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Exploring the Multisystem Features of Long COVID
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Exploring the Multisystem Features of Long COVID

A special issue of COVID (ISSN 2673-8112). This special issue belongs to the section "Long COVID and Post-Acute Sequelae".

Deadline for manuscript submissions: closed (31 May 2026) | Viewed by 37032

Editors

Dr. Andrea Marino

E-Mail Website
Guest Editor
Infectious Diseases Unit, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, 95122 Catania, Italy
Interests: bacterial infections; MDR bacteria; antimicrobial stewardship; antibiotics
Special Issues, Collections and Topics in MDPI journals
Dr. Emmanuele Venanzi Rullo

E-Mail Website
Guest Editor
Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
Interests: antimicrobial resistance; HAI; invasive fungal infections; travel and immigration medicine

Special Issue Information

Dear Colleagues,

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is a complex, multisystem condition where symptoms persist for weeks or months after acute COVID-19. Characterized by persistent symptoms that span multiple organ systems—ranging from neurological and cardiovascular to respiratory and gastrointestinal systems—Long COVID poses significant challenges in diagnosis, management, and rehabilitation. Despite increasing awareness, its pathophysiology remains only partially understood, and evidence-based treatments are still lacking. Emerging research also suggests that genetics may influence susceptibility, severity, and symptom persistence. Key areas of focus include the following: 1) genetic susceptibility to Long COVID (e.g., HLA, FOXP4, ACE2, and TMPRSS2); 2) immune and inflammatory genes (e.g., TLR3, TLR7, IRF7, IFN, and autoantibody IFN); 3) overlap with other post-viral syndromes, e.g., Long COVID shares features with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and dysautonomia (e.g., POTS); 4) epigenetics and viral persistence, e.g., SARS-CoV-2 may alter host gene expression (e.g., via DNA methylation), thereby exacerbating long-term symptoms. Genetic differences in viral clearance (e.g., APOBEC3 antiviral genes) could allow persistent viral fragments to trigger immune reactions; and 5) genetics likely interacts with age, sex (women are more affected), and prior health conditions.

This Special Issue aims to explore the multisystemic nature of Long COVID through original research, reviews, and clinical insights, fostering a multidisciplinary approach that integrates perspectives from infectious diseases, internal medicine, neurology, cardiology, and beyond. By shedding light on the long-term consequences of SARS-CoV-2 infection, we hope to contribute to improved patient care and the development of targeted therapeutic strategies. We look forward to your submissions.

Dr. Andrea Marino
Dr. Emmanuele Venanzi Rullo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. COVID is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1200 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

  • long COVID
  • post-acute COVID-19
  • multisystem involvement
  • PASC
  • COVID-19 sequelae
  • chronic symptoms
  • SARS-CoV-2
  • rehabilitation
  • pathophysiology
  • clinical management
  • genomics studies
  • polygenic risk scores (PRS)
  • personalized medicine
  • biomarker development

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Published Papers (3 papers)

