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Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4+ T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.
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COVID-19/imunologia , Monócitos/imunologia , Doenças do Sistema Nervoso/imunologia , Linfócitos T/imunologia , COVID-19/líquido cefalorraquidiano , COVID-19/complicações , COVID-19/patologia , Diferenciação Celular , Líquido Cefalorraquidiano/imunologia , Encefalite Viral/líquido cefalorraquidiano , Encefalite Viral/imunologia , Perfilação da Expressão Gênica , Humanos , Interferons/genética , Interferons/imunologia , Leucócitos/imunologia , Ativação Linfocitária , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/imunologia , Análise de Célula ÚnicaRESUMO
Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.
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COVID-19 , Metabolismo Energético , Cetonas , Síndrome do Desconforto Respiratório , SARS-CoV-2 , Linfócitos T , Ácido 3-Hidroxibutírico/biossíntese , Ácido 3-Hidroxibutírico/metabolismo , Aminoácidos/biossíntese , Aminoácidos/metabolismo , Animais , COVID-19/complicações , COVID-19/imunologia , COVID-19/patologia , Dieta Cetogênica , Ésteres/metabolismo , Glutationa/biossíntese , Glutationa/metabolismo , Glicólise , Interferon gama/biossíntese , Corpos Cetônicos/metabolismo , Cetonas/metabolismo , Camundongos , Orthomyxoviridae/patogenicidade , Oxirredução , Fosforilação Oxidativa , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
BACKGROUND: Impaired microcirculation is a cornerstone of sepsis development and leads to reduced tissue oxygenation, influenced by fluid and catecholamine administration during treatment. Hyperspectral imaging (HSI) is a non-invasive bedside technology for visualizing physicochemical tissue characteristics. Machine learning (ML) for skin HSI might offer an automated approach for bedside microcirculation assessment, providing an individualized tissue fingerprint of critically ill patients in intensive care. The study aimed to determine if machine learning could be utilized to automatically identify regions of interest (ROIs) in the hand, thereby distinguishing between healthy individuals and critically ill patients with sepsis using HSI. METHODS: HSI raw data from 75 critically ill sepsis patients and from 30 healthy controls were recorded using TIVITA® Tissue System and analyzed using an automated ML approach. Additionally, patients were divided into two groups based on their SOFA scores for further subanalysis: less severely ill (SOFA ≤ 5) and severely ill (SOFA > 5). The analysis of the HSI raw data was fully-automated using MediaPipe for ROI detection (palm and fingertips) and feature extraction. HSI Features were statistically analyzed to highlight relevant wavelength combinations using Mann-Whitney-U test and Benjamini, Krieger, and Yekutieli (BKY) correction. In addition, Random Forest models were trained using bootstrapping, and feature importances were determined to gain insights regarding the wavelength importance for a model decision. RESULTS: An automated pipeline for generating ROIs and HSI feature extraction was successfully established. HSI raw data analysis accurately distinguished healthy controls from sepsis patients. Wavelengths at the fingertips differed in the ranges of 575-695 nm and 840-1000 nm. For the palm, significant differences were observed in the range of 925-1000 nm. Feature importance plots indicated relevant information in the same wavelength ranges. Combining palm and fingertip analysis provided the highest reliability, with an AUC of 0.92 to distinguish between sepsis patients and healthy controls. CONCLUSION: Based on this proof of concept, the integration of automated and standardized ROIs along with automated skin HSI analyzes, was able to differentiate between healthy individuals and patients with sepsis. This approach offers a reliable and objective assessment of skin microcirculation, facilitating the rapid identification of critically ill patients.
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Estado Terminal , Imageamento Hiperespectral , Aprendizado de Máquina , Microcirculação , Humanos , Aprendizado de Máquina/normas , Masculino , Feminino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Idoso , Imageamento Hiperespectral/métodos , Sepse/fisiopatologia , Sepse/diagnóstico , Adulto , Estudo de Prova de Conceito , Monitorização Fisiológica/métodos , Monitorização Fisiológica/instrumentaçãoRESUMO
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.
