New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	4.7	3.7	2013	15.4 Days	CHF 2600
COVID covid	-	-	2021	16.8 Days	CHF 1000
Journal of Clinical Medicine jcm	3.9	5.4	2012	17.9 Days	CHF 2600
Pathophysiology pathophysiology	-	2.8	1994	22.6 Days	CHF 1400
Reports reports	0.9	-	2018	20.6 Days	CHF 1400
Viruses viruses	4.7	7.1	2009	13.8 Days	CHF 2600

28 pages, 1326 KiB

Open AccessArticle

Modeling COVID-19 Disease with Deterministic and Data-Driven Models Using Daily Empirical Data in the United Kingdom

by Janet O. Agbaje, Oluwatosin Babasola, Kabiru Michael Adeyemo, Abraham Baba Zhiri, Aanuoluwapo Joshua Adigun, Samuel Adefisoye Lawal, Oluwole Adegoke Nuga, Roseline Toyin Abah, Umar Muhammad Adam and Kayode Oshinubi

COVID 2024, 4(2), 289-316; https://doi.org/10.3390/covid4020020 - 18 Feb 2024

Viewed by 674

Abstract

The COVID-19 pandemic has had a significant impact on countries worldwide, including the United Kingdom (UK). The UK has faced numerous challenges, but its response, including the rapid vaccination campaign, has been noteworthy. While progress has been made, the study of the pandemic [...] Read more.

The COVID-19 pandemic has had a significant impact on countries worldwide, including the United Kingdom (UK). The UK has faced numerous challenges, but its response, including the rapid vaccination campaign, has been noteworthy. While progress has been made, the study of the pandemic is important to enable us to properly prepare for future epidemics. Collaboration, vigilance, and continued adherence to public health measures will be crucial in navigating the path to recovery and building resilience for the future. In this article, we propose an overview of the COVID-19 situation in the UK using both mathematical (a nonlinear differential equation model) and statistical (time series modeling on a moving window) models on the transmission dynamics of the COVID-19 virus from the beginning of the pandemic up until July 2022. This is achieved by integrating a hybrid model and daily empirical case and death data from the UK. We partition this dataset into before and after vaccination started in the UK to understand the influence of vaccination on disease dynamics. We used the mathematical model to present some mathematical analyses and the calculation of the basic reproduction number (

R_{0}

). Following the sensitivity analysis index, we deduce that an increase in the rate of vaccination will decrease

R_{0}

. Also, the model was fitted to the data from the UK to validate the mathematical model with real data, and we used the data to calculate time-varying

R_{0}

. The homotopy perturbation method (HPM) was used for the numerical simulation to demonstrate the dynamics of the disease with varying parameters and the importance of vaccination. Furthermore, we used statistical modeling to validate our model by performing principal component analysis (PCA) to predict the evolution of the spread of the COVID-19 outbreak in the UK on some statistical predictor indicators from time series modeling on a 14-day moving window for detecting which of these indicators capture the dynamics of the disease spread across the epidemic curve. The results of the PCA, the index of dispersion, the fitted mathematical model, and the mathematical model simulation are all in agreement with the dynamics of the disease in the UK before and after vaccination started. Conclusively, our approach has been able to capture the dynamics of the pandemic at different phases of the disease outbreak, and the result presented will be useful to understand the evolution of the disease in the UK and future and emerging epidemics. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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12 pages, 5999 KiB

Open AccessBrief Report

Feasibility Study of Developing a Saline-Based Antiviral Nanoformulation Containing Lipid-Soluble EGCG: A Potential Nasal Drug to Treat Long COVID

by Nicolette Frank, Douglas Dickinson, William Garcia, Yutao Liu, Hongfang Yu, Jingwen Cai, Sahaj Patel, Bo Yao, Xiaocui Jiang and Stephen Hsu

Viruses 2024, 16(2), 196; https://doi.org/10.3390/v16020196 - 27 Jan 2024

Viewed by 1493

Abstract

A recent estimate indicates that up to 23.7 million Americans suffer from long COVID, and approximately one million workers may be out of the workforce each day due to associated symptoms, leading to a USD 50 billion annual loss of salary. Post-COVID (Long [...] Read more.

A recent estimate indicates that up to 23.7 million Americans suffer from long COVID, and approximately one million workers may be out of the workforce each day due to associated symptoms, leading to a USD 50 billion annual loss of salary. Post-COVID (Long COVID) neurologic symptoms are due to the initial robust replication of SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation of the olfactory epithelium (OE) and the central nervous system (CNS), and the OE becoming a persistent infection site. Previously, our group showed that Epigallocatechin-3-gallate-palmitate (EC16) nanoformulations possess strong antiviral activity against human coronavirus, suggesting this green tea-derived compound in nanoparticle formulations could be developed as an intranasally delivered new drug to eliminate the persistent SARS-CoV-2 infection, leading to restored olfactory function and reduced inflammation in the CNS. The objective of the current study was to determine the compatibility of the nanoformulations with human nasal primary epithelial cells (HNpECs). Methods: Nanoparticle size was measured using the ZetaView Nanoparticle Tracking Analysis (NTA) system; contact antiviral activity was determined by TCID50 assay for cytopathic effect on MRC-5 cells; post-infection inhibition activity was determined in HNpECs; and cytotoxicity for these cells was determined using an MTT assay. The rapid inactivation of OC43 (a β-coronavirus) and 229E (α-coronavirus) viruses was further characterized by transmission electron microscopy. Results: A saline-based nanoformulation containing 0.1% w/v EC16 was able to inactivate 99.9999% β-coronavirus OC43 on direct contact within 1 min. After a 10-min incubation of infected HNpECs with a formulation containing drug-grade EC16 (EGCG-4′ mono-palmitate or EC16m), OC43 viral replication was inhibited by 99%. In addition, all nanoformulations tested for their effect on cell viability were comparable to normal saline, a regularly used nasal irrigation solution. A 1-min incubation of an EC16 nanoformulation with either OC43 or 229E showed an altered viral structure. Conclusion: Nanoformulations containing EC16 showed properties compatible with nasal application to rapidly inactivate SARS-CoV-2 residing in the olfactory mucosa and to reduce inflammation in the CNS, pending additional formulation and safety studies. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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12 pages, 1591 KiB

