Fulminant myocarditis following SARS-CoV-2 mRNA vaccination rescued with venoarterial ECMO: A report of two cases

Objectives: Cases of fulminant myocarditis after mRNA COVID-19 vaccination have been reported. The most severe may need venoarterial extracorporeal membrane oxygenation (V-A ECMO) support. Here we report two cases successfully rescued with V-A ECMO. Method(s): We included all the cases supported with V-A ECMO for refractory cardiogenic shock due to myocarditis secondary to a mRNA SARS-COV2 vaccine in the high-volume adult ECMO Program in Vall Hebron University Hospital since January 2020. Result(s): We identified two cases (table). One of them was admitted for out-of-hospital cardiac arrest. In both, a peripheral V-A ECMO was implanted in the cath lab. An intra-aortic balloon pump was needed in one case for left ventricle unloading. Support could be successfully withdrawn in a mean of five days. No major bleeding or thrombosis complications occurred. Definite microscopic diagnosis could be reached in one case (Image, 3). Treatment was the same, using 1000mg of methylprednisolone/day for 3 days. A cardiac magnetic resonance 10 days after admission showed a significant improvement in systolic function and diffuse oedema and subepicardial contrast intake in different segments (Image, 1-2). Both patients were discharged fully recovered. Conclusion(s): V-A ECMO should be established in cases of COVID-19 vaccine-associated myocarditis with refractory cardiogenic shock during the acute phase. (Table Presented).

Proteomic determinants of disease, mortality and sequelae in COVID-19 patients requiring invasive mechanical ventilation

Introduction: The molecular mechanisms linked to the pathology of severe COVID-19 and its outcomes are poorly described. Aim(s): To analyze the proteomic profile of bronchial aspirates (BAS) samples from critically ill COVID-19 patients in order to identify factors associated with the disease and its prognosis. Method(s): Multicenter study including 74 critically ill non-COVID-19 and COVID-19 patients. BAS was obtained by bronchoaspiration after invasive mechanical ventilation (IMV) initiation. Proximity extension assay (PEA) technology was used for proteomic profiling. Random forest (RF) statistical models were used to predict the variable importance. Result(s): After adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-alpha showed differences between COVID-19 and non-COVID-19 patients. Reduced levels of ENTPD2 and PTN were observed in non-survivors, even after adjustment. AGR2, NQO2, IL-1alpha, OSM and TRAIL, were the top five strongest predictors for ICU mortality and were used to build a prediction model. PTN (HR=4.00) ENTPD2 (HR=2.14) and the prediction model (HR=6.25) were associated with higher risk of death. In survivors, FCRL1, NTF4 and THOP1 correlated with lung function (DLCO levels) 3-months after hospital discharge. Similar findings were observed for Flt3L and THOP1 and radiological features (TSS). The proteins identified are expressed in immune and non-immune lung cells. A poor control of viral infectivity and an inappropriate reparative response seems to be linked to the disease and fatal outcomes, respectively. Conclusion(s): In critically ill COVID-19 patients, specific proteomic profiles are associated with the pathology, mortality and lung sequelae.

Proteomic profiling of severe lung diffusion impairment in the recovery stage of COVID-19-induced ARDS

Background: Around 80% of patients who developed COVID-19-driven ARDS present lung ailment. There is a lack of knowledge of the mechanisms that mediate the pulmonary outcomes. Aim(s): To characterize the factors linked to diffusion impairment in survivors of severe COVID-19. Method(s): Prospective cohort study including 87 COVID-19-induced ARDS survivors. A complete pulmonary evaluation was performed 3 months after hospital discharge. 364 proteins were quantified using the proximity extension assay (PEA). Partial least square-discriminant analysis (PLS-DA) and random forest (RF) were used for multivariable analyses. Result(s): Moderate to severe diffusion impairment (DLCO<60% predicted) was observed in the 30% of the cohort. 15 proteins were differentially detected [false discovery rate (FDR)<0.05] in the univariate analysis. Pleiotrophin showed the highest differences (fold change=2.22 and FDR=0.001). In continuous analysis, proteins were inversely and independently associated with DLCO, and in some cases showed a robust dose-response relationship. PLS-DA and RF identified proteomic profiles related to the severity of diffusion capacity. Clusters identified were enriched in mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis. Proteins are expressed in immune and non-immune lung cells. Conclusion(s): In survivors of COVID-19-driven ARDS, lung dysfunction is linked to plasma factors involved in injury and repair mechanisms. The host proteomic profile provides a novel understanding of post-acute sequelae and may be source of therapeutic strategies and biomarkers.

