated disease. Multivariate regression analysis confirmed that parasitemia did not affect these differences.

Conclusion  The host response may reach full strength at lower parasitemia in Plasmodium vivax or ovale, than in P. falciparum malaria. With hyperparasitemia in P. falciparum malaria, the host response seems to be unable to control parasite multiplication.

Objectif et méthodes  Dans le paludisme àP. vivax ou ovale, la fièvre a tendance à débuter à un niveau de parasitémie plus bas que dans celui àP. falciparum. Mais, l'hyperparasitémie et les complications sont plus susceptibles de survenir dans le paludisme àP. falciparum. Nous avons étudié la relation entre la parasitémie et les paramètres de la réponse de l'hôte avant le traitement chez 97 patients avec P. falciparum (18 avec complications) et 28 patients avec P. vivax ou ovale.

Résultats  Dans les deux types du paludisme, le niveau de parasitémie corrélait avec des taux sanguins élevés de TNF-alpha, LDH, TAT et élastase, et ces paramètres étaient plus élevés dans le paludisme àP. falciparum que dans celui àP. vivax ou ovale. Par contre, les rapports de TNF-alpha, TAT, élastase et LDH par érythrocyte parasitéétaient plus élevés dans le paludisme àP. vivax ou ovale que ans le paludisme non-compliquée àP. falciparum. Ils étaient plus bas en cas de complication. L'analyse de régression multivariée a confirmé que la parasitémie n'affectait pas ces différences.

Conclusion  Dans le paludisme àP .vivax ou P. ovale, la réponse de l'hôte peut atteindre son maximum à une parasitèmie plus basse que dans celui àP. falciparum. En cas d'hyperparasitémie dans le paludisme àP. falciparum, la réponse de l'hôte semble incapable de contrôler la multiplication du parasite.

Objetivos y Métodos  En infecciónes por Plasmodium vivax u ovale, la fiebre tiende a empezar con parasitemias más bajas que en el caso del paludismo por P. falciparum. Sin embargo, es más posible que en este último caso se dé una hiperparasitemia y se presenten complicaciones. Por lo tanto, hemos comparado la relación entre parasitemia y parámetros de respuesta del hospedero antes de la terapia en 97 pacientes con paludismo por P. falciparum(18 con complicaciones) y 28 con paludismo por P.vivax u ovale.

Resultados  En ambos tipos de paludismo, la parasitemia se correlacionó con los niveles en sangre de TNF-alfa, LDH, TAT y elastasa, y estos parámetros fueron más altos en caso de paludismo por P. falciparum que por P. vivax u ovale. En contraste, las tasas de TNF-alpha, TAT, elastasa, y LDH por eritrocito parasitado fueron más altas en casos de paludismo por P. vivax u ovale que en paludismo no complicada por P. falciparum.

Las más bajas fueron en casos de paludismo complicada. Un análisis de regresión multivariada confirmó que la parasitemia no afectaba estas diferencias.

Conclusión  En paludismo, por P. vivax u ovale, la respuesta del hospedero puede alcanzar su máximo con parasitemias mas bajas que en paludismo por P. falciparum. Frente a paludismos por P. falciparum con hiperparasitemias, la respuesta del hospedero parece no ser capaz de controlar la multiplicación de los parásitos.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

In 1911, Ross and Thomson noted that fever and other symptoms tend to start at lower levels of parasitemia in benign tertian malaria than in malignant tertian (Plasmodium falciparum) malaria (Ross & Thomson 1911). Being unaware of sequestering P. falciparum schizonts, they assumed that this difference could be explained by counting the number of the resulting merozoites rather than the single P. vivax schizonts. More recently, it has been shown that high parasitemia and multiorgan failure in P. falciparum malaria are associated with a marked host response, including elevated levels of cytokines and cytokine receptors (Hemmer et al. 1997; Holst et al. 1994; Kern et al. 1989, 1992; Grau et al. 1989; Kwiatkowski et al. 1990), and proteolytic enzymes like neutrophil elastase (Pukrittayakamee et al. 1992; Holst et al. 1999). These host response factors act against malarial parasites (Taverne et al. 1987; Janoff et al. 1988; Neifer et al. 1989), and might also be beneficial in neurosyphilis and in Lyme disease (Wagner von Jauregg 1918; Heimlich 1990).