Open AccessFeature PaperArticle

Different Prognostic Role of Soluble PD-L1 in the Course of Severe and Non-Severe COVID-19

by Francesco Sabbatino, Pasquale Pagliano, Carmine Sellitto, Berenice Stefanelli, Graziamaria Corbi, Valentina Manzo, Emanuela De Bellis, Luigi Liguori, Francesco Antonio Salzano, Stefano Pepe, Amelia Filippelli and Valeria Conti

J. Clin. Med. 2023, 12(21), 6812; https://doi.org/10.3390/jcm12216812 - 27 Oct 2023

Viewed by 733

Abstract

Understanding the link between COVID-19 and patient immune characteristics is crucial. We previously demonstrated that high levels of the soluble Programmed Death-Ligand1 (sPD-L1) at the beginning of the infection correlated with low lymphocyte number and high C-reactive protein (CRP), longer length of stay [...] Read more.

Understanding the link between COVID-19 and patient immune characteristics is crucial. We previously demonstrated that high levels of the soluble Programmed Death-Ligand1 (sPD-L1) at the beginning of the infection correlated with low lymphocyte number and high C-reactive protein (CRP), longer length of stay (LOS), and death. This study investigated whether sPD-L1 can be a prognosis biomarker during COVID-19. Severe and non-severe COVID-19 patients were enrolled at the University Hospital of Salerno. During hospitalization, at admission, and after 12–14 days, patients’ data were collected, and sPD-L1 levels were measured by enzyme-linked immunosorbent assay. The peripheral lymphocyte number negatively correlated with the time of negativization (p = 0.006), length of stay (LOS) (p = 0.032), and CRP (p = 0.004), while sPD-L1 positively correlated with LOS (p = 0.015). Patients with increased sPD-L1 and lymphocyte number showed a shorter LOS than those with decreased sPD-L1 and lymphocyte number (p = 0.038) and those with increased sPD-L1 and decreased lymphocyte number (p = 0.025). Moreover, patients with increased sPD-L1 and decreased CRP had a shorter LOS than those with increased sPD-L1 and CRP (p = 0.034) and those with decreased sPD-L1 and CRP (p = 0.048). In conclusion, while at an early phase of COVID-19, sPD-L1 promotes an immune escape, later, it might act to dampen an excessive immune response, proving its role in COVID-19 prognosis. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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9 pages, 881 KiB

Open AccessArticle

Efficacy of BREATHOX^® Device Inhalation on Acute Symptoms Associated with COVID-19 (BREATH Study): A Randomized Pilot Clinical Trial

by Suzana Tanni, Fernando Wehrmeister, Robson Prudente, Felipe Damatto, Carlos Breda Neto, Leiliane Oliveira, Luana Pagan, Mariana Gatto, Letícia Vieira, Liana Coelho, Diane Rezende, Luiz Machado, Gustavo Mota, Marina Gaiato, Felipe Santaella, Elisângela Campos, Estefânia Franco, Matheus Callegari, Marina Politi Okoshi and Ulla Weinreich

J. Clin. Med. 2023, 12(18), 6075; https://doi.org/10.3390/jcm12186075 - 20 Sep 2023

Cited by 1 | Viewed by 874

Abstract

(1) Background: A high concentration of sodium chloride on in vitro cell culture leads to reduced SARS-CoV-2 replication. Therefore, our aim was to evaluate the effects of inhaling hypertonic NaCl particles (BREATHOX^®) on the duration of COVID-19-induced acute symptoms. (2) Methods: [...] Read more.

