Endothelial dysfunction is an early indicator of sepsis and neutrophil degranulation of septic shock in surgical patients.

BACKGROUND: Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients. METHODS: Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12 h after diagnosis at three Spanish hospitals. RESULTS: There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P = 0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P < 0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P = 0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P = 0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P < 0·001). CONCLUSION: MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.

ANTECEDENTES: La estratificación de la gravedad de una infección se basa actualmente en la puntuación SOFA (Sequential Organ Failure Assessment), que es difícil de calcular fuera de la unidad de cuidados intensivos. Los biomarcadores podrían ayudar a estratificar la gravedad de la infección en pacientes quirúrgicos. MÉTODOS: Se compararon las concentraciones de 10 biomarcadores que denotan disfunción endotelial, 22 que indican granulopoyesis de emergencia y 6 que expresan la degranulación de neutrófilos en tres grupos de pacientes de tres hospitales españoles (100 con infección, 95 con sepsis y 57 con shock séptico) en las primeras doce horas después del diagnóstico. RESULTADOS: Siete biomarcadores que expresan disfunción endotelial (proadrenomedulina, sindecan-1, trombomodulina, angiopoyetina-2, endocan-1, molécula de adhesión endotelial 1 y E-selectina) mostraron una fuerte asociación con la sepsis en comparación con la infección aislada. La proadrenomedulina presentó el valor más alto de la razón de oportunidades (odds ratio, OR) en el análisis multivariable (OR 11,53, i.c. del 95% 4,15-32,08, P = 0,006) y la mejor área bajo la curva para detectar sepsis (AUC 0,86, i.c. del 95% 0,80-0,91, P < 0,001). En la comparación entre sepsis y shock séptico, los biomarcadores que mostraron la asociación más estrecha con el shock séptico fueron dos biomarcadores de degranulación de neutrófilos (proteinasa-3 y lipocalina-2) (OR 8,09, i.c. del 9% 1,34-48,91, P = 0,028; OR 6.62, i.c. del 95% 2,47-17,77, P = 0,002), pero la lipocalina-2 presentó la mejor AUC (0,81, i.c. del 95% 0,73-0,90, P < 0,001). CONCLUSIÓN: la proadrenomedulina y la lipocalina-2 podrían representar alternativas a la puntuación SOFA para detectar sepsis y shock séptico en pacientes quirúrgicos con infección.

Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis.

OBJECTIVE: The impact of endogenous immunoglobulin isotypes on the prognosis of patients with severe sepsis has not been sufficiently explored. The aim of this study was to evaluate the association between immunoglobulin levels in plasma and survival in patients with this condition. DESIGN AND PATIENTS: A prospective multicentre cohort study was conducted. A total of 172 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock were recruited. Patients were classified based on deciles of immunoglobulin concentrations at diagnosis of sepsis. Categorical variables were created and tested for their association with survival during hospitalization in the ICU. RESULTS: Overall, 42 patients died in the ICU during the study. Kaplan-Meier analysis showed that immunoglobulin concentrations below 300 mg dL(-1) for IgG1, 35 mg dL(-1) for IgM and 150 mg dL(-1) for IgA were associated with shorter survival times. Multivariate regression analysis showed that IgG1 < 300 mg dL(-1) was a risk factor for mortality [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.04-6.03; P = 0.042]. The combined presence of IgG1, IgM and IgA levels below the described thresholds had a synergistic impact on mortality risk (OR 5.27, 95% CI 1.41-19.69; P = 0.013). A similar effect was observed for combined low levels of IgG1 and IgA (OR 4.10, 95% CI 1.28-13.12; P = 0.018) and also of IgG1 and IgM (OR 3.10. 95% CI 1.13-8.49; P = 0.028). CONCLUSIONS: The combined presence of low levels of the endogenous immunoglobulins IgG1, IgM and IgA in plasma is associated with reduced survival in patients with severe sepsis or septic shock. Assessment of the concentrations of these immunoglobulins could improve the results of treatment with exogenous immunoglobulins in patients with sepsis.

