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1
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Anderson LN, Hoyt CT, Zucker JD, McNaughton AD, Teuton JR, Karis K, Arokium-Christian NN, Warley JT, Stromberg ZR, Gyori BM, Kumar N. Computational tools and data integration to accelerate vaccine development: challenges, opportunities, and future directions. Front Immunol 2025; 16:1502484. [PMID: 40124369 PMCID: PMC11925797 DOI: 10.3389/fimmu.2025.1502484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/23/2025] [Indexed: 03/25/2025] Open
Abstract
The development of effective vaccines is crucial for combating current and emerging pathogens. Despite significant advances in the field of vaccine development there remain numerous challenges including the lack of standardized data reporting and curation practices, making it difficult to determine correlates of protection from experimental and clinical studies. Significant gaps in data and knowledge integration can hinder vaccine development which relies on a comprehensive understanding of the interplay between pathogens and the host immune system. In this review, we explore the current landscape of vaccine development, highlighting the computational challenges, limitations, and opportunities associated with integrating diverse data types for leveraging artificial intelligence (AI) and machine learning (ML) techniques in vaccine design. We discuss the role of natural language processing, semantic integration, and causal inference in extracting valuable insights from published literature and unstructured data sources, as well as the computational modeling of immune responses. Furthermore, we highlight specific challenges associated with uncertainty quantification in vaccine development and emphasize the importance of establishing standardized data formats and ontologies to facilitate the integration and analysis of heterogeneous data. Through data harmonization and integration, the development of safe and effective vaccines can be accelerated to improve public health outcomes. Looking to the future, we highlight the need for collaborative efforts among researchers, data scientists, and public health experts to realize the full potential of AI-assisted vaccine design and streamline the vaccine development process.
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Affiliation(s)
| | - Charles Tapley Hoyt
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, United States
| | - Jeremy D. Zucker
- Pacific Northwest National Laboratory (DOE), Richland, WA, United States
| | | | - Jeremy R. Teuton
- Pacific Northwest National Laboratory (DOE), Richland, WA, United States
| | - Klas Karis
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, United States
| | | | - Jackson T. Warley
- Pacific Northwest National Laboratory (DOE), Richland, WA, United States
| | | | - Benjamin M. Gyori
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, United States
- Department of Bioengineering, College of Engineering, Northeastern University, Boston, MA, United States
| | - Neeraj Kumar
- Pacific Northwest National Laboratory (DOE), Richland, WA, United States
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2
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Yip JQ, Oo A, Ng YL, Chin KL, Tan KK, Chu JJH, AbuBakar S, Zainal N. The role of inflammatory gene polymorphisms in severe COVID-19: a review. Virol J 2024; 21:327. [PMID: 39707400 PMCID: PMC11662554 DOI: 10.1186/s12985-024-02597-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has profoundly impacted global healthcare systems and spurred extensive research efforts over the past three years. One critical aspect of the disease is the intricate interplay between the virus and the host immune response, particularly the role of inflammatory gene expression in severe COVID-19. While numerous previous studies have explored the role of genetic polymorphisms in COVID-19, research specifically focusing on inflammatory genes and their associations with disease severity remains limited. This review explores the relationship between severe COVID-19 outcomes and genetic polymorphisms within key inflammatory genes. By investigating the impact of genetic variations on immune responses, which include cytokine production and downstream signalling pathways, we aim to provide a comprehensive overview of how genetic polymorphisms contribute to the variability in disease presentation. Through an in-depth analysis of existing literature, we shed light on potential therapeutic targets and personalized approaches that may enhance our understanding of disease pathogenesis and treatment strategies.