We compared four host response parameters in P. falciparum malaria and P. vivax or ovale malaria. Tumour necrosis factor alpha (TNF-alpha), was analysed because this monokine, which is produced in response to parasite products, mediates antiparasitic activity and organ complications of malaria (Taverne et al. 1987; Grau et al. 1989). Thrombin-antithrombin III (TAT) was analysed as a parameter of procoagulant activity (Holst et al. 1999), resulting from TNF-alpha-mediated endothelial activation as expressed by tissue factor formation (Hemmer et al. 1991a; Bierhaus et al. 1995). Human neutrophil elastase (HNE) was analysed because its secretion, which is triggered by plasmodial products and by TNF-alpha, contributes to antiparasitic activity and organ impairment in malaria (Janoff et al. 1988; Pukrittayakamee et al. 1992; Hemmer et al. 1994). Lactate dehydrogenase (LDH) was analysed as a parameter of hemolysis, because the host response in malaria contributes to hemolysis (Clark & Hunt 1983), while products released by lysed erythrocytes augment the TNF-alpha response in malaria (Bate & Kwiatkowski 1994). In relation to parasitemia, the host reactions represented by these parameters appear to be stronger in P. vivax or ovale malaria than in P. falciparum malaria.

Patients, materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

Patients

We analysed data obtained from 125 consecutively recruited patients with malaria. Of these, 97 had P. falciparum malaria, and 28 had benign tertian malaria (22 P. vivax, 6 P. ovale). Eighteen of the 97 patients with P. falciparum malaria, and two of the 28 patients with P. vivax or P. ovale malaria had immigrated from Africa and were considered semi-immune. The study was approved by the ethics committee of the Medical Board of the State of Hamburg, and all patients had given informed consent.

Upon admission, fever had been present between 1 and 30 days (P. falciparum: median 4 days, range: <1–30 days; P. vivax or ovale: median 5 days, range: 1–14 days). Eighteen patients with P. falciparum malaria, all of them Europeans, had one or more complications as defined in a previous study (Kern et al. 1989).

Pre-treatment parasite counts and LDH levels were available for all 97 patients with P. falciparum malaria and for all 28 patients with P. vivax or ovale malaria. Pre-treatment TNF-alpha levels were available for all 97 P. falciparum and 19 of 28 P. vivax or ovale patients, TAT levels for 49 of 97 P. falciparum and for all 28 P. vivax or ovale patients, and human neutrophil elastase (HNE) levels were available for 47 of 97 P. falciparum and 27 of 28 P. vivax or ovale patients.

Blood sampling and analysis of patient samples

Blood samples were drawn for determination of routine parameters including parasitemia, LDH, TNF-alpha, TAT, and HNE. Samples were stored and analysed as described elsewhere (Kern et al. 1989; Hemmer et al. 1991b; Holst et al. 1999).

Statistical analysis

Non-parametrical tests were used throughout this study. Correlations were calculated as Spearman rank correlations. Absolute values of parasitemia and host response parameters and nine different ratios (TNF-alpha/parasitemia, LDH/parasitemia, TAT/parasitemia, HNE/parasitemia, LDH/TNF-alpha, TAT/TNF-alpha, HNE/TNF-alpha, TAT/HNE, LDH/HNE) in patients with severe and mild P. falciparum malaria were compared with the ratios in patients with P. vivax or ovale malaria (Tables 1, 2), using the Mann–Whitney U-test, without and with Holms correction for multiple comparisons.

Table 1.   Parasitemia and host response parameters in P. falciparum and in P. vivax or ovale malaria. Median (range) of absolute values and host response to parasitemia ratios
ParameterNormal range P. falc. malaria; n = 97 median (range) P. vivax or ovale malaria; n = 28 median (range) P. falc. vs. P. vivax or ovale malaria (U test)Multivariate analysis: Higher ratios in P. vivax or ovale than in P. falc. Malaria Odds Ratio (95%CI)
  1. * not significant if Holm's correction is applied.

