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According to a large number of reported cohorts, sepsis has been observed in nearly all deceased patients with COVID-19. We and others have described sepsis, among other pathologies, to be an endotoxin tolerance (ET)-related disease. In this study, we demonstrate that the culture of human blood cells from healthy volunteers in the presence of SARS-CoV-2 proteins induced ET hallmarks, including impairment of proinflammatory cytokine production, low MHC class II (HLA-DR) expression, poor T cell proliferation, and enhancing of both phagocytosis and tissue remodeling. Moreover, we report the presence of SARS-CoV-2 blood circulating proteins in patients with COVID-19 and how these levels correlate with an ET status, the viral RNA presence of SARS-CoV-2 in plasma, as well as with an increase in the proportion of patients with secondary infections.
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COVID-19 , SARS-CoV-2 , Tolerância à Endotoxina , Genes MHC da Classe II , Humanos , RNA ViralRESUMO
BACKGROUND: The use of Renin-Angiotensin system inhibitors (RASi) in patients with coronavirus disease 2019 (COVID-19) has been questioned because both share a target receptor site. METHODS: HOPE-COVID-19 (NCT04334291) is an international investigator-initiated registry. Patients are eligible when discharged after an in-hospital stay with COVID-19, dead or alive. Here, we analyze the impact of previous and continued in-hospital treatment with RASi in all-cause mortality and the development of in-stay complications. RESULTS: We included 6503 patients, over 18 years, from Spain and Italy with data on their RASi status. Of those, 36.8% were receiving any RASi before admission. RASi patients were older, more frequently male, with more comorbidities and frailer. Their probability of death and ICU admission was higher. However, after adjustment, these differences disappeared. Regarding RASi in-hospital use, those who continued the treatment were younger, with balanced comorbidities but with less severe COVID19. Raw mortality and secondary events were less frequent in RASi. After adjustment, patients receiving RASi still presented significantly better outcomes, with less mortality, ICU admissions, respiratory insufficiency, need for mechanical ventilation or prone, sepsis, SIRS and renal failure (p<0.05 for all). However, we did not find differences regarding the hospital use of RASi and the development of heart failure. CONCLUSION: RASi historic use, at admission, is not related to an adjusted worse prognosis in hospitalized COVID-19 patients, although it points out a high-risk population. In this setting, the in-hospital prescription of RASi is associated with improved survival and fewer short-term complications.
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Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19 , Insuficiência Cardíaca , Hospitalização/estatística & dados numéricos , COVID-19/complicações , COVID-19/mortalidade , COVID-19/terapia , Comorbidade , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Sistema de Registros , Respiração Artificial/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Espanha/epidemiologiaRESUMO
OBJECTIVES: No standard therapy, including anticoagulation regimens, is currently recommended for coronavirus disease 2019. Aim of this study was to evaluate the efficacy of anticoagulation in coronavirus disease 2019 hospitalized patients and its impact on survival. DESIGN: Multicenter international prospective registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019). SETTING: Hospitalized patients with coronavirus disease 2019. PATIENTS: Five thousand eight hundred thirty-eight consecutive coronavirus disease 2019 patients. INTERVENTIONS: Anticoagulation therapy, including prophylactic and therapeutic regimens, was obtained for each patient. MEASUREMENTS AND MAIN RESULTS: Five thousand four hundred eighty patients (94%) did not receive any anticoagulation before hospitalization. Two-thousand six-hundred one patients (44%) during hospitalization received anticoagulation therapy and it was not associated with better survival rate (81% vs 81%; p = 0.94) but with higher risk of bleeding (2.7% vs 1.8%; p = 0.03). Among patients admitted with respiratory failure (49%, n = 2,859, including 391 and 583 patients requiring invasive and noninvasive ventilation, respectively), anticoagulation started during hospitalization was associated with lower mortality rates (32% vs 42%; p < 0.01) and nonsignificant higher risk of bleeding (3.4% vs 2.7%; p = 0.3). Anticoagulation therapy was associated with lower mortality rates in patients treated with invasive ventilation (53% vs 64%; p = 0.05) without increased rates of bleeding (9% vs 8%; p = 0.88) but not in those with noninvasive ventilation (35% vs 38%; p = 0.40). At multivariate Cox' analysis mortality relative risk with anticoagulation was 0.58 (95% CI, 0.49-0.67) in patients admitted with respiratory failure, 0.50 (95% CI, 0.49-0.67) in those requiring invasive ventilation, 0.72 (95% CI, 0.51-1.01) in noninvasive ventilation. CONCLUSIONS: Anticoagulation therapy in general population with coronavirus disease 2019 was not associated with better survival rates but with higher bleeding risk. Better results were observed in patients admitted with respiratory failure and requiring invasive ventilation.
