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Pita-Juarez Y, Karagkouni D, Kalavros N, Melms JC, Niezen S, Delorey TM, Essene AL, Brook OR, Pant D, Skelton-Badlani D, Naderi P, Huang P, Pan L, Hether T, Andrews TS, Ziegler CGK, Reeves J, Myloserdnyy A, Chen R, Nam A, Phelan S, Liang Y, Gregory M, He S, Patrick M, Rane T, Wardhani A, Amin AD, Biermann J, Hibshoosh H, Veregge M, Kramer Z, Jacobs C, Yalcin Y, Phillips D, Slyper M, Subramanian A, Ashenberg O, Bloom-Ackermann Z, Tran VM, Gomez J, Sturm A, Zhang S, Fleming SJ, Warren S, Beechem J, Hung D, Babadi M, Padera RF, MacParland SA, Bader GD, Imad N, Solomon IH, Miller E, Riedel S, Porter CBM, Villani AC, Tsai LTY, Hide W, Szabo G, Hecht J, Rozenblatt-Rosen O, Shalek AK, Izar B, Regev A, Popov YV, Jiang ZG, Vlachos IS. A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients. Genome Biol 2025; 26:56. [PMID: 40087773 PMCID: PMC11907808 DOI: 10.1186/s13059-025-03499-5] [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: 07/04/2023] [Accepted: 02/07/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND The molecular underpinnings of organ dysfunction in severe COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we perform single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. RESULTS We identify hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells, and a central role in a pro-fibrotic TGFβ signaling cell-cell communications network. Integrated analysis and comparisons with healthy controls reveal extensive changes in the cellular composition and expression states in COVID-19 liver, providing the underpinning of hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis characteristic of COVID-19 cholangiopathy. We also observe Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition is dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. CONCLUSIONS Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.
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Affiliation(s)
- Yered Pita-Juarez
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Dimitra Karagkouni
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nikolaos Kalavros
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Spatial Technologies Unit, HMS Initiative for RNA Medicine / Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Johannes C Melms
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Columbia Center for Translational Immunology, New York, NY, USA
| | - Sebastian Niezen
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Toni M Delorey
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Adam L Essene
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core, Boston, MA, USA
| | - Olga R Brook
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Deepti Pant
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core, Boston, MA, USA
| | - Disha Skelton-Badlani
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Pourya Naderi
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Pinzhu Huang
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Liuliu Pan
- NanoString Technologies, Inc., Seattle, WA, USA
| | | | - Tallulah S Andrews
- Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, ON, Canada
| | - Carly G K Ziegler
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA, USA
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Program in Immunology, Harvard Medical School, Boston, MA, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Andriy Myloserdnyy
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Rachel Chen
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Andy Nam
- NanoString Technologies, Inc., Seattle, WA, USA
| | | | - Yan Liang
- NanoString Technologies, Inc., Seattle, WA, USA
| | | | - Shanshan He
- NanoString Technologies, Inc., Seattle, WA, USA
| | | | - Tushar Rane
- NanoString Technologies, Inc., Seattle, WA, USA
| | | | - Amit Dipak Amin
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Columbia Center for Translational Immunology, New York, NY, USA
| | - Jana Biermann
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Columbia Center for Translational Immunology, New York, NY, USA
| | - Hanina Hibshoosh
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Molly Veregge
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core, Boston, MA, USA
| | - Zachary Kramer
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Christopher Jacobs
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core, Boston, MA, USA
| | - Yusuf Yalcin
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Devan Phillips
- Present Address: Genentech, 1 DNA Way, South San Francisco, CA, USA
| | - Michal Slyper
- Present Address: Genentech, 1 DNA Way, South San Francisco, CA, USA
| | | | - Orr Ashenberg
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Zohar Bloom-Ackermann
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Victoria M Tran
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - James Gomez
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Alexander Sturm
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Shuting Zhang
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Stephen J Fleming
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | | | - Deborah Hung
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Mehrtash Babadi
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Robert F Padera
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Sonya A MacParland
- Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA, USA
- Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Gary D Bader
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- The Donnelly Centre, Toronto, ON, Canada
| | - Nasser Imad
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Isaac H Solomon
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Eric Miller
- NanoString Technologies, Inc., Seattle, WA, USA
| | - Stefan Riedel
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Caroline B M Porter
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Alexandra-Chloé Villani
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Linus T-Y Tsai
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core, Boston, MA, USA
| | - Winston Hide
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Gyongyi Szabo
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jonathan Hecht
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Orit Rozenblatt-Rosen
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Present Address: Genentech, 1 DNA Way, South San Francisco, CA, USA
| | - Alex K Shalek
- Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA, USA.
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
- Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Program in Immunology, Harvard Medical School, Boston, MA, USA.
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Benjamin Izar
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA.
- Columbia Center for Translational Immunology, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
- Program for Mathematical Genomics, Columbia University Irving Medical Center, New York, NY, USA.