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Sepse , Choque Séptico , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Humanos , Citocinas , Sepse/tratamento farmacológico , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismoRESUMO
Sepsis is a life-threatening syndrome triggered by infection and accompanied by high mortality, with antimicrobial resistances (AMRs) further escalating clinical challenges. The rapid and reliable detection of causative pathogens and AMRs are key factors for fast and appropriate treatment, in order to improve outcomes in septic patients. However, current sepsis diagnostics based on blood culture is limited by low sensitivity and specificity while current molecular approaches fail to enter clinical routine. Therefore, we developed a suppression PCR-based selective enrichment sequencing approach (SUPSETS), providing a molecular method combining multiplex suppression PCR with Nanopore sequencing to identify most common sepsis-causative pathogens and AMRs using plasma cell-free DNA. Applying only 1 mL of plasma, we targeted eight pathogens across three kingdoms and ten AMRs in a proof-of-concept study. SUPSETS was successfully tested in an experimental research study on the first ten clinical samples and revealed comparable results to clinical metagenomics while clearly outperforming blood culture. Several clinically relevant AMRs could be additionally detected. Furthermore, SUPSETS provided first pathogen and AMR-specific sequencing reads within minutes of starting sequencing, thereby potentially decreasing time-to-results to 11-13 h and suggesting diagnostic potential in sepsis.
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Ácidos Nucleicos Livres , Sepse , Humanos , Sepse/diagnóstico , Sepse/microbiologia , Sepse/sangue , Ácidos Nucleicos Livres/sangue , Farmacorresistência Bacteriana/genética , Hemocultura/métodos , DNA Bacteriano/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/genética , Bactérias/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Sequenciamento por Nanoporos/métodosRESUMO
Neutrophil granulocytes (NGs) are among the key players in the defense against Aspergillus fumigatus (A. fumigatus). To better elucidate a pathophysiological understanding of their role and functions, we applied a human cell model using NGs from healthy participants and septic patients to evaluate their inhibitory effects on the growth of A. fumigatus ex vivo. Conidia of A. fumigatus (ATCC® 204305) were co-incubated with NGs from healthy volunteers or septic patients for 16 h. A. fumigatus growth was measured by XTT assays with a plate reader. The inhibitory effect of NGs on 18 healthy volunteers revealed great heterogeneity. Additionally, growth inhibition was significantly stronger in the afternoon than the morning, due to potentially different cortisol levels. It is particularly interesting that the inhibitory effect of NGs was reduced in patients with sepsis compared to healthy controls. In addition, the magnitude of the NG-driven defense against A. fumigatus was highly variable among healthy volunteers. Moreover, daytime and corresponding cortisol levels also seem to have a strong influence. Most interestingly, preliminary experiments with NGs from septic patients point to a strongly diminished granulocytic defense against Aspergillus spp.
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Aspergilose , Aspergillus fumigatus , Humanos , Voluntários Saudáveis , Hidrocortisona , GranulócitosRESUMO
Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.
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Vesículas Extracelulares , Encefalopatia Associada a Sepse , Humanos , Projetos Piloto , Encefalopatia Associada a Sepse/metabolismo , Estudos Longitudinais , Vesículas Extracelulares/metabolismo , Proteoma/metabolismo , Biomarcadores/metabolismo , Arildialquilfosfatase/metabolismoRESUMO
Up to now, sepsis is one of the most threatening diseases and its therapy remains challenging. Sepsis is currently defined as a severely dysregulated immune response to an infection resulting in organ dysfunction. The pathophysiology is mainly driven by exogenous PAMPs ("pathogen-associated molecular patterns") and endogenous DAMPs ("damage-associated molecular patterns"), which can activate PRRs ("pattern recognition receptors") on different cell types (mainly immune cells), leading to the initiation of manifold downstream pathways and a perpetuation of patients' immune response. Sepsis is neither an exclusive pro- nor an anti-inflammatory disease: both processes take place in parallel, resulting in an individual immunologic disease state depending on the severity of each component at different time points. Septic shock is a complex disorder of the macro- and microcirculation, provoking a severe lack of oxygenation further aggravating sepsis defining organ dysfunctions. An in-depth knowledge of the heterogeneity and the time-dependency of the septic immunopathology will be essential for the design of future sepsis trials and therapy planning in patients with sepsis. The big aim is to achieve a more individualized treatment strategy in patients suffering from sepsis or septic shock.