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Anticoagulantes/uso terapêutico , Tratamento Farmacológico da COVID-19 , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , COVID-19/mortalidade , Estudos de Casos e Controles , Correlação de Dados , Comparação Transcultural , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Hospitalização , Humanos , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Respiração Artificial , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/mortalidade , Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The COVID-19 pandemic has seriously challenged worldwide healthcare systems and limited intensive care facilities, leading to physicians considering the use of non-invasive ventilation (NIV) for managing SARS-CoV-2-related acute respiratory failure (ARF). METHODS: We conducted an interim analysis of the international, multicentre HOPE COVID-19 registry including patients admitted for a confirmed or highly suspected SARS-CoV-2 infection until 18 April 2020. Those treated with NIV were considered. The primary endpoint was a composite of death or need for intubation. The components of the composite endpoint were the secondary outcomes. Unadjusted and adjusted predictors of the primary endpoint within those initially treated with NIV were investigated. RESULTS: 1933 patients who were included in the registry during the study period had data on oxygen support type. Among them, 390 patients (20%) were treated with NIV. Compared with those receiving other non-invasive oxygen strategy, patients receiving NIV showed significantly worse clinical and laboratory signs of ARF at presentation. Of the 390 patients treated with NIV, 173 patients (44.4%) met the composite endpoint. In-hospital death was the main determinant (147, 37.7%), while 62 patients (15.9%) needed invasive ventilation. Those requiring invasive ventilation had the lowest survival rate (41.9%). After adjustment, age (adjusted OR (adj(OR)) for 5-year increase: 1.37, 95% CI 1.15 to 1.63, p<0.001), hypertension (adj(OR) 2.95, 95% CI 1.14 to 7.61, p=0.03), room air O2 saturation <92% at presentation (adj(OR) 3.05, 95% CI 1.28 to 7.28, p=0.01), lymphocytopenia (adj(OR) 3.55, 95% CI 1.16 to 10.85, p=0.03) and in-hospital use of antibiotic therapy (adj(OR) 4.91, 95% CI 1.69 to 14.26, p=0.003) were independently associated with the composite endpoint. CONCLUSION: NIV was used in a significant proportion of patients within our cohort, and more than half of these patients survived without the need for intubation. NIV may represent a viable strategy particularly in case of overcrowded and limited intensive care resources, but prompt identification of failure is mandatory to avoid harm. Further studies are required to better clarify our hypothesis. TRIAL REGISTRATION NUMBERS: NCT04334291/EUPAS34399.
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COVID-19/mortalidade , COVID-19/terapia , Ventilação não Invasiva/mortalidade , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/terapia , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , Feminino , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Sistema de Registros , Respiração Artificial/mortalidade , Insuficiência Respiratória/etiologia , SARS-CoV-2RESUMO
Sepsis, among other pathologies, is an endotoxin tolerance (ET)-related disease. On admission, we classified 48 patients with sepsis into 3 subgroups according to the ex vivo response to lipopolysaccharide. This response correlates with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the ET degree. Moreover, the ET-related classification determines the outcome of these patients. Programmed cell death-ligand 1 (PD-L1) expression on septic monocytes is also linked with ET status. In addition to the regulation of cytokine production, one of the hallmarks of ET that significantly affects patients with sepsis is T-cell proliferation impairment or a poor switch to the adaptive response. PD-L1/programmed cell death-1 (PD-1) blocking and knockdown assays on tolerant monocytes from both patients with sepsis and the in vitro model reverted the impaired adaptive response. Mechanistically, the transcription factor hypoxia-inducible factor-1α (HIF1α) has been translocated into the nucleus and drives PD-L1 expression during ET in human monocytes. This fact, together with patient classification according to the ex vivo lipopolysaccharide response, opens an interesting field of study and potential personalized clinical applications, not only for sepsis but also for all ET-associated pathologies.