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Present Address: Genentech, 1 DNA Way, South San Francisco, CA, USA.
| | - Yury V Popov
- Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | - Z Gordon Jiang
- Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | - Ioannis S Vlachos
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Spatial Technologies Unit, HMS Initiative for RNA Medicine / Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
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Luo XT, Hu HR, Sun ZD, Zhang LH, Li Y. Multi-omics analysis reveals that low cathepsin S expression aggravates sepsis progression and worse prognosis via inducing monocyte polarization. Front Cell Infect Microbiol 2025; 15:1531125. [PMID: 40115073 PMCID: PMC11922721 DOI: 10.3389/fcimb.2025.1531125] [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: 11/19/2024] [Accepted: 02/12/2025] [Indexed: 03/23/2025] Open
Abstract
Background Monocytes represent a vital cellular subpopulation in the peripheral blood, crucial in the progression of sepsis. Nonetheless, the prognostic role and precise function of monocytes in sepsis are still inadequately understood. Methods Single-cell transcriptomic sequencing and bioinformatics analysis were performed on peripheral blood samples from septic patients to identify key molecules in cell subsets. Subsequently, the expression pattern of this molecule was validated through diverse biological experiments, encompassing quantitative RT-PCR, western blotting, and immunofluorescence. Finally, the functionality of this molecule was evaluated using its specific agonist. Results A total of 22 monocytes-related biomarkers were identified from single-cell and bulk RNA-seq analyses. Initially, LASSO analysis was performed to derive a prognostic signature composed of 4 key genes, including CD14, CTSS, CXCL8 and THBS1. Subsequently, mendelian randomization and survival analysis demonstrated that only CTSS showed crucially protective role in sepsis development and prognosis. Next, CTSS was confirmed to be lower expressed in peripheral monocytes of septic patients. Inflammatory markers (p < 0.05) and migration ability of LPS-activated monocytes were significantly reduced after CTSS agonist. In addition, CTSS agonist decreased the pulmonary tissue monocyte/macrophages infiltration in septic mice. Conclusion Monocyte marker CTSS represent a promising target for the diagnosis and prognosis evaluation of sepsis and plays a critical role in monocytes activation, tissue inflammatory response and macrophages infiltration. Thus, CTSS agonist probably serves as new drug for clinical protection against sepsis.
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Affiliation(s)
- Xiao-Ting Luo
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Hui-Rong Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Zhen-Dong Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Li-Hong Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yan Li
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Zhao R, Li H, Xu B, Cao J. CXCL5 as a biomarker for early diagnosis and prognosis of sepsis: A comprehensive clinical evaluation. Clin Biochem 2025; 136:110878. [PMID: 39788476 DOI: 10.1016/j.clinbiochem.2025.110878] [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: 08/25/2024] [Revised: 01/04/2025] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
OBJECTIVES Sepsis, a critical condition caused by a dysregulated host response to infection, has high morbidity and mortality rates. Timely diagnosis and treatment are vital for improving patient outcomes. This study explores the potential role of CXCL5 in the diagnosis, severity assessment, and prognosis of sepsis. DESIGN AND METHODS We included 147 sepsis patients, 50 patients with systemic inflammatory response syndrome (SIRS) and 120 healthy controls. Serum CXCL5 levels, inflammation scores (APACHE II, SOFA), and other laboratory indicators were recorded. Univariate and multivariate logistic regression analyses were conducted to assess the relationship between CXCL5 and sepsis diagnosis, severity, and prognosis. A prognostic nomogram was constructed and evaluated using receiver operator characteristic curves, calibration curves, and clinical decision curves. RESULTS Serum CXCL5 levels in sepsis patients were significantly higher than those in patients with SIRS and healthy controls. CXCL5 was identified as a risk factor for sepsis diagnosis. CXCL5 levels were significantly elevated in patients with septic shock (P = 0.04) and in deceased patients compared to survivors (P < 0.001). The prognostic model, incorporating CXCL5, lactate, APACHE II scores, C-reactive protein levels, and respiratory rate, demonstrated high predictive accuracy with an area under the curve of 0.873. Calibration and decision curve analyses demonstrated the model's good predictive performance and potential clinical value. CONCLUSIONS Serum CXCL5 concentration is a promising biomarker for enhancing the diagnostic accuracy and prognostic evaluation of sepsis. The constructed multivariate prediction model offers new insights into sepsis prognosis, but its direct application in clinical practice requires further validation.
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Affiliation(s)
- Rui Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - HangBo Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Banglao Xu
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Ji X, Guo Y, Tang L, Gao C. Identifying and Validating Prognostic Hyper-Inflammatory and Hypo-Inflammatory COVID-19 Clinical Phenotypes Using Machine Learning Methods. J Inflamm Res 2025; 18:3009-3024. [PMID: 40034687 PMCID: PMC11874972 DOI: 10.2147/jir.s504028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/18/2025] [Indexed: 03/05/2025] Open
Abstract
Background COVID-19 exhibits complex pathophysiological manifestations, characterized by significant clinical and biological heterogeneity. Identifying phenotypes may enhance our understanding of the disease's diverse trajectories, benefiting clinical practice and trials. Methods This study included adult patients with COVID-19 from Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, between December 15, 2022, and February 15, 2023. The k-prototypes clustering method was employed using 50 clinical variables to identify phenotypes. Machine learning algorithms were then applied to select key classifier variables for phenotype recognition. Results A total of 1376 patients met the inclusion criteria. K-prototypes clustering revealed two distinct subphenotypes: Hypo-inflammatory subphenotype (824 [59.9%]) and Hyper-inflammatory subphenotype (552 [40.1%]). Patients in Hypo-inflammatory subphenotype were younger, predominantly female, with low mortality and shorter hospital stays. In contrast, Hyper-inflammatory subphenotype patients were older, predominantly male, exhibiting a hyperinflammatory state with higher mortality and rates of organ dysfunction. The AdaBoost model performed best for subphenotype prediction (Accuracy: 0.975, Precision: 0.968, Recall: 0.976, F1: 0.972, AUROC: 0.975). "CRP", "IL-2R", "D-dimer", "ST2", "BUN", "NT-proBNP", "neutrophil percentage", and "lymphocyte count" were identified as the top-ranked variables in the AdaBoost model. Conclusion This analysis identified two phenotypes based on COVID-19 symptoms and comorbidities. These phenotypes can be accurately recognized using machine learning models, with the AdaBoost model being optimal for predicting in-hospital mortality. The variables "CRP", "IL-2R", "D-dimer", "ST2", "BUN", "NT-proBNP", "neutrophil percentage", and "lymphocyte count" play a significant role in the prediction of subphenotypes. Use the identified subphenotypes for risk stratification in clinical practice. Hyper-inflammatory subphenotypes can be closely monitored, and preventive measures such as early admission to the intensive care unit or prophylactic anticoagulation can be taken.
