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Viruses
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COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition
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COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Coronaviruses".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 11263

Special Issue Editors

Dr. Antonio Voza

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Guest Editor
Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
Interests: COVID-19; NIV; antibiotic treatment; pneumonia; sepsis shock
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Fabbri

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Guest Editor
Emergency Department, AUSL della Romagna, Forlì, Italy
Interests: emergency medicine; brain injury; cardiovascular medicine; cardiology; risk stratification; acute heart failure; chest pain; cardiac arrest; sepsis; epidemiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. The precise definition of long COVID may be lacking, but the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. To those symptoms it will be possible to add cognitive and mental impairments, dry cough, chest and joint pains, palpitations, cardiac issues, myalgia, smell and taste dysfunctions, headache, and gastrointestinal issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g., of the lung, brain, and heart) and pathological inflammation. The principle etiological hypothesis could be due to viral persistence, immune dysregulation, and autoimmunity. The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g., D-dimer, CRP, and lymphocyte count); for these reasons, it could be desirable to deepen this topic with a Special Issue.

Dr. Antonio Voza
Dr. Andrea Fabbri
Guest Editors

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Keywords

  • COVID-19
  • pneumonia
  • SARS-CoV-2

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Related Special Issue

Published Papers (7 papers)

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Research

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19 pages, 7619 KiB  
Article
Comparative Transcriptomic Analyses of Peripheral Blood Mononuclear Cells of COVID-19 Patients without Pneumonia and with Severe Pneumonia in the First Year of Follow-Up
by Ozgecan Kayalar, Pelin Duru Cetinkaya, Vahap Eldem, Serap Argun Baris, Nurdan Kokturk, Selim Can Kuralay, Hadi Rajabi, Nur Konyalilar, Deniz Mortazavi, Seval Kubra Korkunc, Sinem Erkan, Gizem Tuşe Aksoy, Gul Eyikudamaci, Pelin Pinar Deniz, Oya Baydar Toprak, Pinar Yildiz Gulhan, Gulseren Sagcan, Neslihan Kose, Aysegul Tomruk Erdem, Fusun Fakili, Onder Ozturk, Ilknur Basyigit, Hasim Boyaci, Emel Azak, Tansu Ulukavak Ciftci, Ipek Kivilcim Oguzulgen, Hasan Selcuk Ozger, Pinar Aysert Yildiz, Ismail Hanta, Ozlem Ataoglu, Merve Ercelik, Caglar Cuhadaroglu, Hacer Kuzu Okur, Muge Meltem Tor, Esra Nurlu Temel, Seval Kul, Yıldız Tutuncu, Oya Itil and Hasan Bayramadd Show full author list remove Hide full author list
Viruses 2024, 16(8), 1211; https://doi.org/10.3390/v16081211 - 28 Jul 2024
Viewed by 1644
Abstract
The multisystemic effects of COVID-19 may continue for a longer time period following the acute phase, depending on the severity of the disease. However, long-term systemic transcriptomic changes associated with COVID-19 disease and the impact of disease severity are not fully understood. We [...] Read more.