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Sepse , Choque Séptico , Humanos , Choque Séptico/terapia , Sepse/terapiaRESUMO
Background: Pulmonary hypertension (PH) is common in patients with left-side valvular diseases, especially with mitral regurgitation (MR). Measurement using pulmonal artery catheter (PAC) is the gold standard to asses pulmonary vascular pressures. During mitral valve surgery echocardiography is routinely used for valvular management and to evaluate pulmonary hemodynamic. The accuracy of echocardiographic measurements is controversial in the literature. We aimed to evaluate the reliability and accuracy of the noninvasive measurement for systolic pulmonary artery pressure (SPAP) using Doppler echocardiography compared to the invasive measurement using PAC in patients presenting with MR undergoing surgery. Methods: This prospective observational study evaluated 146 patients with MR undergoing cardiac surgery between 09/2020 and 10/2021. All patients underwent simultaneous SPAP assessment by PAC and transesophageal echocardiography at three different time points: before heart-lung-machine (HLM), after weaning from HLM and at the end of surgery. Results: Mean patients' age was 61 ± 11.5 years, and 51 (35%) patients were female. Most of patients presented with severe MR (n = 126; 86.3%) or endocarditis (n = 18; 12.3%). Patients underwent either isolated mitral valve surgery (n = 65; 44.5%) or mitral valve surgery combined with other surgeries (n = 81; 55.5%). Mean SPAP was underestimated by transesophageal echocardiographic measurement in comparison to PAC measurement before HLM (41.9 ± 13.1 mmHg vs. 44.8 ± 13.8 mmHg, p < 0.001), after weaning from HLM (37.6 ± 9.3 mmHg vs. 42.4 ± 10.1 mmHg, p < 0.001), and at the end of surgery (35.6 ± 9.1 mmHg vs. 39.9 ± 9.9 mmHg, p < 0.001). This difference remained within the sub-analysis in patients presented with moderate or severe PH during all the time points. Bland-Altman analysis showed that transesophageal echocardiographic measurement underestimate SPAP in comparison to PAC as these two approaches are significantly different from one another. Conclusions: In patients presented with MR, transesophageal Doppler echocardiography could asses the presence of PH with high probability. This assessment is however underestimated and the use of PAC in those patients to diagnose, classify and monitor the therapy of PH remains recommended if required.
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BACKGROUND: Extended focused assessment with sonography for trauma (eFAST) is now an essential part of the primary survey of an emergency patient. The discrepancy between an increasing number of medical students and growing clinical commitments of lecturers is a major challenge in student teaching that needs to be resolved. The practice of using peers in the clinical education of medical students is a well-established tradition and commonly practiced but lacks definition in its implementation. Therefore, we aimed to investigate whether the level of experience of the tutor affects the effectiveness of learning among students using eFAST during a clinical scenario. METHODS: A prospective randomized single-blinded controlled trial, where 168 medical students in the eighth semester were randomized into control and intervention groups. The control group received the 4-h standard ultrasound (US) tutorial from various resident doctors. All residents were at least stage-1-certified in ultrasound. The intervention group received the tutorial from trained peer teachers (TPTs). These TPTs were medical students who were qualified to teach the procedure. All students received an initial tutorial on basic ultrasound principles and a final lecture on recognizing pathological images. Students completed basic questionnaires requesting pre-existing US experience, theoretical and clinical application questions based on eFAST one day later and at the end of the semester. Students also completed a 6-min OSCE (Objective-Structured-Clinical-Exam) station involving clinical emergency scenarios. RESULTS: Eighty-five percent of participants had no previous eFAST experience. Early and later evaluation of the participants show no significant differences between both groups regarding the theoretical and the clinical application examinations, except the early phase OSCE results, which was not repeated in the late-stage results. CONCLUSIONS: Peer-teaching can be utilized to teach practical skills such as eFAST without a loss of clinical application skills. This relieves the burden of removing doctors from patient care situations and maintains teaching standards.
