Publications by authors named "Charbel Maroun Eid"

20 Publications

  • Page 1 of 1

Potential Role of the Galectin-9/TIM-3 Axis in the Disparate Progression of SARS-CoV-2 in a Married Couple: A Case Report.

Biomed Hub 2021 Jan-Apr;6(1):48-58. Epub 2021 Apr 19.

The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

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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http://dx.doi.org/10.1159/000514727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089458PMC
April 2021

Anticoagulation Therapy in Patients With Coronavirus Disease 2019: Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 [HOPE-COVID19]).

Crit Care Med 2021 06;49(6):e624-e633

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

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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http://dx.doi.org/10.1097/CCM.0000000000005010DOI Listing
June 2021

Renin-angiotensin system inhibitors effect before and during hospitalization in COVID-19 outcomes: Final analysis of the international HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID-19) registry.

Am Heart J 2021 07 15;237:104-115. Epub 2021 Apr 15.

Hospital Clínico San Carlos, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.

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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http://dx.doi.org/10.1016/j.ahj.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047303PMC
July 2021

Does there exist an obesity paradox in COVID-19? Insights of the international HOPE-COVID-19-registry.

Obes Res Clin Pract 2021 May-Jun;15(3):275-280. Epub 2021 Mar 3.

University Medical Center Mannheim (UMM), University of Heidelberg, Mannheim, Germany.

Background: Obesity has been described as a protective factor in cardiovascular and other diseases being expressed as 'obesity paradox'. However, the impact of obesity on clinical outcomes including mortality in COVID-19 has been poorly systematically investigated until now. We aimed to compare clinical outcomes among COVID-19 patients divided into three groups according to the body mass index (BMI).

Methods: We retrospectively collected data up to May 31, 2020. 3635 patients were divided into three groups of BMI (<25 kg/m; n = 1110, 25-30 kg/m; n = 1464, and >30 kg/m; n = 1061). Demographic, in-hospital complications, and predictors for mortality, respiratory insufficiency, and sepsis were analyzed.

Results: The rate of respiratory insufficiency was more recorded in BMI 25-30 kg/m as compared to BMI < 25 kg/m (22.8% vs. 41.8%; p < 0.001), and in BMI > 30 kg/m than BMI < 25 kg/m, respectively (22.8% vs. 35.4%; p < 0.001). Sepsis was more observed in BMI 25-30 kg/m and BMI > 30 kg/m as compared to BMI < 25 kg/m, respectively (25.1% vs. 42.5%; p = 0.02) and (25.1% vs. 32.5%; p = 0.006). The mortality rate was higher in BMI 25-30 kg/m and BMI > 30 kg/m as compared to BMI < 25 kg/m, respectively (27.2% vs. 39.2%; p = 0.31) (27.2% vs. 33.5%; p = 0.004). In the Cox multivariate analysis for mortality, BMI < 25 kg/m and BMI > 30 kg/m did not impact the mortality rate (HR 1.15, 95% CI: 0.889-1.508; p = 0.27) (HR 1.15, 95% CI: 0.893-1.479; p = 0.27). In multivariate logistic regression analyses for respiratory insufficiency and sepsis, BMI < 25 kg/m is determined as an independent predictor for reduction of respiratory insufficiency (OR 0.73, 95% CI: 0.538-1.004; p = 0.05).

Conclusions: HOPE COVID-19-Registry revealed no evidence of obesity paradox in patients with COVID-19. However, Obesity was associated with a higher rate of respiratory insufficiency and sepsis but was not determined as an independent predictor for a high mortality.
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http://dx.doi.org/10.1016/j.orcp.2021.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927637PMC
March 2021

Non-invasive ventilation for SARS-CoV-2 acute respiratory failure: a subanalysis from the HOPE COVID-19 registry.

Emerg Med J 2021 Mar 16. Epub 2021 Mar 16.

Cardiovascular Institute, Hospital Clinico San Carlos, Madrid, Community of Madrid, Spain.

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 O 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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http://dx.doi.org/10.1136/emermed-2020-210411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970657PMC
March 2021

[Atrial fibrillation in patients with COVID-19. Usefulness of the CHADS-VASc score: an analysis of the international HOPE COVID-19 registry].

Rev Esp Cardiol 2021 Mar 2. Epub 2021 Mar 2.

Servicio de Cardiología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, España.

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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http://dx.doi.org/10.1016/j.recesp.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923850PMC
March 2021

COVID-19 anosmia and gustatory symptoms as a prognosis factor: a subanalysis of the HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID-19) registry.

Infection 2021 Mar 1. Epub 2021 Mar 1.

Hospital Clínico San Carlos, Madrid, Spain.

