Institute Salud Carlos III Campus Majadahonda

Majadahonda, Spain

Institute Salud Carlos III Campus Majadahonda

Majadahonda, Spain

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Jimenez-Sousa M.A.,Institute Salud Carlos III Campus Majadahonda | Medrano L.M.,Institute Salud Carlos III Campus Majadahonda | Liu P.,Hospital Clinico Universitario | Fernandez-Rodriguez A.,Institute Salud Carlos III Campus Majadahonda | And 7 more authors.
Annals of Intensive Care | Year: 2017

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, being the primary cause of death from infection, especially if not recognized and treated promptly. The aim of this study was to analyze whether IL-6 rs1800795 polymorphism is associated with septic shock-related death in European white patients who underwent major surgery. Methods: We performed a retrospective study on 202 septic shock patients who underwent major cardiac or abdominal surgery. The septic shock was established according to the international septic shock definition. The primary outcome variable was the death within 90 days after diagnosis of septic shock. The IL-6 rs1800795 polymorphism was genotyped by Sequenom’s MassARRAY platform. Results: The median age of the patients was 73 years, 63.4% were male, and more than 40% of patients had heart disease and hypertension. Overall, the survival analysis showed that 111 (55%) patients died with a survival median of 39 days (95% CI 30.7; 47.2). The genetic analysis association with survival was performed under a recessive genetic model (CC vs. GG/CG). Patients with IL-6 rs1800795 CC genotype had higher mortality rate than the IL-6 rs1800795 GG/CG genotype at days 7 [31.6% (6/19) vs. 10.4% (19/183); log-rank test (p = 0.005)] and 28 [57.9% (11/19) vs. 33.3% (61/183); log-rank test (p = 0.009)], and 90 [68.4% (13/19) vs. 53.5% (98/183); log-rank test (p = 0.006)]. The IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death during the first 7 days [adjusted hazard ratio (aHR 4.65; p = 0.002), 28 days (aHR 2.50; p = 0.006), and 90 days (aHR 2.28; p = 0.006)] with septic shock. When patients were stratified by type of surgery, those with IL-6 rs1800795 CC genotype who underwent cardiac surgery had higher risk of death during the first 7 days (aHR 18.39; p = 0.001) and 28 days (aHR 6.1; p = 0.025) than IL-6 rs1800795 GG/GC carrier, whereas patients with IL-6 rs1800795 CC genotype who underwent abdominal surgery had higher risk of death during all follow-up (aHR 1.98; p = 0.050) than IL-6 rs1800795 GG/GC carrier. Conclusions: The presence of IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death in patients who underwent major cardiac or abdominal surgery. These findings need robust validation in bigger independent cohorts. © 2017, The Author(s).


Alvaro-Meca A.,Rey Juan Carlos University | Jimenez-Sousa M.A.,Institute Salud Carlos III | Boyer A.,French Institute of Health and Medical Research | Medrano J.,University of the Basque Country | And 5 more authors.
BMC Infectious Diseases | Year: 2016

Background: Cirrhosis and severe sepsis are factors associated with increased mortality in intensive care unit (ICU), but chronic hepatitis C (CHC) has been less studied in ICU. The aim of this study was to analyze the impact of CHC on the mortality of cirrhotic patients admitted to ICU according to severe sepsis and decompensated cirrhosis. Methods: We carried out a retrospective study based on CHC-cirrhotic patients (CHC-group) admitted to ICU (n=1138) and recorded in the Spanish Minimum Basic Data Set (2005-2010). A control-group (randomly selected cirrhotic patients without HIV, HBV, or HCV infections) was also included (n=4127). The primary outcome variable was ICU mortality. The cumulative mortality rate on days 7, 30, and 90 in patients admitted to the ICUs was calculated by dividing the number of deaths by the number of patients admitted to the ICU. The adjusted hazard ratio (aHR) for death in the ICU was estimated through a semi-parametric Bayesian model of competing risk. Results: The CHC-group had a higher cumulative incidence of severe sepsis than the control-group in compensated cirrhosis (37.4 vs. 31.1%; p=0.024), but no differences between the CHC-group and the control-group in decompensated cirrhosis were found. Moreover, a higher cumulative incidence of severe sepsis was associated with decompensated cirrhosis compared to compensated cirrhosis in the control-group (40.1 vs. 31.1%; p<0.001) whereas this was not observed in the CHC group (38.1 vs. 37.4%; p=0.872). The CHC-group had higher cumulative mortality than the control-group by days 7 (47 vs. 41.3%; p<0.001), 30 (78.5 vs. 73.5%; p<0.001), and 90 (96.3 vs. 95.9%; p<0.001). In a competitive risk model, the CHC-group had a higher risk of dying if the ICU course was complicated by severe sepsis (adjusted hazard ratio (aHR)=1.19; p=0.003), but no significant values in patients with absence of severe sepsis were found (aHR=1.09; p=0.068). When patients were stratified by cirrhosis stage and severe sepsis, CHC patients with compensated cirrhosis had the higher risk of death if they had severe sepsis (aHR=1.35; p=0.002). Moreover, the survival was low in patients with decompensated cirrhosis and severe sepsis but we did not find significant differences between CHC-group and control-group. Conclusions: CHC was associated with an increased risk of death in cirrhotic patients admitted to ICUs, particularly in patients with compensated cirrhosis and severe sepsis. © 2016 Álvaro-Meca et al.


