Biomedicines

Editorial

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4 pages, 194 KiB

Open AccessEditorial

COVID-19 and Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications

by Pasquale Ambrosino, Anna Lanzillo and Mauro Maniscalco

Biomedicines 2022, 10(1), 47; https://doi.org/10.3390/biomedicines10010047 - 27 Dec 2021

Cited by 7 | Viewed by 2872

Abstract

In late 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gave rise to a public health emergency, culminating in the declaration of a pandemic in March 2020 [...] Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

Research

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12 pages, 1275 KiB

Open AccessArticle

Enoxaparin and Pentosan Polysulfate Bind to the SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Inhibiting Vero Cell Infection

by Maria Ennemoser, Julia Rieger, Eva Muttenthaler, Tanja Gerlza, Kurt Zatloukal and Andreas J. Kungl

Biomedicines 2022, 10(1), 49; https://doi.org/10.3390/biomedicines10010049 - 27 Dec 2021

Cited by 15 | Viewed by 3114

Abstract

As with many other pathogens, SARS-CoV-2 cell infection is strongly dependent on the interaction of the virus-surface Spike protein with the glycosaminoglycans of target cells. The SARS-CoV-2 Spike glycoprotein was previously shown to interact with cell-surface-exposed heparan sulfate and heparin in vitro. With [...] Read more.

As with many other pathogens, SARS-CoV-2 cell infection is strongly dependent on the interaction of the virus-surface Spike protein with the glycosaminoglycans of target cells. The SARS-CoV-2 Spike glycoprotein was previously shown to interact with cell-surface-exposed heparan sulfate and heparin in vitro. With the aim of using Enoxaparin as a treatment for COVID-19 patients and as prophylaxis to prevent interpersonal viral transmission, we investigated GAG binding to the Spike full-length protein, as well as to its receptor binding domain (RBD) in solution by isothermal fluorescence titration. We found that Enoxaparin bound to both protein variants with similar affinities, compared to the natural GAG ligand heparan sulfate (with Kd-values in the range of 600–680 nM). Using size-defined Enoxaparin fragments, we discovered the optimum binding for dp6 or dp8 for the full-length Spike protein, whereas the RBD did not exhibit a significant chain-length-dependent affinity for heparin oligosaccharides. The soluble ACE2 receptor was found to interact with unfractionated GAGs in the low µM Kd range, but with size-defined heparins with clearly sub-µM Kd-values. Interestingly, the structural heparin analogue, pentosan polysulfate (PPS), exhibited high binding affinities to both Spike variants as well as to the ACE2 receptor. In viral infection experiments, Enoxaparin and PPS both showed a strong inhibition of infection in a concentration range of 50–500 µg/mL. Both compounds were found to retain their inhibitory effects at 500 µg/mL in a natural biomatrix-like human sputum. Our data suggest the early topical treatment of SARS-CoV-2 infections with inhaled Enoxaparin; some clinical studies in this direction are already ongoing, and they further imply an oral or nasal prophylactic inactivation of the virus by Enoxaparin or PPS for the prevention of inter-personal viral transmission. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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7 pages, 606 KiB

Open AccessArticle

Plasma Leptin Is Increased in Intensive Care Patients with COVID-19—An Investigation Performed in the PronMed-Cohort

by Anders Larsson, Miklós Lipcsey, Michael Hultström, Robert Frithiof and Mats Eriksson

Biomedicines 2022, 10(1), 4; https://doi.org/10.3390/biomedicines10010004 - 21 Dec 2021

Cited by 21 | Viewed by 3358

Abstract

COVID-19 has shaken the world and intensive care units (ICU) have been challenged by numerous patients suffering from a previously unknown disease. Leptin is a polypeptide pleiotropic hormone, mainly expressed by adipocytes. It acts as a proinflammatory cytokine and is associated with several [...] Read more.