Risk factors associated with mortality among elderly patients with COVID-19: Data from 55 intensive care units in Spain.

INTRODUCTION AND OBJECTIVES: Critically-ill elderly ICU patients with COVID-19 have poor outcomes. We aimed to compare the rates of in-hospital mortality between non-elderly and elderly critically-ill COVID-19 ventilated patients, as well as to analyze the characteristics, secondary outcomes and independent risk factors associated with in-hospital mortality of elderly ventilated patients. PATIENTS AND METHODS: We conducted a multicentre, observational cohort study including consecutive critically-ill patients admitted to 55 Spanish ICUs due to severe COVID-19 requiring mechanical ventilation (non-invasive respiratory support [NIRS; include non-invasive mechanical ventilation and high-flow nasal cannula] and invasive mechanical ventilation [IMV]) between February 2020 and October 2021. RESULTS: Out of 5,090 critically-ill ventilated patients, 1,525 (27%) were aged ≥70 years (554 [36%] received NIRS and 971 [64%] received IMV. In the elderly group, median age was 74 years (interquartile range 72-77) and 68% were male. Overall in-hospital mortality was 31% (23% in patients <70 years and 50% in those ≥70 years; p<0.001). In-hospital mortality in the group ≥70 years significantly varied according to the modality of ventilation (40% in NIRS vs. 55% in IMV group; p<0.001). Factors independently associated with in-hospital mortality in elderly ventilated patients were age (sHR 1.07 [95%CI 1.05-1.10], p<0.001); previous admission within the last 30 days (sHR 1.40 [95%CI 1.04-1.89], p = 0.027); chronic heart disease (sHR 1.21 [95%CI 1.01-1.44], p = 0.041); chronic renal failure (sHR 1.43 [95%CI 1.12- 1.82], p = 0.005); platelet count (sHR 0.98 [95% CI 0.98-0.99], p<0.001); IMV at ICU admission (sHR 1.41 [95% CI 1.16- 1.73], p<0.001); and systemic steroids (sHR 0.61 [95%CI 0.48- 0.77], p<0.001). CONCLUSIONS: Amongst critically-ill COVID-19 ventilated patients, those aged ≥70 years presented significantly higher rates of in-hospital mortality than younger patients. Increasing age, previous admission within the last 30 days, chronic heart disease, chronic renal failure, platelet count, IMV at ICU admission and systemic steroids (protective) all comprised independent factors for in-hospital mortality in elderly patients.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients.

OBJECTIVE: To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. DESIGN: A secondary analysis derived from multicenter, observational study. SETTING: Critical Care Units. PATIENTS: Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. INTERVENTIONS: Corticosteroids vs. no corticosteroids. MAIN VARIABLES OF INTEREST: Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. RESULTS: A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0; 95% CI: 0.98-1.15). Corticosteroids were administered in 298/537 (55.5%) patients of "A" phenotype and their use was not associated with ICU mortality (HR=0.85 [0.55-1.33]). A total of 338/623 (54.2%) patients in "B" phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49-1.05]). Finally, 535/857 (62.4%) patients in "C" phenotype received corticosteroids. In this phenotype HR (0.75 [0.58-0.98]) and sHR (0.79 [0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. CONCLUSION: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients Una consideración terapéutica diferencial para el uso de corticoesteroides en COVID-19 según los diferentes fenotipos clínicos establecidos en pacientes críticos

Objective To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. Design A secondary analysis derived from multicenter, observational study. Setting Critical Care Units. Patients Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. Interventions Corticosteroids vs. no corticosteroids. Main variables of interest Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. Results A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0;95% CI: 0.98–1.15). Corticosteroids were administered in 298/537 (55.5%) patients of “A” phenotype and their use was not associated with ICU mortality (HR = 0.85 [0.55–1.33]). A total of 338/623 (54.2%) patients in “B” phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49–1.05]). Finally, 535/857 (62.4%) patients in “C” phenotype received corticosteroids. In this phenotype HR (0.75 [0.58–0.98]) and sHR (0.79 [0.63–0.98]) suggest a protective effect of corticosteroids on ICU mortality. Conclusion Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

Evaluating the Endothelial Impairments in COVID-19 Patients Using Near-Infrared Spectroscopy: the HEMOCOVID-19 trial

HEMOCOVID-19 is a multi-center trial aiming to assess the microvascular and endothelial health of severe COVID-19 patients in the intensive care using near-infrared spectroscopy. Here, we present the preliminary results, showing that peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome. © 2022 The Author(s).

