PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical ß-coronavirus disease.

Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine ß-coronavirus. Tmem176b-/- mice infected with murine ß-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical ß-coronavirus disease.

Epidemiology of acute kidney injury and chronic kidney disease in the intensive care unit. / Epidemiología de la injuria renal aguda y enfermedad renal crónica en la unidad de cuidados intensivos.

OBJECTIVE: To describe the epidemiology of acute kidney injury, its relationship to chronic kidney disease, and the factors associated with its incidence. METHODS: A cohort study and follow-up were conducted in an intensive care unit in Montevideo, Uruguay. We included patients admitted between November 2014 and October 2015 who were older than 15 years of age and who had at least two measurements of serum creatinine. We excluded patients who were hospitalized for less than 48 hours, patients who died at the time of hospitalization, and patients with chronic renal disease who were on hemodialysis or peritoneal dialysis. There were no interventions. Acute kidney injury was defined according to the criteria set forth in Acute Kidney Injury Disease: Improving Global Outcomes, and chronic kidney disease was defined according to the Chronic Kidney Disease Work Group. RESULTS: We included 401 patients, 56.6% male, median age of 68 years (interquartile range (IQR) 51-79 years). The diagnosis at admission was severe sepsis 36.3%, neurocritical 16.3%, polytrauma 15.2%, and other 32.2%. The incidence of acute kidney injury was 50.1%, and 14.1% of the patients suffered from chronic kidney disease. The incidence of acute septic kidney injury was 75.3%. Mortality in patients with or without acute kidney injury was 41.8% and 14%, respectively (p < 0.001). In the multivariate analysis, the most significant variables for acute kidney injury were chronic kidney disease (odds ratio (OR) 5.39, 95%CI 2.04 - 14.29, p = 0.001), shock (OR 3.94, 95%CI 1.72 - 9.07, p = 0.001), and severe sepsis (OR 7.79, 95%CI 2.02 - 29.97, p = 0.003). CONCLUSION: The incidence of acute kidney injury is high mainly in septic patients. Chronic kidney disease was independently associated with the development of acute kidney injury.

OBJETIVO: Describir la epidemiología de la injuria renal aguda, la relación con la enfermedad renal crónica y los factores asociados a su incidencia. MÉTODOS: Estudio de cohorte y seguimiento en una unidad de terapia intensiva de Montevideo - Uruguay. Se incluyeron pacientes ingresados entre noviembre 2014 a octubre 2015, mayores de 15 años con dos mediciones de creatinina sérica. Se excluyeron pacientes con menos de 48 horas de internación o fallecidos en ese tiempo y portadores de enfermedad renal crónica en hemodiálisis o diálisis peritoneal. No hubo intervenciones. La injuria renal aguda se definió según criterios Acute Kidney Injury Disease Improving Global Outcomes y la enfermedad renal crónica según Cronic Kidney Disease Work Group. RESULTADOS: Se incluyeron 401 pacientes, sexo masculino 56,6%, mediana de edad 68 (rango intercuartílico - RIC 51 - 79) años. El diagnóstico al ingreso fue sepsis grave 36,3%, neurocrítico 16,3%, politrauma 15,2% y otros 32,2%. La incidencia de injuria renal aguda fue de 50,1%. El 14,1% eran portadores de enfermedad renal crónica. La incidencia de injuria renal aguda séptica fue de 75,3%. La mortalidad en los pacientes con o sin injuria renal aguda fue de 41,8 y 14% respectivamente (p < 0,001). En el análisis multivariado las variables de mayor significación para la injuria renal aguda fueron enfermedad renal crónica (odds ratio - OR 5,39 IC95% 2,04 - 14,29 p = 0,001), shock (OR 3,94 IC95% 1,72 - 9,07 p = 0,001) y sepsis grave (OR 7,79 IC 95% 2,02 - 29,97 p = 0,003). CONCLUSIÓN: La incidencia de injuria renal aguda es elevada principalmente en pacientes sépticos. La enfermedad renal crónica se asoció de forma independiente al desarrollo de injuria renal aguda.