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Affiliation(s)
- Xiaojing Ji
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China
| | - Yiran Guo
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China
| | - Lujia Tang
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China
| | - Chengjin Gao
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China
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Russkikh IV, Popov OS, Klochkova TG, Sushentseva NN, Apalko SV, Asinovskaya AY, Mosenko SV, Sarana AM, Shcherbak SG. Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis. Sci Rep 2025; 15:6622. [PMID: 39994234 PMCID: PMC11850835 DOI: 10.1038/s41598-025-90426-0] [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: 10/26/2024] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
The clinical manifestations of the cytokine storm (CS) associated with COVID-19 resemble the acute phase of sepsis. Metabolomics may contribute to understanding the specific pathobiology of these two syndromes. The aim of this study was to compare serum metabolomic profiles in CS associated with COVID-19 vs. septic surgery patients. In a retrospective cross-sectional study, serum samples from patients with CS associated with COVID-19, with and without comorbidity, as well as serum samples from patients with surgical sepsis were investigated. Targeted metabolomic analysis was performed on all samples using LC-MS/MS. Analysis revealed that similar alterations in the serum metabolome of patients with COVID-19 and surgical septic patients were associated with amino acid metabolism, nitrogen metabolism, inflammatory status, methionine cycle and glycolysis. The most significant difference was found for serum levels of metabolites of kynurenine synthesis, tricarboxylic acid cycle, gamma-aminobutyric acid and niacinamide. The metabolic pathway of cysteine and methionine metabolism was significantly disturbed in COVID-19 and surgical septic patients. For the first time, the similarities and differences between the serum metabolomic profiles of patients with CS associated with COVID-19 and patients with surgical sepsis were investigated for patients from the Northwest of the Russian Federation.
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Affiliation(s)
- Iana V Russkikh
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
| | - Oleg S Popov
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Tatiana G Klochkova
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation.
| | - Natalia N Sushentseva
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
| | - Svetlana V Apalko
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Anna Yu Asinovskaya
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Sergey V Mosenko
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Andrey M Sarana
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Sergey G Shcherbak
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
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Zhu J, Wu J, Lu M, Jiao Q, Liu X, Liu L, Li M, Zhang B, Yan J, Yu Y, Pan L. Acute lung injury induced by recombinant SARS-CoV-2 spike protein subunit S1 in mice. Respir Res 2025; 26:59. [PMID: 39972348 PMCID: PMC11837662 DOI: 10.1186/s12931-025-03143-7] [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: 10/16/2024] [Accepted: 02/08/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The intricacies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing acute lung injury (ALI) and modulating inflammatory factor dynamics in vivo remain poorly elucidated. The present study endeavors to explore the impact of the recombinant SARS-CoV-2 spike protein S1 subunit (S1SP) on ALI and inflammatory factor profiles in mice, aiming to uncover potential therapeutic targets and intervention strategies for the prevention and management of Coronavirus Disease 2019 (COVID-19). METHODS To mimic COVID-19 infection, K18-hACE2 transgenic mice were intratracheally instilled with S1SP, while C57BL/6 mice were administered LPS to form a positive control group. This setup facilitated the examination of lung injury severity, inflammatory factor levels, and alterations in signaling pathways in mice mimicking COVID-19 infection. Histopathological assessment through HE staining, along with analysis of lung wet/dry ratio and ultrasound imaging, revealed severe lung injury. RESULTS After molding, K18-hACE2 mice exhibited a pronounced reduction in body weight and showed more significant lung injury (P < 0.05). Notably, there was a significant elevation in vascular permeability, total protein, and total white blood cells in bronchoalveolar lavage fluid (BALF) (P < 0.05), indicative of tissue damage. Additionally, the tight junction of lung tissue was compromised (P < 0.05), accompanied by intense oxidative stress marked by decreased SOD activity and elevated MDA content (P < 0.05). Cytokine levels, including IL-6, IL-1β, TNF-α, and MIG, were significantly upregulated in both BALF and serum of S1SP + K18 mice (P < 0.05). Furthermore, S1SP prominently augmented the expression of p-p65/P65 and attenuated IκBα expression in the NF-κB signaling pathway of humanized mice (P < 0.05), corroborating a heightened inflammatory response at the tissue level (P < 0.05). CONCLUSION The administration of S1SP to K18-hACE2 mice resulted in severe lung injury, enhanced vascular permeability, and compromised epithelial barrier function in vivo. This was accompanied by disruption of lung tight junctions, the manifestation of severe oxidative stress and a cytokine storm, as well as the activation of the NF-κB signaling pathway, highlighting key pathological processes underlying COVID-19-induced lung injury.
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Affiliation(s)
- Jiwei Zhu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Jinglin Wu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Manlu Lu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Qianqian Jiao
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Xiaojing Liu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Lu Liu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Mingzhen Li
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Bin Zhang
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China
| | - Junhong Yan
- Department of Ultrasound Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China.
| | - Yan Yu
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China.
| | - Lei Pan
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou, 256603, China.