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Imunidade Adaptativa , Antígeno B7-H1/biossíntese , Endotoxinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Tolerância Imunológica , Sepse/patologia , APACHE , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologiaRESUMO
BACKGROUND: Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) is deemed necessary for effective sepsis management. Here, we evaluated the role of SIGLEC5 as an IC ligand and explored its potential as a biomarker for sepsis. METHODS: In vitro and in vivo assays were conducted to both analyse SIGLEC5's role as an IC ligand, as well as assess its impact on survival in sepsis. A multicentre prospective cohort study was conducted to evaluate the plasmatic soluble SIGLEC5 (sSIGLEC5) as a mortality predictor in the first 60 days after admission in sepsis patients. Recruitment included sepsis patients (n = 346), controls with systemic inflammatory response syndrome (n = 80), aneurism (n = 11), stroke (n = 16), and healthy volunteers (HVs, n = 100). FINDINGS: SIGLEC5 expression on monocytes was increased by HIF1α and was higher in septic patients than in healthy volunteers after ex vivo LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ T-cell proliferation. Administration of sSIGLEC5r (0.8 mg/kg) had adverse effects in mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels of septic patients were higher than HVs and ROC analysis revealed it as a mortality marker with an AUC of 0.713 (95% CI, 0.656-0.769; p < 0.0001). Kaplan-Meier survival curve showed a significant decrease in survival above the calculated cut-off (HR of 3.418, 95% CI, 2.380-4.907, p < 0.0001 by log-rank test) estimated by Youden Index (523.6 ng/mL). INTERPRETATION: SIGLEC5 displays the hallmarks of an IC ligand, and plasma levels of sSIGLEC5 have been linked with increased mortality in septic patients. FUNDING: Instituto de Salud Carlos III (ISCIII) and "Fondos FEDER" to ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), CDF (PI21/01178), RLR (FI19/00334) and JAO (CD21/00059).
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Sepse , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica , Linfócitos T CD8-Positivos/metabolismo , Lectinas , Ligantes , Prognóstico , Estudos Prospectivos , Curva ROC , Sepse/etiologiaRESUMO
Identifying patients' immune system status has become critical to managing SARS-CoV-2 infection and avoiding the appearance of secondary infections during a hospital stay. Despite the high volume of research, robust severity and outcome markers are still lacking in COVID-19. We recruited 87 COVID-19 patients and analyzed, by unbiased automated software, 356 parameters at baseline emergency department admission including: high depth immune phenotyping and immune checkpoint expression by spectral flow cytometry, cytokines and other soluble molecules in plasma as well as routine clinical variables. We identified 69 baseline alterations in the expression of immune checkpoints, Ig-like V type receptors and other immune population markers associated with severity (O2 requirement). Thirty-four changes in these markers/populations were associated with secondary infection appearance. In addition, through a longitudinal sample collection, we described the changes which take place in the immune system of COVID-19 patients during secondary infections and in response to corticosteroid treatment. Our study provides information about immune checkpoint molecules and other less-studied receptors with Ig-like V-type domains such as CD108, CD226, HVEM (CD270), B7H3 (CD276), B7H5 (VISTA) and GITR (CD357), defining these as novel interesting molecules in severe and corticosteroids-treated acute infections.