COVID-19 has shaken the world and intensive care units (ICU) have been challenged by numerous patients suffering from a previously unknown disease. Leptin is a polypeptide pleiotropic hormone, mainly expressed by adipocytes. It acts as a proinflammatory cytokine and is associated with several conditions, known to increase the risk of severe COVID-19. Very little is known about leptin in severe viral disorders. Plasma leptin was analyzed in 222 out of 229 patients with severe COVID-19 on admission to an ICU at Uppsala University Hospital, a tertiary care hospital in Sweden, and compared to plasma leptin in 25 healthy blood donors. COVID-19 was confirmed by positive PCR. Leptin levels were significantly higher in patients with COVID-19 (18.3 ng × mL⁻¹; IQR = 30.4), than in healthy controls (7.8 ng × mL⁻¹; IQR = 6.4). Women had significantly higher leptin values (22.9 ng × mL⁻¹; IQR = 29.8) than men (17.5 ng × mL⁻¹; IQR = 29.9). Mortality at 30 days was 23% but was not associated with increased leptin levels. Neither median duration of COVID-19 before admission to ICU (10 days; IQR = 4) or median length of ICU stay (8 days; IQR = 11) correlated with the plasma leptin levels. Leptin levels in COVID-19 were higher in females than in males. Both treatment (e.g., use of corticosteroids) and prophylaxis (vaccines) have been improved since the start of the COVID-19 pandemic, which may contribute to some difficulties in deciphering relations between COVID-19 and leptin. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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16 pages, 1449 KiB

Open AccessEditor’s ChoiceArticle

Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β

by Chiara Colarusso, Angelantonio Maglio, Michela Terlizzi, Carolina Vitale, Antonio Molino, Aldo Pinto, Alessandro Vatrella and Rosalinda Sorrentino

Biomedicines 2021, 9(12), 1931; https://doi.org/10.3390/biomedicines9121931 - 17 Dec 2021

Cited by 49 | Viewed by 4116

Abstract

Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to [...] Read more.

Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 1582 KiB

Open AccessArticle

The Most Relevant Factors Affecting the Perioperative Death Rate in Patients with Acute Coronary Syndrome and COVID-19, Based on Annual Follow-Up in the ORPKI Registry

by Karol Kaziród-Wolski, Janusz Sielski, Jacek Sidło, Rafał Januszek and Zbigniew Siudak

Biomedicines 2021, 9(12), 1813; https://doi.org/10.3390/biomedicines9121813 - 2 Dec 2021

Cited by 9 | Viewed by 2183

Abstract

Background: The COVID-19 pandemic is significantly affecting the functioning of the entire healthcare system. The disease itself may be associated with thromboembolic complications. The purpose of this study is to compare patients with acute coronary syndrome (ACS) and patients with ACS who were [...] Read more.

Background: The COVID-19 pandemic is significantly affecting the functioning of the entire healthcare system. The disease itself may be associated with thromboembolic complications. The purpose of this study is to compare patients with acute coronary syndrome (ACS) and patients with ACS who were diagnosed with COVID-19 in terms of their clinical profile, management, treatment complications, and prognosis. Methods: We analyzed 47,940 cases of patients treated for ACS in 2020, including 44,952 patients (93.8%) who were not diagnosed with COVID-19 and 2988 patients (6.2%) who tested positive for COVID-19. Results: Patients with COVID-19 were significantly more likely to experience out-of-hospital sudden cardiac arrest (7.9 vs. 1.1%; p < 0.0001) and be transported directly to a catheterization laboratory (21.3% vs. 8.1%; p < 0.0001). Mortality was significantly higher in this group (0.9% vs. 0.4%; p < 0.0001). The risk of perioperative death was increased by age over 65 years, use of glycoprotein IIb/IIIa inhibitors (GPI IIb/IIIa), femoral access, critical left main stem coronary artery (LMCA) vascular lesions, ST elevation myocardial infarction (STEMI), and no-reflow phenomenon. Conclusions: Despite the pandemic, patients with COVID-19 were treated equally to healthy patients. Efficient organization of the healthcare system allowed the prompt transportation of patients to catheterization laboratories. The study group was characterized by a worse prognosis that was affected by multiple factors. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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18 pages, 2051 KiB

Open AccessArticle

Impact of the Innate Inflammatory Response on ICU Admission and Death in Hospitalized Patients with COVID-19

by Jorge Monserrat, Angel Asunsolo, Ana Gómez-Lahoz, Miguel A. Ortega, Jose Maria Gasalla, Óscar Gasulla, Jordi Fortuny-Profitós, Ferran A. Mazaira-Font, Miguel Teixidó Román, Alberto Arranz, José Sanz, Benjamin Muñoz, Juan Arévalo-Serrano, José Miguel Rodríguez, Carlos Martínez-A, Dimitri Balomenos and Melchor Álvarez-Mon

Biomedicines 2021, 9(11), 1675; https://doi.org/10.3390/biomedicines9111675 - 12 Nov 2021

Cited by 8 | Viewed by 2527

Abstract

Objective: To describe the capacity of a broad spectrum of cytokines and growth factors to predict ICU admission and/or death in patients with severe COVID-19. Design: An observational, analytical, retrospective cohort study with longitudinal follow-up. Setting: Hospital Universitario Príncipe de Asturias (HUPA). Participants: [...] Read more.