(1) Background: A high concentration of sodium chloride on in vitro cell culture leads to reduced SARS-CoV-2 replication. Therefore, our aim was to evaluate the effects of inhaling hypertonic NaCl particles (BREATHOX^®) on the duration of COVID-19-induced acute symptoms. (2) Methods: A prospective, open label, randomized, standard of care-controlled group (SOC) pilot trial compared inhaled oral and nasal administered BREATHOX^® (2.0 mg NaCl, particles size between 1–10 μm), with five or ten inhalations per day for ten days. The primary endpoint was the time to resolve COVID-19-related symptoms. Safety outcomes included adverse clinical and laboratory events. (3) Results: A total of 101 individuals were screened and 98 were randomly assigned to BREATHOX^® ten sessions per day (Group 1; 33 patients), BREATHOX^® five sessions per day (Group 2; 32 patients), or SOC (33 patients), and followed up for 28 days. There was an association with cough frequency after 10 days BREATHOX^® compared to SOC [Group 1: hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.06–3.81; Group 2: HR 2.17, 95% CI 1.17–4.04]. No differences between the groups for the reported symptoms’ resolution time were seen after 28 days. After combining both BREATHOX^® groups, the period to cough resolution 10 days after randomization was significantly lower than in SOC (HR 2.10, 95% CI 1.20–3.67). An adverse event occurred in 30% of Group 1, 36% of Group 2, and 9% in SOC individuals. One patient from SOC had a serious adverse event. Nasal burning, sore or itchy nose, and dry mouth were considered related to BREATHOX^® use and resolved after stopping inhalations. (4) Conclusion: BREATHOX^® inhalation is safe and may be effective in reducing the duration of COVID-19-induced coughing. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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7 pages, 234 KiB

Open AccessEditorial

Increased Thrombotic Risk in COVID-19: Evidence and Controversy

by Antonio De Vita, Francesco Franceschi and Marcello Covino

J. Clin. Med. 2023, 12(13), 4441; https://doi.org/10.3390/jcm12134441 - 01 Jul 2023

Cited by 1 | Viewed by 972

Abstract

The pandemic of respiratory disease caused by the novel coronavirus named SARS-CoV-2, which emerged at the end of 2019, is still ongoing [...] Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

9 pages, 609 KiB

Open AccessCommunication

COVID-19: S-Peptide RBD _484–508 Induces IFN-γ T-Cell Response in Naïve-to-Infection and Unvaccinated Subjects with Close Contact with SARS-CoV-2-Positive Patients

by Michela Murdocca, Gennaro Citro, Eleonora Centanini, Rosalinda Giannini, Andrea Latini, Federica Centofanti, Eva Piano Mortari, Dario Cocciadiferro, Antonio Novelli, Sergio Bernardini, Giuseppe Novelli and Federica Sangiuolo

Viruses 2023, 15(7), 1417; https://doi.org/10.3390/v15071417 - 22 Jun 2023

Viewed by 1281

Abstract

Despite the availability on the market of different anti-SARS-CoV-2 vaccines, there are still unanswered questions on whether they can stimulate long-lasting protection. A deep understanding of adaptive immune response to SARS-CoV-2 is important for optimizing both vaccine development and pandemic control measures. Among [...] Read more.

Despite the availability on the market of different anti-SARS-CoV-2 vaccines, there are still unanswered questions on whether they can stimulate long-lasting protection. A deep understanding of adaptive immune response to SARS-CoV-2 is important for optimizing both vaccine development and pandemic control measures. Among cytokines secreted by lymphocytes in response to viral infection, IFN-γ plays a pivotal role both in innate and adaptive immunity. In this study, we report on 28 naïve-to-SARS-Cov-2-infection and unvaccinated subjects, having reported a close and prolonged contact with COVID-19-positive patients. Samples were tested for defective genetic variants in interferon pathway genes by whole exome sequencing and anti-IFN autoantibodies production was investigated. Subject T-cells were cultured and infected with pseudotype particles bearing the S proteins and in parallel stimulated with two S-peptides designed on the RBD region of the spike protein. Our results showed that one of these peptides, RBD 484–508, induces a significant increase in IFN-γ gene expression and protein production in T-cells, comparable to those obtained in cells infected by SARS-CoV-2 pseudovirus. This work deepens our understanding of immune response and highlights the selected peptide as a reasonable approach to induce broad, potent, and variant concern-independent T-cell responses. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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22 pages, 7613 KiB

Open AccessArticle

Inhibition of PERK Kinase, an Orchestrator of the Unfolded Protein Response (UPR), Significantly Reduces Apoptosis and Inflammation of Lung Epithelial Cells Triggered by SARS-CoV-2 ORF3a Protein

by Panagiotis Keramidas, Eleni Papachristou, Rigini M. Papi, Aglaia Mantsou and Theodora Choli-Papadopoulou

Biomedicines 2023, 11(6), 1585; https://doi.org/10.3390/biomedicines11061585 - 30 May 2023

Cited by 4 | Viewed by 2123

Abstract

SARS-CoV-2 ORF3a accessory protein was found to be involved in virus release, immunomodulation and exhibited a pro-apoptotic character. In order to unravel a potential ORF3a-induced apoptotic and inflammatory death mechanism, lung epithelial cells (A549) were transfected with in vitro synthesized ORF3a mRNA. The [...] Read more.

