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COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational...
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COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II)

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 33235

Special Issue Editor

Dr. Pasquale Ambrosino

E-Mail Website
Guest Editor
Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
Interests: cardiovascular risk; endothelial function; arterial stiffness; atherosclerosis; COVID-19; chronic obstructive pulmonary disease; asthma; biomarkers; rehabilitation; chronic disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is the second volume of the Special Issue "COVID-19 and post-acute COVID-19 syndrome: from pathophysiology to novel translational applications".

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) made its first appearance in December 2019, leading to a global health emergency and the pandemic declaration in March 2020. SARS-CoV-2 can cause the coronavirus disease 2019 (COVID-19), a condition with a wide range of clinical presentations, from the absence of symptoms to a severe condition necessitating intensive care unit admittance.

Moreover, reports of persistent clinical manifestations in patients recovering from COVID-19 are emerging, thus suggesting the presence of a post-acute COVID-19 syndrome and the need for multidisciplinary rehabilitation after swab test negativization. This is consistent with the finding of pulmonary abnormalities and long-term cardiovascular complications in a substantial proportion of COVID-19 survivors at hospital discharge and even months after discharge.

Growing evidence points to the key role of systemic inflammation and endothelial dysfunction in the pathogenesis of most COVID-19 manifestations. Accordingly, a prolonged inflammatory response and a persistent endothelial dysfunction have been reported also in asymptomatic and mildly affected patients at different stages of the disease.

However, the pathophysiological mechanisms underlying the acute and post-acute manifestations of COVID-19 have not been fully elucidated. A thorough understanding of these mechanisms would enable the implementation of tailored and comprehensive strategies.

This Special Issue will cover the pathophysiology and diagnostics of COVID-19 and post-acute COVID-19 syndrome, with a focus on new prognostic and therapeutic applications. The Special Issue is open for both basic and functional studies, or for omics-based and translational approaches, and will cover original articles, case reports, high-quality reviews and a limited number of pertinent meta-analyses.

Dr. Pasquale Ambrosino
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COVID-19
  • post-COVID-19 syndrome
  • endothelial function
  • inflammation
  • flow-mediated dilation
  • cardiovascular risk
  • vascular medicine
  • biomarkers
  • rehabilitation
  • disability
  • outcome

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Related Special Issue

Published Papers (9 papers)

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Editorial

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5 pages, 223 KiB  
Editorial
Implementing Translational Research to Understand the Future of COVID-19 and Its Long-Term Consequences: A Degrowth Perspective or the Transformation of a Global Emergency?
by Pasquale Ambrosino, Pasquale Moretta, Anna Lanzillo, Roberto Formisano and Mauro Maniscalco
Biomedicines 2023, 11(1), 117; https://doi.org/10.3390/biomedicines11010117 - 3 Jan 2023
Cited by 1 | Viewed by 1941
Abstract
It has now been three years since the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first gave rise to a global health crisis [...] Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))