Epidemiología de la injuria renal aguda y enfermedad renal crónica en la unidad de cuidados intensivos / Epidemiology of acute kidney injury and chronic kidney disease in the intensive care unit

RESUMEN Objetivo: Describir la epidemiología de la injuria renal aguda, la relación con la enfermedad renal crónica y los factores asociados a su incidencia. Métodos: Estudio de cohorte y seguimiento en una unidad de terapia intensiva de Montevideo - Uruguay. Se incluyeron pacientes ingresados entre noviembre 2014 a octubre 2015, mayores de 15 años con dos mediciones de creatinina sérica. Se excluyeron pacientes con menos de 48 horas de internación o fallecidos en ese tiempo y portadores de enfermedad renal crónica en hemodiálisis o diálisis peritoneal. No hubo intervenciones. La injuria renal aguda se definió según criterios Acute Kidney Injury Disease Improving Global Outcomes y la enfermedad renal crónica según Cronic Kidney Disease Work Group. Resultados: Se incluyeron 401 pacientes, sexo masculino 56,6%, mediana de edad 68 (rango intercuartílico - RIC 51 - 79) años. El diagnóstico al ingreso fue sepsis grave 36,3%, neurocrítico 16,3%, politrauma 15,2% y otros 32,2%. La incidencia de injuria renal aguda fue de 50,1%. El 14,1% eran portadores de enfermedad renal crónica. La incidencia de injuria renal aguda séptica fue de 75,3%. La mortalidad en los pacientes con o sin injuria renal aguda fue de 41,8 y 14% respectivamente (p < 0,001). En el análisis multivariado las variables de mayor significación para la injuria renal aguda fueron enfermedad renal crónica (odds ratio - OR 5,39 IC95% 2,04 - 14,29 p = 0,001), shock (OR 3,94 IC95% 1,72 - 9,07 p = 0,001) y sepsis grave (OR 7,79 IC 95% 2,02 - 29,97 p = 0,003). Conclusión: La incidencia de injuria renal aguda es elevada principalmente en pacientes sépticos. La enfermedad renal crónica se asoció de forma independiente al desarrollo de injuria renal aguda.

ABSTRACT Objective: To describe the epidemiology of acute kidney injury, its relationship to chronic kidney disease, and the factors associated with its incidence. Methods: A cohort study and follow-up were conducted in an intensive care unit in Montevideo, Uruguay. We included patients admitted between November 2014 and October 2015 who were older than 15 years of age and who had at least two measurements of serum creatinine. We excluded patients who were hospitalized for less than 48 hours, patients who died at the time of hospitalization, and patients with chronic renal disease who were on hemodialysis or peritoneal dialysis. There were no interventions. Acute kidney injury was defined according to the criteria set forth in Acute Kidney Injury Disease: Improving Global Outcomes, and chronic kidney disease was defined according to the Chronic Kidney Disease Work Group. Results: We included 401 patients, 56.6% male, median age of 68 years (interquartile range (IQR) 51-79 years). The diagnosis at admission was severe sepsis 36.3%, neurocritical 16.3%, polytrauma 15.2%, and other 32.2%. The incidence of acute kidney injury was 50.1%, and 14.1% of the patients suffered from chronic kidney disease. The incidence of acute septic kidney injury was 75.3%. Mortality in patients with or without acute kidney injury was 41.8% and 14%, respectively (p < 0.001). In the multivariate analysis, the most significant variables for acute kidney injury were chronic kidney disease (odds ratio (OR) 5.39, 95%CI 2.04 - 14.29, p = 0.001), shock (OR 3.94, 95%CI 1.72 - 9.07, p = 0.001), and severe sepsis (OR 7.79, 95%CI 2.02 - 29.97, p = 0.003). Conclusion: The incidence of acute kidney injury is high mainly in septic patients. Chronic kidney disease was independently associated with the development of acute kidney injury.