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BACKGROUND: A pre-existing anticoagulation treatment and predisposing diseases for thromboembolic events represent common problems in patients with sepsis or septic shock; however, these conditions are not addressed in current national guidelines for sepsis and septic shock. One of the aims of this nationwide survey in Germany was therefore to determine how intensive care physicians deal with these problems. METHODS: From October 2019 to May 2020, we conducted a nationwide survey among German medical directors of intensive care units (ICU) addressing anticoagulation and drug-based prophylaxis of venous thromboembolism (VTE) in patients with sepsis and sepsis-induced coagulopathy. One focus was the procedure for patients with a pre-existing anticoagulation treatment or a previously known heparin-induced thrombocytopenia (HIT) type 2 (acute symptomatic vs. dating back years). RESULTS: In most of the participating ICUs pre-existing anticoagulation is largely continued with low molecular weight heparin preparations or unfractionated heparin. In patients with pre-existing HIT type 2 both acute symptomatic and dating back years, argatroban represents the drug of choice. There is a high degree of variability in the definition of the target values, usually being well above the range for pure VTE prophylaxis. CONCLUSION: Data on the continuation of anticoagulation beyond VTE prophylaxis with a subsequently increased risk of bleeding in patients with sepsis and septic shock is limited and treatment decisions are in many cases subject to individual consideration by the practitioner. The results of our survey imply the need for a systematic work-up of this topic in order to support daily practice in many ICUs with the required evidence.
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Sepse , Choque Séptico , Trombocitopenia , Trombose , Tromboembolia Venosa , Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Humanos , Unidades de Terapia Intensiva , Preparações Farmacêuticas , Sepse/complicações , Sepse/tratamento farmacológico , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações , Trombocitopenia/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleRESUMO
BACKGROUND: The 11th revision of the International Classification of Diseases (ICD-11) will come into effect in January 2022. Among other things, The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS3 definition) will be implemented in it. This defines sepsis as a "life-threatening organ dysfunction caused by a dysregulated host response to infection". The aim of the present secondary analysis of a survey on the topic of "sepsis-induced coagulopathy" was to evaluate whether the SEPSIS3 definition, 4 years after its international introduction, has arrived in everyday clinical practice of intensive care units (ICU) run by anesthesiologists in Germany and thus the requirements for its use of the ICD-11 are given. METHODS: Between October 2019 and May 2020, we carried out a nationwide survey among German medical directors of ICUs. In a separate block of questions we asked about the definition of sepsis used in daily practice. In addition, we asked whether the quick-sequential (sepsis-related) organ failure assessment (qSOFA) score is used in screening for sepsis in the hospital to which to the participating ICU belongs. RESULTS: A total of 50 medical directors from anesthesiological ICUs took part in the survey. In total, the ICUs evaluated stated that they had around 14% of the high-care beds registered in Germany. The SEPSIS3 definition is integrated into everyday clinical practice at 78.9% of the university hospitals and 84.0% of the participating teaching hospitals. In contrast, the qSOFA screening test is only used by 26.3% of the participating university hospitals, but at least 52% of the teaching hospitals and 80% of the other hospitals. CONCLUSION: The data show that both SEPSIS3 and qSOFA have become part of everyday clinical practice in German hospitals. The cautious use of qSOFA at university hospitals with simultaneous broad acceptance of the SEPSIS3 definition can be interpreted as an indication that the search for a suitable screening test for sepsis has not yet been completed.
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Classificação Internacional de Doenças , Sepse , Cuidados Críticos , Alemanha , Humanos , Unidades de Terapia Intensiva , Escores de Disfunção Orgânica , Sepse/diagnóstico , Sepse/terapiaRESUMO
We describe screening results for detection of co-infections with Legionella pneumophila in patients infected with severe acute respiratory syndrome coronavirus 2. In total, 93 patients were tested; 1 was positive (1.1%) for L. pneumophila serogroup 1. Co-infections with L. pneumophila occur in coronavirus disease patients and should not be missed.