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Background COVID-19 is an infectious illness, featured by an increased risk of thromboembolism. However, no standard antithrombotic therapy is currently recommended for patients hospitalized with COVID-19. The aim of this study was to evaluate safety and efficacy of additional therapy with aspirin over prophylactic anticoagulation (PAC) in patients hospitalized with COVID-19 and its impact on survival. Methods and Results A total of 8168 patients hospitalized for COVID-19 were enrolled in a multicenter-international prospective registry (HOPE COVID-19). Clinical data and in-hospital complications, including mortality, were recorded. Study population included patients treated with PAC or with PAC and aspirin. A comparison of clinical outcomes between patients treated with PAC versus PAC and aspirin was performed using an adjusted analysis with propensity score matching. Of 7824 patients with complete data, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC. Propensity-score matching yielded 298 patients from each group. In the propensity score-matched population, cumulative incidence of in-hospital mortality was lower in patients treated with PAC and aspirin versus PAC (15% versus 21%, Log Rank P=0.01). At multivariable analysis in propensity matched population of patients with COVID-19, including age, sex, hypertension, diabetes, kidney failure, and invasive ventilation, aspirin treatment was associated with lower risk of in-hospital mortality (hazard ratio [HR], 0.62; [95% CI 0.42-0.92], P=0.018). Conclusions Combination PAC and aspirin was associated with lower mortality risk among patients hospitalized with COVID-19 in a propensity score matched population compared to PAC alone.
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COVID-19 , Anticoagulantes/efeitos adversos , Aspirina/uso terapêutico , Estudos de Coortes , Humanos , Pontuação de Propensão , Sistema de Registros , Estudos RetrospectivosRESUMO
We report the disparate clinical progression of a couple infected by SARS-CoV-2 based on their immune checkpoint (IC) levels and immune cell distribution in blood from admission to exitus in patient 1 and from admission to discharge and recovery in patient 2. A detailed clinical follow-up accompanied by a longitudinal analysis of immune phenotypes and IC levels is shown. The continuous increase in the soluble IC ligand galectin-9 (Gal-9) and the increment in T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) protein in T cells in patient 1 suggests an activation of the Gal-9/TIM-3 axis and, subsequently, a potential cell exhaustion in this patient that did not occur in patient 2. Our data indicate that the Gal-9/TIM-3 axis could be a potential target in this clinical setting, along with a patent effector memory T-cell reduction.
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INTRODUCTION AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Atrial fibrillation (AF) is common in acute situations, where it is associated with more complications and higher mortality. METHODS: Analysis of the international HOPE registry (NCT04334291). The objective was to assess the prognostic information of AF in COVID-19 patients. A multivariate analysis and propensity score matching were performed to assess the relationship between AF and mortality. We also evaluated the impact on mortality and embolic events of the CHA2DS2-VASc score in these patients. RESULTS: Among 6217 patients enrolled in the HOPE registry, 250 had AF (4.5%). AF patients had a higher prevalence of cardiovascular risk factors and comorbidities. After propensity score matching, these differences were attenuated. Despite this, patients with AF had a higher incidence of in-hospital complications such as heart failure (19.3% vs 11.6%, P=.021) and respiratory insufficiency (75.9% vs 62.3%, P=.002), as well as a higher 60-day mortality rate (43.4% vs 30.9%, P=.005). On multivariate analysis, AF was independently associated with higher 60-day mortality (hazard ratio, 1.234; 95%CI, 1.003-1.519). CHA2DS2-VASc score acceptably predicts 60-day mortality in COVID-19 patients (area ROC, 0.748; 95%CI, 0.733-0.764), but not its embolic risk (area ROC, 0.411; 95%CI, 0.147-0.675). CONCLUSIONS: AF in COVID-19 patients is associated with a higher number of complications and 60-day mortality. The CHA2DS2-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.