Guzman-Fulgencio M.,Institute Salud Carlos III Campus Majadahonda | Berenguer J.,Hospital General Universitario Gregorio Maranon | Berenguer J.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Pineda-Tenor D.,Institute Salud Carlos III Campus Majadahonda | And 13 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2014

Interleukin-7 (IL-7) is a critical factor in maintaining or inducing effective antiviral CD4+ and CD8+ T-cell responses. The aim of this study was to examine the association of interleukin-7 receptor-α (IL7RA) polymorphisms with a sustained virologic response (SVR) after hepatitis C virus (HCV) therapy with pegylated interferon-alpha plus ribavirin (pegIFNα/ribavirin) in 177 human immunodeficiency virus (HIV)/HCV-coinfected patients. We performed a retrospective study in 177 naïve patients who started HCV treatment. The IL7RA rs6897932, rs987106, and rs3194051 polymorphisms were genotyped by the GoldenGate® assay. An SVR was defined as undetectable HCV viral load through 24 weeks after the end of HCV treatment. The highest SVR rate was found in patients with the rs6897932 CC (p = 0.029) and rs3194051 GG (p = 0.002) genotypes, and HCV genotypes 2/3 (GT2/3) infected patients with the rs987106 AA genotype (p = 0.048). Additionally, carriers of the rs3194051 GG genotype had a higher likelihood of achieving an SVR [adjusted odds ratio (aOR) = 5.32; 95 % confidence interval (CI) = 1.07–26.94; p = 0.040] than patients with the rs3194051 AA/AG genotype, while rs6897932 CC (aOR = 0.63; p = 0.205) and rs987106 AA (aOR = 0.60; p = 0.213) were not significant. Moreover, three major haplotypes were found: 46.6 % for CTA, 32.4 % for CAG, and 20.7 % for TAA haplotypes. Patients infected with GT2/3 and carriers of the CTA haplotype had lower odds of achieving an SVR (aOR = 0.08; p = 0.004) and the CAG haplotype (favorable alleles) had higher odds of achieving an SVR than other haplotypes (aOR = 21.96; p < 0.001). IL7RA polymorphisms seem to play a significant role in the virological response to pegIFNα/ribavirin therapy in HIV/HCV-coinfected patients, in particular among patients infected with HCV GT2/3. © 2014, Springer-Verlag Berlin Heidelberg.


Guzman-Fulgencio M.,Institute Salud Carlos III | Berenguer J.,Hospital General Universitario Gregorio Maranon | Garcia-Alvarez M.,Institute Salud Carlos III | Micheloud D.,Institute Salud Carlos III | And 8 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2011

The aim of this study was to evaluate the influence of clinical and epidemiological characteristics of 183 HIV/HCV coinfected patients and HCV clearance after antiviral treatment on serum sFas and sFasL levels. Thirty out of 183 patients underwent HCV antiviral therapy with IFN-α + RBV for a duration of 48 weeks. HCV genotype 1 and homeostasis model assessment for insulin resistance (HOMA-IR) had a significant positive relationship, and CD4+/μL had a significant negative relationship with sFas (R-square = 0.582; p < 0.001) and sFasL (R-square = 0.216; p < 0.001) in multivariate linear regression analysis. HCV genotype 1 was the only significant variable associated with the sFas/sFasL ratio (R-square = 0.201; p < 0.001). sFas and sFasL levels had positive significant correlations with serum sICAM-1, sVCAM-1, and HOMA levels (p < 0.05). Among patients on IFN-α + RBV therapy, 15 patients showed a sustained virologic response (SVR), while 15 patients were non-responders (NR). Patients with SVR had significant decreases in sFas (p = 0.008) and sFas/sFasL ratio (p = 0.002), while non-responders had a significant increase in sFasL values (p = 0.013). In conclusion, HCV genotype 1, high HOMA, and low CD4+/μL were associated with high serum levels of sFas and sFasL, which indicate higher levels of inflammation and, possibly, increased cardiovascular risk. Moreover, response to HCV antiviral therapy is known to reduce inflammation. © 2011 Springer-Verlag.


