The Prognostic and Pathophysiologic Role of Pro‐ and Antiinflammatory Cytokines in Severe Malaria

Abstract

Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

“…A predominantly proinflammatory response was associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms. These observations strongly support the conclusions of several correlative clinical and epidemiological studies that have also suggested that proinflammatory responses might be causally associated with both clearance of parasites and clinical disease (14,22,33). Conversely, subjects in group 3 who had no detectable inflammatory response but the highest levels of TGF-␤ were less able to control parasite growth (30) but hardly ever reported a fever or feverishness, again supporting data from studies in malaria endemic populations that anti-inflammatory activity is associated with less severe clinical symptoms (22).…”

“…Evidence also suggests that both TGF-␤ and IL-10 can be produced very rapidly, from innate sources, during murine malaria infections and are required to down-regulate potentially pathogenic inflammatory responses once parasitemia is brought under control (26 -28); however, in both mice and humans, excessive concentrations of TGF-␤ and IL-10 early in infection inhibit type-1 immune responses and thus facilitate parasite growth (29,30). Conversely, in clinical human infections, failure to produce sufficient TGF-␤ or IL-10 is associated with acute (31) and severe malaria (17,32,33), and severe malarial anemia (34,35). Finally, high ratios of IFN-␥, TNF-␣, and IL-12 to TGF-␤ or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do become infected (22).…”

Inflammatory cytokine and humoral responses to Plasmodium falciparum glycosylphosphatidylinositols correlates with malaria immunity and pathogenesis

“…A number of cytokines and bioactive proteins, such as procalcitonin were previously found to contribute to adverse prognosis in human SM 7, 29, 30. In agreement, we found elevated levels of pro inflammatory cytokines in patients with SM; approximately two‐ and threefolds higher for IL‐6 and TNF‐α compared to MM cases at the day of admission, but no significant difference of IL‐10 plasmatic levels between the two groups of patients.…”

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

“…Furthermore, a genetic predisposition to overproduce TNF-␣ in response to infection has been proposed as a mechanism underlying the development of cerebral malaria (34 -36). Collectively, these data suggest that the sequestration of PEs observed in cerebral malaria may result from up-regulated ICAM-1 and other adhesion molecules on the cerebral microvasculature due to excessive or unbalanced proinflammatory responses (6,33,34,36).…”

“…Several other receptors including ICAM-1 and CD31 support sequestration of PEs, are expressed on brain endothelium, and are up-regulated by proinflammatory cytokines (8,11,28,(31)(32)(33)59). Secretion of inflammatory cytokines during infection has been associated with a parasite-derived GPI toxin, which stimulates the release of TNF-␣, IL-1, and IL-6 from monocytes and M s. GPI from P. falciparum has also been shown to be a potent inducer of inducible NO synthase and NO output, presumably via the activation of transcription factors such as NF-B and c-rel (28,46).…”