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COVID-19 , Coinfecção , Legionella pneumophila , Alemanha/epidemiologia , Humanos , SARS-CoV-2 , Centros de Atenção TerciáriaRESUMO
BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be life-threatening, and specific antiviral drugs are currently not available. However, first studies indicated that convalescent plasma treatment might improve the clinical outcome of coronavirus disease 2019 (COVID-19) patients. STUDY DESIGN AND METHODS: In the current study, we investigated the efficacy of convalescent plasma treatment in eight COVID-19 patients. All the patients were critically ill, and seven of them were SARS-CoV-2 RNA-positive when starting treatment. SARS-CoV-2-specific antibodies were determined by an enzyme-linked immunosorbent assay detecting immunoglobulin G (IgG) antibodies against the S1 protein (Euroimmun), and the neutralizing titers were determined with a cell-culture-based neutralization assay. Plasma treatment started between 4 and 23 days after the onset of symptoms. The patients were usually treated by three plasma units, each containing 200-280 ml, which was applied at day 1, 3, and 5. RESULTS: Donor sera had on average lower IgG antibody ratios and neutralizing titers than the COVID-19 patients before the onset of treatment (median ratio of 5.8 and neutralizing titer of 1:320 vs. 7.5 and 1:640, respectively). Nevertheless, we observed an increase of antibody ratios in seven and of neutralizing titers in five patients after treatment; which did, however, not correlate with patient survival. Plasma treatment was effective in three patients, but five deceased despite treatment. Patients who deceased had a later treatment onset than survivors and finally died from multiple organ failure. CONCLUSION: Our data indicate that the efficacy of convalescent plasma treatment of critically ill COVID-19 patients who already had developed strong antiviral immune responses and organ complications is limited.
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Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Doadores de Sangue , COVID-19/terapia , Imunoglobulina G/sangue , SARS-CoV-2/metabolismo , Adulto , Idoso , Animais , COVID-19/sangue , Chlorocebus aethiops , Estado Terminal , Feminino , Humanos , Imunização Passiva , Masculino , Pessoa de Meia-Idade , Células Vero , Soroterapia para COVID-19RESUMO
BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.
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COVID-19/epidemiologia , Estado Terminal/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Unidades de Terapia Intensiva , Aprendizado de Máquina , Adulto , Idoso , COVID-19/terapia , Estudos de Coortes , Estado Terminal/terapia , Serviço Hospitalar de Emergência , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4+ and CD8+ T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4+ and CD8+ T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a++. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a++ T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a++ observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.
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COVID-19/imunologia , Memória Imunológica/imunologia , Pandemias , Síndrome do Desconforto Respiratório/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/virologia , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Subpopulações de Linfócitos T/imunologia , VitronectinaRESUMO
Recent data suggest that the type of anesthesia used during the resection of solid tumors impacts the long-term survival of patients favoring total-intravenous-anesthesia (TIVA) over inhalative-anesthesia (INHA). Here we sought to query this impact on survival in patients undergoing resection of glioblastoma (GBM). All patients receiving elective resection of a newly diagnosed, isocitrate-dehydrogenase-1-(IDH1)-wildtype GBM under general anesthesia between January 2010 and June 2017 in the Department of Neurosurgery, Heidelberg University Hospital, were included. Patients were grouped according to the applied anesthetic technique. To adjust for potential prognostic confounders, patients were matched in a 1:2 ratio (TIVA vs. INHA), taking into account the known prognostic factors: age, extent of resection, O-6-methylguanine-DNA-methyltransferase-(MGMT)-promoter-methylation-status, pre-operative Karnofsky-performance-index and adjuvant radio- and chemotherapy. The primary endpoint was progression-free-survival (PFS) and the secondary endpoint was overall-survival (OS). In the study period, 576 patients underwent resection of a newly diagnosed, IDH-wildtype GBM. Patients with incomplete follow-up-data, on palliative treatment, having emergency or awake surgery; 54 patients remained in the TIVA-group and 417 in the INHA-group. After matching, 52 patients remained in the TIVA-group and 92 in the INHA-group. Median PFS was 6 months in both groups. The median OS was 13.5 months in the TIVA-group and 13.0 months in the INHA-group. No significant survival differences associated with the type of anesthesia were found either before or after adjustment for known prognostic factors. This retrospective study supports the notion that the current anesthetic approaches employed during the resection of IDH-wildtype GBM do not impact patient survival.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Anestésicos Intravenosos , Anestesistas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Metilases de Modificação do DNA , Enzimas Reparadoras do DNA , Glioblastoma/tratamento farmacológico , Glioblastoma/cirurgia , Humanos , Prognóstico , Estudos Retrospectivos , VigíliaRESUMO
BACKGROUND: In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed. METHODS: In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients. RESULTS: A total of 67 senior doctors took part in the survey. The majority (nâ¯= 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (nâ¯= 31; 47.8%) or an academic teaching hospital (nâ¯= 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (nâ¯= 51; 76.1% of the responding ITS). In the majority of cases (nâ¯= 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (nâ¯= 25). In an exemplary case of abdominal sepsis 54.5% of the participants (nâ¯= 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients. CONCLUSION: The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence.