Olfactory and gustatory dysfunctions (OGD) are a frequent symptom of coronavirus disease 2019 (COVID-19). It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2 could be due to olfactory bulb invasion, conversely studies suggest it could be a good prognostic factor. The aim of the current study was to investigate the prognosis value of OGD in COVID-19. These symptoms were recorded on admission from a cohort study of 5868 patients with confirmed or highly suspected COVID-19 infection included in the multicenter international HOPE Registry (NCT04334291). There was statistical relation in multivariate analysis for OGD in gender, more frequent in female 12.41% vs 8.67% in male, related to age, more frequent under 65 years, presence of hypertension, dyslipidemia, diabetes, smoke, renal insufficiency, lung, heart, cancer and neurological disease. We did not find statistical differences in pregnant (p = 0.505), patient suffering cognitive (p = 0.484), liver (p = 0.1) or immune disease (p = 0.32). There was inverse relation (protective) between OGD and prone positioning (0.005) and death (< 0.0001), but no with ICU (0.165) or mechanical ventilation (0.292). On univariable logistic regression, OGD was found to be inversely related to death in COVID-19 patients. The odds ratio was 0.26 (0.15-0.44) (p < 0.001) and Z was - 5.05. The presence of anosmia is fundamental in the diagnosis of SARS.CoV-2 infection, but also could be important in classifying patients and in therapeutic decisions. Even more knowing that it is an early symptom of the disease. Knowing that other situations as being Afro-American or Latino-American, hypertension, renal insufficiency, or increase of C-reactive protein (CRP) imply a worse prognosis we can make a clinical score to estimate the vital prognosis of the patient. The exact pathogenesis of SARS-CoV-2 that causes olfactory and gustative disorders remains unknown but seems related to the prognosis. This point is fundamental, insomuch as could be a plausible way to find a treatment.
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http://dx.doi.org/10.1007/s15010-021-01587-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917537PMC
March 2021

Atrial fibrillation in patients with COVID-19. Usefulness of the CHADS-VASc score: an analysis of the international HOPE COVID-19 registry.

Rev Esp Cardiol (Engl Ed) 2021 Jan 13. Epub 2021 Jan 13.

Servicio de Cardiología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.

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 CHADS-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). CHADS-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 CHADS-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.
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http://dx.doi.org/10.1016/j.rec.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836821PMC
January 2021

Clinical presentation, therapeutic approach, and outcome of young patients admitted for COVID-19, with respect to the elderly counterpart.

Clin Exp Med 2021 May 8;21(2):249-268. Epub 2021 Feb 8.

Hospital Clinico San Carlos, Madrid, Spain.

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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http://dx.doi.org/10.1007/s10238-021-00684-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868661PMC
May 2021

Prevalence and 30-Day Mortality in Hospitalized Patients With Covid-19 and Prior Lung Diseases.

Arch Bronconeumol 2021 04 16;57 Suppl 2:13-20. Epub 2020 Dec 16.

Hospital Clínico San Carlos, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.

Introduction: Patients with pre-existing respiratory diseases in the setting of COVID-19 may have a greater risk of severe complications and even death.

Methods: A retrospective, multicenter, cohort study with 5847 COVID-19 patients admitted to hospitals. Patients were separated in two groups, with/without previous lung disease. Evaluation of factors associated with survival and secondary composite end-point such as ICU admission and respiratory support, were explored.

Results: 1,271 patients (22%) had a previous lung disease, mostly COPD. All-cause mortality occurred in 376 patients with lung disease (29.5%) and in 819 patients without (17.9%) (p<0.001). Kaplan-Meier curves showed that patients with lung diseases had a worse 30-day survival (HR=1.78; 95%C.I. 1.58-2.01; p<0.001) and COPD had almost 40% mortality. Multivariable Cox regression showed that prior lung disease remained a risk factor for mortality (HR, 1.21; 95%C.I. 1.02-1.44; p=0.02). Variables independently associated with all-cause mortality risk in patients with lung diseases were oxygen saturation less than 92% on admission (HR, 4.35; 95% CI 3.08-6.15) and elevated D-dimer (HR, 1.84; 95% CI 1.27-2.67). Age younger than 60 years (HR 0.37; 95% CI 0.21-0.65) was associated with decreased risk of death.

Conclusions: Previous lung disease is a risk factor for mortality in patients with COVID-19. Older age, male gender, home oxygen therapy, and respiratory failure on admission were associated with an increased mortality. Efforts must be done to identify respiratory patients to set measures to improve their clinical outcomes.
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http://dx.doi.org/10.1016/j.arbres.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744014PMC
April 2021

Prognostic Impact of Hyponatremia and Hypernatremia in COVID-19 Pneumonia. A HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19) Registry Analysis.

Front Endocrinol (Lausanne) 2020 30;11:599255. Epub 2020 Nov 30.

Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.

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 1 through April 31, 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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http://dx.doi.org/10.3389/fendo.2020.599255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734292PMC
January 2021

Proteins from SARS-CoV-2 reduce T cell proliferation: A mirror image of sepsis.