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Shirey KA, Joseph J, Coughlan L, Nijhuis H, Varley AW, Blanco JCG, Vogel SN. An adenoviral vector encoding an inflammation-inducible antagonist, HMGB1 Box A, as a novel therapeutic approach to inflammatory diseases. mBio 2025; 16:e0338724. [PMID: 39699172 PMCID: PMC11796352 DOI: 10.1128/mbio.03387-24] [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: 10/30/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
Influenza, as well as other respiratory viruses, can trigger local and systemic inflammation resulting in an overall "cytokine storm" that produces serious outcomes such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We hypothesized that gene therapy platforms could be useful in these cases if the production of an anti-inflammatory protein reflects the intensity and duration of the inflammatory condition. The recombinant protein would be produced and released only in the presence of the inciting stimulus, avoiding immunosuppression or other unwanted side effects that may occur when treating infectious diseases with anti-inflammatory drugs. To test this hypothesis, we developed AdV.C3-Tat/HIV-Box A, an inflammation-inducible cassette that remains innocuous in the absence of inflammation but releases HMGB1 Box A, an antagonist of high mobility group box 1 (HMGB1), in response to inflammatory stimuli such as lipopolysaccharide (LPS) or influenza virus infection. We report here that this novel inflammation-inducible HMGB1 Box A construct in a non-replicative adenovirus (AdV) vector mitigates lung and systemic inflammation therapeutically in response to influenza infection. We anticipate that this strategy will apply to the treatment of multiple diseases in which HMGB1-mediated signaling is a central driver of inflammation.IMPORTANCEMany inflammatory diseases are mediated by the action of a host-derived protein, HMGB1, on Toll-like receptor 4 (TLR4) to elicit an inflammatory response. We have engineered a non-replicative AdV vector that produces HMGB1 Box A, an antagonist of HMGB1-induced inflammation, under the control of an endogenous complement component C3 (C3) promoter sequence, that is inducible by LPS and influenza in vitro and ex vivo in macrophages (Mϕ) and protects mice and cotton rats therapeutically against infection with mouse-adapted and human non-adapted influenza strains, respectively, in vivo. We anticipate that this novel strategy will apply to the treatment of multiple infectious and non-infectious diseases in which HMGB1-mediated TLR4 signaling is a central driver of inflammation.
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Affiliation(s)
- Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - John Joseph
- Sigmovir Biosystems Inc., Rockville, Maryland, USA
| | - Lynda Coughlan
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
- Center for Vaccine Development and Global Health (CVD), University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Haye Nijhuis
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
- Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands
| | | | | | - Stefanie N. Vogel
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
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8
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Ran E, Zou Y, Zhao C, Liu K, Yuan J, Yang W, Zhao L, Yang Q, Yang J, Ju X, Cai L, Lang Y, Li X, Liu K, Liu F. COVID-19 in discharged patients with diabetes and chronic kidney disease: one-year follow-up and evaluation. Front Endocrinol (Lausanne) 2025; 16:1519993. [PMID: 39968301 PMCID: PMC11832373 DOI: 10.3389/fendo.2025.1519993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Purpose To evaluate the all-cause mortality rate and renal outcomes in patients with diabetes and chronic kidney disease (CKD) following hospital discharge for COVID-19. Methods This single-center prospective observational study included 187 discharged COVID-19 patients with diabetes and CKD, admitted between December 2022 and January 2023 at West China Hospital, Sichuan University. Cox regression analysis was used to assess mortality risk, and logistic regression was applied to identify risk factors for rapid CKD progression after discharge. Results During the one-year follow-up, the all-cause mortality rate was 26.7%, with a COVID-19-related acute kidney injury (AKI) incidence of 35.3%, and 35.8% of patients experienced rapid CKD progression after discharge. Cox proportional hazards regression indicated that sepsis and mechanical ventilation were major risk factors for post-discharge all-cause mortality. Logistic regression identified baseline eGFR < 60 mL/min/1.73 m² as an independent risk factor for rapid CKD progression. Conclusions During the one-year follow-up period, we observed that patients with diabetes and CKD exhibited higher all-cause mortality and experienced rapid deterioration of kidney function after acute infection with COVID-19. This underscores the importance of ongoing longitudinal follow-up to more accurately track the long-term health effects of COVID-19 on patients with diabetes and CKD.
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Affiliation(s)
- Enrong Ran
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Nephrology, Suining Central Hospital, Suining, China
| | - Yutong Zou
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chuanyi Zhao
- Department of Clinical Research Management, West China Hospital of Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiamin Yuan
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenjie Yang
- Division of Project Design and Statistics, West China Hospital of Sichuan University, Chengdu, China
| | - Lijun Zhao
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qing Yang
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jia Yang
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuegui Ju
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Linli Cai
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanlin Lang
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xingyuan Li
- Department of Clinical Research Management, West China Hospital of Sichuan University, Chengdu, China
| | - Ke Liu
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fang Liu
- Department of Nephrology, West China Hospital, Sichuan University; Laboratory of Diabetic Kidney Disease, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Clinical Research Management, West China Hospital of Sichuan University, Chengdu, China
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9
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Amsalem I, Shafrir A, Kalish Y, Paltiel O. Pre-infection anticoagulant exposure and SARS-CoV-2 infection outcomes - Differential mortality by age. Thromb Res 2025; 246:109254. [PMID: 39799927 DOI: 10.1016/j.thromres.2025.109254] [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: 08/09/2023] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND The risk of thrombosis increases after SARS-CoV-2 infection. This study aimed to assess associations between pre-infection anticoagulant exposure and SARS-CoV-2 infection-related outcomes in a population-based cohort. METHODS Members of the "Meuhedet" health maintenance organization aged >45 years who tested positive for SARS-CoV-2 infection (03/2020-04/2022) were followed. Pre-infection anticoagulant exposure (PAE) was defined as any anticoagulant therapy prescribed ≥1 month prior to SARS-CoV-2 testing. Univariate analyses, multivariable models adjusting for confounders, propensity-score matching, and an age-stratified analysis were performed to assess associations between PAE and hospitalization, intensive care unit (ICU) admission, 30-day and one-year mortality. RESULTS Of the 127,801 patients included, 2951(2.3 %) had PAE. Comorbidities including ischemic heart disease, diabetes mellitus, hypertension, heart failure, and atrial fibrillation were more common among anticoagulant-exposed than unexposed individuals (p < 0.001). Patients with PAE experienced higher hospitalization (22.7 % vs 5.6 %), ICU admissions (1.9 % vs 0.5 %), 30-day and 1-year mortality rates (4.8 % vs. 0.6, and 8.8 % vs. 1.1 %, respectively), than unexposed individuals, but similar lengths-of-stay. In the multivariable analysis, PAE was independently associated only with hospitalizations (adjusted odds ratio (aOR) = 1.29 [95 % confidence interval (CI): 1.13-1.47]), whereas in the propensity-matched analysis, none of the outcomes differed significantly between the groups. However, in the stratum aged >75 years, 30-day and one-year mortality were significantly reduced in those with PAE (aOR = 0.68 [CI:0.48-0.97], and aOR = 0.73 [CI:0.55-0.97], respectively). CONCLUSION SARS-CoV-2-infected individuals with prior exposure to anticoagulants have more comorbidities and experienced a higher incidence of hospitalization but not mortality compared to unexposed patients. Paradoxically, mortality risks decreased in the oldest stratum of anticoagulant-exposed individuals. Further research is required to assess mechanisms for this apparent protective effect.