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Fibrilação Atrial , COVID-19 , Acidente Vascular Cerebral , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , COVID-19/complicações , Humanos , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Fatores de RiscoRESUMO
There is limited information on the presenting characteristics, prognosis, and therapeutic approaches of young patients hospitalized for coronavirus disease 2019 (COVID-19). We sought to investigate the baseline characteristics, in-hospital treatment, and outcomes of a wide cohort < 65 years admitted for COVID-19. Using the international multicenter HOPE-COVID-19 registry, we evaluated the baseline characteristics, clinical presentation, therapeutic approach, and prognosis of patients < 65 years discharged (deceased or alive) after hospital admission for COVID-19, also compared with the elderly counterpart. Of the included 5746 patients, 2676 were < 65 and 3070 ≥ 65 years. All risk factors and several parameters suggestive of worse clinical presentation augmented through increasing age classes. In-hospital mortality rates were 6.8% and 32.1% in the younger and older cohort, respectively (p < 0.001). Among young patients, mortality, access to ICU and treatment with IMVwere positively correlated with age. Contrariwise, over 65 years of age this trend was broken so that only the association between age and mortality was persistent, while the rates of access to ICU and IMV started to decline. Younger patients also recognized specific predictors of case fatality, such as obesity and gender. Age negatively impacts on mortality, access to ICU and treatment with IMV in patients < 65 years. In elderly patients only case fatality rate keeps augmenting in a stepwise manner through increasing age categories, while therapeutic approaches become more conservative. Besides age, obesity, gender, history of cancer, and severe dyspnea, tachypnea, chest X-ray bilateral abnormalities, abnormal level of creatinine and leucocyte among admission parameters seem to play a central role in the outcome of patients younger than 65 years.
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Envelhecimento , COVID-19/diagnóstico , COVID-19/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , SARS-CoV-2/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem , Tratamento Farmacológico da COVID-19RESUMO
INTRODUCTION AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Atrial fibrillation (AF) is common in acute situations, where it is associated with more complications and higher mortality. METHODS: Analysis of the international HOPE registry (NCT04334291). The objective was to assess the prognostic information of AF in COVID-19 patients. A multivariate analysis and propensity score matching were performed to assess the relationship between AF and mortality. We also evaluated the impact on mortality and embolic events of the CHA2DS2-VASc score in these patients. RESULTS: Among 6217 patients enrolled in the HOPE registry, 250 had AF (4.5%). AF patients had a higher prevalence of cardiovascular risk factors and comorbidities. After propensity score matching, these differences were attenuated. Despite this, patients with AF had a higher incidence of in-hospital complications such as heart failure (19.3% vs 11.6%, P = .021) and respiratory insufficiency (75.9% vs 62.3%, P = .002), as well as a higher 60-day mortality rate (43.4% vs 30.9%, P = .005). On multivariate analysis, AF was independently associated with higher 60-day mortality (hazard ratio, 1.234; 95%CI, 1.003-1.519). CHA2DS2-VASc score acceptably predicts 60-day mortality in COVID-19 patients (area ROC, 0.748; 95%CI, 0.733-0.764), but not its embolic risk (area ROC, 0.411; 95%CI, 0.147-0.675). CONCLUSIONS: AF in COVID-19 patients is associated with a higher number of complications and 60-day mortality. The CHA2DS2-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.
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Increased cytokine levels, acute phase reactants and immune checkpoint expression changes have been described in patients with Coronavirus Disease 2019 (COVID-19). Here, we have reported a monocyte polarization towards a low HLA-DR and high PD-L1 expression after long exposure to proteins from SARS-CoV-2. Moreover, CD86 expression was also reduced over SARS-CoV-2 proteins exposure. Additionally, T-cells proliferation was significantly reduced after stimulation with these proteins. Eventually, patients with long-term SARS-CoV-2 infection also exhibited a significant blockade of T-cells proliferation.