Mortality and Bleeding Complications of COVID-19 Critically Ill Patients with Venous Thrombo-Embolism

Introduction: Venous thrombo-embolism (VTE) disease in critically ill COVID-19 patients is a remarkable issue, especially its relationship with bleeding events and mortality. The objective of this study was to describe the outcomes of critically ill patients with COVID-19 hospitalised in the intensive care unit (ICU) in relationship with VTE during their stay. The secondary objective was to describe prognostic factors in relation with these outcomes. Methods: This was a prospective cohort study of critically ill COVID-19 patients in two Spanish university hospitals that underwent, at the beginning of the study, venous ultrasound of both lower limbs in April 2020. When there was clinical suspicion of new VTE during the 30 day follow up, additional ultrasound or thoracic computed tomography were performed. Global VTE frequency, major bleeding events, and survival were collected, and their predictors were studied. Results: In total, 230 patients were included. Mean age was 60.1 ± 9.9 years and 77% of them were men. After 30 days of follow up, there were 95 VTE events in 86 patients (37.4%). Of these, 60 patients (69.8%) presented with deep vein thrombosis (DVT), 17 patients with pulmonary embolism (PE;19.8%), and nine patients with DVT and PE (10.5%). VTE was related to a longer hospital stay: 50.3 days in VTE patients and 47.2 days in non-VTE patients (p =.014). D-dimer at admission was significantly related to VTE development (p =.007). Major bleeding complications were found in 13 patients (5.7%). None of the demographic variables, treatments, or classic risk factors were related to a higher risk of major bleeding. During the 30 day follow up, 42 patients (18.3%) died. Variables related to mortality were older age (67.4 vs. 58.4 years;p <.001), lower weight (77.9 vs. 87.5 kg;p <.001), lower body mass index (28.2 vs. 30,8 kg/m2;p =.006), hypertension (43.1% vs. 69% of patients;p =.002), lymphocyte count at admission < 0.45 ×109/L (p =.003) and D-dimer at admission > 1 500 ng/mL (p =.014). Patients with VTE at any moment during the follow up tended to die more frequently (50%) than non-VTE patients (34.6%), but this difference was not statistically significant (p =.062). Independent predictors of mortality in the regression model were older age (> 66 years), D-dimer at admission (> 1 500 ng/mL), and low lymphocyte count (< 0.45 ×109/L) with an area under the receiver operating curve of 0.81 (95% confidence interval 0.73 – 0.89). Patients presenting these three conditions presented a mortality of a 100% in the predictive model. Conclusion: VTE frequency in ICU COVID-19 patients is high and the risk of major bleeding is low. Comorbidities and laboratory parameters of admission in these patients can be a useful tool to predict mortality.

Transforming a public university hospital and its area of influence into a comprehensive resource in response to the COVID-19 pandemic.

INTRODUCTION AND OBJECTIVES: The outbreak of COVID-19 has overwhelmed healthcare systems all over the world. The aim of this article is to describe the process of transforming the Vall d'Hebron University Hospital, the second largest hospital in Spain, into a COVID-19 centre coordinating response to the pandemic in its reference area. MATERIALS AND METHODS: The study draws on the experience of the authors in transforming the hospital into a comprehensive resource in response to the COVID-19 pandemic. The strategy is based on four central strategies: early planning, coordination of all healthcare agents in its reference area, definition of clear leadership roles, and the organisation of care based on multidisciplinary teams with minimal recruitment of new staff. RESULTS: The transformation strategy enabled the hospital to cope with the surge in patients without exceeding its capacity. During the response phases, which amounted to a period of 57 days, 3106 patients consulted the ER and 2054 were admitted, 346 of whom were treated at the ICU. To accommodate the number of adult COVID-19 patients, adult ICU availability was progressive increased by 371%, and ordinary beds increased by 240. A total of 671 staff members went on sick leave after testing positive for COVID-19. CONCLUSION: The transformation experience of the hospital provides insight into how effectively adapt the structures and functioning of large hospitals. The relevance of territorial coordination during the pandemic is stressed as an effective strategy that contributed coping the pandemic.