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Affiliation(s)
- Itshak Amsalem
- Jesselson Integrated Heart Center, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.
| | - Asher Shafrir
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Meuhedet Health Services, Tel Aviv, Israel; Institute of Gastroenterology and Liver Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yosef Kalish
- Department of Hematology, Hadassah University Medical Center, Jerusalem, Israel
| | - Ora Paltiel
- Department of Hematology, Hadassah University Medical Center, Jerusalem, Israel; Braun School of Public Health and Community Medicine, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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10
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Witowski A, Palmowski L, Rahmel T, Nowak H, Ehrentraut SF, Putensen C, von Groote T, Zarbock A, Babel N, Anft M, Sitek B, Bracht T, Bayer M, Weber M, Weisheit C, Pfänder S, Eisenacher M, Adamzik M, Katharina R, Koos B, Ziehe D. Activation of the MAPK network provides a survival advantage during the course of COVID-19-induced sepsis: a real-world evidence analysis of a multicenter COVID-19 Sepsis Cohort. Infection 2025; 53:107-115. [PMID: 38896372 PMCID: PMC11825614 DOI: 10.1007/s15010-024-02325-7] [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: 02/13/2024] [Accepted: 06/13/2024] [Indexed: 06/21/2024]
Abstract
PURPOSE There is evidence that lower activity of the RAF/MEK/ERK network is associated with positive outcomes in mild and moderate courses of COVID-19. The effect of this cascade in COVID-19 sepsis is still undetermined. Therefore, we tested the hypothesis that activity of the RAF/MEK/ERK network in COVID-19-induced sepsis is associated with an impact on 30-day survival. METHODS We used biomaterial from 81 prospectively recruited patients from the multicentric CovidDataNet.NRW-study cohort (German clinical trial registry: DRKS00026184) with their collected medical history, vital signs, laboratory parameters, microbiological findings and patient outcome. ERK activity was measured by evaluating ERK phosphorylation using a Proximity Ligation Assay. RESULTS An increased ERK activity at 4 days after diagnosis of COVID-19-induced sepsis was associated with a more than threefold increased chance of survival in an adjusted Cox regression model. ERK activity was independent of other confounders such as Charlson Comorbidity Index or SOFA score (HR 0.28, 95% CI 0.10-0.84, p = 0.02). CONCLUSION High activity of the RAF/MEK/ERK network during the course of COVID-19 sepsis is a protective factor and may indicate recovery of the immune system. Further studies are needed to confirm these results.
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Affiliation(s)
- Andrea Witowski
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
| | - Lars Palmowski
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
| | - Tim Rahmel
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
| | - Hartmuth Nowak
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
- Zentrum für Künstliche Intelligenz, Medizininformatik und Datenwissenschaften, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Germany
| | - Stefan F Ehrentraut
- Klinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany
| | - Christian Putensen
- Klinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany
| | - Thilo von Groote
- Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie, Universitätsklinikum Münster, Münster, Germany
| | - Alexander Zarbock
- Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie, Universitätsklinikum Münster, Münster, Germany
| | - Nina Babel
- Centrum für Translationale Medizin, Medizinische Klinik I, Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | - Moritz Anft
- Centrum für Translationale Medizin, Medizinische Klinik I, Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | - Barbara Sitek
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
- Medizinisches Proteom-Center, Ruhr Universität Bochum, Medizinische Fakultät, Bochum, Germany
| | - Thilo Bracht
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
- Medizinisches Proteom-Center, Ruhr Universität Bochum, Medizinische Fakultät, Bochum, Germany
| | - Malte Bayer
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
- Medizinisches Proteom-Center, Ruhr Universität Bochum, Medizinische Fakultät, Bochum, Germany
| | - Maike Weber
- Medizinisches Proteom-Center, Ruhr Universität Bochum, Medizinische Fakultät, Bochum, Germany
- Center for Protein Diagnostics (PRODI), Medical Proteome Analysis, Ruhr Universität Bochum, Bochum, Germany
| | - Christina Weisheit
- Klinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany
| | - Stephanie Pfänder
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
- University of Lübeck, Lübeck, Germany
| | - Martin Eisenacher
- Medizinisches Proteom-Center, Ruhr Universität Bochum, Medizinische Fakultät, Bochum, Germany
- Center for Protein Diagnostics (PRODI), Medical Proteome Analysis, Ruhr Universität Bochum, Bochum, Germany
| | - Michael Adamzik
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
| | - Rump Katharina
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
| | - Björn Koos
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany.
