Características epidemiológicas de la endocarditis infecciosa. Experiencia de seis años / Epidemiological characteristics of infective endocarditis. Six years of experience

Resumen Introducción: La endocarditis infecciosa continúa siendo una condición amenazante para la vida, que puede afectar cualquier órgano y sistema, con alta mortalidad, atribuible principalmente a Staphylococcus aureus. Implica un reto diagnóstico y terapéutico, que requiere un cuidado multidisciplinario. Objetivo: Describir las características clínicas y microbiológicas en pacientes con endocarditis infecciosa. Materiales y método: Estudio observacional descriptivo basado en la revisión de historias clínicas en un centro médico de referencia en Medellín, Colombia, incluyendo pacientes mayores de 18 años hospitalizados durante el periodo de enero de 2011 a febrero de 2017. Resultados: 130 pacientes, con edad promedio de 53 años (± 16). La hipertensión arterial y la enfermedad renal crónica fueron la comorbilidad más frecuente (55% y 38%, respectivamente). La fiebre fue el síntoma cardinal (90%). Predominó la endocarditis infecciosa de válvula nativa (85.7%), afectando principalmente la mitral (40%). El agente etiológico más frecuente fue S. aureus (sensible a oxacilina 44%), y se complicaron con embolia el 52.5% y con falla cardiaca el 30.8%. La mortalidad intrahospitalaria fue del 39.2%. Conclusiones: La endocarditis infecciosa tiene variadas manifestaciones clínicas, entre las que destacan la embolia sistémica y la falla cardiaca aguda, que condicionan una mortalidad elevada (mayor que la reportada en otros estudios). El aislamiento microbiológico más frecuente es el bacteriano, principalmente S. aureus, como lo muestra la tendencia global.

Abstract Background: Infective endocarditis continues to be a life-threatening condition, can involve every organ system, with high mortality, attributable mainly to Staphylococcus aureus. It implies a diagnostic and therapeutic challenge, which requires multidisciplinary care. Objective: To describe the clinical and microbiological characteristics in patients with infectious endocarditis. Materials and method: Descriptive observational study, based on the review of medical records in a reference medical center in Medellín, Colombia. Including patients over 18 years hospitalized during the period from January 2011 to February 2017. Results: 130 patients, with an average age of 53 years (± 16). Hypertension and chronic kidney disease was the most common comorbidity (55% and 38%, respectively). Fever was the cardinal symptom (90%). Native valve infective endocarditis predominated (85.7%), mainly affecting the mitral valve (40%). The most frequent etiologic agent was Staphylococcus aureus (oxacillin sensitive 44%), embolism was the main complication by 52.5% followed by heart failure (30.8%). In-hospital mortality was 39.2%. Conclusions: Infective endocarditis has varied clinical manifestations, including systemic embolism and acute heart failure, which lead to high mortality (higher than that reported in other studies). The most frequent microbiological isolation is bacterial, mainly Staphylococcus aureus, as shown by the global trend.

Cytomegalovirus Disease, Short-Term Cardiovascular Events and Graft Survival in a Cohort of Kidney Transplant Recipients With High CMV IgG Seroprevalence.

INTRODUCTION: Both cytomegalovirus (CMV) infection and CMV disease have been linked with several long-term indirect effects in kidney transplant recipients. Research questions: We conducted a retrospective study to assess the association between cytomegalovirus disease and risks of death, shortterm cardiovascular events and graft loss in a cohort of renal transplant recipients. DESIGN: The associations between CMV disease and death and cardiovascular events were determined using Cox regression models, while the association between viral disease and graft loss risk was analyzed through a competing risks regression according to the Fine and Gray method. Death with a functioning graft was considered as a competing risk event. RESULTS: A total of 865 consecutive renal transplant recipients were included. The prevalence of seropositive donor/seronegative recipient (D+/R-) group was 89.9% with the remaining patients classified as seropositive recipient (R+). After median follow-up time of 24.4 months, CMV disease was not a risk factor for all-causes mortality (HR = 1.75; 95% CI 0.94-3.25), early cardiovascular events (HR = 0.54; 95% CI 0.16-1.82) or graft loss (subhazard ratio [the HR adjusted for competing risk of death with functioning graft] = 0.99; 95% CI 0.53-1.84). CONCLUSIONS: In this cohort with high prevalence of CMV IgG antibodies, we found no association between cytomegalovirus disease and risk of death or graft loss. The relationship between CMV and cardiovascular disease remains to be unraveled and probably corresponds to a multifactorial phenomenon involving individual risk factors and the immune response to infection rather than the virus effect itself.