The multisystemic effects of COVID-19 may continue for a longer time period following the acute phase, depending on the severity of the disease. However, long-term systemic transcriptomic changes associated with COVID-19 disease and the impact of disease severity are not fully understood. We aimed to investigate the impact of COVID-19 and its severity on transcriptomic alterations in peripheral blood mononuclear cells (PBMCs) following 1 year of the disease. PBMCs were isolated from the peripheral blood of healthy control donors who did not have COVID-19 (C; n = 13), from COVID-19 patients without pneumonia (NP; n = 11), and from COVID-19 patients with severe pneumonia (SP; n = 10) after 1-year of follow-up. Following RNA isolation from PBMCs, high-quality RNAs were sequenced after creating a library. Differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs) were identified using Benjamini–Hochberg correction and they were analysed for hierarchical clustering and principal component analysis (PCA). Intergroup comparisons (C vs. NP, C vs. SP, and NP vs. SP) of DEGs and DElncRNAs were performed and hub genes were determined. Functional enrichment analyses of DEGs and DElncRNAs were made using Metascape (v3.5.20240101) and the first version of NCPATH. The RNA sequencing analysis revealed 4843 DEGs and 1056 DElncRNAs in “C vs. NP”, 1651 DEGs and 577 DElncRNAs in “C vs. SP”, and 954 DEGs and 148 DElncRNAs in “NP vs. SP”, with 291 DEGs and 70 DElncRNAs shared across all groups, respectively. We identified 14 hub genes from 291 DEGs, with functional enrichment analysis showing upregulated DEGs mainly linked to inflammation and osteoclast differentiation and downregulated DEGs to viral infections and immune responses. The analysis showed that 291 common and 14 hub genes were associated with pneumonia and that these genes could be regulated by the transcription factors JUN and NFκB1 carrying the NFκB binding site. We also revealed unique immune cell signatures across DEG categories indicating that the upregulated DEGs were associated with neutrophils and monocytes, while downregulated DEGs were associated with CD4 memory effector T cells. The comparative transcriptomic analysis of NP and SP groups with 52 gene signatures suggestive of IPF risk showed a lower risk of IPF in the SP group than the NP patients. Our findings suggest that COVID-19 may cause long term pathologies by modulating the expression of various DEGs, DeLncRNAs, and hub genes at the cellular level. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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14 pages, 1468 KiB  
Article
Long COVID Clusters of Symptoms Persist beyond Two Years after Infection: Insights from the CARDIO COVID 20–21 Registry
by Juan Pablo Arango-Ibanez, Brayan Daniel Córdoba-Melo, Juliana María Gutiérrez Posso, Mario Miguel Barbosa-Rengifo, Cesar J. Herrera, Miguel Angel Quintana Da Silva, Andrés Felipe Buitrago, María Lorena Coronel Gilio, Freddy Pow-Chong-Long and Juan Esteban Gómez-Mesa
Viruses 2024, 16(7), 1028; https://doi.org/10.3390/v16071028 - 26 Jun 2024
Cited by 1 | Viewed by 1463
Abstract
Long COVID presents with diverse symptoms after COVID-19. Different clusters of symptoms have been reported; however, their persistence beyond 2 years after COVID-19 remains unclear. In this cohort study, we prospectively evaluated individuals with previous severe COVID-19 presenting with long COVID at a [...] Read more.
Long COVID presents with diverse symptoms after COVID-19. Different clusters of symptoms have been reported; however, their persistence beyond 2 years after COVID-19 remains unclear. In this cohort study, we prospectively evaluated individuals with previous severe COVID-19 presenting with long COVID at a two-year follow-up. We characterized the included patients and performed a cluster analysis of symptoms through multiple correspondence analysis and hierarchical clustering. A total of 199 patients with long COVID were included. The median age was 58 years (48–69), 56% were male, and the median follow-up time since the COVID-19 diagnosis was 26 months (IQR: 25, 27). Three symptom clusters