| | - Dominik Ziehe
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany
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Wen Z, Wang T, Luo S, Liu Y. CT scan-derived pectoralis muscle parameters are closely associated with COVID-19 outcomes: A systematic review and meta-analysis. PLoS One 2025; 20:e0316893. [PMID: 39874384 PMCID: PMC11774355 DOI: 10.1371/journal.pone.0316893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 12/17/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND The relationships between pectoralis muscle parameters and outcomes in patients with coronavirus disease 2019 (COVID-19) remain uncertain. METHODS We systematically searched PubMed, Embase, Web of Science and the Cochrane Library from 1 January 2019 to 1 May 2024 to identify non-overlapping studies evaluating pectoralis muscle-associated index on chest CT scan with clinical outcome in COVID-19 patients. Random-effects and fixed-effects meta-analyses were performed, and heterogeneity between studies was quantified using the I2 statistic. The risk of study bias was assessed using the Newcastle-Ottawa scale. Funnel plots for detecting small-study effects. RESULTS A total of 9 studies with 4109 COVID-19 patients were included. The meta-analysis findings revealed a correlation between pectoralis muscle parameters and COVID-19 prognosis. Specifically, patients with higher pectoralis muscle density (PMD) exhibited a lower mortality risk, with an odds ratio (OR) of 0.95 (95% CI: 0.92-0.99). The rate of intubation was lower in COVID-19 patients with a high pectoralis muscle index (PMI) (OR = 0.96, 95% CI: 0.92-1.00). CONCLUSION In summary, a low PMD is associated with a marginally elevated risk of mortality, whereas a decreased PMI represents a risk factor for intubation in COVID-19 patients. These findings suggest that pectoralis muscle parameters on chest CT may be a useful prognostic tool for COVID-19 patients.
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Affiliation(s)
- Zhang Wen
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Wang
- Department of Pediatric Intensive Care Unit, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Sha Luo
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yiwen Liu
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
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12
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Yan Y, Shang L, Xu J, Gu X, Fan G, Wang Y, Cao B. The prevalence and outcomes of viremia in patients with acute respiratory viral infection: a systematic review and meta-analysis. Clin Microbiol Infect 2025:S1198-743X(25)00035-7. [PMID: 39884502 DOI: 10.1016/j.cmi.2025.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Viremia has been detected in a significant proportion of patients with acute respiratory viral infection, yet its clinical value remains underappreciated. OBJECTIVES This study synthesized available evidence to comprehensively assess the prevalence of viremia and its impact on clinical outcomes. METHODS Data sources: Data were retrieved from Medline (via Ovid), Embase, and the WHO COVID-19 database. STUDY ELIGIBILITY CRITERIA This review included original clinical studies analysing the prevalence of viremia in patients with acute respiratory viral infection or its association with clinical outcomes, while excluding non-original research, insufficiently detailed studies, inconsistent pathogen observations, or those with inadequate sample sizes. PARTICIPANTS Patients with acute respiratory viral infection. ASSESSMENT OF RISK OF BIAS Newcastle-Ottawa scale and an adapted version were used. EXPOSURE Respiratory viral infection-related viremia. METHODS OF DATA SYNTHESIS Data synthesis utilized random-effects models to pool prevalence and hazard ratio (HR), OR, and adjusted HR/OR for clinical outcomes. RESULTS In the comprehensive analysis of viremia prevalence, data were pooled from 101 studies, which included a total of 16,388 non-overlapping patients. Viremia was present in 34% (95% CI, 28-41%) of patients with acute respiratory viral infection. A total of 45 studies provided information on the clinical outcomes of 2002 patients with viremia and 3907 patients without viremia. Viremia was associated with increased risks of mortality (OR, 6.83; 95% CI, 4.92-9.48; adjusted HR, 2.91; 95% CI, 1.87-4.53; adjusted OR, 3.68; 95% CI, 2.37-5.71), intensive care unit admission (OR, 4.74; 95% CI, 2.66-8.46; adjusted OR, 4.89; 95% CI, 1.61-14.91), mechanical ventilation (OR, 4.12; 95% CI, 2.25-7.52), and hepatic complications (OR, 3.10; 95% CI, 1.30-7.40). CONCLUSIONS Viremia is prevalent in patients with respiratory viral infection and is associated with elevated risks of adverse clinical outcomes.
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Affiliation(s)
- Yuting Yan
- School of Medicine, Tsinghua University, Beijing, People's Republic of China
| | - Lianhan Shang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Jiuyang Xu
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Xiaoying Gu
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical Research and Data Management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China; Changping Laboratory, Beijing, People's Republic of China
| | - Guohui Fan
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical Research and Data Management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China; Changping Laboratory, Beijing, People's Republic of China
| | - Yeming Wang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Bin Cao
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China; Changping Laboratory, Beijing, People's Republic of China; Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, People's Republic of China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, People's Republic of China.
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13
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Wang Y, Weng L, Wu X, Du B. The role of programmed cell death in organ dysfunction induced by opportunistic pathogens. Crit Care 2025; 29:43. [PMID: 39856779 PMCID: PMC11761187 DOI: 10.1186/s13054-025-05278-x] [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: 08/30/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Sepsis is a life-threatening condition resulting from pathogen infection and characterized by organ dysfunction. Programmed cell death (PCD) during sepsis has been associated with the development of multiple organ dysfunction syndrome (MODS), impacting various physiological systems including respiratory, cardiovascular, renal, neurological, hematological, hepatic, and intestinal systems. It is well-established that pathogen infections lead to immune dysregulation, which subsequently contributes to MODS in sepsis. However, recent evidence suggests that sepsis-related opportunistic pathogens can directly induce organ failure by promoting PCD in parenchymal cells of each affected organ. This study provides an overview of PCD in damaged organ and the induction of PCD in host parenchymal cells by opportunistic pathogens, proposing innovative strategies for preventing organ failure in sepsis.