Jimenez-Sousa M.A.,Institute Salud Carlos III Campus Majadahonda
BMC medical genetics | Year: 2012

Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem. To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development. A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD. Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance. Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.


Garcia-Alvarez M.,HIV and Hepatitis Co infection Unit | Berenguer J.,Hospital General Universitario Gregorio Maranon | Alvarez E.,Hospital General Universitario Gregorio Maranon | Guzman-Fulgencio M.,HIV and Hepatitis Co infection Unit | And 11 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2013

Torque teno virus (TTV) and torque teno mini virus (TTMV) have been potentially related to liver diseases. The aim of the study was to quantify TTV and TTMV in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients to study the relationship between the TTV and TTMV viral loads and the severity of liver disease. We carried out a cross-sectional study in 245 patients coinfected with HIV and HCV (HIV/HCV-group), 114 patients monoinfected with HIV (HIV-group), and 100 healthy blood donors (Control-group). Plasma samples were tested for TTV and TTMV by quantitative real-time polymerase chain reaction (PCR). The prevalences of TTV and TTMV infections in the HIV/HCV-group and the HIV-group were significantly higher than the Control-group (p < 0.05). Furthermore, TTV and TTMV coinfections were found in 92.2 % (226/245) in the HIV/HCV-group, 84.2 % (96/114) in the HIV-group, and 63 % (63/100 %) in the Control-group (p ≤ 0.05). HIV/HCV-coinfected patients with HIV viral load ≥50 copies/mL and patients with severe activity grade had the highest viral loads of TTV and TTMV (p ≤ 0.05). HIV/HCV-coinfected patients with high TTV load (>2.78 log copies/μL) had increased odds of having advanced fibrosis or severe necroinflammatory activity grade in the liver biopsy. Moreover, HIV/HCV-coinfected patients with high TTMV load (>1.88 log copies/μL) had decreased odds of having no/minimal fibrosis and no/mild activity grade, and increased odds of having a high fibrosis progression rate. In conclusion, TTV and TTMV might play a role in the development of liver disease in immunodeficiency patients, such as the patients coinfected with HIV and HCV. © 2012 Springer-Verlag.


Guzman-Fulgencio M.,Institute Salud Carlos III Campus Majadahonda | Medrano J.,Hospital Carlos III | Rallon N.,Hospital Carlos III | Echeverria-Urabayen A.,Service of Neurology | And 8 more authors.
Journal of Infection | Year: 2011

Objective: To evaluate the association between biomarkers of inflammation and endothelial dysfunction and Framingham scores (FS) for risk of coronary heart disease (FS-CHD), stroke (FS-Stroke) or any cardiovascular event (FS-CVE) in HIV-infected on suppressive highly active antiretroviral therapy (HAART). Methods: A cross-sectional study was conducted in 73 HIV-infected patients and 23 healthy controls. Inflammatory molecules and endothelial dysfunction markers were measured using a multiplex immunoassay (plasminogen activator inhibitor type 1 (PAI-1), soluble TNF receptor type 1 (sTNF-R1), soluble CD40 ligand (sCD40L), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecules (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1). Outcome variables were FS-CHD ≥10%, FS-Stroke ≥5% and FS-CVE ≥10%. Results: Significant differences (p < 0.05) were found comparing controls and HIV patients for PAI-1 (5.4 vs. 13.5 ng/dL), sTNF-R1 (0.85 vs. 1.09 ng/dL), sICAM-1 (529 vs. 858 ng/dL), sE-selectin (73.7 vs. 120 ng/dL), sP-selectin (676 vs. 1511 ng/dL) sCD40L (76 vs. 307 ng/dL), FS-CHD (4% vs. 7.8% L), FS-Stroke (2% vs. 2.8%) and FS-CVE (5% vs. 11%). In HIV-infected patients, the adjusted logistic regression analysis revealed that sTNF-R1 levels were significantly associated with increased FS-CHD>10% (OR: 11.51 (95% CI: 1.14; 115.84); p = 0.038) and FS-CVE (OR: 12.41 (95% CI: 1.25; 123.23); p = 0.031). Conclusions: HIV-infected patients show higher levels of soluble inflammatory and endothelial dysfunction markers than controls and have a two-fold increased FS of presenting coronary heart disease, stroke or cardiovascular events at 10 years. Furthermore, sTNF-R1 displayed the best association with FS of coronary heart disease and any cardiovascular event in our patients. © 2011 The British Infection Association.