SARS-CoV-2 ORF3a accessory protein was found to be involved in virus release, immunomodulation and exhibited a pro-apoptotic character. In order to unravel a potential ORF3a-induced apoptotic and inflammatory death mechanism, lung epithelial cells (A549) were transfected with in vitro synthesized ORF3a mRNA. The protein’s dynamic involvement as “stress factor” for the endoplasmic reticulum, causing the activation of PERK kinase and other UPR-involved proteins and therefore the upregulation of their signaling pathway executioners (ATF6, XBP-1s, PERK, phospho eIF2a, ATF4, CHOP, GADD34), has been clearly demonstrated. Furthermore, the overexpression of BAX and BH3-only pro-apoptotic protein PUMA, the upregulation of Bcl-2 family genes (BAX, BAK, BID, BAD), the reduced expression of Bcl-2 in mRNA and protein levels, and lastly, the cleavage of PARP-1 and caspase family members (caspase-3,-8 and -9) indicate that ORF3a displays its apoptotic character through the mitochondrial pathway of apoptosis. Moreover, the upregulation of NFκB, phosphorylation of p65 and IκΒα and the elevated expression of pro-inflammatory cytokines (IL-1b, IL-6, IL-8 and IL-18) in transfected cells with ORF3a mRNA indicate that this protein causes the inflammatory response through NFκB activation and therefore triggers lung injury. An intriguing finding of our study is that upon treatment of the ORF3a-transfected cells with GSK2606414, a selective PERK inhibitor, both complications (apoptosis and inflammatory response) were neutralized, and cell survival was favored, whereas treatment of transfected cells with z-VAD (a pan-caspase inhibitor) despite inhibiting cell death, could not ameliorate the inflammatory response of transfected A549 cells. Given the above, we point out that PERK kinase is a “master tactician” and its activation constitutes the main stimulus for the emergence of ORF3a apoptotic and inflammatory nature and therefore could serve as potential target for developing novel therapeutic approaches against COVID-19. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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12 pages, 475 KiB

Open AccessArticle

Ivermectin Effect on In-Hospital Mortality and Need for Respiratory Support in COVID-19 Pneumonia: Propensity Score-Matched Retrospective Study

by Jara Llenas-García, Alfonso del Pozo, Alberto Talaya, Nuria Roig-Sánchez, Noemí Poveda Ruiz, Carlos Devesa García, Emilio Borrajo Brunete, Inmaculada González Cuello, Ana Lucas Dato, Miriam Navarro and Philip Wikman-Jorgensen

Viruses 2023, 15(5), 1138; https://doi.org/10.3390/v15051138 - 10 May 2023

Viewed by 2173

Abstract

Introduction. There is negligible evidence on the efficacy of ivermectin for treating COVID-19 pneumonia. This study aimed to assess the efficacy of ivermectin for pre-emptively treating Strongyloides stercoralis hyperinfection syndrome in order to reduce mortality and the need for respiratory support in patients [...] Read more.

Introduction. There is negligible evidence on the efficacy of ivermectin for treating COVID-19 pneumonia. This study aimed to assess the efficacy of ivermectin for pre-emptively treating Strongyloides stercoralis hyperinfection syndrome in order to reduce mortality and the need for respiratory support in patients hospitalized for COVID-19. Methods. This single-center, observational, retrospective study included patients admitted with COVID-19 pneumonia at Hospital Vega Baja from 23 February 2020 to 14 March 2021. Because strongyloidiasis is endemic to our area, medical criteria support empiric administration of a single, 200 μg/kg dose of ivermectin to prevent Strongyloides hyperinfection syndrome. The outcome was a composite of all-cause in-hospital mortality and the need for respiratory support. Results. Of 1167 patients in the cohort, 96 received ivermectin. After propensity score matching, we included 192 patients. The composite outcome of in-hospital mortality or need for respiratory support occurred in 41.7% of the control group (40/96) and 34.4% (33/96) of the ivermectin group. Ivermectin was not associated with the outcome of interest (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.35, 1.69; p = 0.52). The factors independently associated with this endpoint were oxygen saturation (aOR 0.78, 95% CI 0.68, 0.89, p < 0.001) and C-reactive protein at admission (aOR: 1.09, 95% CI 1.03, 1.16, p < 0.001). Conclusions. In hospitalized patients with COVID-19 pneumonia, ivermectin at a single dose for pre-emptively treating Strongyloides stercoralis is not effective in reducing mortality or the need for respiratory support measures. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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13 pages, 717 KiB

Open AccessReview

Three Years of COVID-19 Pandemic—Is the Heart Skipping a Beat?

by Maria-Luiza Luchian, Fabian Demeure, Julien Higny, Yannick Berners, Jean Henry, Antoine Guedes, Gabriel Laurence, Lara Saidane, Alexandra Höcher, Bram Roosens, Steven Droogmans, Bernard Cosyns and Andreea Motoc

COVID 2023, 3(5), 715-727; https://doi.org/10.3390/covid3050053 - 04 May 2023

Viewed by 1698

Abstract

In the context of new therapeutic protocols and vaccines developed in the past 3 years, coronavirus 2019 (COVID-19) continues to exert an important impact on the healthcare systems worldwide. Age and a history of cardiovascular or respiratory diseases remain relevant in terms of [...] Read more.