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Affiliation(s)
- Yangyanqiu Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Medical ICU, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Li Weng
- State Key Laboratory of Complex Severe and Rare Diseases, Medical ICU, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xunyao Wu
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical and Science Investigation Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
| | - Bin Du
- State Key Laboratory of Complex Severe and Rare Diseases, Medical ICU, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China.
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical and Science Investigation Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
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14
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Xi Z, Chen J, Wang L, Lu A. Characteristics of lower respiratory microbiota in children's refractory Mycoplasma pneumoniae pneumonia pre- and post-COVID-19 era. Front Cell Infect Microbiol 2025; 14:1438777. [PMID: 39906212 PMCID: PMC11792091 DOI: 10.3389/fcimb.2024.1438777] [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: 05/27/2024] [Accepted: 12/16/2024] [Indexed: 02/06/2025] Open
Abstract
Introduction Little was known about the characteristics of low respiratory tract (LRT) microbiota of refractory M. pneumoniae pneumonia (RMPP) in children before and after the COVID-19 pandemic. Methods Forty-two children diagnosed with RMPP in 2019 (Y2019 group) and 33 children diagnosed with RMPP in 2023 (Y2023 group), entered into the study. The characteristics of the clinical findings were examined, and the LRT microbiota was analyzed by metagenomic next generation sequencing. Results The ratio of consolidate, atelectasis, lung necrosis, and erythema multiforme in Y2023 group was significantly higher than that in Y2019 (P<0.05). Mycoplasmoides pneumoniae was the top species of the LRT microbiota in both groups. The rate of macrolide resistance MP in Y2023 was significantly higher than that in Y2019 (P<0.05), and the mutant site was all 23S rRNA A2063G. There were no significant differences in α-diversity and β-diversity of LRT microbiota between Y2019 and Y2023 group. Trichoderma citrinoviride, Canine mastadenovirus A, Ralstonia pickettii, Lactococcus lactis, Pseudomonas aeruginosa were the biomarkers of LRT microbiota in children with RMPP of Y2023. The abundance of Mycoplasmoides pneumoniae positively correlated with the levels of D-dimer and LDH, negatively correlated with the counts of CD3+ T cells, CD8+ T cells, CD19+ B cells and CD16+CD56+ NK cells. Discussion Our study showed that high abundance of MP was correlated with the severity of RMPP and decrease of immune cells. Trichoderma citrinoviride, Canine mastadenovirus A, Ralstonia pickettii, Lactococcus lactis, Pseudomonas aeruginosa were the biomarkers in microbiota of LRT in children with RMPP post COVID-19 era.
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Affiliation(s)
| | | | | | - Aizhen Lu
- Division of Pulmonology, Children’s Hospital of Fudan University,
Shanghai, China
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15
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Solár P, Šerý O, Vojtíšek T, Krajsa J, Srník M, Dziedzinská R, Králík P, Kessler M, Dubový P, Joukal A, Balcar VJ, Joukal M. The Blood-Cerebrospinal Fluid Barrier as a Potential Entry Site for the SARS-CoV-2 Virus. J Med Virol 2025; 97:e70184. [PMID: 39835622 DOI: 10.1002/jmv.70184] [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: 11/01/2024] [Revised: 12/23/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus responsible for coronavirus disease 2019 (COVID-19). While SARS-CoV-2 primarily targets the lungs and airways, it can also infect other organs, including the central nervous system (CNS). The aim of this study was to investigate whether the choroid plexus could serve as a potential entry site for SARS-CoV-2 into the brain. Tissue samples from 24 deceased COVID-19-positive individuals were analyzed. Reverse transcription real-time PCR (RT-qPCR) was performed on selected brain regions, including the choroid plexus, to detect SARS-CoV-2 viral RNA. Additionally, immunofluorescence staining and confocal microscopy were used to detect and localize two characteristic proteins of SARS-CoV-2: the spike protein S1 and the nucleocapsid protein. RT-qPCR analysis confirmed the presence of SARS-CoV-2 viral RNA in the choroid plexus. Immunohistochemical staining revealed viral particles localized in the epithelial cells of the choroid plexus, with the spike protein S1 detected in the late endosomes. Our findings suggest that the blood-cerebrospinal fluid (B-CSF) barrier in the choroid plexus serves as a route of entry for SARS-CoV-2 into the CNS. This study contributes to the understanding of the mechanisms underlying CNS involvement in COVID-19 and highlights the importance of further research to explore potential therapeutic strategies targeting this entry pathway.
