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The current study aimed at characterizing the dynamics of SARS‐CoV‐2 nucleocapsid (N) antigenemia in a cohort of critically ill adult COVID‐19 patients and assessing its potential association with plasma levels of biomarkers of clinical severity and mortality. Seventy‐three consecutive critically ill COVID‐19 patients (median age, 65 years) were recruited. Serial plasma (n = 340) specimens were collected. A lateral flow immunochromatography assay and reverse‐transcription polymerase chain reaction (RT‐PCR) were used for SARS‐CoV‐2 N protein detection and RNA quantitation and in plasma, respectively. Serum levels of inflammatory and tissue‐damage biomarkers in paired specimens were measured. SARS‐CoV‐RNA N‐antigenemia and viral RNAemia were documented in 40.1% and 35.6% of patients, respectively at a median of 9 days since symptoms onset. The level of agreement between the qualitative results returned by the N‐antigenemia assay and plasma RT‐PCR was moderate (k = 0.57; p, Highlights SARS‐CoV‐2 N‐antigenemia occurs frequently in ICU patients.SARS‐CoV‐2 N‐antigenemia occurs more frequently in ICU patients with viral RNAemia.SARS‐CoV‐2 N‐antigenemia associates with high serum levels of inflammatory biomarkers.

Background The involvement of SARS-CoV-2 antibodies in mediating immunopathogenetic events in COVID-19 patients has been suggested. By using several experimental approaches, we investigated the potential association between SARS-CoV-2 IgGs recognizing the spike (S) protein receptor-binding domain (RBD), neutralizing antibodies (NtAb) targeting S, and COVID-19 severity. Patients and methods This unicenter, retrospective, observational study included 51 hospitalized patients (24 at the intensive care unit; ICU). A total of 93 sera from these patients collected at different time points from the onset of symptoms were analyzed. SARS-CoV-2 RBD IgGs were quantitated by ELISA and NtAb50 titers were measured in a GFP reporterbased pseudotyped virus platform. Demographic and clinical data, complete blood counts, as well as serum levels of ferritin, Dimer-D, C reactive protein (CRP), lactose dehydrogenase (LDH), and interleukin-6 (IL-6) were retrieved from clinical charts. Results The overall correlation between levels of both antibody measurements was good (Rho = 0.82; P = 0 0.1). Four ICU patients died; two of these achieved NtAb50 titers ≥1/160 while the other two exhibited a 1/80 titer. Very weak (Rho=>0.0–0.2–, Estela Giménez holds a Juan Rodés research contract from the Carlos III Health Institute (Ref. JR18/00053). Eliseo Albert holds a Río Hortega research contract from the Carlos III Health Institute (Ref. CM18/00221). Ron Geller holds a Ramón y Cajal fellowship from the Spanish Ministry of Economy and Competitiveness (RYC-2015-17517).

There is limited information on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) T‐cell immune responses in patients with coronavirus disease 2019 (COVID‐19). Both CD4+ and CD8+ T cells may be instrumental in resolution of and protection from SARS‐CoV‐2 infection. Here, we tested 25 hospitalized patients either with microbiologically documented COVID‐19 (n = 19) or highly suspected of having the disease (n = 6) for presence of SARS‐CoV‐2‐reactive CD69+ expressing interferon‐γ (IFN‐γ) producing CD8+ T cells using flow‐cytometry for intracellular cytokine staining assay. Two sets of overlapping peptides encompassing the SARS‐CoV‐2 Spike glycoprotein N‐terminal 1 to 643 amino acid sequence and the entire sequence of SARS‐CoV‐2 M protein were used simultaneously as antigenic stimulus. Ten patients (40%) had detectable responses, displaying frequencies ranging from 0.15 to 2.7% (median of 0.57 cells/µL; range, 0.43‐9.98 cells/µL). The detection rate of SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells in patients admitted to intensive care was comparable (P = .28) to the rate in patients hospitalized in other medical wards. No correlation was found between SARS‐CoV‐2‐reactive IFN‐γ CD8+ T‐cell counts and SARS‐CoV‐2 S‐specific antibody levels. Likewise, no correlation was observed between either SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells or S‐specific immunoglobulin G‐antibody titers and blood cell count or levels of inflammatory biomarkers. In summary, in this descriptive, preliminary study we showed that SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells can be detected in a non‐negligible percentage of patients with moderate to severe forms of COVID‐19. Further studies are warranted to determine whether quantitation of these T‐cell subsets may provide prognostic information on the clinical course of COVID‐19., Highlights SARS‐CoV‐2 specific CD8+ T cells can be detected in 40% of COVID‐19 patients. No correlation was found between SARS‐CoV‐2‐reactive IFN‐γ CD8+ T‐cell countsand SARS‐CoV‐2 S‐specific antibody levels. No correlation was observed between SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells and levels of inflammatory biomarkers.