Heliyon 2020 Dec 30;6(12):e05635. Epub 2020 Nov 30.

The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid, 28046, Spain.

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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http://dx.doi.org/10.1016/j.heliyon.2020.e05635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703472PMC
December 2020

Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.

Age Ageing 2021 02;50(2):326-334

Unidad de Gestión Clínica Área del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga (UMA), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Málaga, Spain.

Background: the coronavirus disease 2019 (COVID-19) is characterized by poor outcomes and mortality, particularly in older patients.

Methods: post hoc analysis of the international, multicentre, 'real-world' HOPE COVID-19 registry. All patients aged ≥65 years hospitalised for COVID-19 were selected. Epidemiological, clinical, analytical and outcome data were obtained. A comparative study between two age subgroups, 65-74 and ≥75 years, was performed. The primary endpoint was all cause in-hospital mortality.

Results: about, 1,520 patients aged ≥65 years (60.3% male, median age of 76 [IQR 71-83] years) were included. Comorbidities such as hypertension (69.2%), dyslipidaemia (48.6%), cardiovascular diseases (any chronic heart disease in 38.4% and cerebrovascular disease in 12.5%), and chronic lung disease (25.3%) were prevalent, and 49.6% were on ACEI/ARBs. Patients aged 75 years and older suffered more in-hospital complications (respiratory failure, heart failure, renal failure, sepsis) and a significantly higher mortality (18.4 vs. 48.2%, P < 0.001), but fewer admissions to intensive care units (11.2 vs. 4.8%). In the overall cohort, multivariable analysis demonstrated age ≥75 (OR 3.54), chronic kidney disease (OR 3.36), dementia (OR 8.06), peripheral oxygen saturation at admission <92% (OR 5.85), severe lymphopenia (<500/mm3) (OR 3.36) and qSOFA (Quick Sequential Organ Failure Assessment Score) >1 (OR 8.31) to be independent predictors of mortality.

Conclusion: patients aged ≥65 years hospitalised for COVID-19 had high rates of in-hospital complications and mortality, especially among patients 75 years or older. Age ≥75 years, dementia, peripheral oxygen saturation <92%, severe lymphopenia and qSOFA scale >1 were independent predictors of mortality in this population.
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http://dx.doi.org/10.1093/ageing/afaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717146PMC
February 2021

Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis.

Genome Med 2019 10 29;11(1):66. Epub 2019 Oct 29.

Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916, Barcelona, Spain.

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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http://dx.doi.org/10.1186/s13073-019-0674-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820973PMC
October 2019

Oxygen Saturation on Admission Is a Predictive Biomarker for PD-L1 Expression on Circulating Monocytes and Impaired Immune Response in Patients With Sepsis.

Front Immunol 2018 4;9:2008. Epub 2018 Sep 4.

Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

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 (SaO): group I (SaO ≤ 92%, = 42) and group II (SaO > 92%, = 43). Blood samples were taken before any treatment, and the immune response after 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 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 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 SaO 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 SaO ≤ 92% and high PD-L1 levels.
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http://dx.doi.org/10.3389/fimmu.2018.02008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131191PMC
September 2019

Effect of intensive multifactorial treatment on vascular progenitor cells in hypertensive patients.

PLoS One 2018 5;13(1):e0190494. Epub 2018 Jan 5.

Vascular Biology Research Laboratory, Hospital Clínico San Carlos-IdISSC, Madrid, Spain.

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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755814PMC
February 2018

PD-L1 Overexpression During Endotoxin Tolerance Impairs the Adaptive Immune Response in Septic Patients via HIF1α.

J Infect Dis 2018 01;217(3):393-404

Innate Immunity Group.

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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http://dx.doi.org/10.1093/infdis/jix279DOI Listing
January 2018

A System Dynamics Model to Predict the Human Monocyte Response to Endotoxins.

Front Immunol 2017 3;8:915. Epub 2017 Aug 3.

Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

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.
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http://dx.doi.org/10.3389/fimmu.2017.00915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540970PMC
August 2017

Perception survey on the value of the hospital pharmacist at the emergency department.

Farm Hosp 2017 May 1;41(3):357-370. Epub 2017 May 1.

Emergency Department at the Hospital Universitario La Paz, IdiPaz®, Madrid..

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.
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http://dx.doi.org/10.7399/fh.2017.41.3.10687DOI Listing
May 2017

Appropriate use of red blood cell transfusion in emergency departments: a study in five emergency departments.

Blood Transfus 2017 May 7;15(3):199-206. Epub 2016 Jul 7.

Department of Surgical Specialties, Biochemistry and Immunology, School of Medicine, University of Malaga, Málaga, Spain.

Background: Transfusion of blood components continues to be an important therapeutic resource into the 21 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.
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http://dx.doi.org/10.2450/2016.0324-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448824PMC
May 2017