Objective: To describe the capacity of a broad spectrum of cytokines and growth factors to predict ICU admission and/or death in patients with severe COVID-19. Design: An observational, analytical, retrospective cohort study with longitudinal follow-up. Setting: Hospital Universitario Príncipe de Asturias (HUPA). Participants: 287 patients diagnosed with COVID-19 admitted to our hospital from 24 March to 8 May 2020, followed until 31 August 2020. Main outcome measures: Profiles of immune response (IR) mediators were determined using the Luminex Multiplex technique in hospitalized patients within six days of admission by examining serum levels of 62 soluble molecules classified into the three groups: adaptive IR-related cytokines (n = 19), innate inflammatory IR-related cytokines (n = 27), and growth factors (n = 16). Results: A statistically robust link with ICU admission and/or death was detected for increased serum levels of interleukin (IL)-6, IL-15, soluble (s) RAGE, IP10, MCP3, sIL1RII, IL-8, GCSF and MCSF and IL-10. The greatest prognostic value was observed for the marker combination IL-10, IL-6 and GCSF. Conclusions: When severe COVID-19 progresses to ICU admission and/or death there is a marked increase in serum levels of several cytokines and chemokines, mainly related to the patient’s inflammatory IR. Serum levels of IL-10, IL-6 and GCSF were most prognostic of the outcome measure. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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7 pages, 1795 KiB

Open AccessCommunication

A Rapid and Simple Multiparameter Assay to Quantify Spike-Specific CD4 and CD8 T Cells after SARS-CoV-2 Vaccination: A Preliminary Report

by Mojtaba Shekarkar Azgomi, Marco Pio La Manna, Giusto Davide Badami, Paolo Ragonese, Antonino Trizzino, Francesco Dieli and Nadia Caccamo

Biomedicines 2021, 9(11), 1576; https://doi.org/10.3390/biomedicines9111576 - 29 Oct 2021

Cited by 4 | Viewed by 2843 | Correction

Abstract

mRNA and Adenovirus vaccines for COVID-19 are used to induce humoral and cell-mediated immunity, with the aim to generate both SARS-CoV-2 B and T memory cells. In present study, we described a simple assay to detect and quantify Spike-specific CD4⁺ and CD8 [...] Read more.

mRNA and Adenovirus vaccines for COVID-19 are used to induce humoral and cell-mediated immunity, with the aim to generate both SARS-CoV-2 B and T memory cells. In present study, we described a simple assay to detect and quantify Spike-specific CD4⁺ and CD8⁺ T cell responses induced by vaccination in healthy donors and in subjects with B cell compart impairment, in which antibody response is absent due to primary immunodeficiencies or CD20 depleting therapy. We detect and quantified memory T cell immune responses against SARS-CoV-2 evocated by vaccination in both groups, irrespective to the humoral response. Furthermore, we identified TNF-α as the main cytokine produced by T memory cells, after antigen-specific stimulation in vitro, that could be considered, other than IFN-γ, an additional biomarker of induction of T memory cells upon vaccination. Further studies on the vaccine-induced T cell responses could be crucial, not only in healthy people but also in immunocompromised subjects, where antigen specific T cells responses play a protective role against SARS-CoV-2. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 1925 KiB

Open AccessEditor’s ChoiceArticle

Hydrogen Sulfide Inhibits TMPRSS2 in Human Airway Epithelial Cells: Implications for SARS-CoV-2 Infection

by Giulia Pozzi, Elena Masselli, Giuliana Gobbi, Prisco Mirandola, Luis Taborda-Barata, Luca Ampollini, Paolo Carbognani, Cristina Micheloni, Francesco Corazza, Daniela Galli, Cecilia Carubbi and Marco Vitale

Biomedicines 2021, 9(9), 1273; https://doi.org/10.3390/biomedicines9091273 - 20 Sep 2021

Cited by 27 | Viewed by 3776

Abstract

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, [...] Read more.