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Affiliation(s)
- Jia Qi Yip
- Tropical Infectious Diseases Research & Education Centre (TIDREC), Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Institute for Advanced Studies, Advanced Studies Complex, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Adrian Oo
- Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- Infectious Disease Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Yan Ling Ng
- Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- Infectious Disease Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Kim Ling Chin
- Institute for Advanced Studies, Advanced Studies Complex, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kim-Kee Tan
- Tropical Infectious Diseases Research & Education Centre (TIDREC), Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Justin Jang Hann Chu
- Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- Infectious Disease Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
- NUSMed Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
| | - Sazaly AbuBakar
- Tropical Infectious Diseases Research & Education Centre (TIDREC), Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Nurhafiza Zainal
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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Logotheti S, Pavlopoulou A, Rudsari HK, Galow AM, Kafalı Y, Kyrodimos E, Giotakis AI, Marquardt S, Velalopoulou A, Verginadis II, Koumenis C, Stiewe T, Zoidakis J, Balasingham I, David R, Georgakilas AG. Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: the paradigm of radiotherapy. Pharmacol Ther 2024; 260:108670. [PMID: 38823489 DOI: 10.1016/j.pharmthera.2024.108670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 05/16/2024] [Accepted: 05/25/2024] [Indexed: 06/03/2024]
Abstract
Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of CVDs. Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.
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Affiliation(s)
- Stella Logotheti
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece; Biomedical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | | | - Anne-Marie Galow
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - Yağmur Kafalı
- Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Efthymios Kyrodimos
- First Department of Otorhinolaryngology, Head and Neck Surgery, Hippocrateion General Hospital Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Aris I Giotakis
- First Department of Otorhinolaryngology, Head and Neck Surgery, Hippocrateion General Hospital Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Stephan Marquardt
- Institute of Translational Medicine for Health Care Systems, Medical School Berlin, Hochschule Für Gesundheit Und Medizin, 14197 Berlin, Germany
| | - Anastasia Velalopoulou
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ioannis I Verginadis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Constantinos Koumenis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany; German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), 35043 Marburg, Germany; Genomics Core Facility, Philipps-University, 35043 Marburg, Germany; Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Jerome Zoidakis
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece; Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany; Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Alexandros G Georgakilas
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece.
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Özbek M, Toy HI, Takan I, Asfa S, Arshinchi Bonab R, Karakülah G, Kontou PI, Geronikolou SA, Pavlopoulou A. A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis. Viruses 2022; 15:104. [PMID: 36680144 PMCID: PMC9866184 DOI: 10.3390/v15010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic "cytokine storm". Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies.
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Affiliation(s)
- Melih Özbek
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Halil Ibrahim Toy
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Işil Takan
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Seyedehsadaf Asfa
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Reza Arshinchi Bonab
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Gökhan Karakülah
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | | | - Styliani A. Geronikolou
- Clinical, Translational and Experimental Surgery Research Centre, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
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Ferraresi A, Isidoro C. Will Omics Biotechnologies Save Us from Future Pandemics? Lessons from COVID-19 for Vaccinomics and Adversomics. Biomedicines 2022; 11:52. [PMID: 36672560 PMCID: PMC9855897 DOI: 10.3390/biomedicines11010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The COVID-19 pandemic had cross-cutting impacts on planetary health, quotidian life, and society. Mass vaccination with the current gene-based vaccines has helped control the pandemic but unfortunately it has not shown effectiveness in preventing the spread of the virus. In addition, not all individuals respond to these vaccines, while others develop adverse reactions that cannot be neglected. It is also a fact that some individuals are more susceptible to infection while others develop effective immunization post-infection. We note here that the person-to-person and population variations in vaccine efficacy and side effects have been studied in the field of vaccinomics long before the COVID-19 pandemic. Additionally, the field of adversomics examines the mechanisms of individual differences in the side effects of health interventions. In this review, we discuss the potential of a multi-omics approach for comprehensive profiling of the benefit/risk ratios of vaccines. Vaccinomics and adversomics stand to benefit planetary health and contribute to the prevention of future pandemics in the 21st century by offering precision guidance to clinical trials as well as promoting precision use of vaccines in ways that proactively respond to individual and population differences in their efficacy and safety. This vision of pandemic prevention based on personalized instead of mass vaccination also calls for equity in access to precision vaccines and diagnostics that support a vision and practice of vaccinomics and adversomics in planetary health.
