Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity

Goeijenbier, Marco; Gasem, M Hussein; Meijers, Joost C M; Hartskeerl, Rudy A; Ahmed, Ahmed; Goris, Marga G A; Isbandrio, Bambang; Osterhaus, Albert D M E; Schuller, Simone; Martina, Byron E E; van Gorp, Eric C M; Nally, Jarlath E; Wagenaar, Jiri F P (2015). Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity. Journal of infection, 71(4), pp. 437-446. Elsevier 10.1016/j.jinf.2015.05.016

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OBJECTIVES

Previous studies concluded that haemorrhage is one of the most accurate prognostic factors of mortality in leptospirosis. Therefore, endothelial cell activation was investigated in relation to disease severity in severe leptospirosis.

METHODS

Prospective cohort study of severe leptospirosis patients. Plasma levels of sE-selectin and Von Willebrand factor (VWF) were determined. Consequently, an in vitro endothelial cell model was used to assess endothelial activation after exposure to virulent Leptospira. Finally, immune activation, as a potential contributing factor to endothelial cell activation, was determined by soluble IL2-receptor (sIL-2r) and soluble Fas-ligand (sFasL) levels.

RESULTS

Plasma levels of sE-selectin and VWF strongly increased in patients compared to healthy controls. Furthermore, sE-selectin was significantly elevated (203 ng/ml vs. 157 ng/ml, p < 0.05) in survivors compared to non-survivors. Endothelial cells exposed to virulent Leptospira showed increased VWF expression. E-selectin and ICAM-1 expression did not change. Immunohistochemistry revealed the presence of intracellular Leptospira and qPCR suggested replication. In vivo analysis showed that increased levels of sFasL and sIL-2r were both strongly associated with mortality. Furthermore sIL-2r levels were increased in patients that developed bleeding and significantly correlated to duration of hospital stay.

DISCUSSION

Markers of endothelial activation and immune activation were associated with disease severity in leptospirosis patients.

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