Plasma Superoxide Dismutase-1 as a Surrogate Marker of Vivax Malaria Severity

Abstract

BackgroundSevere outcomes have been described for both Plasmodium falciparum and P. vivax infections. The identification of sensitive and reliable markers of disease severity is fundamental to improving patient care. An intense pro-inflammatory response with oxidative stress and production of reactive oxygen species is present in malaria. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and antioxidant agents such as superoxide dismutase-1 (SOD-1) are likely candidate biomarkers for disease severity. Here we tested whether plasma levels of SOD-1 could serve as a biomarker of severe vivax malaria.Methodology/Principal FindingsPlasma samples were obtained from residents of the Brazilian Amazon with a high risk for P. vivax transmission. Malaria diagnosis was made by both microscopy and nested PCR. A total of 219 individuals were enrolled: non-infected volunteers (n = 90) and individuals with vivax malaria: asymptomatic (n = 60), mild (n = 50) and severe infection (n = 19). SOD-1 was directly associated with parasitaemia, plasma creatinine and alanine amino-transaminase levels, while TNF-alpha correlated only with the later enzyme. The predictive power of SOD-1 and TNF-alpha levels was compared. SOD-1 protein levels were more effective at predicting vivax malaria severity than TNF-alpha. For discrimination of mild infection, elevated SOD-1 levels showed greater sensitivity than TNF-alpha (76% vs. 30% respectively; p<0.0001), with higher specificity (100% vs. 97%; p<0.0001). In predicting severe vivax malaria, SOD-1 levels exhibited higher sensitivity than TNF-alpha (80% vs. 56%, respectively; p<0.0001; likelihood ratio: 7.45 vs. 3.14; p<0.0001). Neither SOD-1 nor TNF-alpha could discriminate P. vivax infections from those caused by P. falciparum.ConclusionSOD-1 is a powerful predictor of disease severity in individuals with different clinical presentations of vivax malaria.

Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria

“…The study sample includes 78 subjects with symptomatic malaria, 106 subjects with asymptomatic malaria, and 80 uninfected individuals. These individuals have already been analyzed by our group in other studies (1,(3)(4)(5)(6)(7). Active and passive case detections were performed using both microscopy and nested PCR.…”

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

“…Mice overexpressing SOD-1 develop oxidative injury associated with an increased vulnerability to Plasmodium berghei (26). Recent investigations from our group also indicate that SOD-1 is a surrogate marker of severe vivax malaria with a better predictive power than TNF-a (29). Although intriguing, the specific link between the free heme release from Hb, expression of SOD-1, and the severity of malaria has never been addressed.…”

Biomarkers for susceptibility to infection and disease severity in human malaria

“…Nevertheless, less specific markers, such as those that indicate inflammatory status, are also extremely important in the light of their high sensitivity in predicting disease severity (Andrade et al 2010d). Intense research focused on the immunopathogenesis of severe malaria will contribute to the identification of useful surrogate and specific biomarkers for cases of severe malaria.…”

“…Recently, we have shown that haemolysis related to high plasma levels of indirect bilirubin, total heme and Cu/Zn superoxide dismutase (SOD1) is consistently associated with severe vivax malaria (Andrade et al 2010a). Furthermore, SOD1 is a better predictor of severe vivax malaria than are plasma levels of TNF-α (Andrade et al 2010d), but this biomarker cannot be used to discriminate between P. vivax and P. falciparum infections. In a recent study of a cohort of patients with different clinical presentations of vivax malaria, we described a series of promising markers of severe disease (Andrade et al 2010c).…”