In the context of new therapeutic protocols and vaccines developed in the past 3 years, coronavirus 2019 (COVID-19) continues to exert an important impact on the healthcare systems worldwide. Age and a history of cardiovascular or respiratory diseases remain relevant in terms of prognosis for all COVID-19 patients, independent of the viral strain, by conveying a worse outcome and increased rates of in-hospital mortality. Previous studies reported heterogenous cardiovascular manifestations in COVID-19 patients from acute myocarditis or myopericarditis, acute coronary syndromes, stress cardiomyopathy, de novo arrhythmias to pulmonary embolism, or in some rare cases, endocarditis. In this review, we assessed the potential acute, in-hospital and long-term cardiac complications in patients diagnosed with COVID-19. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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15 pages, 1690 KiB

Open AccessArticle

Molecular Dynamics Simulations Suggest SARS-CoV-2 3CLpro Mutations in Beta and Omicron Variants Do Not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins

by Vitor Martins de Freitas Amorim, Robson Francisco de Souza, Cristiane Rodrigues Guzzo and Anacleto Silva de Souza

COVID 2023, 3(4), 622-636; https://doi.org/10.3390/covid3040044 - 17 Apr 2023

Viewed by 1928

Abstract

In the course of SARS-CoV-2 infection, the 3CL or nsp5 protease plays a pivotal role as the most important viral protease required for the maturation of viral proteins during host infection. Herein, we simulated for 500 ns 3CLpro^WT, 3CLpro^H41A, [...] Read more.

In the course of SARS-CoV-2 infection, the 3CL or nsp5 protease plays a pivotal role as the most important viral protease required for the maturation of viral proteins during host infection. Herein, we simulated for 500 ns 3CLpro^WT, 3CLpro^H41A, 3CLpro^Beta, and 3CLpro^Omicron, in complex with the substrates nsp 4|5 and nsp 5|6. Our results show that mutations in the 3CLpro present in the SARS-CoV-2 variants of concern (VOCs) did not lead to significant conformational changes or changes in substrate binding affinities. However, significantly high cleavage rates for the boundary between nsp4 and nsp5 were obtained for 3CLpro^Beta and 3CLpro^Omicron and may play a key role in viral replication and virus fitness gain. Our molecular dynamics data suggest that the cleavage rate of nsp4|5 may be related to the increased amount of viral load observed for these VOCs, releasing more nsp4 than other non-structural proteins. This study is limited by being fully computational. However, our results suggest that the cleavage rate may be affected by mutations. Based on our hydrogen bonding analyses, we also discovered that Gly143 and Glu166 are key residues in substrate recognition, suggesting that these residues may be incorporated as pharmacophoric centers for Beta and Omicron variants in drug design. Our results suggest that Gly143 and Glu166 are essential residues to interact with Gln6 of the different substrates and, therefore, are potential broad-spectrum pharmacophoric centers of SARS-CoV-2 3CLpro. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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23 pages, 14038 KiB

Open AccessArticle

High-Affinity Neutralizing DNA Aptamers against SARS-CoV-2 Spike Protein Variants

by Mohamad Ammar Ayass, Natalya Griko, Victor Pashkov, Trivendra Tripathi, Wanying Cao, Nazanin Javan, Jun Dai, Jin Zhang, Kevin Zhu and Lina Abi-Mosleh

COVID 2023, 3(4), 520-542; https://doi.org/10.3390/covid3040038 - 07 Apr 2023

Cited by 2 | Viewed by 2366

Abstract

The continuous emergence of new variants of concern for SARS-CoV-2 has created a challenge for existing therapies. To address this, we developed a series of single-stranded DNA aptamers that not only bind specifically to the trimer S protein of SARS-CoV-2 but also block [...] Read more.

The continuous emergence of new variants of concern for SARS-CoV-2 has created a challenge for existing therapies. To address this, we developed a series of single-stranded DNA aptamers that not only bind specifically to the trimer S protein of SARS-CoV-2 but also block the interaction between the trimer S protein and ACE2 receptors. The systematic evolution of ligands by exponential enrichment (SELEX) was performed to select the aptamers for SARS-CoV-2 trimer S protein. ELISA-based assay and flow cytometry were performed to test the apatmers’ binding and inhibition of trimer S protein in vitro. Binding affinity was measured using surface plasmon resonance. Significance was determined in Prism 9.0 using the one-way ANOVA test (Dunnett’s multiple comparisons test) or two-way ANOVA test (Tukey’s multiple comparisons test) for comparisons. The p values < 0.05 were considered statistically significant. After 12 rounds of SELEX, eight highly enriched aptamers were able to bind to the trimer S protein of the SARS-CoV-2 Wuhan original strain as well as the trimer S proteins of the Delta, Delta plus, Alpha, Lambda, Mu, and Omicron variants, with affinities in the nM range, while also inhibiting their interaction with ACE2 receptors in Vero E6 cells. Modifications to our best aptamer were made by adding forward and reverse primer sequences and truncation. The modified aptamers AYA2012004_L and AYA2012004_L-M1 showed up to 70% inhibition of the binding of virus-like particles (VLPs) expressing S protein to the ACE2 receptor expressed in HEK293T cells. Our findings imply that the selected aptamers can prevent SARS-CoV-2 from entering host cells and hence suppress the viral infection. In addition, the findings suggest that the selected aptamers might be an innovative therapy for the treatment of COVID-19. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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10 pages, 331 KiB

Open AccessArticle

Role of Selective Digestive Decontamination in the Prevention of Ventilator-Associated Pneumonia in COVID-19 Patients: A Pre-Post Observational Study

by Emanuela Biagioni, Elena Ferrari, Ilenia Gatto, Lucia Serio, Carlotta Farinelli, Irene Coloretti, Marta Talamonti, Martina Tosi, Marianna Meschiari, Roberto Tonelli, Claudia Venturelli, Cristina Mussini, Enrico Clini, Mario Sarti, Andrea Cossarizza, Stefano Busani and Massimo Girardis

J. Clin. Med. 2023, 12(4), 1432; https://doi.org/10.3390/jcm12041432 - 10 Feb 2023

Cited by 4 | Viewed by 1582

Abstract

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator-associated pneumonia (VAP) in COVID-19 patients without changes in the microbiological pattern of antibiotic resistance. This [...] Read more.