Asociación de variables clínicas de hipoperfusión con el lactato y la mortalidad / Association of clinical variables of hypoperfusion with lactate and mortality

Resumen Introducción: entre los pacientes con infección la hiperlactatemia identifica una población de mayor gravedad. Este estudio pretende determinar en pacientes de urgencias la correlación y asociación entre los parámetros clínicos de perfusión y los valores de lactato en el momento de admisión; así como el cambio en los parámetros clínicos con la depuración del lactato. Además, determinar la asociación entre estas variables y la mortalidad intrahospitalaria. Métodos: cohorte prospectiva de pacientes que ingresaron con sospecha de infección a un hospital de tercer nivel. Se midió el lactato en la admisión a las 6 y 24 horas, concomitantemente con las variables llenado capilar, índice de choque y presión de pulso, entre otras. Se realizó correlación de Spearman entre las variables clínicas, los niveles de lactato y su depuración; así como curvas ROC para determinar la capacidad discriminativa de las variables clínicas para detectar hiperlactatemia. Se realizó un modelo de regresión logística multivariable para mortalidad. Resultados: se evaluaron 2257 pacientes, 651 correspondían a infección confirmada. No se encontró ninguna correlación de utilidad entre las variables clínicas y el lactato (r<0.25); y tampoco se detectó adecuada capacidad discriminativa para la detección de hiperlactatemia con ninguna variable clínica (AUC<0.61). En el modelo de regresión logística multivariada el valor del lactato al ingreso fue la única variable que se asoció de manera independiente con mortalidad (OR=1.4, IC95%=1.3-1.6). Conclusiones: entre los pacientes que ingresan a urgencias con infección no se encontró correlación entre las variables clínicas y el lactato; sin embargo, el lactato al ingreso es un marcador pronóstico independiente de mortalidad. (Acta Med Colomb 2017: 42: 97-105).

Abstract Introduction: among patients with infection, hyperlactatemia identifies a population of greater severity. This study aims to determine the correlation and association between clinical perfusion parameters and lactate values in emergency patients at the time of admission, as well as the change in clinical parameters with lactate clearance. In addition, to determine the association between these variables and in-hospital mortality. Methods: Prospective cohort of patients admitted with suspected infection to a third level hospital. Lactate was measured at admission, at 6 and 24 hours, concomitantly with the variables capillary filling, shock index and pulse pressure, among others. Among the clinical variables, Spearman correlation, lactate levels and their clearance, as well as ROC curves to determine the discriminative ability of clinical variables to detect hyperlactatemia were performed. A multivariate logistic regression model for mortality was carried out. Results: 2257 patients were evaluated. 651 were confirmed with infections. No utility correlation was found between clinical variables and lactate (r <0.25), and no discriminative capacity was detected for the detection of hyperlactatemia with any clinical variable (AUC <0.61). In the multivariate logistic regression model the lactate value at admission was the only variable that was independently associated with mortality (OR = 1.4, 95% CI = 1.3-1.6). Conclusions: no correlation was found between clinical variables and lactate among patients admitted to the emergency department with infection; however lactate at admission is an independent prognostic marker of mortality. (Acta Med Colomb 2017: 42: 97-105).

Variants in LTA, TNF, IL1B and IL10 genes associated with the clinical course of sepsis.

The aim of this study was to explore the association between some SNPs of the TNF, LTA, IL1B and IL10 genes with cytokine concentrations and clinical course in Colombian septic patients. We conducted a cross-sectional study to genotype 415 septic patients and 205 patients without sepsis for the SNPs -308(G/A) rs1800629 of TNF; +252 (G/A) rs909253 of LTA; -511(A/G) rs16944 and +3953(C/T) rs1143634 of IL1B; and -1082(A/G) rs1800896, -819(C/T) rs1800871 and -592(C/A) rs1800872 of IL10. The association of theses SNPs with the following parameters was evaluated: (1) the presence of sepsis; (2) severity and clinical outcomes; (3) APACHE II and SOFA scores; and (4) procalcitonin, C-reactive protein, tumor necrosis factor, lymphotoxin alpha, interleukin 1 beta and interleukin 10 plasma concentrations. We found an association between the SNP LTA +252 with the development of sepsis [OR 1.29 (1.00-1.68)]; the SNP IL10 -1082 with sepsis severity [OR 0.53 (0.29-0.97)]; the TNF -308 with mortality [OR 0.33 (0.12-0.95)]; and the IL10 -592 and IL10 -1082 with admission to the intensive care unit (ICU) [OR 3.36 (1.57-7.18)] and [OR 0.18 (0.04-0.86)], respectively. None of the SNPs were associated with cytokine levels, procalcitonin and C-reactive protein serum concentrations, nor with APACHE II and SOFA scores. Our results suggest that these genetic variants play an important role in the development of sepsis and its clinical course.

[Development and validation of a predictive model for bacteremia in patients hospitalized by the emergency department with suspected infection]. / Desarrollo y validación de un modelo predictor para bacteriemia en pacientes hospitalizados por el servicio de urgencias con sospecha de infección.