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Dysnatremia is associated with increased mortality in patients with community-acquired pneumonia. SARS-COV2 (Severe-acute-respiratory syndrome caused by Coronavirus-type 2) pneumonia can be fatal. The aim of this study was to ascertain whether admittance dysnatremia is associated with mortality, sepsis, or intensive therapy (IT) in patients hospitalized with SARS-COV2 pneumonia. This is a retrospective study of the HOPE-COVID-19 registry, with data collected from January 1th through April 31th, 2020. We selected all hospitalized adult patients with RT-PCR-confirmed SARS-COV2 pneumonia and a registered admission serum sodium level (SNa). Patients were classified as hyponatremic (SNa <135 mmol/L), eunatremic (SNa 135-145 mmol/L), or hypernatremic (SNa >145 mmol/L). Multivariable analyses were performed to elucidate independent relationships of admission hyponatremia and hypernatremia, with mortality, sepsis, or IT during hospitalization. Four thousand six hundred sixty-four patients were analyzed, median age 66 (52-77), 58% males. Death occurred in 988 (21.2%) patients, sepsis was diagnosed in 551 (12%) and IT in 838 (18.4%). Hyponatremia was present in 957/4,664 (20.5%) patients, and hypernatremia in 174/4,664 (3.7%). Both hyponatremia and hypernatremia were associated with mortality and sepsis. Only hyponatremia was associated with IT. In conclusion, hyponatremia and hypernatremia at admission are factors independently associated with mortality and sepsis in patients hospitalized with SARS-COV2 pneumonia. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04334291, NCT04334291.
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COVID-19/mortalidade , Mortalidade Hospitalar/tendências , Hipernatremia/fisiopatologia , Hiponatremia/fisiopatologia , Sistema de Registros/estatística & dados numéricos , SARS-CoV-2/isolamento & purificação , Idoso , COVID-19/epidemiologia , COVID-19/virologia , Feminino , Seguimentos , Saúde Global , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation. METHODS: Bead arrays were used to compare global DNA methylation changes in patients with sepsis, non-infectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming. RESULTS: Here, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance. CONCLUSION: We have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.
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Citocinas/genética , Metilação de DNA , DNA/análise , Mediadores da Inflamação/metabolismo , Inflamação/complicações , Monócitos/patologia , Insuficiência de Múltiplos Órgãos/complicações , Sepse/diagnóstico , Idoso , Estudos de Casos e Controles , DNA/genética , Feminino , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Insuficiência de Múltiplos Órgãos/genética , Fenótipo , Sepse/etiologia , Sepse/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Most hypertensive patients, despite a proper control of their cardiovascular risk factors, have cardiovascular complications, evidencing the importance of controlling and/or reversing target-organ damage. In this sense, endothelial dysfunction has been associated with the presence of cardiovascular risk factors and related cardiovascular outcomes. Since hypertension often clusters with other risk factors such as dyslipemia, diabetes and obesity, in this study we have investigated the effect of intensive multifactorial treatment on circulating vascular progenitor cell levels on high-risk hypertensive patients. DESIGN: We included108 hypertensive patients receiving intensive multifactorial pharmacologic treatment and dietary recommendations targeting blood pressure, dyslipemia, hyperglycemia and weight for 12 months. After the treatment period, blood samples were collected and circulating levels of endothelial (CD34+/KDR+, CD34+/VE-cadherin+) and smooth muscle (CD14+/endoglin+) progenitor cells were identified by flow cytometry. Additionally, plasma concentration of vascular endothelial growth factor (VEGF) was determined by ELISA. RESULTS: Most hypertensive patients (61±12 years, 47% men) showed cardiovascular parameters within normal ranges at baseline. Moreover, body mass index and the majority of the biochemical parameters (systolic and diastolic blood pressure, fasting glucose, total cholesterol, HDL-c, LDL-c, creatinine and hs-CRP) significantly decreased overtime. After 12 months of intensive treatment, CD34+/KDR+ and CD14+/endoglin+ levels did not change, but CD34+/VE-cadherin+ cells increased significantly at month 12 [0.9(0.05-0.14)% vs 0.05(0.02-0.09)% P<0.05]. However, VEGF plasma concentration decreased significantly overtime [89.1(53.9-218.7) vs [66.2(47.5-104.6) pg/mL, P<0.05]. CONCLUSIONS: Long-term intensive treatment in hypertensive patients further improves cardiovascular risk and increases circulating EPCs, suggesting that these cells could be a therapeutic target.
