Understanding the most severe presentations of malaria is key to lowering the mortality associated with the infectious disease, which currently stands around 500,000 deaths a year. Researchers have now reinforced the idea that kidney dysfunction is a contributing factor to severe Plasmodium vivax malaria cases.
Malaria, caused by a handful of Plasmodium parasites and spread by mosquitos in tropical and sub-tropical areas of the world, affects over 200m people a year. Historically, P. vivax has been associated with more mild presentations of disease, with P. falciparum causing increased severity and mortality. However, severe cases of P. vivax have been more frequently reported in recent years. These cases are often associated with impaired immune response, inflammation, and kidney involvement.
In the new work, Bruno Andrade of the Oswaldo Cruz Foundation in Brazil, and colleagues analysed data on 572 individuals from the Brazilian Amazon, including 179 patients with P. vivax infection – 18 of whom had severe disease – and 165 healthy controls. The researchers studied levels of creatinine, a marker of kidney function, as well as markers of inflammation, and followed the course of disease in the patients.
Severity of disease was associated with abnormal creatinine increases, and patients who died from severe disease had the highest levels of creatinine. In addition, the levels of several immune molecules – including IFN-γ/IL-10 ratios and CRP values – could predict outcome in subjects with elevated creatinine, differentiating those who died. The results suggest that severe disease from P. vivax is associated with creatinine elevation and exacerbated inflammation.
“We predict that the systemic inflammation observed in more severely ill malaria patients could be contributing to kidney dysfunction through different mechanisms,” the researchers say. “The identification of key factors driving the pathogenesis of this type of disease presentation and experimental models still are necessary to guide future studies and approaches.”
Abstract
Background: Although Plasmodium vivax infection is a frequent cause of malaria worldwide, severe presentations have been more regularly described only in recent years. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are relatively scarce. Here, renal dysfunction is retrospectively analyzed in a large cohort of vivax malaria patients with an attempt to dissect its association with disease severity and mortality, and to determine the role of inflammation in its progression.
Methods: A retrospective analysis of a databank containing 572 individuals from the Brazilian Amazon, including 179 patients with P. vivax monoinfection (161 symptomatic malaria, 12 severe non-lethal malaria, and 6 severe lethal disease) and 165 healthy controls, was performed. Data on levels of cytokines, chemokines, C-reactive protein (CRP), fibrinogen, creatinine, hepatic enzymes, bilirubin levels, free heme, and haptoglobin were analyzed to depict and compare profiles from patients per creatinine levels.
Results: Elevated creatinine levels were found predominantly in women. Vivax malaria severity was highly associated with abnormal creatinine increases, and nonsurvivors presented the highest values of serum creatinine. Indication of kidney dysfunction was not associated with parasitemia levels. IFN-γ/IL-10 ratio and CRP values marked the immune biosignature of vivax malaria patients, and could distinguish subjects with elevated creatinine levels who did not survive from those who did. Patients with elevated serum creatinine or severe vivax malaria displayed indication of cholestasis. Biomarkers of hemolysis did not follow increases in serum creatinine.
Conclusion: These findings reinforce the hypothesis that renal dysfunction is a key component in P. vivax malaria associated with clinical severity and mortality, possibly through intense inflammation and immune imbalance. Our study argues for systematic evaluation of kidney function as part of the clinical assessment in vivax malaria patients, and warrants additional studies in experimental models for further mechanism investigations.
Authors
Luís AB Cruz, Manoel Barral-Netto, Bruno B Andrade
[link url="http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006306"]PLOS Neglected Tropical Diseases abstract[/link]