Epidemiología, diagnóstico y tratamiento de la sepsis severa en Uruguay: un estudio multicéntrico prospectivo / Epidemiology, diagnosis and treatment of severe sepsis in Uruguay: a prospective, multi-center study

Objetivo: conocer las características epidemiológicas de pacientes que ingresan por sepsis severa (SS) y shock séptico (ShS); valorar la implementación de recomendaciones de la campaña Sobrevivir a las Sepsis (CSS) y determinar variables asociadas con mal pronóstico vital. Diseño: estudio prospectivo, observacional, cohorte única, multicéntrico, durante un año (setiembre 2011 - agosto 2012). Ámbito: cinco centros de Montevideo, del subsector público y privado con cobertura de 800.000 habitantes. Pacientes y métodos: 153 pacientes que ingresaron con diagnóstico de SS y ShS a las unidades de cuidados intensivos (UCI) de forma consecutiva. Variables de interés principales: aquellas relacionadas con características del paciente y episodio de sepsis, medidas diagnósticas y terapéuticas según la CSS en las primeras 48 horas, y pronósticas en UCI, hospital y a los seis meses. Resultados: se incluyeron 153 pacientes, la mediana de edad fue 68 años, la de Acute Physiology and Chronic Health Evaluation (APACHE II) fue de 24; 73,9% recibieron asistencia respiratoria mecánica (ARM), con una mediana de 8 días. La mediana de estadía en CTI fue de 12 y la de estadía hospitalaria fue de 19 días. De los episodios de SS, ShS, 69,3% de los casos fue comunitario; 77,8% presentó shock, y 37,9% inmunodebilidad-inmunocompromiso. Predominó la sepsis de origen respiratorio en 30,1%, se aisló microorganismos en 64,1%, siendo bacterianas 95,9%. La mortalidad en CTI fue 49,7%, hospitalaria 54,9% y a seis meses 58,8%. Se asociaron a mayor mortalidad hospitalaria: edad, APACHE II, inmunodebilidad-compromiso, demoras de ingreso a UCI e inicio de antimicrobianos y balance positivo. Conclusiones: los pacientes ingresan a UCI con formas severas o estado biológico comprometido. Existen demoras y limitaciones en el diagnóstico y terapéutica inicial, situaciones que se asocian a mayor mortalidad hospitalaria.

Abstract Objective: to learn about the epidemiological characteristics of patients who are admitted for severe sepsis (SS) and septic shock (Ssh); to assess the implementation of recommendations in the Surviving Sepsis Campaign and to determine variables associated to a bad vital prognosis. Design: prospective, observational study, single cohort, multi-center, conducted in five centers in Montevideo, the public and private sub-sector with coverage for 800,000 inhabitants during one year (September 2011- August 2012). Method: 153 patients who were consecutively admitted with a SS and Ssh diagnosis in the intensive care units. Main relevant variables: those related to characteristics of patients themselves and the sepsis episode, diagnostic and therapeutic measures according to the Surviving Sepsis Campaign in the first 48 hours, and prognostic in the ICU, the hospital and six months later. Results: 153 patients were included, average age was 68 years old and APACHE II 24; 73.9 % of patients needed mechanic ventilation during an average of 8 days. Median length of stay in the ICU was 12 and median hospital stay was 19 days. 69.3% of sepsis were community acquired, 77.8% evidenced shock and 37.9% presented immune deficiency were immunocompromised. Respiratory origin prevailed in 30.2% of patients and in 64.1% of patients the microorganism was identified, bacteria being 95.9% of cases. Mortality in the ICU was 49.7%, in the hospital it was 54.9% and 58.8%. The following were associated to a greater hospital mortality: APACHE II, immune-deficiency, delays in admittance to the ICU and initiation of antimicrobial, and positive balance.