Design and Immunogenicity of a Pan-SARS-CoV-2 Synthetic DNA Vaccine

Background. First-generation COVID-19 vaccines are matched to spike protein of the Wuhan-H1 (WT) strain. Convalescent and vaccinee samples show reduced neutralization of SARS-CoV-2 variants of concern (VOC). Next generation DNA vaccines could be matched to single variants or synthetically designed for broader coverage of multiple VOCs. Methods. The synthetic consensus (SynCon®) sequence for INO-4802 SARSCoV-2 spike with focused RBD changes and dual proline mutations was codon-optimized (Figure 1). Sequences for wild-type (pWT) and B.1.351 (pB.1.351) were similarly optimized. Immunogenicity was evaluated in BALB/c mice. Pre-clinical efficacy was assessed in the Syrian Hamster model. Figure 1. Design Strategy for INO-4802 Results. INO-4802 induced potent neutralizing antibody responses against WT, B.1.1.7, P.1, and B.1.351 VOC in a murine model. pWT vaccinated animals showed a 3-fold reduction in mean neutralizing ID50 for the B.1.351 pseudotyped virus. INO-4802 immunized animals had significantly higher (p = 0.0408) neutralizing capacity (mean ID50 816.16). ID50 of pB.1.351 serum was reduced 7-fold for B.1.1.7 and significantly lower (p = 0.0068) than INO-4802 (317.44). INO-4802 neutralized WT (548.28) comparable to pWT. INO-4802 also neutralized P.1 (1026.6) (Figure 2). pWT, pB.1.351 or INO-4802 induced similar T-cell responses against all variants. INO-4802 skewed towards a TH1-response. All hamsters vaccinated with INO-4802 or pB.1.351 were protected from weight loss after B.1.351 live virus challenge. 4/6 pWT immunized hamsters were completely protected. pWT immunized hamsters neutralized WT (1090) but not B.1.351 (39.16). INO-4802 neutralized both WT (672.2) and B.1.351 (1121) (Figure 3). We observed higher increase of binding titers following heterologous boost with INO-4802 (3.6 - 4.4 log2-fold change) than homologous boost with pWT (2.0 - 2.4 log2 fold change) (Figure 4). Conclusion. Vaccines matching single VOCs, like pB.1.351 and pWT, elicit responses against the matched antigen but have reduced cross-reactivity. Presenting a pan-SARS-CoV-2 approach, INO-4802 may offer substantial advantages in terms of cross-strain protection, reduced susceptibility to escape mutants and non-restricted geographical use.

HEMOCOVID-19 Study: An International Clinical Study to Evaluate Microvascular and Endothelial Impairments in Severe COVID-19 Patients Using Near-Infrared Spectroscopy

We present the HEMOCOVID-19 study spanning four countries and eight hospitals where near-infrared spectroscopy is utilized to evaluate microvascular and endothelial health of severe COVID-19 patients at the intensive care. © 2021 SPIE. All rights reserved.

Circulating micrornas as biomarkers of COVID-19 severity

RATIONALE: The identification of minimally invasive and easily-accessible biomarkers to support the management of coronavirus disease 2019 (COVID-19) in hospitalized patients constitutes a hot topic in clinical research. MicroRNAs (miRNAs) have been proposed as clinical indicators to assist in medical decision-making. Here, we aimed to examine the circulating miRNA profile of hospitalized COVID-19 patients and to evaluate its potential as a source of biomarkers for the management of the disease. METHODS: Observational, prospective and multicenter study which included 84 patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, recruited during the first pandemic wave in Spain (March-May 2020). Patients were stratified according to disease severity: hospitalized patients admitted to the clinical wards without requiring critical care (n = 47) and hospitalized patients admitted to the ICU (n = 37). An additional study considering ICU non-survivors (n=17) and survivors (n = 20) was performed. Expression profiling of 41 miRNAs was performed in plasma samples using RT-qPCR. The panel included miRNAs associated with: i) immune/inflammatory response;ii) lung damage;iii) respiratory viral infections;iv) myocardial damage;v) coagulation. Quality control was performed using spike-ins and hemolysis tests. Predictive models were constructed using a variable selection process based on LASSO regression. RESULTS: Ten circulating miRNAs were deregulated in ICU compared to ward patients. LASSO analysis identified a signature of three miRNAs that displayed an optimal discrimination ability to distinguish between ICU and ward patients (AUC = 0.88) (Figure 1A). Among ICU patients, six miRNAs were downregulated when comparing nonsurvivors to survivors. A signature based on two miRNAs was found to be a relevant predictor of mortality during ICU stay (AUC = 0.84) (Figure 1B). The discrimination potential of the miRNA signature was higher than the observed for clinical laboratory parameters such as leukocyte counts (including neutrophil count, lymphocyte count and the neutrophil-tolymphocyte ratio), CRP or D-dimer (maximum AUC for these variables = 0.76). CONCLUSIONS: The severity of COVID-19 impacts on the circulating miRNA profile. The results suggest the potential usefulness of the circulating miRNA signature for the management of the disease over contemporaneous tests, at least in ICU patients.