were identified: Cluster 1 is characterized by fatigue, myalgia/arthralgia, a low prevalence of symptoms, and a lack of specific symptoms; Cluster 2 is defined by a high prevalence of fatigue, myalgia/arthralgia, and cardiorespiratory symptoms, including palpitations, shortness of breath, cough, and chest pain; and Cluster 3 is demonstrated a high prevalence of ageusia, anosmia, fatigue, and cardiorespiratory symptoms. Our study reinforces the concept of symptom clustering in long COVID, providing evidence that these clusters may persist beyond two years after a COVID-19 diagnosis. This highlights the chronic and debilitating nature of long COVID and the importance of developing strategies to mitigate symptoms in these patients. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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10 pages, 844 KiB  
Article
Prognostic Value of D-dimer to Lymphocyte Ratio (DLR) in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Validation Study in a National Cohort
by Crhistian-Mario Oblitas, Pablo Demelo-Rodríguez, Luis-Antonio Alvarez-Sala-Walther, Manuel Rubio-Rivas, Francisco Navarro-Romero, Vicente Giner Galvañ, Lucía de Jorge-Huerta, Eva Fonseca Aizpuru, Gema María García García, José Luis Beato Pérez, Paula María Pesqueira Fontan, Arturo Artero Mora, Juan Antonio Vargas Núñez, Nuria Ramírez Perea, José Miguel García Bruñén, Emilia Roy Vallejo, Isabel Perales-Fraile, Ricardo Gil Sánchez, José López Castro, Ángel Luis Martínez González, Luis Felipe Díez García, Marina Aroza Espinar, José-Manuel Casas-Rojo and Jesús Millán Núñez-Cortésadd Show full author list remove Hide full author list
Viruses 2024, 16(3), 335; https://doi.org/10.3390/v16030335 - 22 Feb 2024
Cited by 1 | Viewed by 1186
Abstract
Background: This study aimed to validate the role of the D-dimer to lymphocyte ratio (DLR) for mortality prediction in a large national cohort of hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: A retrospective, multicenter, observational study that included hospitalized patients due to SARS-CoV-2 [...] Read more.
Background: This study aimed to validate the role of the D-dimer to lymphocyte ratio (DLR) for mortality prediction in a large national cohort of hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: A retrospective, multicenter, observational study that included hospitalized patients due to SARS-CoV-2 infection in Spain was conducted from March 2020 to March 2022. All biomarkers and laboratory indices analyzed were measured once at admission. Results: A total of 10,575 COVID-19 patients were included in this study. The mean age of participants was 66.9 (±16) years, and 58.6% (6202 patients) of them were male. The overall mortality rate was 16.3% (n = 1726 patients). Intensive care unit admission was needed in 10.5% (n = 1106 patients), non-invasive mechanical ventilation was required in 8.8% (n = 923 patients), and orotracheal intubation was required in 7.5% (789 patients). DLR presented a c-statistic of 0.69 (95% CI, 0.68–0.71) for in-hospital mortality with an optimal cut-off above 1. Multivariate analysis showed an independent association for in-hospital mortality for DLR > 1 (adjusted OR 2.09, 95% CI 1.09–4.04; p = 0.03); in the same way, survival analysis showed a higher mortality risk for DLR > 1 (HR 2.24; 95% CI 2.03–2.47; p < 0.01). Further, no other laboratory indices showed an independent association for mortality in multivariate analysis. Conclusions: This study confirmed the usefulness of DLR as a prognostic biomarker for mortality associated with SARS-CoV-2 infection, being an accessible, cost-effective, and easy-to-use biomarker in daily clinical practice. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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Review