Resumo Objetivo: conhecer as características epidemiológicas dos pacientes admitidos por Sepse Severa (SS) e Choque Séptico (ShS); avaliar a implementação das recomendações da Campanha Sobreviver à Sepse (CSS) e determinar variáveis associadas com mal prognóstico vital. Estudo: prospectivo, observacional, coorte única, multicêntrico, realizado em cinco centros, dos setores público e privado, de Montevidéu, com cobertura de 800.000 habitantes, no período setembro 2011 - agosto 2012. Pacientes e métodos: pacientes com diagnóstico de SS e ShS admitidos, em forma consecutiva, nas Unidades de Cuidados Intensivos (UCI). Foram estudadas as variáveis relacionadas com as características do paciente e com o episódio de sepse, as medidas diagnósticas e terapêuticas segundo a CSS nas primeiras 48 horas, e as prognósticas na UCI, no hospital e aos 6 meses. Resultados: foram incluídos 153 pacientes; a mediana de idade foi 68 anos e de APACHE II 24; em 73,9% dos pacientes foi feita assistência respiratória mecânica - ARM, com uma mediana de 8 dias. As medianas de dias de permanência foram 12 dias na UCI e 9 no hospital. 69.3% das Sepses foram comunitárias, 77,8% apresentaram choque e 37,9% imunodebilidade-imunocompromisso. Na maioria dos pacientes a origem foi respiratória (30,1%) e foi possível isolar o microrganismo em 64,1%, sendo bactérias em 95,9% dos casos. A mortalidade na UCI foi de 49,7%, a hospitalar 54,9% e aos 6 meses 58,8%. Estavam associados a maior mortalidade hospitalar: idade, APACHE II, imunodebilidade-compromisso, demora na admissão a UCI e início de antimicrobianos, e balance positivo. Conclusões: os pacientes foram admitidos nas UCI com formas severas de sepse e/ou estado biológico comprometido. Existem demoras e limitações no diagnóstico e na terapêutica inicial, situações que estão associadas a maior mortalidade hospitalar.

Ralstonia pickettii bacteremia in hemodialysis patients: a report of two cases. / Bacteriemia por Ralstonia pickettii en pacientes en hemodiálisis: reporte de dos casos.

Ralstonia pickettii is a low-virulence gram-negative bacillus that may be associated with infections related to health care and may cause bacteremia. Ralstonia pickettii bacteremia is uncommon but is related to the contamination of medical products, mainly in immunodepressed patients. We present two cases of patients on chronic hemodialysis with Ralstonia pickettii bacteremia linked to contamination of the dialysis water. Similar cases have been published with links to intravenous fluid administration, medication ampules, and the use of extracorporeal oxygenation membranes, among other factors. The detection of Ralstonia pickettii bacteremia should provoke suspicion and a search for contaminated medical products, fluids, and/or medications.

Bacteriemia por Ralstonia pickettii en pacientes en hemodiálisis: reporte de dos casos / Ralstonia pickettii bacteremia in hemodialysis patients: a report of two cases

RESUMEN Ralstonia pickettii es un bacilo gram negativo de baja virulencia que puede asociarse a infecciones relacionadas a los cuidados de la salud y provocar bacteriemias. La bacteriemia por Ralstonia pickettii es poco frecuente pero se relaciona con la contaminación de productos de uso médico principalmente en pacientes inmunodeprimidos. Presentamos dos casos en pacientes en hemodiálisis crónica vinculados a contaminación del agua de diálisis. Se han publicado casos similares vinculados a la administración de fluídos intravenosos, ampollas de medicación, asociado a membranas de circulación extracorpórea, entre otros. La detección de una bacteriemia por Ralstonia pickettii, debe sospechar e iniciar la búsqueda de productos de uso médico contaminados, fluídos y/o medicación.

ABSTRACT Ralstonia pickettii is a low-virulence gram-negative bacillus that may be associated with infections related to health care and may cause bacteremia. Ralstonia pickettii bacteremia is uncommon but is related to the contamination of medical products, mainly in immunodepressed patients. We present two cases of patients on chronic hemodialysis with Ralstonia pickettii bacteremia linked to contamination of the dialysis water. Similar cases have been published with links to intravenous fluid administration, medication ampules, and the use of extracorporeal oxygenation membranes, among other factors. The detection of Ralstonia pickettii bacteremia should provoke suspicion and a search for contaminated medical products, fluids, and/or medications.