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Affiliation(s)
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
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6
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Sagulkoo P, Suratanee A, Plaimas K. Immune-Related Protein Interaction Network in Severe COVID-19 Patients toward the Identification of Key Proteins and Drug Repurposing. Biomolecules 2022; 12:biom12050690. [PMID: 35625619 PMCID: PMC9138873 DOI: 10.3390/biom12050690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 02/05/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is still an active global public health issue. Although vaccines and therapeutic options are available, some patients experience severe conditions and need critical care support. Hence, identifying key genes or proteins involved in immune-related severe COVID-19 is necessary to find or develop the targeted therapies. This study proposed a novel construction of an immune-related protein interaction network (IPIN) in severe cases with the use of a network diffusion technique on a human interactome network and transcriptomic data. Enrichment analysis revealed that the IPIN was mainly associated with antiviral, innate immune, apoptosis, cell division, and cell cycle regulation signaling pathways. Twenty-three proteins were identified as key proteins to find associated drugs. Finally, poly (I:C), mitomycin C, decitabine, gemcitabine, hydroxyurea, tamoxifen, and curcumin were the potential drugs interacting with the key proteins to heal severe COVID-19. In conclusion, IPIN can be a good representative network for the immune system that integrates the protein interaction network and transcriptomic data. Thus, the key proteins and target drugs in IPIN help to find a new treatment with the use of existing drugs to treat the disease apart from vaccination and conventional antiviral therapy.
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Affiliation(s)
- Pakorn Sagulkoo
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand;
- Center of Biomedical Informatics, Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut’s University of Technology North Bangkok, Bangkok 10800, Thailand;
- Intelligent and Nonlinear Dynamics Innovations Research Center, Science and Technology Research Institute, King Mongkut’s University of Technology North Bangkok, Bangkok 10800, Thailand
| | - Kitiporn Plaimas
- Advance Virtual and Intelligent Computing (AVIC) Center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
- Omics Science and Bioinformatics Center, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence:
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Georgakopoulou VE, Lembessis P, Skarlis C, Gkoufa A, Sipsas NV, Mavragani CP. Hematological Abnormalities in COVID-19 Disease: Association With Type I Interferon Pathway Activation and Disease Outcomes. Front Med (Lausanne) 2022; 9:850472. [PMID: 35372456 PMCID: PMC8968418 DOI: 10.3389/fmed.2022.850472] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/21/2022] [Indexed: 12/29/2022] Open
Abstract
Increased expression of interferon (IFN)-stimulated genes (ISGs) in peripheral blood, has been previously reported in viral infections, as well as in autoimmune disorders, in association with reduced leukocyte and platelet counts. Though cytopenias are common in patients with COVID-19 disease and predict severe outcomes, the underlying mechanisms have not been fully elucidated. In the current study, we aimed to determine the prevalence of hematological abnormalities in the setting of active COVID-19 infection and to explore whether they associate with disease outcomes and activation of type I IFN pathway. One-hundred-twenty-three consecutive SARS-CoV2 infected patients were included in the study. Clinical and laboratory parameters were recorded for all study participants. In 114 patients, total RNA was extracted from whole peripheral blood and subjected to real time PCR. The relative expression of three interferon stimulated genes (ISGs; IFIT1, MX-1, and IFI44) was determined and a type I IFN score reflecting peripheral type I IFN activity was calculated. The rates of anemia, leukopenia, and thrombocytopenia were 28.5, 14.6, and 24.4%, respectively. Among leukocytopenias, eosinopenia, and lymphopenia were the most prominent abnormalities being found in 56.9 and 43.1%, respectively. Of interest, patients with either eosinopenia and/or thrombocytopenia but no other hematological abnormalities displayed significantly increased peripheral type I IFN scores compared to their counterparts with normal/high eosinophil and platelet counts. While eosinopenia along with lymphopenia were found to be associated with increased risk for intubation and severe/critical disease, such an association was not detected between other hematological abnormalities or increased type I IFN scores. In conclusion, hematological abnormalities are commonly detected among patients with COVID-19 infection in association with severe disease outcomes and activation of the type I IFN pathway.
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Affiliation(s)
- Vasiliki E. Georgakopoulou
- Department of Infectious Diseases and COVID-19 Unit, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Lembessis
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Charalampos Skarlis
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Gkoufa
- Department of Infectious Diseases and COVID-19 Unit, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos V. Sipsas
- Department of Infectious Diseases and COVID-19 Unit, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Clio P. Mavragani
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Fourth Department of Internal Medicine, School of Medicine, University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece
- Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Clio P. Mavragani
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