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, requiring angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to enter target cells. Therefore, these surface proteins are considered potential druggable targets. Hydrogen sulfide (H₂S) is a gasotransmitter produced by several cell types and is also part of natural compounds, such as sulfurous waters that are often inhaled as low-intensity therapy and prevention in different respiratory conditions. H₂S is a potent biological mediator, with anti-oxidant, anti-inflammatory, and, as more recently shown, also anti-viral activities. Considering that respiratory epithelial cells can be directly exposed to H₂S by inhalation, here we tested the in vitro effects of H₂S-donors on TMPRSS2 and ACE2 expression in human upper and lower airway epithelial cells. We showed that H₂S significantly reduces the expression of TMPRSS2 without modifying ACE2 expression both in respiratory cell lines and primary human upper and lower airway epithelial cells. Results suggest that inhalational exposure of respiratory epithelial cells to natural H₂S sources may hinder SARS-CoV-2 entry into airway epithelial cells and, consequently, potentially prevent the virus from spreading into the lower respiratory tract and the lung. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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13 pages, 2959 KiB

Open AccessArticle

Enisamium Inhibits SARS-CoV-2 RNA Synthesis

by Stefano Elli, Denisa Bojkova, Marco Bechtel, Thomas Vial, David Boltz, Miguel Muzzio, Xinjian Peng, Federico Sala, Cesare Cosentino, Andrew Goy, Marco Guerrini, Lutz Müller, Jindrich Cinatl, Victor Margitich and Aartjan J. W. te Velthuis

Biomedicines 2021, 9(9), 1254; https://doi.org/10.3390/biomedicines9091254 - 17 Sep 2021

Cited by 5 | Viewed by 4378

Abstract

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of [...] Read more.

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 1691 KiB

Open AccessEditor’s ChoiceArticle

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

by Bianca Maria Rotoli, Amelia Barilli, Rossana Visigalli, Francesca Ferrari and Valeria Dall’Asta

Biomedicines 2021, 9(9), 1220; https://doi.org/10.3390/biomedicines9091220 - 14 Sep 2021

Cited by 30 | Viewed by 4646

Abstract

Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to [...] Read more.

Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to date accepted, but the precise mechanisms underlying the associated coagulopathy remain unclear. Whether the alterations in vascular homeostasis directly depend upon the SARS-CoV-2 infection of endothelial cells or, rather, occur secondarily to the activation of the inflammatory response is still a matter of debate. Here, we address the effect of the SARS-CoV-2 spike S1 protein on the activation of human lung microvascular endothelial cells (HLMVEC). In particular, the existence of an endothelium-macrophage crosstalk in the response to the spike protein has been explored. Methods and Results. The effect of the spike protein is addressed in human lung microvascular endothelial cells (HLMVEC), either directly or after incubation with a conditioned medium (CM) of human monocyte-derived macrophages (MDM) previously activated by the spike S1 protein (CM-MDM). Both MDM and HLMVEC are activated in response to the S1 protein, with an increased expression of pro-inflammatory mediators. However, when HLMVEC are exposed to CM-MDM, an enhanced cell activation occurs in terms of the expression of adhesion molecules, pro-coagulant markers, and chemokines. Under this experimental condition, ICAM-1 and VCAM-1, the chemokines CXCL8/IL-8, CCL2/MCP1, and CXCL10/IP-10 as well as the protein tissue factor (TF) are markedly induced. Instead, a decrease of thrombomodulin (THBD) is observed. Conclusion. Our data suggest that pro-inflammatory mediators released by spike-activated macrophages amplify the activation of endothelial cells, likely contributing to the impairment of vascular integrity and to the development of a pro-coagulative endothelium. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 13795 KiB

Open AccessArticle

Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

by Deborah Giordano, Luigi De Masi, Maria Antonia Argenio and Angelo Facchiano

Biomedicines 2021, 9(8), 1038; https://doi.org/10.3390/biomedicines9081038 - 18 Aug 2021

Cited by 16 | Viewed by 3232

Abstract

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the [...] Read more.

