Perfil de expressão de citocinas e gravidade da lesão valvar reumática

Abstract

Background: Rheumatic fever (RF) and subsequent rheumatic heart disease (RHD) remain a serious public health problem in developing countries. The pathogenesis of the disease consists of the triad characterized by the presence of group A streptococci (Streptococcus pyogenes), a genetically susceptible host, and an exacerbated immune response. The pattern of immune response after exposure to group A streptococcus is one of the main determinants of the rheumatic inflammatory process leading to valve lesions. However, the evolution of RHD is variable, making it essential to identify the patients who present a higher risk of disease progression with subsequent need for valve intervention. The objective of the present study was to analyze cytokine serum levels in the different stages of RHD, and their correlation with disease severity. Methods: This is an observational, cross-sectional study, including 89 patients with RHD from the Bias Fortes outpatient clinic of the UFMG Medical School. Careful clinical examination was performed by the principal investigator to quantify the valvular lesions, with subsequent echocardiogram performed to better define the morphological aspect of the valve and to obtain measurements and hemodynamic calculations. Next, blood samples were collected for cytokine measurements. Serum samples were analyzed using cytometric bead array (CBA) assay for the measurement of interleukins (IL): IL-10, IL-6, IL-2, IL-4, IL17A, tumor necrosis factor- (TNF-) and interferon- (IFN-). Results: The mean age of the patients was 41 ± 11.5 years with a high prevalence of women (85%). Half of the patients (49.4%) reported a history of acute RF, not associated with the need for valve intervention (p = 0.086). Mitral valve was the most affected, with 60 patients (67.4%) presenting isolated mitral involvement, 23 (25.9%) with mitral and aortic involvement and 6 patients (6.7%) with mitral, aortic and tricuspid involvement. At the time of inclusion in the study, 64 patients had already undergone valvular intervention (valve replacement or percutaneous or open valvuloplasty), denoting a RHD of greater severity, which required an invasive procedure to alter the disease evolution. Twenty-five patients, with the same demographic characteristics as the others, had stable RHD, with mild or moderate valve lesions, without the need for any cardiac intervention. Patients with no previous valvular intervention reported earlier onset of secondary prophylaxis with benzathine penicillin compared to patients with more severe RHD (15.7 ± 10.5 years versus 23.9 ± 10.2 years, respectively, p = 0.002), despite the frequency of penicillin use at study entry was similar between the groups (76.6% versus 92.0%, respectively, p = 0.096). When the patients were stratified according to valve intervention, it was observed that the peripheral serum concentration (pg/ml) of inflammatory cytokines was higher in the group with more severe disease than in those with low disease progression (IL-6: p = 0.007; TNF-: p = 0.017; IL-2: p = 0.018; IL-17A: p = 0.019; IFN-: p = 0.026). The same was seen for IL-4 (p = 0.007). Interestingly, the expression of the anti-inflammatory cytokine, IL10, was not different between groups (p = 0.366). Cluster analysis of all cytokines showed a different segregation between intervention and non-intervention groups, with IL-6/TNF- and IL-6/IL-17A associated with intervention and non-intervention, respectively. Conclusions: Patients with severe RHD requiring valvular intervention had a more intense inflammatory response evidenced by high concentrations of inflammatory cytokines, as compared to patients with more favorable disease evolution. In addition, the early initiation of secondary prophylaxis of RF with the use of penicillin was more frequent in patients with stable evolution of RHD, supported by the hypothesis that streptococcal reinfections play a fundamental role in the progression of heart disease.