Research

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28 pages, 13013 KiB  
Article
Comprehensive Analysis of Disease Pathology in Immunocompetent and Immunocompromised Hosts following Pulmonary SARS-CoV-2 Infection
by Santhamani Ramasamy, Afsal Kolloli, Ranjeet Kumar, Seema Husain, Patricia Soteropoulos, Theresa L. Chang and Selvakumar Subbian
Biomedicines 2022, 10(6), 1343; https://doi.org/10.3390/biomedicines10061343 - 7 Jun 2022
Cited by 10 | Viewed by 3001
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic disproportionately affects immunocompetent and immunocompromised individuals, with the latter group being more vulnerable to severe disease and death. However, the differential pathogenesis of SARS-CoV-2 in the context of a specific immunological niche remains unknown. Similarly, systematic analysis [...] Read more.
The Coronavirus disease 2019 (COVID-19) pandemic disproportionately affects immunocompetent and immunocompromised individuals, with the latter group being more vulnerable to severe disease and death. However, the differential pathogenesis of SARS-CoV-2 in the context of a specific immunological niche remains unknown. Similarly, systematic analysis of disease pathology in various extrapulmonary organs in immunocompetent and immunocompromised hosts during SARS-CoV-2 infection is not fully understood. We used a hamster model of SARS-CoV-2 infection, which recapitulates the pathophysiology of patients with mild-to-moderate COVID-19, to determine the dynamics of SARS-CoV-2 replication and histopathology at organ-level niches and map how COVID-19 symptoms vary in different immune contexts. Hamsters were intranasally infected with low (LD) or high (HD) inoculums of SARS-CoV-2, and the kinetics of disease pathology and viral load in multiple organs, antibody response, inflammatory cytokine expression, and genome-wide lung transcriptome by RNAseq analysis were determined and compared against corresponding responses from chemically induced immunocompromised hamsters. We observed transient body weight loss proportional to the SARS-CoV-2 infectious dose in immunocompetent hamsters. The kinetics of viral replication and peak viral loads were similar between LD and HD groups, although the latter developed more severe disease pathology in organs. Both groups generated a robust serum antibody response. In contrast, infected immunocompromised animals showed more prolonged body weight loss and mounted an inadequate SARS-CoV-2-neutralizing antibody response. The live virus was detected in the pulmonary and extrapulmonary organs for extended periods. These hamsters also had persistent inflammation with severe bronchiolar-alveolar hyperplasia/metaplasia. Consistent with the differential disease presentation, distinct changes in inflammation and immune cell response pathways and network gene expression were seen in the lungs of SARS-CoV-2-infected immunocompetent and immunocompromised animals. Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))
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27 pages, 4201 KiB  
Article
Evaluation in a Cytokine Storm Model In Vivo of the Safety and Efficacy of Intravenous Administration of PRS CK STORM (Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells)
by Juan Pedro Lapuente, Gonzalo Gómez, Joaquín Marco-Brualla, Pablo Fernández, Paula Desportes, Jara Sanz, Mario García-Gil, Fernando Bermejo, Juan Víctor San Martín, Alicia Algaba, Juan Carlos De Gregorio, Daniel Lapuente, Almudena De Gregorio, Belén Lapuente, Sergio Gómez, María de las Viñas Andrés and Alberto Anel
Biomedicines 2022, 10(5), 1094; https://doi.org/10.3390/biomedicines10051094 - 8 May 2022
Cited by 2 | Viewed by 3372
Abstract
Our research group has been developing a series of biological drugs produced by coculture techniques with M2-polarized macrophages with different primary tissue cells and/or mesenchymal stromal cells (MSC), generally from fat, to produce anti-inflammatory and anti-fibrotic effects, avoiding the overexpression of pro-inflammatory cytokines [...] Read more.
Our research group has been developing a series of biological drugs produced by coculture techniques with M2-polarized macrophages with different primary tissue cells and/or mesenchymal stromal cells (MSC), generally from fat, to produce anti-inflammatory and anti-fibrotic effects, avoiding the overexpression of pro-inflammatory cytokines by the innate immune system at a given time. One of these products is the drug PRS CK STORM, a medium conditioned by allogenic M2-polarized macrophages, from coculture, with those macrophages M2 with MSC from fat, whose composition, in vitro safety, and efficacy we studied. In the present work, we publish the results obtained in terms of safety (pharmacodynamics and pharmacokinetics) and efficacy of the intravenous application of this biological drug in a murine model of cytokine storm associated with severe infectious processes, including those associated with COVID-19. The results demonstrate the safety and high efficacy of PRS CK STORM as an intravenous drug to prevent and treat the cytokine storm associated with infectious processes, including 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 (Volume II))
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12 pages, 2196 KiB  
Article
The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients
by Elisabeth Berghäll, Michael Hultström, Robert Frithiof, Miklos Lipcsey and Victoria Hahn-Strömberg
Biomedicines 2022, 10(5), 934; https://doi.org/10.3390/biomedicines10050934 - 19 Apr 2022
Cited by 5 | Viewed by 2817 | Correction
Abstract
Background: Severe coronavirus disease 2019 (COVID-19) causes a strong inflammatory response. To obtain an overview of inflammatory mediators and effector cells, we studied 25 intensive-care-unit patients during the timeframe after off-label chloroquine treatment and before an introduction of immunomodulatory drugs. Material and methods: [...] Read more.