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Research

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18 pages, 949 KB  
Article
Cardiovascular and Multisystem Outcomes Identified at Short- and Long-Term Follow-Up After COVID-19 Hospitalization: A Retrospective Cohort Study
by Sofia Teodora Muntean, Andreea-Raluca Cozac-Szoke, Andreea Cătălina Tinca, Diana Maria Chiorean, Adrian Horațiu Sabău, Iuliu Gabriel Cocuz, Raluca Niculescu, Claudia Raluca Mariean, Nadja Emily Pop, Ovidiu Simion Cotoi and Anca Ileana Sin
COVID 2026, 6(7), 124; https://doi.org/10.3390/covid6070124 - 16 Jul 2026
Viewed by 323
Abstract
Background: Persistent cardiovascular and multisystem manifestations remain an important concern following hospitalization for coronavirus disease 2019 (COVID-19). However, the spectrum of newly identified conditions during follow-up and their relationship with acute disease severity remain incompletely characterized. This study aimed to describe cardiovascular and [...] Read more.
Background: Persistent cardiovascular and multisystem manifestations remain an important concern following hospitalization for coronavirus disease 2019 (COVID-19). However, the spectrum of newly identified conditions during follow-up and their relationship with acute disease severity remain incompletely characterized. This study aimed to describe cardiovascular and multisystem diagnoses, identified during short-term and long-term follow-up and to evaluate the association between acute-phase clinical characteristics, biomarkers, and subsequent outcomes. Methods: We conducted a retrospective observational cohort study including 762 adults hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between January 2021 and December 2022. Follow-up data were obtained from patients who re-presented to the same hospital during short-term follow-up (mean 4.33 months; n = 130) or long-term follow-up (mean 2.06 years; n = 186). Newly documented cardiovascular and non-cardiovascular diagnoses recorded during routine clinical care were analyzed separately for each follow-up cohort. Multivariable logistic regression was used to identify predictors of in-hospital mortality and cardiovascular outcomes. Results: At least one newly documented diagnosis was identified in 120/130 patients (92.3%) during short-term follow-up and in 175/186 patients (94.1%) during long-term follow-up. Cardiovascular diagnoses were identified in 32.3% and 45.2% of patients attending short-term and long-term follow-up, respectively. Hypertension and atherosclerosis were the most frequent cardiovascular diagnoses during short-term follow-up, whereas heart failure and ischemic heart disease predominated among patients attending long-term follow-up. Pulmonary fibrosis was the most common non-cardiovascular diagnosis at both follow-up periods. Elevated D-dimer and fibrinogen levels during acute COVID-19 were independently associated with in-hospital mortality, whereas acute-phase NT-proBNP was not independently associated with cardiovascular diagnoses identified during follow-up. Conclusions: Patients who re-presented for clinical evaluation after hospitalization for COVID-19 exhibited a substantial burden of newly documented cardiovascular and multisystem diagnoses. Given the retrospective design, independent follow-up cohorts, and absence of a non-COVID control group, these findings should be interpreted as observational post-hospitalization data rather than evidence of causal or progressive post-COVID-19 disease. Prospective controlled longitudinal studies are needed to better define the long-term health consequences of SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Exploring the Multisystem Features of Long COVID)
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28 pages, 2209 KB  
Article
Dynamic Neuroimmune–Endothelial Network Remodeling in Long COVID: A Longitudinal Multilayer Graph Analysis
by Liya Vajdi, Dmitriy Klyuyev, Olga Ponamareva, Zeine Kulbayeva, Ahmadreza Vajdi and Bo Hu
COVID 2026, 6(7), 120; https://doi.org/10.3390/covid6070120 - 7 Jul 2026
Viewed by 391
Abstract
Background: Long COVID is a heterogeneous post-viral condition in which persistent neurological, autonomic, cognitive, and psychometric symptoms often occur without clear isolated biomarker abnormalities. This mismatch suggests that disease persistence may be driven not only by changes in individual markers, but by longitudinal [...] Read more.
Background: Long COVID is a heterogeneous post-viral condition in which persistent neurological, autonomic, cognitive, and psychometric symptoms often occur without clear isolated biomarker abnormalities. This mismatch suggests that disease persistence may be driven not only by changes in individual markers, but by longitudinal reorganization of biological and clinical interactions. Materials and Methods: This observational longitudinal study evaluated patients with persistent symptoms after confirmed SARS-CoV-2 infection at 3 and 6 months. Clinical assessment included neurological examination, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and COMPASS-31. Biomarkers representing hypoxia signaling, oxidative/redox stress, endothelial and renin–angiotensin system activity, glycation-related processes, and complement regulation were analyzed. Correlation analysis, association-level biomarker–clinical network modeling, and complementary Graphical LASSO-based sparse network estimation were used to compare network density, community organization, centrality, and edge rewiring between time points. Results: Conventional paired analysis identified HIF-1α as the only continuous variable with a statistically significant longitudinal change (Wilcoxon statistic = 610.0, p=0.000350), whereas association-level network analysis revealed a broader systems-level signal. The association-level biomarker–clinical network preserved a similar global size at 3 and 6 months, with 16 nodes, 27 versus 26 edges, and densities of 0.225 versus 0.217. However, this apparent stability concealed substantial rewiring: 19 edges were shared, 8 were lost, and 7 emerged. Complementary Graphical LASSO analysis with 1000 bootstrap resamples supported this pattern by identifying a conservative sparse conditional-dependency core, including seven shared conditional-dependency edges across time points and selective weakening of four early conditional dependencies. The C3–C4 relationship reversed from negative to positive correlation (r=−0.618 to r=0.618), indicating marked remodeling of complement-associated regulation. A psychometric–autonomic module involving Beck, HADS I, HADS II, and COMPASS-31 remained stable across both assessments. Conclusions: Long COVID progression was characterized by dynamic remodeling of immune, endothelial/RAS, oxidative-redox, hypoxia-related, autonomic, and psychometric interactions. Longitudinal network analysis identified a systems-level interaction structure that was not captured by isolated biomarker comparisons alone and that was further supported by complementary sparse conditional-dependency analysis. Full article
(This article belongs to the Special Issue Exploring the Multisystem Features of Long COVID)
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Review

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27 pages, 1876 KB  
Review
Silent Invasion: COVID-19′s Hidden Damage to Human Organs
by Ulugbek Ochilov, Gulomjon Kholov, Otabek Fayzulloyev, Odilshoh Bobokalonov, Shokhida Naimova, Nilufar Akhmedova, Mehriniso Ochilova, Mukhayyo Kutliyeva and Shakhlo Kakharova
COVID 2025, 5(9), 156; https://doi.org/10.3390/covid5090156 - 15 Sep 2025
Cited by 6 | Viewed by 35167
Abstract
Background: SARS-CoV-2, originally described as a respiratory pathogen, has been identified as a multisystem disease with complex and interconnected pathophysiological processes. Methods: The PRISMA framework was used to systematically review the evidence and identify and synthesize it in PubMed, Scopus, and Web of [...] Read more.
Background: SARS-CoV-2, originally described as a respiratory pathogen, has been identified as a multisystem disease with complex and interconnected pathophysiological processes. Methods: The PRISMA framework was used to systematically review the evidence and identify and synthesize it in PubMed, Scopus, and Web of Science databases between January 2020 and May 2025. Of the 1410 screened records, 161 peer-reviewed studies involving more than 2 million patients were included in the analysis. The frequency of organ involvement, important biomarkers, and long-term outcomes were derived, and the quality of the studies was assessed using standardized tools. Results: The quantitative synthesis showed that 78%, 32%, 43%, and 28% of hospitalized patients had pulmonary, cardiovascular, 43% neurological, and 28% renal issues, respectively, with 10–35% showing persistent organ dysfunction at 6 months post-infection. The most common were cytokine storm (IL-6 (Interleukin-6) > 100 pg/mL in 72% of severe cases), endothelial dysfunction (biomarkers elevated in 87% of patients), and microvascular thrombosis (D-dimer > 2000 ng/mL in 46% of patients). Most domains were scored as having moderate-to-high confidence in the quality assessment. Conclusions: COVID-19 has long-term, multi-organ sequelae that require integrated multidisciplinary management. Healthcare systems should be ready to participate in long-term monitoring, rehabilitation, and special therapeutic development. The results offer a strong evidence base for clinical practice and post-pandemic health policy. Full article
(This article belongs to the Special Issue Exploring the Multisystem Features of Long COVID)
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