There is scarce information on the frequency of co-detection of respiratory pathogens (RP) in patients with Covid-19. Documentation of coinfections in Covid-19 pneumonia patients may be relevant for appropriate clinical and therapeutic management of patients. Between March 4th and March 28th, 2020, a total of 183 adult patients testing positive by SARS CoV-2 RT-PCR on respiratory specimens were hospitalized with interstitial pneumonia at our center, of whom 103 were tested for other RP by a multiplexed PCR assay. Three patients had a positive result for either one (n=2; Coronavirus HKU1 or Mycoplasma pneumoniae) or two targets (n=1; Influenza virus A (H3) and Respiratory syncytial virus B). Twenty-three patients testing negative by SARS CoV-2 RT-PCR and presentig with clinical, laboratory findings and imaging compatibe with Covid-19 pneumonia underwent RP screening. Of these, 6 (26%) had a positive result for a single RP. Our data indicate that despite the apparent rarity of coinfections in patients with Covid-19 pneumonia, routine testing for RP should be advised, since agents for which specific therapy can be prescribed may be detected.

ObjectivesThere is an imperative need to determine the durability of adaptive immunity to SARS-CoV-2. We enumerated SARS-CoV-2-reactive CD4+ and CD8+ T cells targeting S1 and M proteins and measured RBD-specific serum IgG over a period of 2-6 months after symptoms onset in a cohort of subjects who had recovered from severe clinical forms of COVID-19.MethodsWe recruited 58 patients (38 males and 20 females; median age, 62.5 years), who had been hospitalized with bilateral pneumonia, 60% with one or more comorbidities. IgG antibodies binding to SARS-CoV-2 RBD were measured by ELISA. SARS-CoV-2-reactive CD69+-expressing-IFNγ-producing-CD4+ and CD8+ T cells were enumerated in heparinized whole blood by flow cytometry for ICS.ResultsDetectable SARS-CoV-2-S1/M-reactive CD69+-IFN-γ CD4+ and CD8+ T cells were displayed in 17 (29.3%) and 6 (10.3%) subjects respectively, at a median of 84 days after onset of symptoms (range, 58-191 days). Concurrent comorbidities increased the risk (OR, 3.15; 95% CI, 1.03-9.61; P=0.04) of undetectable T-cell responses in models adjusted for age, sex and hospitalization ward. Twenty-one out of the 35 patients (60%) had detectable RBD-specific serum IgGs at a median of 118 days (range, 60 to 145 days) after symptoms onset. SARS-CoV-2 RBD-specific IgG serum levels were found to drop significantly over time.ConclusionA relatively limited number of subjects who developed severe forms of COVID-19 had detectable SARS-CoV-2-S1/M IFNγ CD4+ and CD8+ T cells at midterm after clinical diagnosis. Our data also indicated that serum levels of RBD-specific IgGs decline over time, becoming undetectable in some patients.

Background Traditionally, procalcitonin (PCT) is considered a diagnostic marker of bacterial infections. However, slightly elevated levels of PCT have also been found in patients with heart failure. In this context, it has been suggested that PCT may serve as a proxy for underrecognized infection, endotoxemia, or heightened proinflammatory activity. Nevertheless, the clinical utility of PCT in this setting is scarce. We aimed to evaluate the association between PCT and the risk of long-term outcomes. Methods and results We measured at admission PCT of 261 consecutive patients admitted for acute heart failure (AHF) after excluding active infection. Cox and negative binomial regression methods were used to evaluate the association between PCT and the risk of death and recurrent rehospitalizations, respectively. At a median follow-up of 2 years (IQR: 1.0–2.8), 108 deaths, 170 all-cause rehospitalizations and 96 AHF-rehospitalizations were registered. In an adjusted analysis, including well-established risk factors such as natriuretic peptides and indices of renal function, the logarithm of PCT was associated with a higher risk of death (HR = 1.43, CI 95%: 1.12–1.82; p = 0.004), all-cause rehospitalizations (IRR = 1.22, CI 95% 1.02–1.44; p = 0.025) and AHF-rehospitalizations (IRR = 1.28, CI 95%: 1.02–1.61; p = 0.032). The association with these endpoints persisted after adjustment for other inflammatory biomarkers such as white blood cells, C-reactive protein and interleukins. Conclusion In patients with AHF and no evidence of infection, PCT was independently and positively associated with the risk of long-term death and recurrent rehospitalizations.