Background: Severe coronavirus disease 2019 (COVID-19) causes a strong inflammatory response. To obtain an overview of inflammatory mediators and effector cells, we studied 25 intensive-care-unit patients during the timeframe after off-label chloroquine treatment and before an introduction of immunomodulatory drugs. Material and methods: Blood samples were weekly examined with flow cytometry (FCM) for surface and intracytoplasmic markers, cytokine assays were analyzed for circulating interleukins (ILs), and blood smears were evaluated for morphological changes. Samples from healthy volunteers were used for comparison. Organ function data and 30-day mortality were obtained from medical records. Results: Compared to that of the healthy control group, the expression levels of leukocyte surface markers, i.e., the cluster of differentiation (CD) markers CD2, CD4, CD8, CD158d, CD25, CD127, and CD19, were lower (p < 0.001), while those of leukocytes expressing CD33 were increased (p < 0.05). An aberrant expression of CD158d on granulocytes was found on parts of the granulocyte population. The expression levels of intracellular tumor necrosis factor alpha (TNFα) and IL-1 receptor type 2 in leukocytes were lower (p < 0.001), and the plasma levels of TNFα, IL-2, IL-6, IL-8, IL-10 (p < 0.001), interferon gamma (IFNγ) (p < 0.01), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.05) were higher in patients with severe COVID-19 than in the control group. The expression levels of CD33+ leukocytes and circulating IL-6 were higher (p < 0.05) among patients with arterial oxygen partial pressure-to-fractional inspired oxygen (PaO2/FiO2) ratios below 13.3 kPa compared to in the remaining patients. The expression levels of TNFα, IL-2, IL-4, IL-6, IL-8, and IL-10 were higher in patients treated with continuous renal replacement therapy (CRRT) (p < 0.05), and the levels of the maximum plasma creatinine and TNFα Spearman’s rank-order correlation coefficient (rho = 0.51, p < 0.05) and IL-8 (rho = 0.44, p < 0.05) correlated. Blood smears revealed neutrophil dysplasia with pseudo-Pelger forms being most common. Conclusion: These findings suggest that patients with severe COVID-19, in addition to augmented ILs, lymphopenia, and increased granulocytes, also had effects on the bone marrow. Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))
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15 pages, 2669 KiB  
Article
Immune-Mediated Inflammatory Responses of Alveolar Epithelial Cells: Implications for COVID-19 Lung Pathology
by Amelia Barilli, Rossana Visigalli, Francesca Ferrari, Massimiliano G. Bianchi, Valeria Dall’Asta and Bianca Maria Rotoli
Biomedicines 2022, 10(3), 618; https://doi.org/10.3390/biomedicines10030618 - 7 Mar 2022
Cited by 18 | Viewed by 3653
Abstract
Background. Clinical and experimental evidence point to a dysregulated immune response caused by SARS-CoV-2 as the primary mechanism of lung disease in COVID-19. However, the pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. This study aims to explore the [...] Read more.
Background. Clinical and experimental evidence point to a dysregulated immune response caused by SARS-CoV-2 as the primary mechanism of lung disease in COVID-19. However, the pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. This study aims to explore the inflammatory responses of alveolar epithelial cells to either the spike S1 protein or to a mixture of cytokines secreted by S1-activated macrophages. Methods and Results. The exposure of alveolar A549 cells to supernatants from spike-activated macrophages caused a further release of inflammatory mediators, with IL-8 reaching massive concentrations. The investigation of the molecular pathways indicated that NF-kB is involved in the transcription of IP-10 and RANTES, while STATs drive the expression of all the cytokines/chemokines tested, with the exception of IL-8 which is regulated by AP-1. Cytokines/chemokines produced by spike-activated macrophages are also likely responsible for the observed dysfunction of barrier integrity in Human Alveolar Epithelial Lentivirus-immortalized cells (hAELVi), as demonstrated by an increased permeability of the monolayers to mannitol, a marked decrease of TEER and a disorganization of claudin-7 distribution. Conclusion. Upon exposure to supernatants from S1-activated macrophages, A549 cells act both as targets and sources of cytokines/chemokines, suggesting that alveolar epithelium along with activated macrophages may orchestrate lung inflammation and contribute to alveolar injury, a hallmark of ARDS. Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))
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20 pages, 328 KiB  
Article
The Role of Genetic Factors in the Development of Acute Respiratory Viral Infection COVID-19: Predicting Severe Course and Outcomes
by Mikhail M. Minashkin, Nataliya Y. Grigortsevich, Anna S. Kamaeva, Valeriya V. Barzanova, Alexey A. Traspov, Mikhail A. Godkov, Farkhad A. Ageev, Sergey S. Petrikov and Nataliya V. Pozdnyakova
Biomedicines 2022, 10(3), 549; https://doi.org/10.3390/biomedicines10030549 - 25 Feb 2022
Cited by 17 | Viewed by 3453
Abstract
The aim of this study was to identify single nucleotide variants in genes associated with susceptibility to or severe outcomes of COVID-19. A total of 319 genomic DNA samples from patients with varying degrees of disease severity and 78 control DNA samples from [...] Read more.
The aim of this study was to identify single nucleotide variants in genes associated with susceptibility to or severe outcomes of COVID-19. A total of 319 genomic DNA samples from patients with varying degrees of disease severity and 78 control DNA samples from people who had regular or prolonged contact with patients with COVID-19 but did not have clinical manifestations and/or antibodies to SARS-CoV-2. Seven SNPs were identified that were statistically associated with disease risk or severe course, rs1799864 in the CCR2 gene (OR = 2.21), rs1990760 in the IFIH1 gene (OR = 2.41), rs1800629 in the TNF gene (OR = 1.98), rs75603675 in the TMPRSS2 gene (OR = 1.86), rs7842 in the C3AR1 gene (OR = 2.08), rs179008 in the gene TLR7 (OR = 1.85), rs324011 in the C3AR1 gene (OR = 2.08), rs179008 in the TLR7 gene (OR = 1.85), and rs324011 in the STAT6 gene (OR = 1.84), as well as two variants associated with protection from COVID-19, rs744166 in the STAT3 gene (OR = 0.36) and rs1898830 in the TLR2 gene (OR = 0.47). The genotype in the region of these markers can be the criterion of the therapeutic approach for patients with 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 (Volume II))