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Doenças Cardiovasculares/patologia , Hipertensão/terapia , Células-Tronco/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Sepsis is a pathology in which patients suffer from a proinflammatory response and a dysregulated immune response, including T cell exhaustion. A number of therapeutic strategies to treat human sepsis, which are different from antimicrobial and fluid resuscitation treatments, have failed in clinical trials, and solid biomarkers for sepsis are still lacking. Herein, we classified 85 patients with sepsis into two groups according to their blood oxygen saturation (SaO2): group I (SaO2 ≤ 92%, n = 42) and group II (SaO2 > 92%, n = 43). Blood samples were taken before any treatment, and the immune response after ex vivo LPS challenge was analyzed, as well as basal expression of PD-L1 on monocytes and levels of sPD-L1 in sera. The patients were followed up for 1 month. Taking into account reinfection and exitus frequency, a significantly poorer evolution was observed in patients from group I. The analysis of HLA-DR expression on monocytes, T cell proliferation and cytokine profile after ex vivo LPS stimulation confirmed an impaired immune response in group I. In addition, these patients showed both, high levels of PD-L1 on monocytes and sPD-L1 in serum, resulting in a down-regulation of the adaptive response. A blocking assay using an anti-PD-1 antibody reverted the impaired response. Our data indicated that SaO2 levels on admission have emerged as a potential signature for immune status, including PD-L1 expression. An anti-PD-1 therapy could restore the T cell response in hypoxemic sepsis patients with SaO2 ≤ 92% and high PD-L1 levels.
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Antígeno B7-H1/metabolismo , Biomarcadores/sangue , Células Sanguíneas/imunologia , Monócitos/imunologia , Oxigênio/sangue , Sepse/diagnóstico , Linfócitos T/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Bloqueadores/farmacologia , Antígeno B7-H1/imunologia , Células Cultivadas , Testes Diagnósticos de Rotina , Feminino , Humanos , Tolerância Imunológica , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sepse/imunologia , Sepse/mortalidade , Análise de SobrevidaRESUMO
OBJECTIVE: To determine the perception and evaluation of the Emergency pharmacist by the medical and nursing staff at the Emergency department. METHODS: A multicenter study based on a survey sent to the Spanish Society of Hospital Pharmacists (SEFH) for Emergency pharmacists (EPh) to distribute among the Emergency staff. Descriptive statistics were used, with a 95% confidence interval. RESULTS: 102 (12%) questionnaires were completed by 73 Emergency Physicians (71.6%) and 29 Emergency Nurses (28.4%), out of 835 surveys sent. The most common pharmaceutical activities, and perceived as more relevant for patient safety, were: consultation solution, prescription validation, and medication reconciliation. 63% of respondents supported the prospective review of high-risk medications, while 89% believed that the Pharmacist improves the quality of care. EPh are considered useful for training healthcare staff and patients, and 77% of respondents considered them as an integral member of the team. They would resort more to Pharmacists if they were present at the hospital department. CONCLUSIONS: The results show the acceptance of Hospital Pharmacists in the Emergency Department; their functions are known and valued. They are considered an integral member of the team, who will provide safety and improve patient care. Medication reconciliation and prescription validation are highlighted because of their relevance in terms of safety. Further studies are needed to assess health outcomes and their economic impact.
Objetivo: Determinar la percepción y valoración del farmacéutico de Urgencias por el personal médico y de enfermería de este servicio.Métodos: Estudio multicéntrico basado en una encuesta que se envió a la SEFH para que los farmacéuticos de Urgencias lo dirigieran al personal de esta unidad. Se aplica una estadística descriptiva con intervalos de confianza del 95%.Resultados: 102 (12%) encuestas cumplimentadas por 73 médicos (71,6%) y 29 enfermeras (28,4%) de Urgencias, de un total de 835 enviadas. Se aprecian como actividades farmacéuticas más comunes y relevantes para la seguridad del paciente: la resolución de consultas, la validación de prescripciones y la conciliación de la medicación. El 63% apoya la validación prospectiva de los medicamentos de alto riesgo. Para el 89% el farmacéutico mejora la calidad de la atención. Lo consideran útil en la formación del personal sanitario y de los pacientes y, para un 77% del total, es parte integral del equipo. Recurren más a él si está presente en el servicio. Conclusiones: Los resultados muestran la aceptación del farmacéutico de hospital en Urgencias; se conocen y valoran sus funciones. Es considerado parte integral del equipo, aporta seguridad y mejora la atención de los pacientes. Se refuerzan la conciliación de la medicación y la validación de las prescripciones por su relevancia en la seguridad. Su visibilidad facilita que recurran a sus servicios, si bien un reciente informe de la SEFH refleja una reducida presencia en las Urgencias hospitalarias. Hacen falta más estudios que valoren los resultados en salud y su repercusión económica.