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28 pages, 2301 KiB  
Review
The Silent Syndrome of Long COVID and Gaps in Scientific Knowledge: A Narrative Review
by Rosilene da Silva, Antonio Carlos Rosário Vallinoto and Eduardo José Melo dos Santos
Viruses 2024, 16(8), 1256; https://doi.org/10.3390/v16081256 - 5 Aug 2024
Viewed by 1048
Abstract
COVID-19 is still a major public health concern, mainly due to the persistence of symptoms or the appearance of new symptoms. To date, more than 200 symptoms of long COVID (LC) have been described. The present review describes and maps its relevant clinical [...] Read more.
COVID-19 is still a major public health concern, mainly due to the persistence of symptoms or the appearance of new symptoms. To date, more than 200 symptoms of long COVID (LC) have been described. The present review describes and maps its relevant clinical characteristics, pathophysiology, epidemiology, and genetic and nongenetic risk factors. Given the currently available evidence on LC, we demonstrate that there are still gaps and controversies in the diagnosis, pathophysiology, epidemiology, and detection of prognostic and predictive factors, as well as the role of the viral strain and vaccination. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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13 pages, 1200 KiB  
Review
Clinical Spectrum of Long COVID: Effects on Female Reproductive Health
by Syeda Maham and Mee-Sup Yoon
Viruses 2024, 16(7), 1142; https://doi.org/10.3390/v16071142 - 16 Jul 2024
Viewed by 1023
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has presented numerous health challenges, including long-term COVID, which affects female reproductive health. This review consolidates the current research on the impact of SARS-CoV-2 on the menstrual cycle, ovarian function, fertility, and overall gynecological health. This study [...] Read more.
The COVID-19 pandemic caused by SARS-CoV-2 has presented numerous health challenges, including long-term COVID, which affects female reproductive health. This review consolidates the current research on the impact of SARS-CoV-2 on the menstrual cycle, ovarian function, fertility, and overall gynecological health. This study emphasizes the role of angiotensin-converting enzyme receptors in viral entry and the subsequent tissue-specific pathological effects. It also explores the potential influence of long COVID on hormonal balance and immune responses, contributing to menstrual irregularities and impaired ovarian function. The findings indicate a higher prevalence of long-term COVID-19 among women, highlighting the substantial implications for reproductive health and the need for sex-sensitive longitudinal studies. Enhanced surveillance and targeted research are essential to develop effective interventions that prioritize women’s reproductive well-being following SARS-CoV-2 infection. This review advocates for a sex-informed approach to ongoing COVID-19 research and healthcare strategies, aiming to provide up-to-date and pertinent data for healthcare providers and the general public, ultimately improving outcomes for females affected by long COVID. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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17 pages, 1884 KiB  
Review
Exploring the Complexities of Long COVID
by Jackson Donald, Shymaa E. Bilasy, Catherine Yang and Ahmed El-Shamy
Viruses 2024, 16(7), 1060; https://doi.org/10.3390/v16071060 - 30 Jun 2024
Viewed by 1716
Abstract
Since the emergence of the SARS-CoV-2 virus in 2019, nearly 700 million COVID-19 cases and 7 million deaths have been reported globally. Despite most individuals recovering within four weeks, the Center for Disease Control (CDC) estimates that 7.5% to 41% develop post-acute infection [...] Read more.
Since the emergence of the SARS-CoV-2 virus in 2019, nearly 700 million COVID-19 cases and 7 million deaths have been reported globally. Despite most individuals recovering within four weeks, the Center for Disease Control (CDC) estimates that 7.5% to 41% develop post-acute infection syndrome (PAIS), known as ‘Long COVID’. This review provides current statistics on Long COVID’s prevalence, explores hypotheses concerning epidemiological factors, such as age, gender, comorbidities, initial COVID-19 severity, and vaccine interactions, and delves into potential mechanisms, including immune responses, viral persistence, and gut dysbiosis. Moreover, we conclude that women, advanced age, comorbidities, non-vaccination, and low socioeconomic status all appear to be risk factors. The reasons for these differences are still not fully understood and likely involve a complex relationship between social, genetic, hormonal, and other factors. Furthermore, individuals with Long COVID-19 seem more likely to endure economic hardship due to persistent symptoms. In summary, our findings further illustrate the multifaceted nature of Long COVID and underscore the importance of understanding the epidemiological factors and potential mechanisms needed to develop effective therapeutic strategies and interventions. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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43 pages, 2419 KiB  
Review
Myocardial Oedema as a Consequence of Viral Infection and Persistence—A Narrative Review with Focus on COVID-19 and Post COVID Sequelae
by Noel G. Panagiotides, Michael Poledniczek, Martin Andreas, Martin Hülsmann, Alfred A. Kocher, Christoph W. Kopp, Aleksandra Piechota-Polanczyk, Annika Weidenhammer, Noemi Pavo and Patricia P. Wadowski
Viruses 2024, 16(1), 121; https://doi.org/10.3390/v16010121 - 14 Jan 2024
Cited by 2 | Viewed by 2691
Abstract
Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation [...] Read more.
Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed. Full article
(This article belongs to the Special Issue COVID-19: Prognosis and Long-Term Sequelae, 2nd Edition)
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