BACKGROUND: Positive blood cultures usually indicate disseminated infection that is associated with a poor prognosis and higher mortality. We seek to develop and validate a predictive model to identify factors associated with positive blood cultures in emergency patients. METHODS: Secondary analysis of data from two prospective cohorts (EPISEPSIS: developing cohort, and DISEPSIS: validation cohort) of patients with suspected or confirmed infection, assembled in emergency services in 10 hospitals in four cities in Colombia between September 2007 and February 2008. A logistic multivariable model was fitted to identify clinical and laboratory variables predictive of positive blood culture. RESULTS: We analyzed 719 patients in developing and 467 in validation cohort with 32% and 21% positive blood cultures, respectively. The final predictive model included variables with significant coefficients for both cohorts: temperature > 38° C, Glasgow < 15 and platelet < 150.000 cells/mm³, with calibration (goodness-of-fit H-L) p = 0.0907 and p = 0.7003 and discrimination AUC = 0.68 (95% CI = 0.65-0.72) and 0.65 (95% CI = 0.61-0.70) in EPISEPSIS and DISEPSIS, respectively. Specifically, temperature > 38 °C and platelets < 150.000 cells/mm³ and normal Glasgow; or Glasgow < 15 with normal temperature and platelets exhibit a LR between 1,9 (CI 95% = 1,2-3,1) and 2,3 (CI 95% = 1,7-3,1). Glasgow < 15 with any of low platelets or high temperature shows a LR between 2,2 (CI 95% = 1,1-4,4) and 2,6 (CI 95% = 1,7-4,3). DISCUSSION: Temperature > 38° C, platelet count < 150,000 cells/mm³ and GCS < 15 are variables associated with increased likelihood of having a positive blood culture.

Desarrollo y validación de un modelo predictor para bacteriemia en pacientes hospitalizados por el servicio de urgencias con sospecha de infección / Development and validation of a predictive model for bacteremia in patients hospitalized by the emergency department with suspected infection

Background: Positive blood cultures usually indicate disseminated infection that is associated with a poor prognosis and higher mortality. We seek to develop and validate a predictive model to identify factors associated with positive blood cultures in emergency patients. Methods: Secondary analysis of data from two prospective cohorts (EPISEPSIS: developing cohort, and DISEPSIS: validation cohort) of patients with suspected or confirmed infection, assembled in emergency services in 10 hospitals in four cities in Colombia between September 2007 and February 2008. A logistic multivariable model was fitted to identify clinical and laboratory variables predictive of positive blood culture. Results: We analyzed 719 patients in developing and 467 in validation cohort with 32% and 21% positive blood cultures, respectively. The final predictive model included variables with significant coefficients for both cohorts: temperature > 38° C, Glasgow < 15 and platelet < 150.000 cells/mm³, with calibration (goodness-of-fit H-L) p = 0.0907 and p = 0.7003 and discrimination AUC = 0.68 (95% CI = 0.65-0.72) and 0.65 (95% CI = 0.61-0.70) in EPISEPSIS and DISEPSIS, respectively. Specifically, temperature > 38 °C and platelets < 150.000 cells/mm³ and normal Glasgow; or Glasgow < 15 with normal temperature and platelets exhibit a LR between 1,9 (CI 95% = 1,2-3,1) and 2,3 (CI 95% = 1,7-3,1). Glasgow < 15 with any of low platelets or high temperature shows a LR between 2,2 (CI 95% = 1,1-4,4) and 2,6 (CI 95% = 1,7-4,3). Discussion: Temperature > 38° C, platelet count < 150,000 cells/mm³ and GCS < 15 are variables associated with increased likelihood of having a positive blood culture.

Introducción: Un hemocultivo positivo usualmente indica infección diseminada, la que se asocia con peor pronóstico y mayor mortalidad. Por tanto, buscamos desarrollar y validar un modelo de predicción que permita identificar los factores asociados con la positividad de los hemocultivos en pacientes del servicio de urgencias. Métodos: Análisis secundario de datos de dos cohortes prospectivas (EPISEPSIS: cohorte de desarrollo y DISEPSIS: cohorte de validación) de pacientes con sospecha o confirmación de infección, ensambladas en servicios de urgencias de 10 instituciones hospitalarias en cuatro ciudades de Colombia entre septiembre de 2007 y febrero de 2008. Se ajustó un modelo logístico multivariado para identificar variables clínicas y de laboratorio predictoras de hemocultivos positivos. Resultados: Se analizaron 719 pacientes en la cohorte de desarrollo y 467 en la cohorte de validación, con 32 y 21% de hemocultivos positivos, respectivamente. El modelo predictor final incluyó las variables con coeficientes significativos para ambas cohortes: temperatura ≥ 38 °C, Glasgow < 15 y plaquetas ≤ 150.000 céls/mm³ con calibración (bondad de ajuste de H-L) p = 0,0907 y p = 0,7003 y discriminación AUC: 0,68 (IC 95%: 0,65-0,72) y 0,65 (IC 95%: 0,61-0,70) en EPISEPSIS y DISEPSIS, respectivamente. Temperatura ≥ 38 °C y recuento de plaquetas ≤ 150.000 céls/mm³ con Glasgow normal; o Glasgow < 15 con temperatura y plaquetas normales tiene un LR entre 1,9 (IC 95%: 1,2-3,1) y 2,3 (IC 95%: 1,7-3,1). La escala de Glasgow < 15 puntos junto con cualquiera entre recuento de plaquetas o temperatura alteradas tiene un LR entre 2,2 (IC 95%: 1,1-4,4) y 2,6 (IC 95%: 1,7-4,3). Discusión: La temperatura ≥ 38 °C, el recuento de plaquetas ≤ 150.000 céls/mm³ y la escala de Glasgow < 15 son las variables asociadas con mayor probabilidad de tener un hemocultivo positivo.

Undiagnosed Obstructive Lung Disease in the United States. Associated Factors and Long-term Mortality.

RATIONALE: Understanding factors associated with undiagnosed obstructive lung disease and its impact on mortality could inform the ongoing discussions about benefits and risks of screening and case finding. OBJECTIVES: To define factors associated with undiagnosed obstructive lung disease and its long-term mortality. METHODS: Cross-sectional analysis of participants, aged 20 to 79 years, in two National Health and Nutritional Examination Surveys (NHANES), NHANES III (1988-1994) and NHANES 2007-2012, with longitudinal follow-up of NHANES III participants. MEASUREMENTS AND MAIN RESULTS: We classified participants with spirometry-confirmed obstructive disease, based on the fixed ratio definition (FEV1/FVC < 0.7), as "diagnosed" (physician diagnosis of either asthma or chronic obstructive pulmonary disease), and "undiagnosed" (no recorded physician diagnosis). For the longitudinal analysis of NHANES III participants, mortality was the outcome of interest. We tested the contribution of self-reported health status and comorbidity burden (exposure) to the odds of being undiagnosed using logistic models adjusted for demographics, smoking status, and lung function. We estimated hazard ratios (HRs) for all-cause mortality for diagnosed and undiagnosed subjects participating in NHANES III who had spirometry using Cox- proportional regression analysis. Among those with spirometry-defined obstruction, 71.2% (SE, 1.8) in NHANES III and 72.0% (SE, 1.9) in NHANES 2007-2012 were undiagnosed. In multivariate models, undiagnosed obstructive disease was consistently associated in both surveys with self-reported good/excellent health status, lower comorbidity burden, higher lung function, and being of racial/ethnic minority. Among NHANES III participants (median follow up, 14.5 yr), both undiagnosed (HR, 1.23; 95% confidence interval, 1.08-1.40) and correctly diagnosed participants (HR, 1.74; 95% confidence interval, 1.45-2.09) had higher risk for all-cause mortality than participants without obstruction. CONCLUSIONS: Undiagnosed obstructive lung disease is common among American adults and remained unchanged over 2 decades. Although undiagnosed subjects appear healthier than those with a diagnosis, their risk of death was increased compared with subjects without obstruction. These findings need to be considered when judging the implications of case-finding programs for obstructive lung disease.

Immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study*.

OBJECTIVES: To perform a complete immunological characterization of compensatory anti-inflammatory response syndrome in patients with sepsis and to explore the relationship between these changes and clinical outcomes of 28-day mortality and secondary infections. DESIGN: Prospective single-center study conducted between April 2011 and December 2012. SETTING: ICUs from Hospital Universitario San Vicente Fundación at Medellin, Colombia. PATIENTS: One hundred forty-eight patients with severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At days 0, 1, 3, 5, 10, and 28, we determined the expression of HLA-DR in monocytes and the apoptosis and the proliferation index in T lymphocytes, as well as the levels of tumor necrosis factor-α, interleukin-6, interleukin-1ß, interleukin-10, and transforming growth factor-ß in both plasma and cell culture supernatants of peripheral blood mononuclear cells. The mean percentage of HLA-DR was 60.7 at enrollment and increased by 0.9% (95% CI, 0.7-1.2%) per day. The mean percentage of CD4 T cells and CD8 T cells AV+/7-AAD- at enrollment was 37.2% and 20.4%, respectively, but it diminished at a rate of -0.5% (95% CI, -0.7% to -0.3%) and -0.3% (95% CI, -0.4% to -0.2%) per day, respectively. Plasma levels of interleukin-6 and interleukin-10 were 290 and 166 pg/mL and decreased at a rate of -7.8 pg/mL (95% CI, -9.5 to -6.1 pg/mL) and -4 pg/mL (95% CI, -5.1 to -2.8 pg/mL) per day, respectively. After controlling for confounders, only sustained plasma levels of interleukin-6 increase the risk of death (hazard ratio 1.003; 95% CI, 1.001-1.006). CONCLUSIONS: We found no evidence to support a two-phase model of sepsis pathophysiology. However, immunological variables did behave in a mixed and time-dependent manner. Further studies should evaluate changes over time of interleukin-6 plasma levels as a prognostic biomarker for critically ill patients.

Characterization of nCD64 expression in neutrophils and levels of s-TREM-1 and HMGB-1 in patients with suspected infection admitted in an emergency department / Caracterización de la expresión de nCD64 en neutrófilos y de los niveles de s-TREM-1 y HMGB-1 en pacientes con sospecha de infección admitidos en el departamento de emergencias

Introduction: The nCD64 receptor, the soluble triggering receptor expressed in myeloid cells (s-TREM-1), and the high mobility group-box 1 protein (HMGB-1) have been proposed as significant mediators in sepsis. Objective: To evaluate the prognostic value of these markers in patients with suspected infection recently admitted in an emergency department (ED). Materials and methods: All patients who presented to the ED with suspected infection were eligible for enrollment in this study. Baseline clinical data, Sequential Organ Failure Assessment score (SOFA) score, APACHE II score, HMGB-1 levels, s-TREM-1 levels, and nCD64 levels were analyzed. The HMGB-1 and sTREM-1 serum concentrations were determined using commercially available ELISA kits, and CD64 on the surface of neutrophils was measured by flow cytometry. Results:. A total of 579 patients with suspected infection as their admission diagnosis were enrolled in this study. The median patient age was 50 years (IQR = 35-68). Morbidity during the 28-day followup period was 11.1% (n=64). The most frequent diagnosis at the time of admission was communityacquired pneumonia (CAP) in 23% (n=133) patients, followed by soft tissue infection in 16.6% (n=96), and urinary tract infection in 15% (n=87). After multivariable analysis, no significant association was identified between any biomarker and 28-day mortality. Conclusion: In the context of a tertiary care hospital emergency department in a Latin-American city, the nCD64 receptor, s-TREM-1, and HMGB-1 biomarkers do not demonstrate prognostic utility in the management of patients with infection. The search continues for more reliable prognostic markers in the early stages of infection.

Introducción. El receptor CD64, receptor soluble ´desencadenador´ expresado en células mieloides (sTREM-1) y la proteína del grupo Box-1 de alta movilidad (HMGB-1), se han propuesto como mediadores en la sepsis. Objetivo. Evaluar el valor pronóstico de estos marcadores en pacientes con sospecha de infección, recientemente admitidos en un departamento de emergencias. Materiales y métodos. Se incluyeron en el estudio pacientes que consultaron al hospital con sospecha de infección. Se analizó la base de datos clínica, el puntaje SOFA, el puntaje APACHE II, los niveles de HMGB-1, los niveles de sTREM-1 y los niveles de nCD64. Se determinaron las concentraciones en suero de HMGB-1 y sTREM-1, usando kits de ELISA disponibles comercialmente, y la de CD64 se midió por citometría de flujo. Resultados. Se analizaron 579 pacientes con sospecha de infección al ingreso. La edad media fue de 50 años (rango intercuartílico=35-68), y 11,1 % (n=64) murieron durante el seguimiento de 28 días. El diagnóstico más frecuente en el momento del ingreso fue neumonía adquirida en la comunidad, en 23 % (n=133) de los pacientes, seguida de infección de tejidos blandos, en 16,6 % (n=96), e infección urinaria, en 15 % (n=87). Después de un análisis multivariado, no hubo asociación significativa entre ningún biomarcador y la mortalidad a los 28 días. Conclusión. Los resultados sugieren que en el contexto de un departamento de emergencias de tercer nivel de una ciudad latinoamericana típica, los tres marcadores evaluados no ofrecieron ninguna ventaja en el pronóstico de infección. La búsqueda de marcadores pronósticos más confiables en estadios tempranos de la infección aún continúa abierta.

A latent class approach for sepsis diagnosis supports use of procalcitonin in the emergency room for diagnosis of severe sepsis.

BACKGROUND: Given the acknowledged problems in sepsis diagnosis, we use a novel way with the application of the latent class analysis (LCA) to determine the operative characteristics of C-reactive protein (CRP), D-dimer (DD) and Procalcitonin (PCT) as diagnostic tests for sepsis in patients admitted to hospital care with a presumptive infection. METHODS: Cross-sectional study to determine the diagnostic accuracy of three biological markers against the gold standard of clinical definition of sepsis provided by an expert committee, and also against the likelihood of sepsis according to LCA. Patients were recruited in the emergency room within 24 hours of hospitalization and were follow-up daily until discharge. RESULTS: Among 765 patients, the expert committee classified 505 patients (66%) with sepsis, 112 (15%) with infection but without sepsis and 148 (19%) without infection. The best cut-offs points for CRP, DD, and PCT were 7.8 mg/dl, 1616 ng/ml and 0.3 ng/ml, respectively; but, neither sensitivity nor specificity reach 70% for any biomarker. The LCA analysis with the same three tests identified a "cluster" of 187 patients with several characteristics suggesting a more severe condition as well as better microbiological confirmation. Assuming this subset of patients as the new prevalence of sepsis, the ROC curve analysis identified new cut-off points for the tests and suggesting a better discriminatory ability for PCT with a value of 2 ng/ml. CONCLUSIONS: Under a "classical" definition of sepsis three typical biomarkers (CRP, PCT and DD) are not capable enough to differentiate septic from non-septic patients in the ER. However, a higher level of PCT discriminates a selected group of patients with severe sepsis.

In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4.

BACKGROUND: During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are therefore potential targets for therapeutic intervention. Indeed statins, compounds that inhibit cellular synthesis of cholesterol and have anti-inflammatory and immunomodulatory properties were shown to inhibit HIV-1 infection by R5 tropic strains but not by X4 strains in vitro, mainly by altering the chemokine receptor/ligands axes. Therefore, the objective of this study was to characterize in vivo, the capacity of statins to modulate in HIV seronegative and chronically HIV-1-infected adults the expression of CCR5 and CXCR4, of their ligands and the tropism of circulating HIV-1 strains. METHODS: Samples from asymptomatic HIV-1-infected adults enrolled in a clinical trial aimed at evaluating the antiretroviral activity of lovastatin were used to evaluate in vivo the modulation by lovastatin of CCR5, CXCR4, their ligands, and the shift in plasma viral tropism over one year of intervention. In addition, ten HIV negative adults received a daily oral dose of 40 mg of lovastatin or 20 mg of atorvastatin; seven other HIV negative individuals who received no treatment were followed as controls. The frequency and phenotype of immune cells were determined by flow-cytometry; mRNA levels of chemokine receptors and their ligands were determined by real-time PCR. Viral tropism was determined by PCR and sequencing, applying the clonal and clinical model of analyses. RESULTS: Our study shows that long-term administration of lovastatin in HIV-infected individuals does not induce a shift in viral tropism, or induce a significant modulation of CCR5 and CXCR4 on immune cells in HIV-infected patients. Similar results were found in HIV seronegative control subjects, treated with lovastatin or atorvastatin, but a significant increase in CCL3 and CCL4 transcription was observed in these individuals. CONCLUSIONS: These findings suggest that long-term administration of statins at therapeutic doses, does not significantly affect the expression of HIV-1 co-receptors or of their ligands. In addition it is important to point out that based on the results obtained, therapeutic administration of statins in HIV-infected patients with lipid disorders is safe in terms of selecting X4 strains.

Characterization of nCD64 expression in neutrophils and levels of s-TREM-1 and HMGB-1 in patients with suspected infection admitted in an emergency department.

INTRODUCTION: The nCD64 receptor, the soluble triggering receptor expressed in myeloid cells (s-TREM-1), and the high mobility group-box 1 protein (HMGB-1) have been proposed as significant mediators in sepsis. OBJECTIVE: To evaluate the prognostic value of these markers in patients with suspected infection recently admitted in an emergency department (ED). MATERIALS AND METHODS: All patients who presented to the ED with suspected infection were eligible for enrollment in this study. Baseline clinical data, Sequential Organ Failure Assessment score (SOFA) score, APACHE II score, HMGB-1 levels, s-TREM-1 levels, and nCD64 levels were analyzed. The HMGB-1 and sTREM-1 serum concentrations were determined using commercially available ELISA kits, and CD64 on the surface of neutrophils was measured by flow cytometry. RESULTS: . A total of 579 patients with suspected infection as their admission diagnosis were enrolled in this study. The median patient age was 50 years (IQR = 35-68). Morbidity during the 28-day followup period was 11.1% (n=64). The most frequent diagnosis at the time of admission was communityacquired pneumonia (CAP) in 23% (n=133) patients, followed by soft tissue infection in 16.6% (n=96), and urinary tract infection in 15% (n=87). After multivariable analysis, no significant association was identified between any biomarker and 28-day mortality. CONCLUSION: In the context of a tertiary care hospital emergency department in a Latin-American city, the nCD64 receptor, s-TREM-1, and HMGB-1 biomarkers do not demonstrate prognostic utility in the management of patients with infection. The search continues for more reliable prognostic markers in the early stages of infection.

Randomized clinical trial of lovastatin in HIV-infected, HAART naïve patients (NCT00721305).

BACKGROUND: Evidence suggests that statins may modify the immune response against HIV. The aim was to evaluate the antiretroviral and immunomodulatory effects of lovastatin in HIV-infected patients, naïve for antiretroviral therapy. METHODS: Randomized, double-blinded, placebo-controlled, phase-II clinical trial. Primary outcomes were plasma viral load and circulating CD4+ T cell count, after 6 and 12 months of treatment; secondary outcomes were CD8+ T cell count, expression of activation markers (CD38 and HLA-DR) on T cells, and clinical outcomes. With a power of 90% to detect both a decrease of 0.3 log10 in plasma HIV-1 RNA copies and an increase of 20% in the CD4+ T cell count, we estimated a required sample size of 110 HIV-infected patients (55 per group). The results were analyzed by a model of repeated measurements using Generalized Estimating Equations. RESULTS: Patients were randomized to receive either lovastatin (n = 55) or placebo (n = 57). During the 12-month follow-up, there was no effect of lovastatin either on viral load (estimated average change = 0.157 copies/mL; CI 95% = -0.099 to 0.414), or on the CD4+ T cell count (estimated average change = -26.1 cells/µL; CI 95% = -89.8 to 37.6). Moreover, there were no significant differences in secondary outcomes. CONCLUSIONS: Daily administration of lovastatin (40 mg) for one year in HIV-infected patients, naïve for antiretroviral therapy, had no significant effect on HIV replication, the CD4+ T cell count, or the activation level of T cells. (www.clinicaltrials.gov; ID NCT00721305).

D-dimer is a significant prognostic factor in patients with suspected infection and sepsis.

PURPOSE: The aim of the study was to determine whether C-reactive protein (CRP), procalcitonin (PCT), and d-dimer (DD) are markers of mortality in patients admitted to the emergency department (ED) with suspected infection and sepsis. BASIC PROCEDURES: We conducted a prospective cohort in a university hospital in Medellín, Colombia. Patients were admitted between August 1, 2007, and January 30, 2009. Clinical and demographic data and Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores as well as blood samples for CRP, PCT, and DD were collected within the first 24 hours of admission. Survival was determined on day 28 to establish its association with the proposed biomarkers using logistic regression and receiver operating characteristic curves. MAIN FINDINGS: We analyzed 684 patients. The median Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores were 10 (interquartile range [IQR], 6-15) and 2 (IQR, 1-4), respectively. The median CRP was 9.6 mg/dL (IQR, 3.5-20.4 mg/dL); PCT, 0.36 ng/mL (IQR, 0.1-3.7 ng/mL); and DD, 1612 ng/mL (IQR, 986-2801 ng/mL). The median DD in survivors was 1475 ng/mL (IQR, 955-2627 ng/mL) vs 2489 ng/mL (IQR, 1698-4573 ng/mL) in nonsurvivors (P=.0001). The discriminatory ability showed area under the curve-receiver operating characteristic for DD, 0.68; CRP, 0.55; and PCT, 0.59. After multivariate analysis, the only biomarker with a linear relation with mortality was DD, with an odds ratio of 2.07 (95% confidence interval, 0.93-4.62) for values more than 1180 and less than 2409 ng/mL and an odds ratio of 3.03 (95% confidence interval, 1.38-6.62) for values more than 2409 ng/mL. PRINCIPAL CONCLUSIONS: Our results suggest that high levels of DD are associated with 28-day mortality in patients with infection or sepsis identified in the emergency department.

Diagnostic accuracy of HMGB-1, sTREM-1, and CD64 as markers of sepsis in patients recently admitted to the emergency department.

OBJECTIVES: The objectives were to evaluate the diagnostic accuracy for sepsis in an emergency department (ED) population of the cluster of differentiation-64 (CD64) glycoprotein expression on the surface of neutrophils (nCD64), serum levels of soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1), and high-mobility group box-1 protein (HMGB-1). METHODS: Patients with any of the following as admission diagnosis were enrolled: 1) suspected infection, 2) fever, 3) delirium, or 4) acute hypotension of unexplained origin within 24 hours of ED presentation. Levels of nCD64, HMGB-1, and s-TREM-1 were measured within the first 24 hours of the first ED evaluation. Baseline clinical data, Sepsis-related Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, daily clinical and microbiologic information, and 28-day mortality rate were collected. Because there is not a definitive criterion standard for sepsis, the authors used expert consensus based on clinical, microbiologic, laboratory, and radiologic data collected for each patient during the first 7 days of hospitalization. This expert consensus defined the primary outcome of sepsis, and the primary data analysis was based in the comparison of sepsis versus nonsepsis patients. The cut points to define sensitivity and specificity values, as well as positive and negative likelihood ratios (LRs) for the markers related to sepsis diagnosis, were determined using receiver operative characteristics (ROC) curves. The patients in this study were a prespecified nested subsample population of a larger study. RESULTS: Of 631 patients included in the study, 66% (95% confidence interval [CI] = 62% to 67%, n = 416) had sepsis according with the expert consensus diagnosis. Among these sepsis patients, SOFA score defined 67% (95% CI = 62% to 71%, n = 277) in severe sepsis and 1% (95% CI = 0.3% to 3%, n = 6) in septic shock. The sensitivities for sepsis diagnosis were CD64, 65.8% (95% CI = 61.1% to 70.3%); HMGB-1, 57.5% (95% CI = 52.7% to 62.3%); and s-TREM-1, 60% (95% CI = 55.2% to 64.7%). The specificities were CD64, 64.6% (95% CI = 57.8% to 70.8%), HMGB-1, 57.8% (95% CI = 51.1% to 64.3%), and s-TREM-1, 59.2% (95% CI = 52.5% to 65.6%). The positive LR (LR+) for CD64 was 1.85 (95% CI = 1.52 to 2.26) and the negative LR (LR-) was 0.52 (95% CI = 0.44 to 0.62]; for HMGB-1 the LR+ was 1.36 (95% CI = 1.14 to 1.63) and LR- was 0.73 (95% CI = 0.62 to 0.86); and for s-TREM-1 the LR+ was 1.47 (95% CI = 1.22 to 1.76) and the LR- was 0.67 (95% CI = 0.57 to 0.79). CONCLUSIONS: In this cohort of patients suspected of having any infection in the ED, the accuracy of nCD64, s-TREM-1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis.

Toward an operative diagnosis in sepsis: a latent class approach.

BACKGROUND: Recent data have suggested that 18 million of new sepsis cases occur each year worldwide, with a mortality rate of almost 30%. There is not consensus on the clinical definition of sepsis and, because of lack of training or simply unawareness, clinicians often miss or delay this diagnosis. This is especially worrying; since there is strong evidence supporting that early treatment is associated with greater clinical success. There are some difficulties for sepsis diagnosis such as the lack of an appropriate gold standard to identify this clinical condition. This situation has hampered the assessment of the accuracy of clinical signs and biomarkers to diagnose sepsis. METHODS/DESIGN: Cross-sectional study to determine the operative characteristics of three biological markers of inflammation and coagulation (D-dimer, C-reactive protein and Procalcitonin) as diagnostic tests for sepsis, in patients admitted to hospital care with a presumptive infection as main diagnosis. DISCUSSION: There are alternative techniques that have been used to assess the accuracy of tests without gold standards, and they have been widely used in clinical disciplines such as psychiatry, even though they have not been tested in sepsis diagnosis. Considering the main importance of diagnosis as early as possible, we propose a latent class analysis to evaluate the accuracy of three biomarkers to diagnose sepsis.

Guía de práctica clínica para el diagnóstico y tratamiento de la sepsis en el servicio de urgencias de adultos / Clinical guidelines for diagnosis and treatment of sepsis in adult's emergency room

La respuesta que desarrolla un hospedero frente a una infección puede llevar a un espectro de manifestaciones que incluye desde la sepsis hasta la disfunción orgánica múltiple y la muerte. Dada la complejidad del fenómeno fisiopatológico, las manifestaciones clínicas son muy variadas y, en ocasiones, tan sutiles que para detectarlas se requiere un alto índice de sospecha por parte del médico tratante. El juicio clínico se debe complementar con los exámenes de laboratorio pertinentes para lograr el diagnóstico oportuno, lo que permite iniciar las medidas de tratamiento adecuadas: la optimización hemodinámica temprana, la terapia antimicrobiana y las medidas de soporte.

Host response against infection may produce a wide spectrum of clinical manifestations, from sepsis toorgan dysfunction and death. Since the underlying process is complex, clinical findings are varied and may be so subtle that a high level of diagnostic suspicion is required. Clinical judgment should becomplemented with appropriate laboratory tests so that the correct treatment, including haemodynamicoptimization, antimicrobial therapy and general supportive measures, can be started early.

Proceso de atención y prescripción en neumonía adquirida en la comunidad en hospitales universitarios en Colombia / Health care processes and prescription in community-acquired pneumonia in Colombian University Hospitals

Objetivo: Describir la severidad, el patrón de estudio, prescripción y la frecuencia de seguimiento de las guías de manejo de NAC en cuatro hospitales universitarios en Colombia. Tipo de Estudio: Cohorte bidireccional. Lugar de Estudio: Cuatro hospitales universitarios en tres ciudades de Colombia. Pacientes y Métodos: Mayores de 15 años hospitalizados entre enero de 2001 y diciembre de 2002 por NAC. Recolección de información sobre estado clínico, estudios paraclínicos y manejo en las primeras 24 horas. Clasificación en grupos de severidad. Evaluación de frecuencia de toma de exámenes, prescripción de antimicrobianos y proporción de seguimiento de las guías en cada grupo de severidad y cada hospital. Resultados: Se incluyeron 734 pacientes, edad promedio 56 años, 50.5/100 género masculino, promedio de estancia hospitalaria 8.6 días, 39/100 en clases IV y V de Fine y mortalidad total de 6.1/100. La frecuencia de toma de muestra de esputo [valor total de la cohorte (rango entre hospitales)] fue 46/100 (10 - 67/100), radiografía de tórax 95/100 (57/100-100/100), hemocultivos 34/100 (0–63/100) y gases arteriales 71/100 (10-88/100), que muestra entre grupos de severidad y hospitales amplia variación. Al menos 45 esquemas diferentes de antimicrobianos se utilizaron en el manejo de estos pacientes. Hubo gran variabilidad en el seguimiento de las guías de tratamiento (total 44/100, rango 22 a 72/100) entre grupos de severidad y hospitales, sin que este factor afectara la mortalidad.Conclusión: Existen diferencias entre el manejo de la NAC en la práctica clínica y las recomendaciones de las guías y amplia variabilidad entre instituciones, pero un efecto de la falta de la adherencia sobre la mortalidad no puede excluirse.