Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

An 8-gene machine learning model improves clinical prediction of severe dengue progression.

BACKGROUND: Each year 3-6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed. METHODS: We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were "locked" prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared the accuracy of the locked XGBoost model and clinical warning signs in predicting SD. RESULTS: We identified eight SD-associated DEGs in the public datasets and built an 8-gene XGBoost model that accurately predicted SD progression in the independent validation cohort with 86.4% (95% CI 68.2-100) sensitivity and 79.7% (95% CI 75.5-83.9) specificity. Given the 5.8% proportion of SD cases in this cohort, the 8-gene model had a positive and negative predictive value (PPV and NPV) of 20.9% (95% CI 16.7-25.6) and 99.0% (95% CI 97.7-100.0), respectively. Compared to clinical warning signs at presentation, which had 77.3% (95% CI 58.3-94.1) sensitivity and 39.7% (95% CI 34.7-44.9) specificity, the 8-gene model led to an 80% reduction in the number needed to predict (NNP) from 25.4 to 5.0. Importantly, the 8-gene model accurately predicted subsequent SD in the first three days post-fever onset and up to three days prior to SD progression. CONCLUSIONS: The 8-gene XGBoost model, trained on heterogeneous public datasets, accurately predicted progression to SD in a large, independent, prospective cohort, including during the early febrile stage when SD prediction remains clinically difficult. The model has potential to be translated to a point-of-care prognostic assay to reduce dengue morbidity and mortality without overwhelming limited healthcare resources.

[Case fatality rate-related factors in patients with bacteremia hospitalized due medical conditions in an institution of third level in Colombia, 2014-2016]. / Factores relacionados con letalidad en pacientes con bacteriemia hospitalizados por patología médica en una institución de tercer nivel en Colombia, 2014-2016.

BACKGROUND: Bloodstream infections are an increasing problem and currently represent a threat to public health, overcoming diseases such as HIV. Bacteremia accounts for approximately 15% of all nosocomial infections and affects 1% of all hospitalized patients. AIM: To describe the clinical, epidemiological and microbiological characteristic of episodes of nosocomial bacteremia occurring in a Colombian hospital. METHODS: Retrospective, observational, cross-sectional study including adult patients, hospitalized in the internal medicine unit at the University Hospital of Santander, Bucaramanga, Colombia, during years 2014 to 2016, who met the criteria of the CDC for bloodstream infection. The protocol was approved by the Hospital Ethics Committee and by the Research Ethics Committee of the Industrial University of Santander. RESULTS: We reviewed 450 clinical records with 148 patients and 182 microbiological isolates. 53% were male. The most frequent comorbidities were: high blood pressure (46.6%), HIV infection (29.7%). The vascular and urinary systems were the most frequent anatomical sites as the source of the infection (respectively 37.3% and 38.3%). Case fatality rate was 29%. The pathogens most frequently isolated were: Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa (globally: 49.8%) and Staphylococcus aureus 12.1%. The multivariate analysis showed a relationship between anemia and in-hospital mortality (OR = 17.3, 95%CI 2.95-102.0). CONCLUSIONS: Bacteremia is a frequent infection during hospital care that presents high mortality. It is noteworthy the predominance of Enterobacteriaceae isolates with broad profiles of resistance. The history of HIV infection is one of the most frequent which deserves to be evaluated as a risk group.

Factores relacionados con letalidad en pacientes con bacteriemia hospitalizados por patología médica en una institución de tercer nivel en Colombia, 2014-2016 / Case fatality rate-related factors in patients with bacteremia hospitalized due medical conditions in an institution of third level in Colombia, 2014-2016

Resumen Introducción: Las infecciones del torrente sanguíneo son un problema creciente y actualmente son una amenaza para la salud pública. La bacteriemia representa aproximadamente 15% de todas las infecciones nosocomiales y afecta a 1% de los pacientes hospitalizados. Objetivo: Describir las características clínicas, epidemiológicas y microbiológicas de episodios de bacteriemia nosocomial ocurridos en un hospital colombiano. Pacientes y Métodos: Estudio retrospectivo, observacional, de corte transversal, con inclusión de pacientes adultos, hospitalizados por el Servicio de Medicina Interna en el Hospital Universitario de Santander, Bucaramanga, Colombia, durante los años 2014 a 2016. El protocolo fue aprobado por el Comité de Ética en Investigación de la Universidad Industrial de Santander. Resultados: Se revisaron 450 historias clínicas, con 148 pacientes y 182 aislados microbianos. Los antecedentes más frecuentes fueron: hipertensión arterial (46,6%) e infección por VIH (29,7%). El sistema vascular y urinario ocuparon los sitios anatómicos más frecuentes (37,3 y 38,3%, respectivamente). La letalidad fue de 29%. Los patógenos más frecuentemente aislados fueron: Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa (en suma: 49,8%) y Staphylococcus aureus 12,1%. El análisis multivariado mostró relación de la anemia con mortalidad intrahospitalaria (OR = 17,3; IC95% 2,95-102,0). Conclusiones: La bacteriemia es una infección frecuente durante la atención hospitalaria que presenta gran mortalidad. Es destacable el predominio de aislados de enterobacterias multiresistentes. El antecedente de infección por VIH es uno de los más frecuentes el que amerita ser evaluado como grupo de riesgo.

Abstract Background: Bloodstream infections are an increasing problem and currently represent a threat to public health, overcoming diseases such as HIV. Bacteremia accounts for approximately 15% of all nosocomial infections and affects 1% of all hospitalized patients. Aim: To describe the clinical, epidemiological and microbiological characteristic of episodes of nosocomial bacteremia occurring in a Colombian hospital. Methods: Retrospective, observational, cross-sectional study including adult patients, hospitalized in the internal medicine unit at the University Hospital of Santander, Bucaramanga, Colombia, during years 2014 to 2016, who met the criteria of the CDC for bloodstream infection. The protocol was approved by the Hospital Ethics Committee and by the Research Ethics Committee of the Industrial University of Santander. Results: We reviewed 450 clinical records with 148 patients and 182 microbiological isolates. 53% were male. The most frequent comorbidities were: high blood pressure (46.6%), HIV infection (29.7%). The vascular and urinary systems were the most frequent anatomical sites as the source of the infection (respectively 37.3% and 38.3%). Case fatality rate was 29%. The pathogens most frequently isolated were: Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa (globally: 49.8%) and Staphylococcus aureus 12.1%. The multivariate analysis showed a relationship between anemia and in-hospital mortality (OR = 17.3, 95%CI 2.95-102.0). Conclusions: Bacteremia is a frequent infection during hospital care that presents high mortality. It is noteworthy the predominance of Enterobacteriaceae isolates with broad profiles of resistance. The history of HIV infection is one of the most frequent which deserves to be evaluated as a risk group.