Tendencia y estacionalidad del virus respiratorio sincitial en Valladolid durante el periodo 1993-2010 / Trend and seasonality of respiratory syncytial virus in Valladolid (Spain) during 1993-2010

Objetivo: Describir la tendencia y la estacionalidad de las infecciones por el virus respiratorio sincitial (VRS) en el Área de Salud de Valladolid Este durante el periodo 1993-2010.Pacientes y métodos: Se incluyeron en el estudio las muestras analizadas entre enero de 1993 y diciembre de 2010 por el Servicio de Microbiología e Inmunología del Hospital Clínico Universitario de Valladolid. Las muestras se clasificaron en función de la edad del paciente y el método de diagnóstico. El análisis virológico se llevó a cabo mediante técnicas de diagnóstico rápido, cultivo celular o microarrays. Se calcularon las tasas anuales referidas al área cubierta por el hospital para identificar la tendencia desde 1993 hasta 2010. Los meses epidémicos se establecieron mediante el índice epidémico, y la periodicidad mediante el método cosinor. Resultados: De 4.103 muestras analizadas de pacientes con síntomas respiratorios, en 1.644 (40,1%) se confirmó la presencia de VRS. Casi el 90% de los casos confirmados se dieron en pacientes menores de 2 años, y el 59,5% en menores de 1 año. Las tasas fluctuaron cada 2-4 años, alcanzando valores máximos en 2002 y 2003, con 41,5 y 44,9 casos por 100.000 habitantes-año, respectivamente. Aunque se produjeron casos durante todo el año, los periodos epidémicos se dieron entre septiembre y marzo, detectándose la mayor incidencia en enero y la menor en julio. Conclusiones: Los datos epidemiológicos (prevalencia del virus en muestras respiratorias y distribución por edad) fueron similares a los descritos en otros estudios. Los periodos epidémicos se describieron entre septiembre y marzo, alcanzado el máximo de incidencia en enero y el mínimo en julio. A pesar de ello, a lo largo de los 18 años estudiados sólo en 5 años no hubo circulación de VRS durante 2-3 meses, y en 8 más el VRS estuvo ausente durante un mes. No hay ningún dato que permita anticipar la ausencia de circulación del virus, aspecto importante para la profilaxis de esta infección (AU)

Purpose: The aim of the study is to describe the trend and seasonality of respiratory syncytial virus (RSV) infections in the East Valladolid Health Administrative-Division during the period1993-2010.Patients and Methods: Samples processed in the area of Eastern Valladolid by the Department of Microbiology and Immunology at the Hospital Clínico Universitario of Valladolid between January 1993 and December 2010 were included in the analysis. Cases were classified by age and diagnostic method. Virological diagnosis of the cases was carried out through rapid assay methods, shell-vial cell culture assay or microarray techniques. Annual rates were calculated to identify the trend of the infection from 1993 to 2010. The epidemic index was used to establish epidemic months and cosinor method to evaluate periodicity. Results: From 4,103 samples processed, collected from patients with respiratory symptoms, 1,644 (40.1%) were confirmed to be RSV possitive. Almost 90% of the confirmed cases appeared in patients under 2 years old, 59.5% in younger than1 year old children. The infection trend seems to fluctuate every 2-4 years with higher rate in 2002 and 2003, accounting for 41.5 and 44.9 cases detected per 100,000 inhabitants-year, respectively. Although cases were detected throughout all the year, epidemic periods were detected from September to March with highest values in January and lowest values in July. Conclusions: Epidemiological data (VRS prevalence in respiratory samples and distribution of cases by age) was similar to those obtained in previous studies. Epidemic periods were described from September to March with the highest numbers of cases in January and lowest values in July. In spite of this, along the eighteen years studied there were eight years without RSV detection in one month and only five years without detection in 2-3 months. There is no data that allows to predict the lack of circulation for RSV, being an important factor for the prophylaxis of the infection (AU)

Intubated patients developing tracheobronchitis or pneumonia have distinctive complement system gene expression signatures in the pre-infection period: A pilot study

Introduction: It remains unknown why some intubated patients remain infection-free while others develop tracheobronchitis (VAT) or pneumonia (VAP). Objective: To identify and compare VAP/VAT gene expression "signatures" using genome-wide oligonucleotide microarrays. Material and methods: A prospective translational study of gene expression profiles of VAP and VAT groups was carried out, establishing comparisons in both pre-infection and infection phases. Pathway and functional analyses were performed with Ingenuity Pathway Analysis (IPA). Data analysis and hierarchical clustering of the genes involved in the signalling pathways expressed differentially in the two groups were performed with GeneSpring GX 11.0. Results: Eight patients developing respiratory infections (3 VAP and 5 VAT) after 4 days of mechanical ventilation were assessed. Comparison of gene expression profiles in the pre-infection period revealed 5595 genes expressed differentially between VAP and VAT (p<0.01, fold change >2). Comparative IPA analysis identified a significant depression of the complement system signalling pathway in the VAP group, affecting the classical pathway along with the final common pathway (p<0.05). In addition, the cAMP and calcium signalling pathways were also significantly depressed in the VAP group during the pre-infection phase also. Conclusion: Intubated patients complicated with pneumonia developed immune impairment in the pre-infection period, manifesting as a relatively lower expression of genes involved in the complement system that differed from patients developing tracheobronchitis. These findings suggest that a significant proportion of VAP episodes cannot be prevented, but might be treatable through pre-emptive therapy (AU)

Introducción: Seguimos sin saber por qué algunos pacientes intubados no sufren infecciones mientras que otros presentan traqueobronquitis (TAV) o neumonía (NAV). Objetivo: Identificar y comparar los patrones de la expresión genética de la NAV/TAV usando micromatrices multigénicas oligonucleotídicas. Material y métodos: Se realizó un estudio aplicado prospectivo de los patrones de la expresión genética de los grupos con NAV y TAV, estableciendo comparaciones tanto en la fase previa a la infección como en la fase infecciosa. Se realizaron análisis de vías y funcionales con Ingenuity Pathway (IPA). Los análisis de datos y el agrupamiento jerárquico de los genes implicados en las vías de señalización expresados de forma diferenciada en ambos grupos se realizaron con GeneSpring GX 11.0. Resultados: Se evaluaron ocho pacientes que presentaron infecciones respiratorias (3 NAV y 5 TAV) después de 4 días con la ventilación mecánica. La comparación de los perfiles de la expresión genética durante el período previo a la infección reveló 5.595 genes expresados de forma diferenciada entre la NAV y la TAV (p<0,01, cambio múltiplo>2). Los análisis comparativos de los IPA identificaron una depresión importante de la vía de señalización del sistema del complemento en el grupo con NAV, que afectó a la vía clásica además de a la vía común final (p<0,05). Por otra parte, el monofosfato cíclico de adenosina y las vías de señalización del calcio también se vieron muy deprimidos en el grupo (..)(AU)

Respuesta inmune respiratoria al año de vida en el niño prematuro / Respiratory immune response in first year of a preterm infant

Introducción: Existe un gran desconocimiento acerca de la evolución del sistema inmune en la mucosa respiratoria del niño prematuro a largo plazo. La inmadurez y las infecciones respiratorias pueden influir sobre la respuesta inmune de las mucosas. El propósito de este estudio era evaluar la secreción respiratoria de los mediadores inmunológicos al año de vida en niños prematuros. Pacientes y métodos: Desde octubre de 2008 hasta abril de2009 se reclutaron 77 prematuros nacidos en 6 servicios de pediatría de Castilla y León, así como 14 controles sanos a término. Los prematuros fueron citados al año de edad gestacional corregida y los niños a término al año de vida, momento en el cual se les realizó un lavado nasal para determinar los niveles de 27 mediadores inmunológicos mediante un ensayo de Biorad®. Resultados: Los niños prematuros tenían niveles más elevados de quimiocinas (eotaxina, IP-10), citocinas Th-1 (IFN-epsilon), Th-2 (IL-13), Th-17 (IL-17) y factores de crecimiento celular (PDGF-bb, VEGF, FGF-b, G-CSF y GM-CSF) que los niños a término. Cuando se compararon los niveles de mediadores entre los niños que habían recibido profilaxis para el virus respiratorios incitial con palivizumab y los que no, los segundos tenían niveles significativamente más altos de MCP-1, IL-1RA, IL-10,IL-12p70 y VEGF (p <0,05) que los primeros. Conclusiones: Este trabajo demuestra por vez primera la influencia de la prematuridad sobre los perfiles de secreción respiratoria de las citocinas y quimiocinas a largo plazo. Por otra parte, nuestros resultados indican que la evaluación del impacto de la profilaxis de la infección respiratoria es un camino interesante para comprender la maduración de la respuesta inmune de la mucosa respiratoria del prematuro(AU)

Introduction: There is a big unawareness about a long term respiratory mucous immune system evolution in the preterm infant. Immaturity and respiratory infections can have a big influence on the mucous immune responses. This investigation’s purpose is the evaluation of respiratory secretion of inflammatory immunological mediators in the first year of a preterm infant. Patients and methods: Between October 2008 and April 2009, 77 preterm infants were born in 6 pediatric services of Castilla y Leon, plus to another 14 healthy controls results. Children were invited on their first corrected gestational age and the ones of healthy controls results. Nasal washing were applied to determine 27 immunological mediators’ levels by applying a Biorad test. Results: The preterm infants has higher chemokine (eotaxin,IP-10), cytokines Th-1 (IFN-epsilon), Th-2 (IL-13), Th-17 (IL-17) and cell growing factors (PDGF-bb, VEGF, FGF-b, G-CSF and GM-CSF)levels than a healthy control results children. When a comparison was made between children that received prophylaxis for their respiratory syncytial virus with palivizumab and the ones that did not receive it, the second group showed higher MCP-1, IL-1RA, IL-10, IL-12p70 and VEGF (p <0,05) levels. Conclusions: This work proves, for the first time, the influence of the premature birth on chemokine and cytokines respiratory secretion levels in a long term concepts. On other hand, our results indicate that prophylaxis impact in the respiratory infection is an interesting way to understand respiratory mucous immune response maturation in the preterm infant(AU)

Intubated patients developing tracheobronchitis or pneumonia have distinctive complement system gene expression signatures in the pre-infection period: a pilot study.

INTRODUCTION: It remains unknown why some intubated patients remain infection-free while others develop tracheobronchitis (VAT) or pneumonia (VAP). OBJECTIVE: To identify and compare VAP/VAT gene expression "signatures" using genome-wide oligonucleotide microarrays. MATERIAL AND METHODS: A prospective translational study of gene expression profiles of VAP and VAT groups was carried out, establishing comparisons in both pre-infection and infection phases. Pathway and functional analyses were performed with Ingenuity Pathway Analysis (IPA). Data analysis and hierarchical clustering of the genes involved in the signalling pathways expressed differentially in the two groups were performed with GeneSpring GX 11.0. RESULTS: Eight patients developing respiratory infections (3 VAP and 5 VAT) after 4 days of mechanical ventilation were assessed. Comparison of gene expression profiles in the pre-infection period revealed 5595 genes expressed differentially between VAP and VAT (p<0.01, fold change >2). Comparative IPA analysis identified a significant depression of the complement system signalling pathway in the VAP group, affecting the classical pathway along with the final common pathway (p<0.05). In addition, the cAMP and calcium signalling pathways were also significantly depressed in the VAP group during the pre-infection phase also. CONCLUSION: Intubated patients complicated with pneumonia developed immune impairment in the pre-infection period, manifesting as a relatively lower expression of genes involved in the complement system that differed from patients developing tracheobronchitis. These findings suggest that a significant proportion of VAP episodes cannot be prevented, but might be treatable through pre-emptive therapy.