Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria

doi:10.1016/S0140-6736(97)09439-7

The Lancet

Volume 351, Issue 9118, 13 June 1998, Pages 1768-1772

https://doi.org/10.1016/S0140-6736(97)09439-7 Get rights and content

Summary

Background

Severe anaemia is a major complication of malaria but little is known about its pathogenesis. Experimental models have implicated tumour necrosis factor (TNF) in induction of bone-marow suppression and eythrophagocytosis. Conversely, interleukin 10 (IL-10), which mediates feed-back regulation of TNF, stimulates bone-marrow function in vitro and counteracts anaemia in mice. We investigated the associations of these cytokines with malarial anaemia.

Methods

We enrolled 175 African children with malaria into two studies in 1995 and 1996. In the first study, children were classified as having severe anaemia (n=10), uncomplicated malaria (n=26), or cerebral anaemia (n=41). In the second study, patients were classified as having cerebral malaria (n=33) or being fully conscious (n=65), and the two groups were subdivided by measured haemoglobin as normal (>110 g/L), moderate anaemia (60–90 g/L), and severe anaemia (>50 g/L). IL-10 and TNF concentrations were measured by ELISA in plasma samples from all patients.

Findings

IL-10 concentrations were significantly lower in patients with severe anaemia than in all other groups. In 1995, geometric mean plasma IL-10 in patients with severe anaemia was 270 pg/mL (95% CI 152–482) compared with 725 pg/mL (465–1129) in uncomplicated malaria and 966 pg/mL (612–1526) in cerebral malaria (p<0·03). In 1996, fully conscious patients with severe anaemia also had significantly lower IL-10 concentrations than all other groups, including cerebral-malaria patients with severe anaemia and all patients with moderate anaemia (p<0·001). In both studies, TNF concentrations were significantly higher in cerebral malaria than in fully conscious patients (p<0·01). By contrast, the ratio of TNF to IL-10 was significantly higher in fully conscious patients with severe anaemia than in all other groups (p<0·001).

Interpretation

Our findings identify severe malarial anaemia as a distinct disorder in which insufficient IL-10 response to high TNF concentrations may have a central role.

Introduction

Severe malarial anaemia is one of the most important complications of malaria in African children and carries a high mortality rate in areas of intense Plasmodium falciparum transmission.¹ The pathogenesis of severe anaemia has, however, received little attention. Increased destruction of infected and uninfected red blood cells and suppression of erythropoiesis seem to be important causative factors of severe anaemia.² These mechanisms are generally present in all malaria cases, and whether severe anaemia represents the extreme of a continuum of pathology or constitutes a separate disease entity is not clear.

In a previous study, we showed that bone-marrow inhibition in human malaria was not due to defective erythropoietin production.³ Increased destruction of red blood cells⁴ and bone-marrow suppression⁵ have been associated with tumour necrosis factor (TNF) in experimental murine malaria. Repeated injections of TNF causes chronic anaemia in rats,⁶ but the importance of TNF in severe malarial anaemia in human beings has not been studied. TNF is a proinflammatory cytokine, concentrations of which are raised in patients with malaria, especially those with cerebral malaria.7, 8 The production of TNF is downregulated by anti-inflammatory cytokines such as interleukin 10 (IL-10),⁹ which also has raised concentrations in malaria.¹⁰ IL-10 stimulates bone-marow formation in murine osteogenic stroma,¹¹ and IL-10-deficient mice develop severe anaemia.¹² To investigate a possible role for TNF and IL-10 in severe malarial anaemia, we measured plasma concentrations of TNF and IL-10 in Ghanaian children with severe anaemia, cerebral malarial, or uncomplicated malaria, and in healthy children with similar exposure to P falciparum infection.

Section snippets

Patients and methods

Children admitted during the malaria season (June to August) of 1995 and 1996 to the emergency room at the Department of Child Health, Korle-Bu Teaching Hospital, Ghana, were included. The general inclusion criteria were asexual P falciparum parasitaemia of more than 10 000/μL (in 1996, >1 parasite per white blood cell) and axillary temperature of more than 37·5°C. Children with any disease other than malaria or with a positive sickling test (metabisulphite method) were excluded from the study.

Results

In 1995, 41 patients with cerebral malaria, ten with severe anaemia, and 26 with uncomplicated malaria were enrolled (table 1). Parasitaemias were generally high on admission in all groups. Geometric mean parasite density per μL was 82 000 (95% CI 30 000–222 000), 108 000 (59 000–207 000), and 75 000 (46 000–120 000) in severe anaemia, cerebral, and uncomplicated malaria, respectively (p=0·45). Whereas haemoglobin concentrations formed part of the definition of uncomplicated malaria and severe

Discussion

Acute malaria is associated with the destruction of infected red blood cells and non-responsiveness of the bone marrow to the resulting drop in haemoglobin.3, 16 Severe malarial anaemia may, therefore, constitute the extreme end of a continuum of haemoglobin values. However, we found strikingly lower IL-10 concentrations in patients with severe anaemia than in patients with moderate anaemia or cerebral malarial, which suggests that severe anaemia has a specific pathology. One study suggested

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ArticlesLow plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients and methods

Results

Discussion

Parasitol Today

Ballières Clin Haematol

Lancet

Cell

Trans R Soc Trop Med Hyg

Clin Immunol Immunopathol

Immunol Today

Immunol Today

Blood

Adv Parasitol

Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria

Br J Haematol

Anaemia and resistance to malaria in transgenic mice expressing human tumour necrosis factor

Immunology

Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis

Br J Haematol

Cachectin/tumor necrosis factor-α alters red blood cell kinetics and induces anemia in vivo

FASEB J

Tumor necrosis factor and disease severity in children with Plasmodium falciparum malaria

N Engl J Med

Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees

J Exp Med

High levels of circulating IL-10 in human malaria

Clin Exp Immunol

Articles
Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria