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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.

BackgroundLittle is known about the comparative kinetics of SARS-CoV-RNA load in the lower respiratory tract and in blood compartment in patients admitted to the intensive care unit, and how these relate to biomarkers of COVID-19 severity.MethodsSeventy-three consecutive critically ill COVID-19 patients (median age, 65 years) were recruited. Serial lower respiratory tract (n=165) and plasma (n=340) specimens were collected. RT-PCR and lateral flow immunochromatography assay were used for SARS-CoV-2 RNA quantitation and N protein detection in plasma, respectively. Serum levels of inflammatory and tissue-damage biomarkers in paired specimens were analyzed.ResultsSARS-CoV-RNA was detected in the lower respiratory tract of most patients (92%). Viral RNAemia and N-antigenemia were documented in 35.6% and 40.1% of patients, respectively. Viral RNAemia and N-antigenemia cleared at a faster rate than SARS-CoV-2 RNA in tracheal aspirates (TA). SARS-CoV-2 RNA load was higher (PPP≤0.008) in paired serum specimens. Neither the dynamics of SARS-CoV-2 RNA load in TA and plasma, nor N-antigenemia detection rate differed between surviving and deceased patients. Yet, a trend towards a higher mortality was seen in patients with viral RNAemia (OR; 2.82; 95% CI, 0.94-8.47; P=0.06).ConclusionNeither SARS-CoV-2 replication rate in the lower respiratory tract nor its presence in the blood appeared to critically impact on survival in ICU COVID-19 patients.SUMMARYSARS-CoV-2 RNA load in the lower respiratory tract and plasma and N-antigenemia followed different kinetics, correlated modestly with serum levels of inflammatory and tissue-damage biomarkers and lymphopenia and did not appear to increase overall mortality risk in critically ill adult COVID-19 patients.

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 limited information on SARS-CoV-2 T-cell immune responses in patients with Covid-19. Both CD4+ and CD8+ T cells may be instrumental in the resolution of and protection from SARS-CoV-2 infection. Here, we tested 25 hospitalized patients with either microbiologically documented Covid-19 (n=19) or highly suspected of having the disease (n=6) for the presence of SARS-CoV-2-reactive- CD69+-expressing interferon-gamma;-producing-(IFN-gamma;) CD8+ T cells by a flow-cytometry for intracelular cytokine staining assay. Two sets of overlapping peptides encompassing the SARS-CoV-2 Spike glycoprotein N-terminal 1-643 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/microlitre; range, 0.43-9.98 cells/microlitre). The detection rate of SARS-CoV-2-reactive IFN-gamma; CD8+ T cells in patients admitted to intensive care was comparable (P=0.28) to that in patients hospitalized in other medical wards. No correlation was found between SARS-CoV-2-reactive IFN-gamma; CD8+ T-cell counts and SARS-CoV-2 S-specific antibody levels. Likewise, no correlation was observed between either SARS-CoV-2-reactive IFN-gamma; CD8+ T cells or S-specific IgG-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-gamma; 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.

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.

This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies.

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.

Introduccion y objetivos. Publicaciones recientes respaldan el papel pronostico del recuento leucocitario (RL) en pacientes con infarto agudo de miocardio (IAM). El objetivo de este trabajo fue determinar el valor predictivo atribuible al RL, con independencia de otras variables de contrastado valor pronostico, para predecir mortalidad a largo plazo en pacientes con IAM sin elevacion del segmento ST (IAMSEST) y con elevacion del segmento ST (IAMEST). Pacientes y metodo. Analizamos a 1.118 pacientes admitidos de forma consecutiva con el diagnostico de IAM (IAMSEST = 569; IAMEST = 549). El RL se obtuvo en la primera determinacion analitica. Se utilizaron modelos de regresion de Cox para determinar el grado de asociacion entre el RL y la mortalidad total para ambos tipos de IAM. La mediana de seguimiento fue de 10 ± 2 meses. El RL se incluyo en ambos modelos categorizado en los siguientes puntos de corte (x 10³ celulas/ml): < 10 (RL1); 10-14,9 (RL2) y = 15 (RL3). Resultados. Durante el seguimiento se registraron 105 muertes (18,5%) en pacientes con IAMSEST y 109 (19,9%) con IAMEST. Las hazard ratio ajustadas para las categorias RL2 y RL3 frente a RL1 en el grupo con IAMSEST fueron: 1,61 (1,03-2,51; p = 0,036) y 2,07 (1,08-3,94; p = 0,027), y en el IAMEST: 2,22 (1,35-3,63; p = 0,002) y 2,07 (1,13-3,76; p = 0,017), respectivamente. Conclusiones. El RL determinado en las primeras horas de un IAM demostro ser un predictor independiente de otras variables de contrastado valor pronostico para predecir la mortalidad total a largo plazo en el IAMSEST y el IAMEST.