Parasitemia (1/nL)013 (<2–1070)<2 (<2–47)p < 0.001  
TNF-alpha (pg/mL)<1530.4 (<15–896)31 (<15–891)n.s.  
TNF-alpha/parasitemia ratios 1.5 (0.15–58)10 (2.2–76)p < 0.00117.2 (1.46–83)p = 0.024
TAT (μg/mL)1.0-4.18 (1.5–80)8.45 (2.3–77.4)n.s.  
TAT/parasitemia ratios 0.4 (0.007–10.5)4.4 (0.11–44.7)p < 0.00117.5 (5.02–62.5)p = 0.002
LDH (U/L)<240272 (110–1230)220 (127–419)n.s.  
LDH/parasitemia ratios 16.5 (0.68–476)169 (4.7–419)p < 0.0014.65 (1.58–13.5)p = 0.005
HNE (ng/mL)<80179 (26–4845)124 (50.7–417)p < 0.05*  
HNE/parasitemia ratios 6.1 (0.63–153)54.6 (5.1–241)p < 0.0018.77 (2.39–32.3)p = 0.001
Table 2.   Parasitemia and host response parameters in severe and in mild P. falciparum malaria: Median (range) of absolute values and host response to parasitemia ratios
ParameterNormal rangeSevere P. falc. malaria; n = 18 median (range)Mild P. falc. malaria; n = 79 median (range)Mild vs. severe P. falc. (U test)Mild P. falc. vs. P. vivax or ovale malaria (U test)Multivariate analysis: Higher ratios in mild than in severe P. falc. malaria: Odds Ratio (95% CI)Signif.Multivariate analysis: Higher ratios in P. vivax or ovale than in mild P. falc. malaria: Odds Ratio (95%CI)Signif.
  1. * not significant if Holm's correction is applied.

Parasitemia (1/nL)0226 (19.8–1070)9.78 (<2–180)p < 0.001p < 0.001    
TNF-alpha (pg/mL)<15139.5 (35–896)24.9 (<15–317)p < 0.001n.s.    
TNF-alpha/parasitemia ratios 0.71 (0.18–14.5)1.88 (0.14–58.1)p < 0.015*p < 0.0014.48 (1.38–14.5)p = 0.01340.0 (3.33–500)p = 0.004
TAT (μg/mL)1.0-4.113 (2.6–80)5.75 (1.5–55)p < 0.05*n.s.    
TAT/parasitemia ratios 0.065 (0.007–10.5)0.697 (0.067–8.5)p < 0.001p < 0.00110.6 (2.2–50)p = 0.00313.5 (2.42–45.4)p = 0.002
LDH (U/L)<240468 (202–1230)254 (110–711)p < 0.001n.s.    
LDH/parasitemia ratios 2.4 (0.68–76)24 (1.29–476)p < 0.005p < 0.0016.7 (1.43–31.3)p = 0.0167.10 (1.50–33.6)p = 0.013
HNE (ng/mL)<80408 (102–4845)122.5 (26–357)p < 0.001n.s.    
HNE/parasitemia ratios 2.3 (0.64–152.8)8.53 (1.41–153)p < 0.001p < 0.00140.0 (4.44–333)p = 0.00118.2 (2.03–167)p = 0.009

The statistical influence of parasitemia (>20/nl of blood vs.≤20/nl of blood), species (P. falciparumvs.P. vivax or ovale), gender, age (≤40vs. >40 years), semi-immunity, and disease severity on LDH/parasitemia, TNF-alpha/parasitemia, TAT/parasitemia, and HNE/parasitemia ratios was tested by logistic regression (SPSS 11.0 statistical package, SPSS GmbH, Munich, Germany). Host response/parasitemia ratios were analysed as dichotomous variables, using the median for splitting. Each independent variable was first tested in a bivariate fashion. Those independent variables that were found to influence the dependent variable were tested together in a multivariate analysis. This was necessary to correct for the influence of parasite density, and to ascertain that the influence of parasite species or clinical severity on host response/parasitemia ratios was independent of parasitemia or other variables.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

Parasitemia, TNF-alpha, TAT, HNE, and LDH were significantly higher in severe than in mild P. falciparum malaria but the difference was not significant between mild P. falciparum and P. vivax or ovale malaria. Parasitemia and HNE levels were significantly higher in P. falciparum than in P. vivax or ovale malaria (P < 0.001 and P < 0.05 respectively). LDH levels were not significantly higher, but they were elevated in 60 of 97 patients with P. falciparum and in 10 of 28 patients with P. vivax or ovale malaria (P = 0.015). Median levels of TNF-alpha and TAT were elevated in P. falciparum and in P. vivax or ovale malaria to a similar extent.

A different picture emerged when host response/parasitemia ratios were compared. The ratios of TNF-alpha/parasitemia, LDH/parasitemia, TAT/parasitemia, and HNE/parasitemia were higher in P. vivax or ovale malaria than in P. falciparum malaria.

