Low anti-SARS-CoV-2 S antibody levels predict increased mortality and dissemination of viral components in the blood of critical COVID-19 patients.

BACKGROUND: Anti-SARS-CoV-2 S antibodies prevent viral replication. Critically ill COVID-19 patients show viral material in plasma, associated with a dysregulated host response. If these antibodies influence survival and viral dissemination in ICU-COVID patients is unknown. PATIENTS/METHODS: We studied the impact of anti-SARS-CoV-2 S antibodies levels on survival, viral RNA-load in plasma, and N-antigenaemia in 92 COVID-19 patients over ICU admission. RESULTS: Frequency of N-antigenaemia was >2.5-fold higher in absence of antibodies. Antibodies correlated inversely with viral RNA-load in plasma, representing a protective factor against mortality (adjusted HR [CI 95%], p): (S IgM [AUC ≥ 60]: 0.44 [0.22; 0.88], 0.020); (S IgG [AUC ≥ 237]: 0.31 [0.16; 0.61], <0.001). Viral RNA-load in plasma and N-antigenaemia predicted increased mortality: (N1-viral load [≥2.156 copies/ml]: 2.25 [1.16; 4.36], 0.016); (N-antigenaemia: 2.45 [1.27; 4.69], 0.007). CONCLUSIONS: Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. Our findings support that these antibodies contribute to prevent systemic dissemination of SARS-CoV-2.

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.

BACKGROUND: COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. METHODS: A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. RESULTS: The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). CONCLUSIONS: SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

A Prognostic Enrichment Strategy for Selection of Patients With Acute Respiratory Distress Syndrome in Clinical Trials.

OBJECTIVES: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials. DESIGN: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated different thresholds for patient's age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age (< 50, 50-70, > 70 yr), PaO2/FIO2 (≤ 100, 101-150, > 150 mm Hg), plateau pressure (< 29, 29-30, > 30 cm H2O), and number of extrapulmonary organ failure (< 2, 2, > 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84-0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model. CONCLUSIONS: Combined thresholds for patient's age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials.

Synergistic impact of innate immunity hyper-activation and endothelial dysfunction on the magnitude of organ failure in the infection-sepsis continuum.

OBJECTIVES: identifying host response biomarkers implicated in the emergence of organ failure during infection is key to improving early detection of this complication. METHODS: twenty biomarkers of innate immunity, T-cell response, endothelial dysfunction, coagulation and immunosuppression were profiled in 180 surgical patients with infections of diverse severity (IDS) and 53 with no infection (nIDS). Those better differentiating IDS/nIDS in the area under the curve (AUC) were combined to test their association with the Sequential Organ Failure Assessment (SOFA) score by linear regression analysis in IDS. Results were validated in another IDS cohort of 174 patients. RESULTS: C-reactive protein, procalcitonin, pentraxin-3, lipocalin-2, TNF-α, angiopoietin-2, TREM-1 and IL-15 yielded AUCs ≥ 0.75 to differentiate IDS from nIDS. The combination of lipocalin-2, IL-15, TREM-1, angiopoietin-2 (Dys-4) showed the strongest association with SOFA in IDS (adjusted regression coefficient; standard error; p): Dys-4 (3.55;0.44; <0.001), Lipocalin-2 (2.24; 0.28; <0.001), angiopoietin-2 (1.92; 0.33; <0.001), IL-15 (1.78; 0.40; <0.001), TREM-1(1.74; 0.46; <0.001), TNF-α (1.60; 0.31; <0.001), pentraxin-3 (1.12; 0.18; <0.001), procalcitonin (0.85; 0.12; <0.001). Dys-4 provided similar results in the validation cohort. CONCLUSIONS: there is a synergistic impact of innate immunity hyper-activation (lipocalin-2, IL-15, TREM-1) and endothelial dysfunction (angiopoietin-2) on the magnitude of organ failure during infection.

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial.

PURPOSE: We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). METHODS: We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. RESULTS: Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference - 5.2%, 95% CI - 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. CONCLUSION: NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF.

[Variations in echocardiography after bariatric surgery. Biliopancreatic diversion vs vertical gastrectomy]. / Variaciones de la ecocardiografía tras la cirugía bariátrica. Derivación biliopancreática vs. gastrectomía vertical.