Complicaciones y mortalidad en esofagectomía por cáncer en unidades de medicina intensiva / Complications and mortality in esophagectomy to treat cancer in intensive care units

Introducción: la esofagectomía continúa siendo el tratamiento de elección del cáncer esofágico. Objetivos: describir la frecuencia de complicaciones y mortalidad tras esofagectomía por cáncer esofágico. Material y método: estudio retrospectivo, multicéntrico, entre los años 2001 y 2011. Se incluyeron pacientes sometidos a esofagectomía programada por cáncer esofágico durante la estadía en unidades de cuidados intensivos. Resultados: se incluyeron 224 pacientes, hombres 72%, media de edad 61 años y desvío estándar ± 11 años. El abordaje quirúrgico fue transhiatal en 69,7% y transtorácico en 30,3%. La morbilidad fue de 70,5% y la mortalidad de 13,8%. Las complicaciones detectadas fueron respiratorias 50,8%, infecciosas 51,3%, cardiovasculares 27,6% y quirúrgicas 23,6%. El síndrome de dificultad respiratoria aguda (p = 0,03), fugas anastomóticas (p = 0,001), sepsis grave (p = 0,001), mediastinitis (p = 0,02) e injuria renal aguda (p = 0,01) se asociaron con la mortalidad. La sepsis grave fue la principal causa de muerte a foco mediastinal o respiratorio, o ambos. En el análisis multivariado las variables asociadas de forma independiente con la mortalidad fueron el fracaso de extubación (OR 3,9; IC 95% 1,02-15,30; p = 0,03), radioterapia preoperatoria (OR 6,0; IC 95% 1,70-21,30; p = 0,02), transfusión intraoperatoria (OR 5,6; IC 95% 2,07-15,60; p = 0,001) y sepsis grave (OR 29; IC 95% 1,72-21,30; p = 0,001). Conclusiones: la morbimortalidad en esofagectomía es elevada. Las complicaciones más frecuentes fueron las respiratorias e infecciosas. La principal causa de muerte fue la sepsis grave. Se asociaron a mayor mortalidad el fracaso de extubación, radioterapia preoperatoria, transfusión intraoperatoria y la sepsis grave.

Introduction: esophagectomy is still the most widely used treatment for esophageal cancer. Objectives: to describe frequency of complications and mortality after esophagectomy to treat complications and mortality of esophagectomy for esophageal cancer. Method: retrospective, multi-center study between 2001 and 2011. The study included patients who underwent programmed esophagectomy to treat esophageal cancer during their stay in intensive care units. Results: 224 patients were included in the study, 72% were men, average age was 61 years old and ± 11 standard deviation. Surgical approach was transhiatal in 69.7% of cases and transthoracic in 30.3%. Morbility was 70.5% and mortality 13.8%. Complications identified were respiratory 50.8%, infectious 51.3%, cardiovascular 27.6% and surgical 23.6%. Acute respiratory distress syndrome (p = 0.03), anostomotic leaks (p = 0.001), severe sepsis (p = 0.001), mediastinitis (p = 0.02) and acute renal injury (p = 0.01) were associated to mortality. Severe sepsis was the main cause of death with mediastinal or respiratory focus, or both. In the multivariate analysis, failure of extubation (OR 3.9; IC 95% 1.02-15.30; p = 0.03), intraoperative transfusion (OR 5.6; IC 95% 2.07-15.60; p = 0.001) and severe sepsis (OR 29; IC 95% 1.72-21.30; p = 0.001) were the variables independently associated. Conclusions: morbimortality rates are high in esophagectomy. The most common complications were respiratory and infectious. Severe sepsis was the main cause of death. Failure to extubate, preoperative radiotherapy, intraoperative transfusion and severe sepsis were associated to greater mortality rates.