These ratios were also significantly higher in P. vivax or ovale malaria than in mild P. falciparum malaria (Table 1). The difference between P. vivax or ovale malaria and P. falciparum malaria remained significant when P. falciparum patients with parasitemia levels above 47.1 parasitized erythrocytes/nl of blood (the highest parasitemia observed in the P. vivax or ovale group) were excluded from analysis. Within the P. falciparum malaria group, all four ratios were significantly higher in mild than in severe disease (P < 0.015).

Multivariate analysis confirmed that the four host response/parasitemia ratios were influenced by the parasite species and by clinical severity. The influence of parasite species on the TNF alpha/parasitemia ratio was significant when patients with parasitemias above 50 parasitized erythrocytes/nl (which were not seen in P. vivax or ovale malaria), or patients with complicated malaria were excluded.

The TNF-alpha/parasitemia and TAT/parasitemia ratios were also influenced by parasitemia itself as indicated by lower ratios in cases with higher parasitemias. However, the influence of the parasite species and of disease severity on these ratios was independent of parasitemia. Gender, age, or semi-immunity had no influence on host response/parasitemia ratios.

The slope of the regression line between parasitemia and TNF-alpha levels is lowest in severe P. falciparum malaria, higher in mild P. falciparum malaria, and highest in P. vivax or ovale malaria (Figure 1). This indicates that, in relation to parasitemia, the TNF-alpha response is stronger in P. vivax or ovale malaria, than in mild or severe P. falciparum malaria. The correlations between parasitemia and TNF-alpha serum levels are significant in severe P. falciparum malaria, in mild P. falciparum malaria, and in P. vivax or ovale malaria (Figure 1).

image

Figure 1.  Relationship between parasitemia (parasitized erythrocytes per nL of blood) and TNF-alpha serum levels (pg/mL) in severe P. falciparum malaria (18 patients), mild P. falciparum malaria (79 patients) and P. vivax or ovale malaria (19 patients). The slope of the regression graph is higher in P. vivax/ovale malaria than in mild or severe P. falciparum malaria, and higher in mild than in severe P. falciparum malaria.

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The ratios between different host response parameters (i.e. TAT/TNF-alpha, HNE/TNF-alpha, LDH/TNF-alpha, TAT/HNE, TAT/LDH, and LDH/HNE) did not differ between P. vivax or ovale malaria and P. falciparum malaria (P > 0.1).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

Our results suggest that, in relation to parasitemia, the host response is activated more strongly in P. vivax or ovale malaria than in P. falciparum malaria. As the host response helps to limit parasitemia, a stronger host response to the parasitized erythrocyte in P. vivax or P. ovale malaria may explain why parasitemia levels remain lower than in P. falciparum malaria. Conversely, higher parasitemia levels explain why the host response in absolute terms is stronger in P. falciparum malaria than in P. vivax or ovale malaria.

Exhaustion of the host response with high parasitemia in severe P. falciparum malaria did not explain why the ratios of host response to parasitemia were higher in P. vivax or ovale than in P. falciparum malaria, for two reasons. First, these differences remained significant when patients with high parasitemia or with complications were excluded from analysis. Secondly, in multivariate analysis, the presence of complications predicted lower TNF-alpha/parasitemia ratios independently of parasitemia. For the same two reasons, it is unlikely that a non-linear relationship between TNF-alpha production and TNF-alpha serum levels could explain the observed differences between these two types of malaria.

Parasitemia counts obtained from peripheral blood underestimate the total parasite load, because of endothelial sequestration of parasitized erythrocytes, and to the common finding of two or more parasites per erythrocyte in P. falciparum malaria. The total parasite load is therefore higher, and the resulting ratios of host response to per parasite load in P. falciparum malaria would be even lower than the values presented in the results section. This means that the differences between the higher ratios in P. vivax or ovale malaria and the lower ratios in P. falciparum malaria would be even greater than reported here.

Endothelial sequestration of parasitized erythrocytes contributes to endothelial activation and damage in P. falciparum malaria (Berendt et al. 1990; Pino et al. 2003). Therefore, procoagulant alterations, reflecting endothelial involvement (Hemmer et al. 1991a; Bierhaus et al. 1995), can be expected to be stronger in P. falciparum than in P. vivax or ovale malaria, both in absolute terms and in relation to parasitemia and TNF-alpha levels. This, however, was not the case in the present study, as TAT levels and TAT/TNF-alpha ratios were similar in both malaria types, and TAT/parasitemia ratios were higher in P. vivax or ovale than in P. falciparum malaria. This is in agreement with the finding that synthesis of procoagulant tissue factor by endothelial cells is induced by serum from malaria patients in a TNF-alpha dependent manner (Hemmer et al. 1991a; Bierhaus et al. 1995), but not by P. falciparum parasitized erythrocytes, which bind to the vascular endothelium (mature stages; authors’ data, not shown). Similarly, binding and phagocytosis of P. falciparum-parasitized erythrocytes by monocytes fails to stimulate TNF-alpha production (McGilvray et al. 2000). These findings indicate that endothelial sequestration of parasitized erythrocytes is unlikely to augment the host response in P. falciparum malaria.