INTRODUCTION: Introduction: obesity has become a worldwide health problem due to its relationship with cardiovascular morbimortality, thus bariatric surgery is considered as one of the main solutions for the correction of excess weight and, consequently, the improvement of its associated heart diseases. Objective: to compare vertical gastrectomy (VG) and biliopancreatic diversion (BPD) by observing echocardiographic characteristics both before and after surgery, as well as to evaluate surgical outcome in terms of the BAROS scale. Methods: results were collected from the echocardiographic testing requested for the preoperative study of patients who underwent surgery over the course of 24 months (from January 2014 to December 2015), as well as their anthropometric data. These were compared with postoperative parameters measured at 3 years after surgery. Results: finally, 26 patients were selected (13 VG and 13 BPD) with a mean age of 42 yrs. VG: initial BMI: 44.6 ± 7.1; final BMI: 31.8 ± 11.3 (p < 0.01); BPD: initial BMI: 48.1 ± 14.2; final BMI: 32.7 ± 10.4 (p < 0.01). Echocardiography: normal systolic function: 100% vs 92%; normal diastolic function: 88.5% vs 69.2%; no valvulopathy: 80% vs 69%; normal left atrium: 76.9% vs 73.1% (p > 0.05); HTA: 38.5% vs 19.2% (p < 0.05), preoperatively and postoperatively, respectively. Conclusions: no significant differences were found between the two groups studied with different techniques, although a slight deterioration in diastolic function was found in both groups. The comorbidities associated with obesity improved in both groups, and the surgery was scored as positive. The scant variation revealed by echocardiography prompts to reconsider its systematic preoperative use in these patients given the low cost-benefit ratio.

INTRODUCCIÓN: Introducción: la obesidad se ha convertido en un problema de salud a nivel mundial por su relación con la morbimortalidad cardiovascular. La cirugía bariátrica se plantea como una de las soluciones para la corrección del exceso de peso y mejoría de las cardiopatías asociadas. Objetivo: comparar la gastrectomía vertical con la derivación biliopancreática de tipo Scopinaro para observar la repercusión de los cambios que se producen en la estructura cardiaca tras la cirugía. Además, evaluar el resultado quirúrgico en función de la escala BAROS. Material y métodos: se recogieron los resultados de la ecocardiografía incluida en el estudio preoperatorio de los pacientes candidatos a cirugía bariátrica de nuestro hospital, intervenidos en un periodo de 2 años, junto a los datos antropométricos y de comorbilidad. Estos se compararon con los resultados postoperatorios medidos a los 3 años de la cirugía. Resultados: finalmente se seleccionaron 26 pacientes (13 GV y 13 DBP), con una edad media de 42 años. GV: IMC inicial de 44,6 ± 7,1; IMC final de 31,8 ± 11,3 (p < 0,01). DBP: IMC inicial de 48,1 ± 14,2; IMC final de 32,7 ± 10,4 (p < 0,01). Ecocardiografía: función sistólica normal: 100% vs. 92%; función diastólica normal: 88,5% vs. 69,2%; sin valvulopatía: 80% vs. 69%; aurícula izquierda normal: 76,9% vs. 73,1% (p > 0,05); HTA: 38% vs. 19% (p < 0,05), en el preoperatorio y postoperatorio, respectivamente. Conclusiones: no se encontraron diferencias significativas entre los dos grupos estudiados con técnicas diferentes, si bien pudo encontrarse un ligero deterioro de la función diastólica en ambos grupos. Las comorbilidades asociadas a la obesidad mejoraron en ambos grupos y el grado de evaluación de la cirugía fue positivo. La escasa variación de la ecocardiografía hace replantearse su uso sistemático en el preoperatorio de estos pacientes por el bajo índice coste-beneficio.

Author Correction: Combined quantification of procalcitonin and HLA-DR improves sepsis detection in surgical patients.

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Combined quantification of procalcitonin and HLA-DR improves sepsis detection in surgical patients.

Early recognition of sepsis is a key factor to improve survival to this disease in surgical patients, since it allows prompt control of the infectious source. Combining pro-inflammatory and immunosupression biomarkers could represent a good strategy to improve sepsis detection. Here we evaluated the combination of procalcitonin (PCT) with gene expression levels of HLA-DRA to detect sepsis in a cohort of 154 surgical patients (101 with sepsis and 53 with no infection). HLA-DRA expression was quantified using droplet digital PCR, a next-generation PCR technology. Area under the receiver operating curve analysis (AUROC) showed that the PCT/HLA-DRA ratio outperformed PCT to detect sepsis (AUROC [CI95%], p): PCT: 0.80 [0.73-0.88], <0.001; PCT/HLA-DRA: 0.85 [0.78-0.91], <0.001. In the multivariate analysis, the ratio showed a superior ability to predict sepsis compared to that of PCT (OR [CI 95%], p): PCT/HLA-DRA: 7.66 [1.82-32.29], 0.006; PCT: 4.21 [1.15-15.43] 0.030. Multivariate analysis was confirmed using a new surgical cohort with 74 sepsis patients and 21 controls: PCT/HLA-DRA: 34.86 [1.22-995.08], 0.038; PCT: 5.52 [0.40-75.78], 0.201. In conclusion, the combination of PCT with HLA-DRA is a promising strategy for improving sepsis detection in surgical patients.