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator-associated pneumonia (VAP) in COVID-19 patients without changes in the microbiological pattern of antibiotic resistance. This observational pre-post study included adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID-19 intensive care units (ICUs) in an Italian hospital from 22 February 2020 to 8 March 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulfate, colistin sulfate, and amphotericin B suspension applied in the patient’s oropharynx and the stomach via a nasogastric tube. Three-hundred-and-forty-eight patients were included in the study. In the 86 patients (32.9%) who received SDD, the occurrence of VAP decreased by 7.7% (p = 0.192) compared to the patients who did not receive SDD. The onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation, and hospital mortality were similar in the patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0.536, CI 0.338–0.851; p = 0.017). Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID-19 patients. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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27 pages, 6141 KiB

Open AccessReview

Coagulation Disorders in Sepsis and COVID-19—Two Sides of the Same Coin? A Review of Inflammation–Coagulation Crosstalk in Bacterial Sepsis and COVID-19

by Georgeana Tuculeanu, Ecaterina Constanta Barbu, Mihai Lazar, Cristina Emilia Chitu-Tisu, Emanuel Moisa, Silvius Ioan Negoita and Daniela Adriana Ion

J. Clin. Med. 2023, 12(2), 601; https://doi.org/10.3390/jcm12020601 - 11 Jan 2023

Cited by 7 | Viewed by 2927

Abstract

Sepsis is a major cause of morbidity and mortality worldwide. Sepsis-associated coagulation disorders are involved in the pathogenesis of multiorgan failure and lead to a subsequently worsening prognosis. Alongside the global impact of the COVID-19 pandemic, a great number of research papers have [...] Read more.

Sepsis is a major cause of morbidity and mortality worldwide. Sepsis-associated coagulation disorders are involved in the pathogenesis of multiorgan failure and lead to a subsequently worsening prognosis. Alongside the global impact of the COVID-19 pandemic, a great number of research papers have focused on SARS-CoV-2 pathogenesis and treatment. Significant progress has been made in this regard and coagulation disturbances were once again found to underlie some of the most serious adverse outcomes of SARS-CoV-2 infection, such as acute lung injury and multiorgan dysfunction. In the attempt of untangling the mechanisms behind COVID-19-associated coagulopathy (CAC), a series of similarities with sepsis-induced coagulopathy (SIC) became apparent. Whether they are, in fact, the same disease has not been established yet. The clinical picture of CAC shows the unique feature of an initial phase of intravascular coagulation confined to the respiratory system. Only later on, patients can develop a clinically significant form of systemic coagulopathy, possibly with a consumptive pattern, but, unlike SIC, it is not a key feature. Deepening our understanding of CAC pathogenesis has to remain a major goal for the research community, in order to design and validate accurate definitions and classification criteria. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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8 pages, 248 KiB

Open AccessArticle

Safety Profile of Molnupiravir in the Treatment of COVID-19: A Descriptive Study Based on FAERS Data

by Greta Santi Laurini, Nicola Montanaro and Domenico Motola

J. Clin. Med. 2023, 12(1), 34; https://doi.org/10.3390/jcm12010034 - 21 Dec 2022

Cited by 9 | Viewed by 2402

Abstract

Concerns have been raised about the actual benefit and safety of molnupiravir, a new antiviral treatment for coronavirus disease 2019 (COVID-19). In order to provide additional evidence to support its use, we aimed to evaluate the real safety profile based on post-marketing pharmacovigilance [...] Read more.

Concerns have been raised about the actual benefit and safety of molnupiravir, a new antiviral treatment for coronavirus disease 2019 (COVID-19). In order to provide additional evidence to support its use, we aimed to evaluate the real safety profile based on post-marketing pharmacovigilance data. Molnupiravir safety data were captured from the FDA Adverse Event Reporting System (FAERS). We performed a descriptive analysis of the baseline demographic characteristics of patients who experienced at least one adverse drug reaction (ADRs) related to molnupiravir, and then evaluated those most frequently reported. As of 31 March 2022, 612 reports of ADRs related to molnupiravir were submitted to the FDA, 301 (49.18%) were related to females and 281 (45.92%) to males. Most reports (524; 85.62%) were submitted by healthcare professionals and 345 (56.37%) concerned serious outcomes. The most common reported ADRs were diarrhoea (57; 4.51%), rash (36; 2.85), nausea (29; 2.30%), and COVID-19 pneumonia (22; 1.74%). The most frequent adverse reactions reported with molnupiravir in the U.S. post-marketing experience are consistent with the safety evaluation of the antiviral medicine. Even if no evident safety concerns emerged, an unexpectedly high rate of serious adverse reactions together with a few cases of potential new adverse reactions occurred. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

