Plasma interleukin-6 levels in Mediterranean spotted fever.

Abstract

Mediterranean spotted fever (MSF) is a rickettsiosis endemic to Mediterranean countries caused by Rickettsia conorii, an obligate intracellular bacterium with endothelial cell tropism [1]. In a previous study we found an association between high plasma levels of tumor necrosis factor alpha (TNF-α) and severe MSF, raising the question of whether TNF-α is a causal contributor to disease pathogenesis or whether it is a nonspecific epiphenomenon [2]. In order to better characterize the role of proinflammatory cytokines in the pathogenesis of MSF we conducted the present study in which the plasma levels of interleukin-6 (IL-6) were analyzed and the variables significantly associated with disease severity were examined. The prospective study included 19 patients consecutively diagnosed with MSF at our hospital and 20 healthy controls. In all cases the diagnosis of MSF was confirmed by indirect immunofluorescence to R. conorii. Patients were considered to have severe MSF if they developed significant dysfunction of a major organ, as evidenced by neurological symptoms, or if they experienced a recent rise in serum creatinine levels, respiratory failure, or shock [3, 4]. Plasma IL-6 and TNF-α levels were determined using an enzyme-linked immunosorbent assay. The nonparametric Mann Whitney and Spearman’s correlation coefficient tests were used for the univariate analysis of clinical associations and analytical correlations, respectively. Multivariate analyses were performed to identify the variables significantly associated with disease severity in MSF patients. Plasma IL-6 levels were significantly higher in MSF patients on admission than in healthy controls (mean, 49.6 pg/ml [SD, 57.8], vs <4.0 pg/ml in all controls; P<0.001). Only two patients with active MSF had normal (undetectable) levels of IL-6. All patients had fever and rash, with the rash being purpuric in eight cases. Five patients developed severe MSF. Patients with severe MSF had higher plasma IL-6 levels than milder cases (mean, 97.1 pg/ml vs 32.7 pg/ml, respectively), but the difference was not statistically significant (P=0.10). Plasma IL-6 levels correlated significantly with plasma TNF-α (r=0.65, P=0.003) and serum C-reactive protein (r=0.49, P=0.03) levels, and inversely with the blood lymphocyte count (r= −0.76, P<0.001). In view of the association between severe MSF and increased levels of both IL-6 and TNF-α, we performed a stepwise logistic regression analysis to identify whether both cytokines contributed independently to the development of severe MSF. In this analysis, the only variable that approached statistical significance was plasma TNF-α (odds ratio of presenting severe MSF for each 10 pg/ml increase in TNF-α levels, 1.98; 95% confidence interval, 0.97–4.05; P=0.06), leaving plasma IL-6 outside the regression model. Several experimental studies give support to the hypothesis that proinflammatory cytokines might play a role in the pathogenesis of MSF. In vitro, activated macrophages and endothelial cells infected by R. conorii synthesize proinflammatory cytokines like TNF-α and IL6 [5, 6]. In addition, we reported high plasma levels of TNF-α and soluble TNF-α receptors in patients diagnosed with MSF, and the higher levels were associated with severe disease [2, 7]. In the present study, we also found high levels of IL-6 in plasma during the acute phase of MSF. As in many other inflammatory conditions, plasma IL-6 levels correlated J. Oristrell Internal Medicine Service, Corporacio Parc Tauli, C/ Parc Tauli s/n, 08208 Sabadell, Barcelona, Spain