Introduccion y objetivos.El indice de Charlson (iCh) ha sido utilizado como variable de ajuste en modelos multivariables como indicador de comorbilidad. Debido a que su valor pronostico per se para complicaciones cardiovasculares tras un infarto agudo de miocardio no ha sido ampliamente evaluado, nos propusimos determinar su valor predictivo para muerte de cualquier causa y/o reinfarto, a 30 dias y 1 ano del evento indice. Pacientes y metodo. Se incluyo a 1.035 pacientes con el diagnostico de infarto (508 con elevacion del segmento ST y 527 sin elevacion del segmento ST). La presencia de eventos se determino a 30 dias (13,9%) y a un ano (26,3%). El iCh se calculo junto con otras variables de valor pronostico en el momento del ingreso, y se establecieron 4 grupos: 1, iCh = 0 (control); 2, iCh = 1; 3, iCh = 2, y 4, iCh ≥ 3. Para el analisis multivariable se utilizo la regresion de riesgos proporcionales de Cox; su poder discriminativo se evaluo mediante el indice C. Resultados. Los riesgos relativos (RR) y el intervalo de confianza [IC] del 95% para las categorias del iCh fueron: a los 30 dias, para la categoria 2, RR = 1,69; IC del 95%, 1,10-2,59; para la 3, RR = 1,78; IC del 95%,1,08-2,92, y para la 4, RR = 1,57; IC del 95%, 0,87-2,83; los valores a 1 ano fueron, para la categoria 2, RR = 1,62; IC del 95%, 1,18-2,23; para la 3, RR = 2,00; IC del 95%, 1,39-2,89, y para la 4, RR = 2,24; IC del 95%, 1,50-3,36. La diferencia en el indice C del modelo con y sin la variable iCh fue 0,765 y 0,750 a los 30 dias y 0,751 y 0,735 a 1 ano. Conclusiones. El iCh proporciono informacion pronostica independiente para muerte y/o reinfarto a los 30 dias y a 1 ano tras el infarto indice. Palabras clave: Infarto agudo de miocardio. Comorbilidad. Indice de Charlson.

Objectives. The relative value of classic markers, myocardial damage variables, and levels of acute-phase reactants in establishing the pre-discharge prognosis of acute coronary syndrome without ST-segment elevation was analyzed. Method. We prospectively studied 385 consecutive patients admitted from our chest pain unit with a highprobability diagnosis of acute coronary syndrome without ST-segment elevation. The clinical and electrocardiographic data, myocardial damage markers (troponin I, CK-Mb mass, myoglobin), and acute-phase reactants (high-sensitivity C-reactive protein, fibrinogen) were recorded. Results. During admission, 15 deaths (3.9%) and 16 complicative infarctions (4.2%) occurred, for a total of 31 major events (death and/or infarction: 8.1%). Age (p = 0.03), insulin-dependent diabetes (p = 0.009), and C-reactive protein (p = 0.05) were independently related to death. Fibrinogen was related to infarction (p = 0.01); by fibrinogen quartiles: 1.4%; 1.4%; 2.9%, and 11.7% (p = 0.02). Age (p = 0.01), insulin-dependent diabetes (p = 0.02), and C-reactive protein (p = 0.04) were independent predictors of major events; by C-reactive protein quartiles: 1.4%; 5.5%; 5.4%, and 16.7% (p = 0.004). Troponin I was related to major events (p = 0.03), but it was not an independent predictor. Conclusions. Acute-phase reactants add independent information to clinical variables in the short-term risk stratification of patients with an acute coronary syndrome. The predictive power of troponins is lower than that of

Background: Brain natriuretic peptide (BNP) is elevated in patients with end-stage renal disease and could reflect left ventricular dysfunction. Aim: To evaluate the plasma levels of BNP in two groups of asymptomatic patients on different dialysis programs and to correlate their variations with echocardiographic parameters. Methods: Group A consisted of 36 patients on chronic hemodialysis (HD), and group B included 38 patients on continuous ambulatory peritoneal dialysis (CAPD). ECG and echocardiography were performed, and concomitantly plasma BNP levels were determined before and after a regular 4-hour session in HD patients and before performing a dialysate exchange in patients on CAPD. Results: BNP values in group A were found to be higher than in group B (419 ± 76 vs. 193 ± 56 pg/ml; p < 0.03). The cutoff point which discriminated both groups was 194 pg/ml (sensitivity: 64% and specificity: 76%; p = 0.001). Significant differences were found with respect to the following echocardiographic data (group A vs. group B): left atrial (LA) size (40 ± 13 vs. 34 ± 1 mm), LA volume (59 ± 16 vs. 41 ± 32 ml), transmitral flow E/A (1.17 ± 0.01 vs. 0.9 ± 0.06), the movement of the mitral valve annulus e/a (tissue Doppler imaging; 1.19 ± 0.15 vs. 1.05 ± 0.13) and left ventricular mass index (133 ± 10 vs. 108 ± 11). Conclusion: Patients on CAPD had lower levels of BNP, and echocardiographic findings indicated decreased volume overload. In asymptomatic patients, marked increases in BNP levels may reflect early stages of pathological processes that precede the development of apparent cardiac manifestations (left ventricular hypertrophy). Only echocardiographic parameters of cardiac dysfunction should be used as diagnostic criteria.

[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).