Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance

Abstract

Background: Despite clinical descriptions of severe vivax malaria cases having been reported, data regarding immunological and inflammatory patterns are scarce. In this report, the inflammatory and immunological status of both mild and severe vivax malaria cases are compared in order to explore immunopathological events in this disease.

Methods and results: Active and passive malaria case detections were performed during 2007 in Buritis, Rondônia, in the Brazilian Amazon. A total of 219 participants enrolled the study. Study individuals were classified according to the presence of Plasmodium vivax infection within four groups: non-infected (n = 90), asymptomatic (n = 60), mild (n = 50) and severe vivax infection (n = 19). A diagnosis of malaria was made by microscopy and molecular assays. Since at present no clear criteria define severe vivax malaria, this study adapted the consensual criteria from falciparum malaria. Patients with severe P. vivax infection were younger, had lived for shorter time in the endemic area, and recalled having experienced less previous malaria episodes than individuals with no malaria infection and with mild or asymptomatic infection. Strong linear trends were identified regarding increasing plasma levels of C reactive protein (CRP), serum creatinine, bilirubins and the graduation of disease severity. Plasma levels of tumour necrosis factor (TNF), interferon-gamma(IFN-gamma) and also IFN-gamma/interleukin-10 ratios were increased and exhibited a linear trend with gradual augmentation of disease severity. Both laboratory parameters of organ dysfunction and inflammatory cytokines were reduced during anti-parasite therapy in those patients with severe disease.

Conclusion: Different clinical presentations of vivax malaria infection present strong association with activation of pro-inflammatory responses and cytokine imbalance. These findings are of utmost importance to improve current knowledge about physiopathological concepts of this serious widespread disease.

Figure 1

The Hepatic-Inflammatory Parasitic score. In a primary investigation, 580 individuals from Buritis, Rondonia, Brazil were evaluated to standardize the Hepatic-Inflammatory Parasitic (HIP) score. This sample included non-infected individuals (n = 183) and those infected with Plasmodium presenting malaria-related symptoms (n = 195) or asymptomatic infection (n = 202). The threshold plasma values of (A) aspartate aminotransferase (AST), (B) alanino amino-transaminase (ALT), (C) total bilirubin, (D) fibrinogen, (E) C reactive protein (CRP) and (F) parasitaemia were established in order to categorize the individuals according to the HIP score. Once the HIP score was created, it was applied in another sample from the same endemic area composed by 219 individuals: non-infected (n = 90), asymptomatic (n = 60), mild (n = 50) and severe vivax infection (n = 19). Area under the curve (AUC) was calculated, together with the cut-off value, which presents the higher likelihood ratio, and P values are plotted. The HIP score is described in Methods.

Figure 2

General trend of the Inflammatory profile in vivax malaria. Plasma levels of (A) TNF, (B) IFN-gamma, (C) IL-10 and (D) IFN-gamma/IL-10 ratios were estimated in non-infected individuals and those presenting different manifestations of the vivax malaria clinical spectrum. Study participants were stratified in groups as follows: non-infected (NI; n = 90); asymptomatic infection (Asy; n = 60); mild infection (Mild; n = 50); and severe infection (Sev; n = 19). One-Way ANOVA with trend analysis was performed to check the statistical significance between the groups studied. P values are plotted in each graph.

Figure 3

Kinetic of organ damage indicators during antimalarial treatment in individuals with severe vivax disease. Plasma levels of (A) CRP, (B) creatinine, (C), ALT and (D) total bilirubin were estimated before treatment (at admission to the Hospital) and after seven days of inhospital care in individuals with severe vivax infection who achieved cure (n = 13). Wilcoxon matched pairs test was performed to calculate the statistical significance. P values are plotted in each graph.

Figure 4

Kinetic of immunologic indicators during antimalarial treatment in individuals with severe vivax disease. (A) IFN-gamma/IL-10 ratios and (B) TNF plasma levels were estimated before treatment (at admission to the Hospital) and after seven days of in-hospital care in individuals with severe vivax infection who achieved cure (n = 13). Wilcoxon matched pairs test was performed to calculate the statistical significance. P values are plotted in each graph.