Assuntos
Serviço Hospitalar de Emergência , Farmacêuticos , Atitude do Pessoal de Saúde , Humanos , Reconciliação de Medicamentos , Enfermeiras e Enfermeiros , Médicos , Papel Profissional , Estudos Prospectivos , Espanha , Inquéritos e Questionários , Recursos HumanosRESUMO
BACKGROUND: Transfusion of blood components continues to be an important therapeutic resource into the 21st century. Between 5 and 58% of transfusions carried out are estimated to be unnecessary. According to several studies, at least 20% of packed red blood cell transfusions (RBCT) are administered in hospital emergency departments (ED), but few data are available about the appropriateness of RBCT in this setting. This multicentre, cross-sectional observational study aims to assess the appropriateness of RBCT indications and transfused volumes in patients who attend ED. MATERIALS AND METHODS: The study cohort is made up of consecutive consenting adult patients (≥18 years old) who received RBCT in ED over a 3-month period and for whom relevant clinical data were collected and analysed. RESULTS: Data from 908 RBCT episodes (2±1 units per transfused patient) were analysed. RBCT was considered appropriate in 21.4% (n=195), with significant differences according to RBCT indication (p<0.001), hospital level (p<0.001) and prescribing physician (p=0.002). Pre-transfusion haemoglobin level (Hb) negatively correlated with RBCT appropriateness (r=-0.616; p<0.01). Only 72.4% of appropriate RBCT had a post-transfusion Hb assessment (n=516). Of these, 45% were considered to be over-transfused (n=232), with significant differences according to RBCT indication (p=0.012) and prescribing physician (p=0.047). Overall, 584/1,433 (41%) of evaluable RBC units were unnecessarily transfused. DISCUSSION: The appropriateness of RBCT in ED is similar to other hospital departments, but the rate of over-transfusion was high. These data support the need for a reassessment after transfusion of each RBC unit before further units are prescribed. In view of these results, we recommend that physicians should be made more aware of the need to prescribe RBCT appropriately in order to reduce over-transfusion.
Assuntos
Serviço Hospitalar de Emergência , Transfusão de Eritrócitos/métodos , Adulto , Estudos Transversais , Hemoglobinas/análise , HumanosRESUMO
System dynamics is a powerful tool that allows modeling of complex and highly networked systems such as those found in the human immune system. We have developed a model that reproduces how the exposure of human monocytes to lipopolysaccharides (LPSs) induces an inflammatory state characterized by high production of tumor necrosis factor alpha (TNFα), which is rapidly modulated to enter into a tolerant state, known as endotoxin tolerance (ET). The model contains two subsystems with a total of six states, seven flows, two auxiliary variables, and 14 parameters that interact through six differential and nine algebraic equations. The parameters were estimated and optimized to obtain a model that fits the experimental data obtained from human monocytes treated with various LPS doses. In contrast to publications on other animal models, stimulation of human monocytes with super-low-dose LPSs did not alter the response to a second LPSs challenge, neither inducing ET, nor enhancing the inflammatory response. Moreover, the model confirms the low production of TNFα and increased levels of C-C motif ligand 2 when monocytes exhibit a tolerant state similar to that of patients with sepsis. At present, the model can help us better understand the ET response and might offer new insights on sepsis diagnostics and prognosis by examining the monocyte response to endotoxins in patients with sepsis.