20 pages, 2482 KiB

Open AccessArticle

Biopsychosocial Response to the COVID-19 Lockdown in People with Major Depressive Disorder and Multiple Sclerosis

by Sara Siddi, Iago Giné-Vázquez, Raquel Bailon, Faith Matcham, Femke Lamers, Spyridon Kontaxis, Estela Laporta, Esther Garcia, Belen Arranz, Gloria Dalla Costa, Ana Isabel Guerrero, Ana Zabalza, Mathias Due Buron, Giancarlo Comi, Letizia Leocani, Peter Annas, Matthew Hotopf, Brenda W. J. H. Penninx, Melinda Magyari, Per S. Sørensen, Xavier Montalban, Grace Lavelle, Alina Ivan, Carolin Oetzmann, Katie M. White, Sonia Difrancesco, Patrick Locatelli, David C. Mohr, Jordi Aguiló, Vaibhav Narayan, Amos Folarin, Richard J. B. Dobson, Judith Dineley, Daniel Leightley, Nicholas Cummins, Srinivasan Vairavan, Yathart Ranjan, Zulqarnain Rashid, Aki Rintala, Giovanni De Girolamo, Antonio Preti, Sara Simblett, Til Wykes, PAB Members, Inez Myin-Germeys, Josep Maria Haro and on behalf of the RADAR-CNS Consortium Show full author list Hide full author list

J. Clin. Med. 2022, 11(23), 7163; https://doi.org/10.3390/jcm11237163 - 01 Dec 2022

Cited by 5 | Viewed by 2782

Abstract

Background: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS). Methods: Data were collected as a part of the RADAR-CNS (Remote [...] Read more.

Background: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS). Methods: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse—Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender. Results: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods. Conclusions: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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13 pages, 2074 KiB

Open AccessArticle

Growth Arrest of Alveolar Cells in Response to Cytokines from Spike S1-Activated Macrophages: Role of IFN-γ

by Amelia Barilli, Rossana Visigalli, Francesca Ferrari, Giulia Recchia Luciani, Maurizio Soli, Valeria Dall'Asta and Bianca Maria Rotoli

Biomedicines 2022, 10(12), 3085; https://doi.org/10.3390/biomedicines10123085 - 01 Dec 2022

Cited by 3 | Viewed by 1276

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia and high-permeability pulmonary edema. A hallmark of the disease is the presence of lung inflammation with features of diffuse alveolar damage. The molecular pathogenetic mechanisms of COVID-19-associated ARDS (CARDS), secondary to SARS-CoV-2 infection, [...] Read more.

Acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia and high-permeability pulmonary edema. A hallmark of the disease is the presence of lung inflammation with features of diffuse alveolar damage. The molecular pathogenetic mechanisms of COVID-19-associated ARDS (CARDS), secondary to SARS-CoV-2 infection, are still not fully understood. Here, we investigate the effects of a cytokine-enriched conditioned medium from Spike S1-activated macrophage on alveolar epithelial A549 cells in terms of cell proliferation, induction of autophagy, and expression of genes related to protein degradation. The protective effect of baricitinib, employed as an inhibitor of JAK-STAT, has been also tested. The results obtained indicate that A549 exhibits profound changes in cell morphology associated to a proliferative arrest in the G0/G1 phase. Other alterations occur, such as a blockade of protein synthesis and the activation of autophagy, along with an increase of the intracellular amino acids content, which is likely ascribable to the activation of protein degradation. These changes correlate to the induction of IFN-regulatory factor 1 (IRF-1) due to an increased secretion of IFN-γ in the conditioned medium from S1-activated macrophages. The addition of baricitinib prevents the observed effects. In conclusion, our findings suggest that the IFN-γ-IRF-1 signaling pathway may play a role in the alveolar epithelial damage observed in COVID-19-related ARDS. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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5 pages, 995 KiB

Open AccessCase Report

Survival by Mediastinal Chest Drain Due to Pneumomediastinum Resulting from COVID-19

by Johanna Elisabeth Lingens, Jan Berend Lingens, Achim Gutersohn and Christian Hönemann

COVID 2022, 2(12), 1710-1714; https://doi.org/10.3390/covid2120122 - 29 Nov 2022

Cited by 1 | Viewed by 3136

Abstract

Pneumomediastinum, pneumothorax, and subcutaneous emphysema may occur as rare complications of COVID-19. They are associated with worsened prognosis and survival from SARS-CoV-2 pneumonia. The treatment of pneumomediastinum involves supportive care and management of underlying diseases. Our case presents a female patient suffering from [...] Read more.