Assuntos
Anticoagulantes , Transtornos da Coagulação Sanguínea , Heparina de Baixo Peso Molecular/uso terapêutico , Sepse , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/etiologia , COVID-19 , Alemanha , Heparina/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Sepse/complicaçõesRESUMO
PURPOSE: Despite antifungal prophylaxis, liver transplanted patients are endangered by invasive fungal infections (IFI). Routinely used microbiological procedures are hallmarked by significant weaknesses, which may lead to a delay in antifungal treatment. METHODS: Culture-based fungal findings, routinely used biomarkers of infection/inflammation (e.g., procalcitonin or C-reactive protein), as well as corresponding plasma concentrations of soluble Intercellular Adhesion Molecule (ICAM)-1 were analysed in 93 patients during a period of 28 days following liver transplantation (LTX). RESULTS: Plasmatic sICAM-1 was significantly elevated in patients affected by an IFI within the first 28 days in comparison to fungally colonised or unobtrusive LTX patients. sICAM-1 might therefore be helpful for the identification of IFI patients after LTX (e.g., Receiver Operating Characteristic (ROC)-Area Under the Curve (AUC): 0.714 at 14d after LTX). The diagnostic performance of sICAM-1 was further improved by its combined use with different other IFI biomarkers (e.g., midregional proadrenomedullin). CONCLUSION: The diagnostic deficiencies of routinely used microbiological procedures for IFI detection in patients after LTX may be reduced by plasmatic sICAM-1 measurements. Clinical Trial Notation. German Clinical Trials Register: DRKS00005480.
Assuntos
Biomarcadores/sangue , Molécula 1 de Adesão Intercelular/genética , Infecções Fúngicas Invasivas/sangue , Transplante de Fígado/efeitos adversos , Adulto , Antifúngicos/uso terapêutico , Proteína C-Reativa/genética , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Infecções Fúngicas Invasivas/complicações , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/patologia , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) require adequate sedation or general anesthesia. To date, there is lack of consensus regarding who should administer sedation in these patients. Several studies have investigated the safety and efficacy of non-anesthesiologist-administered sedation for ERCP; however, data regarding anesthesiologist-administered sedation remain limited. This prospective single-center study investigated the safety and efficacy of anesthesiologist-administered sedation and the rate of successful performed ERCP procedures. METHODS: The study included 200 patients who underwent ERCP following anesthesiologist-administered sedation with propofol and remifentanil. Procedural data, oxygen saturation, systolic blood pressure (SBP), heart rate, recovery score, patient and endoscopist satisfaction, as well as 30-day mortality and morbidity data were analyzed. RESULTS: Sedation-related complications occurred in 36 of 200 patients (18%) and included hypotension (SBP < 90 mmHg) and hypoxemia (O2 saturation < 90%) in 18 patients (9%) each. Most events were minor and did not necessitate discontinuation of the procedure. However, ERCP was terminated in 2 patients (1%) secondary to sedation-related complications. Successful cannulation was performed in all patients. The mean duration of the examination was 25 ± 16 min. Mean recovery time was 14 ± 10 min, and high post-procedural satisfaction was observed in both, patients (mean visual analogue scale [VAS] 9.6 ± 0.8) and endoscopists (mean VAS 9.3 ± 1.3). CONCLUSION: This study suggests that anesthesiologist-administered sedation is safe in patients undergoing ERCP and is associated with a high rate of successful ERCP, shorter procedure time, and more rapid post-anesthesia recovery, with high patient and endoscopist satisfaction.