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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12 pages, 1367 KiB

Open AccessArticle

Role of SpO2/FiO2 Ratio and ROX Index in Predicting Early Invasive Mechanical Ventilation in COVID-19. A Pragmatic, Retrospective, Multi-Center Study

by Ana Alberdi-Iglesias, Francisco Martín-Rodríguez, Guillermo Ortega Rabbione, Ana I. Rubio-Babiano, María G. Núñez-Toste, Ancor Sanz-García, Carlos del Pozo Vegas, Miguel A. Castro Villamor, José L. Martín-Conty, Cristina Jorge-Soto and Raúl López-Izquierdo

Biomedicines 2021, 9(8), 1036; https://doi.org/10.3390/biomedicines9081036 - 18 Aug 2021

Cited by 29 | Viewed by 3615

Abstract

The ability of COVID-19 to compromise the respiratory system has generated a substantial proportion of critically ill patients in need of invasive mechanical ventilation (IMV). The objective of this paper was to analyze the prognostic ability of the pulse oximetry saturation/fraction of inspired [...] Read more.

The ability of COVID-19 to compromise the respiratory system has generated a substantial proportion of critically ill patients in need of invasive mechanical ventilation (IMV). The objective of this paper was to analyze the prognostic ability of the pulse oximetry saturation/fraction of inspired oxygen ratio (SpO2/FiO2) and the ratio of SpO2/FiO2 to the respiratory rate–ROX index–as predictors of IMV in an emergency department in confirmed COVID-19 patients. A multicenter, retrospective cohort study was carried out in four provinces of Spain between March and November 2020. The discriminative power of the predictive variable was assessed through a prediction model trained using a derivation sub-cohort and evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) on the validation sub-cohort. A total of 2040 patients were included in the study. The IMV rate was 10.1%, with an in-hospital mortality rate of 35.3%. The performance of the SpO2/FiO2 ratio was better than the ROX index–AUC = 0.801 (95% CI 0.746–0.855) and AUC = 0.725 (95% CI 0.652–0.798), respectively. In fact, a direct comparison between AUCs resulted in significant differences (p = 0.001). SpO2 to FiO2 ratio is a simple and promising non-invasive tool for predicting risk of IMV in patients infected with COVID-19, and it is realizable in emergency departments. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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15 pages, 2345 KiB

Open AccessEditor’s ChoiceArticle

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

by Pasquale Ambrosino, Ilenia Calcaterra, Antonio Molino, Pasquale Moretta, Roberta Lupoli, Giorgio Alfredo Spedicato, Antimo Papa, Andrea Motta, Mauro Maniscalco and Matteo Nicola Dario Di Minno

Biomedicines 2021, 9(8), 957; https://doi.org/10.3390/biomedicines9080957 - 4 Aug 2021

Cited by 72 | Viewed by 5693

Abstract

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a [...] Read more.

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p < 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 1177 KiB

Open AccessArticle

Acceleration of Biological Aging and Underestimation of Subjective Age Are Risk Factors for Severe COVID-19

by Tatiana N. Berezina and Stanislav Rybtsov

Biomedicines 2021, 9(8), 913; https://doi.org/10.3390/biomedicines9080913 - 29 Jul 2021

Cited by 13 | Viewed by 4080

Abstract

In an epidemic, it is important to have methods for reliable and rapid assessment of risk groups for severe forms of the disease for their priority vaccination and for the application of preventive lockdown measures. The aim of this study was to investigate [...] Read more.

In an epidemic, it is important to have methods for reliable and rapid assessment of risk groups for severe forms of the disease for their priority vaccination and for the application of preventive lockdown measures. The aim of this study was to investigate risk factors for severe forms of COVID-19 in adults using indicators of biological and subjective aging. Longitudinal studies evaluated the severity of the disease and the number of cases. Respondents (447) were divided into “working group” and “risk group” (retirees with chronic diseases). During the lockdown period (in mid-2020), accelerated aging was observed in the group of workers (by 3.9–8 years for men and an increase at the tendency level for women). However, the respondents began to feel subjectively younger (by 3.3–7.2 years). In the risk group, there were no deviations from the expected biopsychological aging. The number of cases at the end of 2020 was 31% in workers and 0% in the risk group. Reasonably, the risk group followed the quarantine rules more strictly by 1.5 times. In working men, indicators of relative biological and relative subjective aging (measured in both 2019 and mid-2020) significantly influenced the incidence at the end of 2020. In women, only the indicators obtained in mid-2020 had a significant impact. The relative biological aging of an individual tested in the middle of 2020 had a direct impact on the risk of infection (p < 0.05) and on the probability of death (p < 0.0001). On the contrary, an increase in the relative subjective (psychological) aging index reduced the risk of infection (at the tendency level, p = 0.06) and the risk of death (p < 0.0001). Both the risk of infection and the risk of death increased with calendar age at the tendency level. Conclusions: Indicators of individual relative biological and subjective aging affect the probability of getting COVID-19 and its severity. The combination of high indicators of biological aging and underestimated indicators of subjective aging is associated with increased chances of developing severe forms of the disease. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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Review