Review

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16 pages, 1149 KiB  
Review
Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target
by Pasquale Ambrosino, Ilenia Lorenza Calcaterra, Marco Mosella, Roberto Formisano, Silvestro Ennio D’Anna, Tiziana Bachetti, Giuseppina Marcuccio, Brurya Galloway, Francesco Paolo Mancini, Antimo Papa, Andrea Motta, Matteo Nicola Dario Di Minno and Mauro Maniscalco
Biomedicines 2022, 10(4), 812; https://doi.org/10.3390/biomedicines10040812 - 30 Mar 2022
Cited by 39 | Viewed by 7894
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that [...] Read more.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting. Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))
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Other

2 pages, 179 KiB  
Correction
Correction: Berghäll et al. The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients. Biomedicines 2022, 10, 934
by Elisabeth Berghäll, Michael Hultström, Robert Frithiof, Miklos Lipcsey and Victoria Hahn-Strömberg
Biomedicines 2023, 11(11), 2965; https://doi.org/10.3390/biomedicines11112965 - 3 Nov 2023
Viewed by 596
Abstract
In original publication [...] Full article
(This article belongs to the Special Issue COVID-19 and Post-acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications (Volume II))
15 pages, 2979 KiB  
Systematic Review
Putative Role of the Lung–Brain Axis in the Pathogenesis of COVID-19-Associated Respiratory Failure: A Systematic Review
by Francesco Gentile, Tommaso Bocci, Silvia Coppola, Tommaso Pozzi, Leo Modafferi, Alberto Priori and Davide Chiumello
Biomedicines 2022, 10(3), 729; https://doi.org/10.3390/biomedicines10030729 - 21 Mar 2022
Cited by 5 | Viewed by 5085
Abstract
The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other [...] Read more.
The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other organs may be damaged as well, including the heart, kidneys, and brain. Current evidence reports a high frequency of neurological manifestations in COVID-19, with significant prognostic implications. Importantly, emerging literature is showing that the virus may spread to the central nervous system through neuronal routes, hitting the brainstem and cardiorespiratory centers, potentially exacerbating the respiratory illness. In this systematic review, we searched public databases for all available evidence and discuss current clinical and pre-clinical data on the relationship between the lung and brain during COVID-19. Acknowledging the involvement of these primordial brain areas in the pathogenesis of the disease may fuel research on the topic and allow the development of new 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 (Volume II))
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