Introdução: a esofagectomia continua sendo o tratamento de eleição para câncer esofágico. Objetivos: descrever a frequência de complicações e mortalidade depois de esofagectomia por câncer esofágico. Material e método: estudo retrospectivo, multicêntrico, no período 2001- 2011. Foram incluídos pacientes sometidos a esofagectomia programada por câncer esofágico durante internação em unidades de cuidados intensivos. Resultados: foram incluídos 224 pacientes, homens 72%, com idade média 61 anos e desvio padrão ± 11 anos. A abordagem cirúrgica foi transhiatal em 69,7% e transtorácica em 30,3%. A morbilidade foi de 70,5% e a mortalidade de 13,8%. As complicações detectadas foram: respiratórias 50,8%, infecciosas 51,3%, cardiovasculares 27,6% e cirúrgicas 23,6%. A síndrome de dificuldade respiratória aguda (p = 0,03), fugas anastomóticas (p = 0,001), sepse grave (p = 0,001), mediastinite (p = 0,02) e dano renal agudo (p = 0,01) foram associados à mortalidade. A sepse grave foi a principal causa de morte associada a foco mediastinal ou respiratório, ou ambos. A análise multivariada mostrou como variáveis associadas de forma independente com a mortalidade o fracasso de extubaçao (OR 3,9; IC 95% 1,02-15,30; p = 0,03), radioterapia pré-operatória (OR 6,0; IC 95% 1,70-21,30; p = 0,02), transfusão intra-operatória (OR 5,6; IC 95% 2,07-15,60; p = 0,001) e sepse grave (OR 29; IC 95% 1,72-21,30; p = 0,001). Conclusões: a morbimortalidade por esofagectomia é elevada. As complicações mais frequentes foram as respiratórias e infecciosas. A principal causa de morte foi sepse grave. O fracasso de extubação, a radioterapia pré-operatória, a transfusão intra-operatória e a sepse grave foram associados a maior mortalidade.

Vasculitis primaria del Sistema Nervioso Central: un desafío diagnóstico / Central Nervous System Primary Vasculitis: a diagnostic challenge

La vasculitis primaria del Sistema Nervioso Central (VPSNC) es una variedad poco frecuente de vasculitis que compromete el encéfalo y la medula espinal exclusivamente. La presentación es heterogénea y poco sistematizable, pudiendo comprometer más de una estructura encefálica al mismo tiempo. El diagnóstico se establece con un cuadro clínico compatible, asociado a una angiografía que evidencie un patrón de vasculitis y/o biopsia de parénquima encefálico o meninges. Las alteraciones documentadas en la Resonancia Nuclear Magnética son constantes pero inespecíficas pudiendo la angiografía no evidenciar lesión sugestiva si el afectado es un pequeño vaso. Presentamos tres casos clínicos de probable VPSNC basado en la presentación clínica, los hallazgos imagenológicos compatibles así como la respuesta terapéutica a ella. En los casos analizados se constataron alteraciones en la resonancia nuclear magnética encefálica que sugerían compromiso de varias estructuras encefálicas, con un líquido cefalorraquídeo inflamatorio y alteraciones en el electroencefalograma. El tratamiento de inducción, se realizó en base a bolos de metil-prednisolona y el de mantenimiento fue con corticoides vía oral. Presentaron una excelente respuesta al tratamiento instituido tanto clínica como imagenológicamente.

The primary central nervous system vasculitis is an uncommon variety of vasculitis that exclusively compromises the encephalon and the bone marrow. It arises as heterogeneous and unsystematized and it could compromise more than one encephalic structure at the same time. The diagnosis is made based on compatible symptoms supported by an angiography showing evidence of a vasculitis pattern or/and an encephalic parenchyma or meninges biopsy. The alterations documented in the Nuclear Magnetic Resonance are frequent but unspecific and it is possible to find no evidence of the injury if only a small vessel is affected. We present three clinical cases of probably PCNSV in which the diagnosis was made based on: the clinical presentation, imaginologicfindingsand therapeutic response. In the cases studied the alterations of the NMR were confirmed, the results suggested that several encephalic structures were compromised with CSF (cerebrospinal fluid) inflammatory and alterations on the EEG. The induction therapy included Methilprednisolone boluses; and the maintenance therapy, locally applied steroids. The response to the treatment was excellent clinically as well as imaginologically.