Jump to: Editorial, Research, Other

21 pages, 1424 KiB

Open AccessReview

Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects

by Vamika Karn, Shaista Ahmed, Lung-Wen Tsai, Rajni Dubey, Shreesh Ojha, Himanshu Naryan Singh, Mukesh Kumar, Piyush Kumar Gupta, Soumi Sadhu, Niraj Kumar Jha, Ashutosh Kumar, Soumya Pandit and Sanjay Kumar

Biomedicines 2021, 9(10), 1373; https://doi.org/10.3390/biomedicines9101373 - 1 Oct 2021

Cited by 43 | Viewed by 5491

Abstract

The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, [...] Read more.

The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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15 pages, 34002 KiB

Open AccessReview

Epigenetic Mechanisms Underlying COVID-19 Pathogenesis

by Syuzo Kaneko, Ken Takasawa, Ken Asada, Norio Shinkai, Amina Bolatkan, Masayoshi Yamada, Satoshi Takahashi, Hidenori Machino, Kazuma Kobayashi, Masaaki Komatsu and Ryuji Hamamoto

Biomedicines 2021, 9(9), 1142; https://doi.org/10.3390/biomedicines9091142 - 2 Sep 2021

Cited by 10 | Viewed by 5036

Abstract

In 2019, a novel severe acute respiratory syndrome called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported and was declared a pandemic by the World Health Organization (WHO) in March 2020. With the advancing development of [...] Read more.

In 2019, a novel severe acute respiratory syndrome called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported and was declared a pandemic by the World Health Organization (WHO) in March 2020. With the advancing development of COVID-19 vaccines and their administration globally, it is expected that COVID-19 will converge in the future; however, the situation remains unpredictable because of a series of reports regarding SARS-CoV-2 variants. Currently, there are still few specific effective treatments for COVID-19, as many unanswered questions remain regarding the pathogenic mechanism of COVID-19. Continued elucidation of COVID-19 pathogenic mechanisms is a matter of global importance. In this regard, recent reports have suggested that epigenetics plays an important role; for instance, the expression of angiotensin I converting enzyme 2 (ACE2) receptor, an important factor in human infection with SARS-CoV-2, is epigenetically regulated; further, DNA methylation status is reported to be unique to patients with COVID-19. In this review, we focus on epigenetic mechanisms to provide a new molecular framework for elucidating the pathogenesis of SARS-CoV-2 infection in humans and of COVID-19, along with the possibility of new diagnostic and therapeutic strategies. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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19 pages, 2203 KiB

Open AccessReview

Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans

by Zhipeng Yan, Ming Yang and Ching-Lung Lai

Biomedicines 2021, 9(8), 966; https://doi.org/10.3390/biomedicines9080966 - 5 Aug 2021

Cited by 115 | Viewed by 16972

Abstract

The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for [...] Read more.

The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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2 pages, 734 KiB

Open AccessCorrection

Correction: Shekarkar Azgomi et al. A Rapid and Simple Multiparameter Assay to Quantify Spike-Specific CD4 and CD8 T Cells after SARS-CoV-2 Vaccination: A Preliminary Report. Biomedicines 2021, 9, 1576

by Mojtaba Shekarkar Azgomi, Marco Pio La Manna, Giusto Davide Badami, Paolo Ragonese, Antonino Trizzino, Francesco Dieli and Nadia Caccamo

Biomedicines 2023, 11(9), 2378; https://doi.org/10.3390/biomedicines11092378 - 25 Aug 2023

Viewed by 901

Abstract

In the original publication, there was a mistake in Figure 1A, as published [...] Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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8 pages, 728 KiB

Open AccessCase Report

Clinical and Radiological Deterioration in a Case of Creutzfeldt–Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration

by Dumitru Ciolac, Renata Racila, Carolina Duarte, Maria Vasilieva, Diana Manea, Nadejda Gorincioi, Alexandra Condrea, Igor Crivorucica, Eremei Zota, Daniela Efremova, Veaceslav Crivorucica, Mihail Ciocanu, Alexandru Movila and Stanislav A. Groppa

Biomedicines 2021, 9(11), 1730; https://doi.org/10.3390/biomedicines9111730 - 19 Nov 2021

Cited by 15 | Viewed by 3384

Abstract

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt–Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD [...] Read more.