PubMed | Institute Salud Carlos III Campus Majadahonda
Type: Journal Article | Journal: The Journal of infection | Year: 2011

To evaluate the association between biomarkers of inflammation and endothelial dysfunction and Framingham scores (FS) for risk of coronary heart disease (FS-CHD), stroke (FS-Stroke) or any cardiovascular event (FS-CVE) in HIV-infected on suppressive highly active antiretroviral therapy (HAART).A cross-sectional study was conducted in 73 HIV-infected patients and 23 healthy controls. Inflammatory molecules and endothelial dysfunction markers were measured using a multiplex immunoassay (plasminogen activator inhibitor type 1 (PAI-1), soluble TNF receptor type 1 (sTNF-R1), soluble CD40 ligand (sCD40L), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecules (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1). Outcome variables were FS-CHD 10%, FS-Stroke 5% and FS-CVE 10%.Significant differences (p < 0.05) were found comparing controls and HIV patients for PAI-1 (5.4 vs. 13.5 ng/dL), sTNF-R1 (0.85 vs. 1.09 ng/dL), sICAM-1 (529 vs. 858 ng/dL), sE-selectin (73.7 vs. 120 ng/dL), sP-selectin (676 vs. 1511 ng/dL) sCD40L (76 vs. 307 ng/dL), FS-CHD (4% vs. 7.8% L), FS-Stroke (2% vs. 2.8%) and FS-CVE (5% vs. 11%). In HIV-infected patients, the adjusted logistic regression analysis revealed that sTNF-R1 levels were significantly associated with increased FS-CHD>10% (OR: 11.51 (95% CI: 1.14; 115.84); p = 0.038) and FS-CVE (OR: 12.41 (95% CI: 1.25; 123.23); p = 0.031).HIV-infected patients show higher levels of soluble inflammatory and endothelial dysfunction markers than controls and have a two-fold increased FS of presenting coronary heart disease, stroke or cardiovascular events at 10 years. Furthermore, sTNF-R1 displayed the best association with FS of coronary heart disease and any cardiovascular event in our patients.


PubMed | Institute Salud Carlos III Campus Majadahonda
Type: Journal Article | Journal: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology | Year: 2015

Interleukin-7 (IL-7) is a critical factor in maintaining or inducing effective antiviral CD4+ and CD8+ T-cell responses. The aim of this study was to examine the association of interleukin-7 receptor- (IL7RA) polymorphisms with a sustained virologic response (SVR) after hepatitis C virus (HCV) therapy with pegylated interferon-alpha plus ribavirin (pegIFN/ribavirin) in 177 human immunodeficiency virus (HIV)/HCV-coinfected patients. We performed a retrospective study in 177 nave patients who started HCV treatment. The IL7RA rs6897932, rs987106, and rs3194051 polymorphisms were genotyped by the GoldenGate assay. An SVR was defined as undetectable HCV viral load through 24 weeks after the end of HCV treatment. The highest SVR rate was found in patients with the rs6897932 CC (p=0.029) and rs3194051 GG (p=0.002) genotypes, and HCV genotypes 2/3 (GT2/3) infected patients with the rs987106 AA genotype (p=0.048). Additionally, carriers of the rs3194051 GG genotype had a higher likelihood of achieving an SVR [adjusted odds ratio (aOR)=5.32; 95 % confidence interval (CI)=1.07-26.94; p=0.040] than patients with the rs3194051 AA/AG genotype, while rs6897932 CC (aOR=0.63; p=0.205) and rs987106 AA (aOR=0.60; p=0.213) were not significant. Moreover, three major haplotypes were found: 46.6 % for CTA, 32.4 % for CAG, and 20.7 % for TAA haplotypes. Patients infected with GT2/3 and carriers of the CTA haplotype had lower odds of achieving an SVR (aOR=0.08; p=0.004) and the CAG haplotype (favorable alleles) had higher odds of achieving an SVR than other haplotypes (aOR=21.96; p<0.001). IL7RA polymorphisms seem to play a significant role in the virological response to pegIFN/ribavirin therapy in HIV/HCV-coinfected patients, in particular among patients infected with HCV GT2/3.


PubMed | Institute Salud Carlos III Campus Majadahonda
Type: | Journal: BMC medical genetics | Year: 2012

Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem.To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development.A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD.Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI=0.46-0.95); p=0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI=0.54-0.90); p=0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI=1.17-2.83); p=0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI=1.01-1.71); p=0.043; additive model). After adjusting for multiple testing, results lost significance.Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.

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