Cytokine Response Signatures in Disease Progression and Development of Severe Clinical Outcomes for Leptospirosis

Abstract

BackgroundThe role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS).Methodology/Principal FindingsWe performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-α were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P = 0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P = 0.0519) among fatal cases who developed SPHS than among who did not.Conclusion/SignificanceThis study shows that severe cases of leptospirosis are differentiated from mild disease by a “cytokine storm” process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis.

Specific CD4+T-Cell Reactivity and Cytokine Release in Different Clinical Presentations of Leptospirosis

“…Some authors have proposed that severe cases of leptospirosis are differentiated from mild disease by a "cytokine storm" (14). Elevated cytokine production in severe disease compared to mild disease is consistent with our data, since patients with severe disease revealed more prominent production of all cytokines tested.…”

“…Elevated IL-10 levels have been shown to be associated with fatal cases (13) and to be higher in patients with severe disease than in those with mild disease (14). In addition, conflicting data about the predictive value of the IL-10/TNF-␣ ratio as a marker for disease severity in leptospirosis have been published.…”

“…Some previous studies have investigated cytokine concentrations in serum specimens in relation to the severity of the disease (11)(12)(13)(14). Besides the general production of cytokines, CD3…”

Endothelial Glycocalyx Damage is Associated with Leptospirosis Acute Kidney Injury

“…This definition has been used in other studies. 17 Other infectious diseases (hepatitis A, dengue, typhoid fever, and others) were excluded.…”

Decrease in antithrombin III and prothrombin serum levels contribute to coagulation disorders during leptospirosis

“…Similar to sepsis, human leptospirosis was reported to be associated with high plasma levels of inflammatory cytokines such as TNF-a, IL-6, IL-8, IL-1b and IL-12 (Matsui et al, 2011;Wang et al, 2012;Reis et al, 2013). Indeed, the production of inflammatory cytokines such as TNF-a by CD4+ T-cells after stimulation with antigens of Leptospira was highest in patients with severe disease (Volz et al, 2015).…”