Acute glycometabolic derangement in non-diabetic patients with acute myocardial infarction (AMI) has been reported with discrepant prognostic results. The aim of the present study was to assess the prognostic impact of glycated haemoglobin (HbA1c) levels, reflecting long-term glycometabolic disturbance, in a population of patients without known diabetes mellitus.We examined 601 consecutive prospective patients diagnosed with AMI and unknown diabetes mellitus. We analysed metabolic function as a stratified variable using three groups of patients according to HbA1c: Group 1 (5.5%): 222 patients (37%); Group 2 (5.5 to 6.4%): 337 patients (56%); Group 3 (6.4%): 42 patients (7%). Association between HbA1c groups and classic cardiovascular risk factor and in-hospital outcomes were assessed through univariate and multivariate analysis.In-hospital mortality was 5% (32/601 patients). Higher HbA1c was associated with poor glycometabolic control, older patients, obesity, hypertension, Killip's class1, increased heart rate, initial bundle branch block, atrial fibrillation and higher mortality during follow-up. In a multivariate adjusted risk, in-hospital mortality was associated with age (odds ratio (OR)= 1.056; 1-1.1; p=0.006), Killip's class1 (OR=2.4; 1-6.1; p=0.05) and HbA1c (OR=1.5; 1.15-1.9; p=0.002). Hypertension (OR=0.39; 0.18-0.87; p=0.022) and angiotensin-converting enzyme inhibitors (OR=0.28; 0.12-0.69; p=0.005) were protective factors.HbA1c is an important risk marker in the absence of a history of diabetes mellitus in patients with AMI. The optimal management strategy in these patients may contribute to decreased in-hospital mortality.

The aim of this study was to evaluate the impact of glucose levels on admission and High Risk Ventricular Tachyarrhythmia (HRVT) in hospital mortality in patients with Acute Myocardial Infarction (AMI).We studied 1.258 consecutive patients admitted to the Coronary Care Unit with a diagnosis of AMI. Ventricular Fibrillation, sustained and nonsustained Ventricular Tachycardia were considered as HRVT. Association between admission glucose, in-hospital mortality and HRVT was assessed with Cox regression analysis.The overall incidence of in-hospital HRVT was 20% (254/1258 patients) and in-hospital mortality (115/1.258) was higher in patients with HRVT (20% vs 6%) (p0.001). Diabetes Mellitus (DM) was present in 441 patients (35%). Optimal threshold level of glycemia admission to predict ventricular arrhythmia was 180 mg/dl (AUC = 0.716; 0.66- 0.76)(p0.001). Patients with euglycemia on admission (120 mg/dL) had lowest prevalence of HRVT (13%)(OR=0.6;0.46-0.78) in contrast to non DM patients who presented glucose 180 mg/dL that exhibited 2-fold increase of in-hospital HRVT (36%; OR=2.2; 1.6-3)(p0.001). Multivariate risk adjusted hazard ratio (HR) analysis showed that, blood pressure100 mmHg (HR=2.4; 1.6-3.6)(p0.001), White Blood Count (WBC)10.000 cell count (HR=1.44;1.02-2)(p=0.04) and admission glycemia 180 mg/dL (HR=1.5; 1.04-2.3)( p=0.03) had a significantly increased risk in in-hospital HRTV only in NDM patients.The higher glycemia on admission the higher prevalence of life-threatening arrhythmia and mortality regardless diabetes status in patients presenting with AMI. Elevated initial glucose level and WBC count considered along with other clinical data can assist in life-threatening ventricular arrhythmia in non diabetic patients.