Pneumomediastinum, pneumothorax, and subcutaneous emphysema may occur as rare complications of COVID-19. They are associated with worsened prognosis and survival from SARS-CoV-2 pneumonia. The treatment of pneumomediastinum involves supportive care and management of underlying diseases. Our case presents a female patient suffering from COVID-19 pneumonia with life-threatening mediastinal emphysema. According to guidelines, literature, and other clinical sources, no further therapy options were recommended, and survival was improbable. During an interdisciplinary case discussion, we decided to establish a mediastinal drain and tracheal cannula. This achieved a significant reduction of emphysema as well as an improvement in the patient’s clinical condition and long-term survival. This case demonstrates a rarely used invasive therapy for pneumomediastinum. Furthermore, it demonstrates the importance of cooperation with other centers, interdisciplinary teamwork, and of presenting case reviews—especially when guidelines are unavailable. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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14 pages, 545 KiB

Open AccessArticle

Low Intensity Respiratory Muscle Training in COVID-19 Patients after Invasive Mechanical Ventilation: A Retrospective Case-Series Study

by Koldo Villelabeitia-Jaureguizar, César Calvo-Lobo, David Rodríguez-Sanz, Davinia Vicente-Campos, José Adrián Castro-Portal, Marta López-Cañadas, Ricardo Becerro-de-Bengoa-Vallejo and José López Chicharro

Biomedicines 2022, 10(11), 2807; https://doi.org/10.3390/biomedicines10112807 - 04 Nov 2022

Cited by 2 | Viewed by 1669

Abstract

Worldwide, healthcare systems had to respond to an exponential increase in COVID-19 patients with a noteworthy increment in intensive care units (ICU) admissions and invasive mechanical ventilation (IMV). The aim was to determine low intensity respiratory muscle training (RMT) effects in COVID-19 patients [...] Read more.

Worldwide, healthcare systems had to respond to an exponential increase in COVID-19 patients with a noteworthy increment in intensive care units (ICU) admissions and invasive mechanical ventilation (IMV). The aim was to determine low intensity respiratory muscle training (RMT) effects in COVID-19 patients upon medical discharge and after an ICU stay with IMV. A retrospective case-series study was performed. Forty COVID-19 patients were enrolled and divided into twenty participants who received IMV during ICU stay (IMV group) and 20 participants who did not receive IMV nor an ICU stay (non-IMV group). Maximal expiratory pressure (PE_max), maximal inspiratory pressure (PI_max), COPD assessment test (CAT) and Medical Research Council (MRC) dyspnea scale were collected at baseline and after 12 weeks of low intensity RMT. A greater MRC dyspnea score and lower PI_max were shown at baseline in the IMV group versus the non-IMV group (p < 0.01). RMT effects on the total sample improved all outcome measurements (p < 0.05; d = 0.38–0.98). Intragroup comparisons after RMT improved PI_max, CAT and MRC scores in the IMV group (p = 0.001; d = 0.94–1.09), but not for PI_max in the non-IMV group (p > 0.05). Between-groups comparison after RMT only showed MRC dyspnea improvements (p = 0.020; d = 0.74) in the IMV group versus non-IMV group. Furthermore, PI_max decrease was only predicted by the IMV presence (R² = 0.378). Low intensity RMT may improve respiratory muscle strength, health related quality of life and dyspnea in COVID-19 patients. Especially, low intensity RMT could improve dyspnea level and maybe PI_max in COVID-19 patients who received IMV in ICU. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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9 pages, 941 KiB

Open AccessArticle

Reduced Risk of Progression from Non-Severe to Severe COVID-19 in Hospitalized Dialysis Patients by Full COVID-19 Vaccination

by Mitsuru Ichii, Masafumi Kurajoh, Yujiro Okute, Yasutaka Ihara, Takumi Imai, Tomoaki Morioka, Katsuhito Mori, Tetsuo Shoji, Yoshihiro Tsujimoto, Takanobu Ubai and Masanori Emoto

J. Clin. Med. 2022, 11(21), 6348; https://doi.org/10.3390/jcm11216348 - 27 Oct 2022

Cited by 2 | Viewed by 1336

Abstract

Coronavirus disease 2019 (COVID-19) vaccination reduces the risk of progression to severe COVID-19 in the general population. To examine that preventive effect in dialysis patients, the association of vaccination status with severe COVID-19 progression was investigated in this retrospective observational study conducted from [...] Read more.

Coronavirus disease 2019 (COVID-19) vaccination reduces the risk of progression to severe COVID-19 in the general population. To examine that preventive effect in dialysis patients, the association of vaccination status with severe COVID-19 progression was investigated in this retrospective observational study conducted from December 2020 to May 2022 of 100 such patients hospitalized for non-severe COVID-19 at Inoue Hospital (Suita, Japan). Fifty-seven were fully vaccinated, defined as receiving a COVID-19 vaccine second dose at least 14 days prior to the onset of COVID-19, while 43 were not. Among all patients, 13 (13.0%) progressed to severe COVID-19 with a median (interquartile range) time of 6 (2.5–9.5) days, while 87 (87.0%) were discharged after 11 (8–16) days. Kaplan–Meier analysis showed that fully vaccinated patients had a significantly lower rate of progression to severe COVID-19 (p = 0.001, log-rank test). Cox proportional hazard analysis also indicated that full COVID-19 vaccination was significantly associated with reduced instances of progression to severe COVID-19 (hazard ratio 0.104, 95% confidence interval 0.022 to 0.483; p = 0.004) after balancing patient background characteristics using an inverse probability of treatment weight method. These results suggest that full vaccination status contributes to reducing the risk of progression from non-severe to severe COVID-19 in dialysis patients. Full article

(This article belongs to the Topic New Advances in Pathophysiology and Therapy of COVID-19 and Other Coronavirus Diseases)

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