As TNF-alpha production in P. falciparum malaria is inhibited by interleukin 10 (Ho et al. 1995), the lower TNF-alpha/parasitemia ratios in P. falciparum compared with P. vivax or ovale malaria might be explained by the fact that P. falciparum-parasitized erythrocytes also bind to dendritic cells (Urban et al. 1999), where they upregulate interleukin 10 production (Urban et al. 2001). This has not yet been described in P. vivax or ovale malaria. As the TNF-alpha response contributes to parasite clearance in malaria (Taverne et al. 1987; Kremsner et al. 1995; Mordmüller et al. 1997), the suppression of TNF-alpha production in P. falciparum malaria is probably advantageous for the parasite.

Antiplasmodial effects of TNF-alpha may be mediated through activation of neutrophils and secretion of HNE (Waki et al. 1993; Kumaratilake & Ferrante 2000). This study demonstrates that not only TNF-alpha/parasitemia, but also HNE/parasitemia ratios were significantly lower in P. falciparum malaria than in P. vivax or ovale malaria. This indicates that, per parasitized erythrocyte, not only the TNF-alpha response, but also the secretion of elastase by neutrophils is lower in P. falciparum malaria. This is in accordance with the observation that neutrophil chemotaxis is impaired in P. falciparum malaria (Nielsen et al. 1986), and may interfere with the capability of neutrophils to attack malarial parasites and parasitized erythrocytes (Celada et al. 1983; Golenser et al. 1992). Our observation that LDH/parasitemia ratios are higher in P. vivax or ovale than in P. falciparum malaria suggests that destruction of erythrocytes and elevated LDH levels may be caused not only by schizonts, but also by host reactions against parasitized and non-parasitized erythrocytes (Clark & Hunt 1983; Mohan et al. 1995).

Lower TNF-alpha/parasitemia ratios in P. falciparum than in P. vivax or ovale malaria do not necessarily prove that less TNF-alpha is produced per parasitized erythrocyte. Instead, they might reflect a higher cellular uptake of TNF-alpha in P. falciparum malaria. The uptake of TNF-alpha involves TNF receptors (Ortiz et al. 2001), and binding of TNF-alpha to the p55 TNF receptor leads to elevated plasma levels of TAT and HNE (van der Poll et al. 1996). However, the ratios of TAT/TNF-alpha and HNE/TNF-alpha did not differ between the two types of malaria, while the TAT/parasitemia and HNE/parasitemia ratios were lower in P. falciparum than in P. vivax or ovale malaria. Besides, TNF receptors are shed into the circulation in P. falciparum malaria (Kern et al. 1992). Thus, a higher cellular uptake of TNF-alpha in P. falciparum than in P. vivax or ovale malaria appears less likely.

Our findings suggest that the host response helps to control parasitemia and to prevent organ failure in benign tertian malaria, where fever paroxysms are followed by marked increases in TNF-alpha serum levels (Karunaweera et al. 1992). In P. falciparum malaria, TNF-alpha production capacity correlates with parasite clearance (Kremsner et al. 1995). All in all, this study suggests that P. falciparum malaria per se is not associated with a stronger host response than P. vivax or P. ovale malaria. Rather, failure to control parasite proliferation in P. falciparum malaria can lead to overwhelming parasitemia, and subsequently to the excessive host response seen in severe malaria. This might explain why endothelial damage and organ failure are common in P. falciparum malaria, but not in P. vivax or ovale malaria. Further research on human malaria should focus on the question of why the immune system is relatively successful in P. vivax or ovale malaria.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References

The authors thank Dr Günther Kundt, Institute of Medical Informatics and Biometry of the University of Rostock, for his extensive help with the statistical analysis. Financial support was obtained from the German Research Council (Deutsche Forschungsgemeinschaft, Grants Di 355/1-1, Di 355/2-1 and He 3137/2-1).

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  1. Top of page
  2. Summary
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. References
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