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt–Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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11 pages, 2095 KiB

Open AccessCase Report

A Case Report of a Patient on Therapeutic Warfarin Who Died of COVID-19 Infection with a Sudden Rise in D-Dimer

by Reita N. Agarwal, Hersheth Aggarwal, Ashmit Verma and Manish K. Tripathi

Biomedicines 2021, 9(10), 1382; https://doi.org/10.3390/biomedicines9101382 - 3 Oct 2021

Cited by 4 | Viewed by 4191

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has disrupted social and economic life globally. The global pandemic COVID-19 caused by this novel SARS-CoV-2 shows variable clinical manifestations, complicated further by cytokine storm, co-infections, and coagulopathy, leading to severe cases and death. Thrombotic [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has disrupted social and economic life globally. The global pandemic COVID-19 caused by this novel SARS-CoV-2 shows variable clinical manifestations, complicated further by cytokine storm, co-infections, and coagulopathy, leading to severe cases and death. Thrombotic complications arise due to complex and unique interplay between coronaviruses and host cells, inflammatory response, and the coagulation system. Heparin and derivatives are World Health Organization (WHO) recommended anticoagulants for moderate and severe Corona Virus Disease 19 (COVID-19), that can also inhibit viral adhesion to the cell membrane by interfering with heparan sulfate-dependent binding to angiotensin-converting enzyme 2 (ACE2) receptor. Heparin also possesses anti-inflammatory, immunomodulatory, antiviral, and anti-complement activity, which offers a benefit in limiting viral and microbial infectivity and anticoagulation from the immune-thrombosis system. Here we present a case study of the pathophysiology of unexpected COVID-19 coagulopathy of an obese African American patient. While being on therapeutic warfarin since admission, he had a dismal outcome due to cardio-pulmonary arrest after the sudden rise in D-dimer value from 1.1 to >20. This indicates that for such patients on chronic warfarin anticoagulation with “moderate COVID 19 syndromes”, warfarin anticoagulation may not be suitable compared to heparin and its derivatives. Further research should be done to understand the beneficial role of heparin and its derivatives compared to warfarin for COVID-19 inflicted patients. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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15 pages, 708 KiB

Open AccessSystematic Review

Long-Term Impact of COVID-19: A Systematic Review of the Literature and Meta-Analysis

by Diana C. Sanchez-Ramirez, Kaylene Normand, Yang Zhaoyun and Rodrigo Torres-Castro

Biomedicines 2021, 9(8), 900; https://doi.org/10.3390/biomedicines9080900 - 27 Jul 2021

Cited by 137 | Viewed by 14060

Abstract

Background: The long-term impact of COVID-19 is still unknown. This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond [...] Read more.

Background: The long-term impact of COVID-19 is still unknown. This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond 3 months post infection. Methods: A systematic search was performed on PubMed, Web of Science, and Ovid MEDLINE on 22 May 2021, to identify studies that reported persistent effects of COVID-19 beyond 3 months follow-up. Data on the proportion of patients who had the outcome were collected and analyzed using a one-group meta-analysis. Results: Data were extracted from 24 articles that presented information on a total of 5323 adults, post-infection, between 3 to 6 months after symptom onset or hospital discharge. The pooled prevalence of CT abnormalities was 59% (95% CI 44–73, I² = 96%), abnormal lung function was 39% (95% CI 24–55, I² = 94%), fatigue was 38% (95% CI 27–49, I² = 98%), dyspnea was 32% (95% CI 24–40, I² = 98%), chest paint/tightness was 16% (95% CI 12–21, I² = 94%), and cough was 13%, (95% CI 9–17, I² = 94%). Decreased functional capacity and HRQoL were found in 36% (95% CI 22–49, I² = 97%) and 52% (95% CI 33–71, I² = 94%), respectively. On average, 8 out of 10 of the patients had returned to work or reported no work impairment. Conclusion: Post-COVID-19 patients may experience persistent respiratory symptoms, fatigue, decreased functional capacity and decreased quality of life up to 6 months after infection. Further studies are needed to establish the extent to which post-COVID-19 effects continue beyond 6 months, how they interact with each other, and to clarify their causes and their effective management. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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