Background Low lymphocyte count (LLC), a surrogate for inflammation, has emerged as a potential risk factor for cardiovascular outcomes, especially new ischemic events. To identify patients with non-ST segment elevation acute coronary syndromes (NSTEACS) who benefit from an invasive revascularization strategy remains a challenge. We sought to determine if patients with high-risk NSTEACS who exhibited LLC have a greater reduction in long-term post-discharge myocardial infarction (MI) when managed under a revascularization invasive strategy (RIS) as compared with conservative strategy (CS). Methods Nine hundred seventy two consecutive patients with high-risk NSTEACS were treated under two revascularization strategies (RS): 1) CS, from January 2001 to October 2002 (345 patients; 35.5%) and 2) RIS, from November 2002 to May 2005 (627 patients; 64.5%). LLC was defined as lymphocytes count ≤ 1200 cells/ml (1 vs. 2–4 quartiles). The association between the type of RS and MI was stratified by lymphocyte count status and assessed by Cox regression adapted for competing events. Results At 3-year follow-up, 145 deaths (14.9%), 135 MI (13.9%) and 76 revascularization procedures (7.8%) were registered. In a multivariable setting, LLC patients exhibited a greater MI risk reduction when managed under RIS (HR: 0.40; 95% CI = 0.22–0.72, p = 0.003). Conversely, when LLC was not present, no difference in the rate of MI was detected between the two RS. Conclusions LLC identifies a subgroup of patients with greater reduction in the risk of postdischarge MI when a RIS is applied.

Although traditionally an elevated white blood cell count (WBC), an indicator of systemic inflammation, has been accepted as part of the healing response following acute myocardial infarction (AMI), it has frequently been shown to be a predictor of adverse cardiovascular events. The present study was designed to assess the association between WBC and long-term mortality in AMI patients either with ST-segment elevation (STEMI) or without ST-segment elevation (non-STEMI). Patients and method. The study included 1118 consecutive patients who were admitted with the diagnosis of AMI: 569 non-STEMI and 549 STEMI. The WBC was measured in the 24 hours following admission. Patients were divided into 3 groups: WBC1 (count,10 x 103 cells/mL), WBC2 (count, 10-14.9 x 10(3) cells/mL), and WBC3 (count,or =15x10(3) cells/mL). All-cause mortality was recorded during a median follow-up period of 10+/-2 months. The relationship between WBC and mortality was assessed by Cox regression analysis for both types of AMI.Long-term mortality during follow-up was 18.5% in non-STEMI patients and 19.9% in STEMI patients. In non-STEMI patients, the adjusted hazard ratios for those in the WBC3 and WBC2 groups compared with those in the WBC1 group were 2.07 (1.08-3.94; P=.027) and 1.61 (1.03-2.51; P=.036), respectively. The corresponding figures in STEMI patients were 2.07 (1.13-3.76; P=.017) and 2.22 (1.35-3.63; P=.002), respectively.WBC on admission was an independent predictor of long-term mortality in both non-STEMI and STEMI patients.

[EN] Introduction and objectives: Pharmacoinvasive strategy represents an attractive alternative to primary angioplasty. Using cardiovascular magnetic resonance imaging we compared the left ventricular outcome of the pharmacoinvasive strategy and primary angioplasty for the reperfusion of ST-segment elevation myocardial infarction. Methods: Cardiovascular magnetic resonance was performed 1 week and 6 months after infarction in two consecutive cohorts of patients included in a prospective university hospital ST-segment elevation myocardial infarction registry. During the period 2004-2006, 151 patients were treated with pharmacoinvasive strategy (thrombolysis followed by routine non-immediate angioplasty). During the period 2007-2008, 93 patients were treated with primary angioplasty. A propensity score matched population was also evaluated. Results: At 1-week cardiovascular magnetic resonance, pharmacoinvasive strategy and primary angioplasty patients showed a similar extent of area at risk (29 ± 15 vs. 29 ± 17%, P = .9). Non-significant differences were detected by cardiovascular magnetic resonance at 1 week and at 6 months in infarct size, salvaged myocardium, microvascular obstruction, ejection fraction, end-diastolic volume index and end-systolic volume index (P > .2 in all cases). The same trend was observed in 1-to-1 propensity score matched patients. The rate of major adverse cardiac events (death and/or re-infarction) at 1 year was 6% in pharmacoinvasive strategy and 7% in primary angioplasty patients (P = .7). Conclusions: A pharmacoinvasive strategy including thrombolysis and routine non-immediate angioplasty represents a widely available and logistically attractive approach that yields identical short-term and long-term cardiovascular magnetic resonance-derived left ventricular outcome compared to primary angioplasty. © 2010 Sociedad Española de Cardiología., The present study was supported by the "Instituto de Salud Carlos III'' (PI080128 and Heracles grants).