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Affiliation(s)
- Peter Solár
- Department of Anatomy, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Omar Šerý
- Department of Forensic Medicine, St. Anne's Faculty Hospital, Brno, Czech Republic
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Tomáš Vojtíšek
- Department of Forensic Medicine, St. Anne's Faculty Hospital, Brno, Czech Republic
- Department of Forensic Medicine, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jan Krajsa
- Department of Forensic Medicine, St. Anne's Faculty Hospital, Brno, Czech Republic
- Department of Forensic Medicine, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Michal Srník
- Department of Forensic Medicine, St. Anne's Faculty Hospital, Brno, Czech Republic
- Department of Forensic Medicine, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Radka Dziedzinská
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Petr Králík
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Markéta Kessler
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Petr Dubový
- Department of Anatomy, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Andrea Joukal
- Department of Anatomy, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Vladimir J Balcar
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
- Neuroscience Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney NSW, Sydney, New South Wales, Australia
| | - Marek Joukal
- Department of Anatomy, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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16
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Behzadi P, Chandran D, Chakraborty C, Bhattacharya M, Saikumar G, Dhama K, Chakraborty A, Mukherjee S, Sarshar M. The dual role of toll-like receptors in COVID-19: Balancing protective immunity and immunopathogenesis. Int J Biol Macromol 2025; 284:137836. [PMID: 39613064 DOI: 10.1016/j.ijbiomac.2024.137836] [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: 06/09/2024] [Revised: 11/01/2024] [Accepted: 11/17/2024] [Indexed: 12/01/2024]
Abstract
Toll-like receptors (TLRs) of human are considered as the most critical immunological mediators of inflammatory pathogenesis of COVID-19. These immunoregulatory glycoproteins are located on the surface and/or intracellular compartment act as innate immune sensors. Upon binding with distinct SARS-CoV-2 ligand(s), TLRs signal activation of different transcription factors that induce expression of the proinflammatory mediators that collectively induce 'cytokine storm'. Similarly, TLR activation is also pivotal in conferring protection to infection and invasion as well as upregulating the tissue repair pathways. This dual role of the human TLRs in deciding the fate of SARS-CoV-2 has made these receptor proteins as the critical mediators of immunoprotective and immunopathogenic consequences associated with COVID-19. Herein, pathbreaking discoveries exploring the immunobiological importance of the TLRs in COVID-19 and developing TLR-directed therapeutic intervention have been reviewed by accessing the up-to-date literatures available in the public domain/databases. In accordance with our knowledge in association with the importance of TLRs' role against viruses and identification of viral particles, they have been recognized as suitable candidates with high potential as vaccine adjuvants. In this regard, the agonists of TLR4 and TLR9 have effective potential in vaccine technology while the others need further investigations. This comprehensive review suggests that basal level expression of TLRs can act as friends to keep our body safe from strangers but act as a foe via overexpression. Therefore, selective inhibition of the overexpressed TLRs appears to be a solution to counteract the cytokine storm while TLR-agonists as vaccine adjuvants could lessen the risk of infection in the naïve population.
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Affiliation(s)
- Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, 37541-374, Iran.
| | | | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, 700126, West Bengal, India
| | - Manojit Bhattacharya
- Department of Zoology, Fakir Mohan University, VyasaVihar, Balasore, 756020, Odisha, India
| | - Guttula Saikumar
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Izatnagar, Uttar Pradesh, 243122, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Izatnagar, Uttar Pradesh, 243122, India.
| | - Ankita Chakraborty
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, 713340, West Bengal, India
| | - Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, 713340, West Bengal, India.
| | - Meysam Sarshar
- Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, 00146, Rome, Italy
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17
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Liu P, Li M, Li L, Jia W, Dong H, Qi G. Impact of SARS-CoV-2 infection on patients with myasthenia gravis: a retrospective study in a Chinese population. Front Neurol 2024; 15:1482932. [PMID: 39722700 PMCID: PMC11668631 DOI: 10.3389/fneur.2024.1482932] [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: 08/19/2024] [Accepted: 11/26/2024] [Indexed: 12/28/2024] Open
Abstract
Background and purpose Myasthenia gravis (MG) is characterized by fluctuating muscle weakness due to immune-mediated damage to acetylcholine receptors. Viral infections can exacerbate symptoms of muscle weakness, and the clinical status of patients with MG may influence the outcomes of such infections. Here, we identified factors of symptom exacerbation, severe SARS-CoV-2 infection, and pneumonia in patients with MG who are infected with SARS-CoV-2. Methods The clinical characteristics and outcomes of 341 MG patients infected with SARS-CoV-2 across multiple regions in China were determined. Results The median age of the patients was 49 years (range: 35-60 years) and the median disease duration was 4 years (range: 2-8 years). Among the patients, 67 (49.0%) were male and 174 (51.0%) were female. Multivariate analysis indicated that thymectomy [OR, 1.654 (95% CI, 1.036-2.643); p = 0.035], severe SARS-CoV-2 infection [OR, 4.275 (95% CI, 2.206-8.286); p < 0.001], and pyridostigmine bromide [OR, 1.955 (95% CI, 1.192-3.206); p = 0.008] were associated with exacerbation of MG symptoms in patients infected with SARS-CoV-2. Age was significantly associated with severe SARS-CoV-2 infection [OR, 1.023 (95% CI, 1.001-1.046); p = 0.008], while patients with cardiac/vascular comorbidities exhibited an increased likelihood of severe SARS-CoV-2 infection [OR, 3.276 (95% CI, 1.027-10.449); p = 0.045]. Likewise, steroid treatment [OR, 6.140 (95% CI, 2.335-16.140); p < 0.001] was associated with a significantly increased likelihood of severe SARS-CoV-2 infection compared with symptomatic treatment. Additionally, gender [OR, 0.323 (95% CI, 0.120-0.868); p = 0.025] and SARS-CoV-2 severity [OR, 6.067 (95% CI, 1.953-18.850); p = 0.002] were associated with the occurrence of pneumonia. Conclusion We identified factors that were associated with the exacerbation of MG symptoms in patients infected with SARS-CoV-2, including thymectomy, severe SARS-CoV-2 infection, and the use of pyridostigmine bromide. Due to the retrospective nature of the study, these findings should be interpreted as associations rather than predictive factors. However, the results confirm the established relationships between severe SARS-CoV-2 infection and age, cardiovascular comorbidities, and the use of steroid treatment, suggesting that these factors should be considered when managing MG patients during SARS-CoV-2 infection.
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Affiliation(s)
- Peng Liu
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Myasthenia Gravis, Shijiazhuang, China
| | - Mengna Li
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
| | - Liqing Li
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
| | - Wenli Jia
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
| | - Huimin Dong
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
| | - Guoyan Qi
- Center of Treatment of Myasthenia Gravis, People’s Hospital of Shijiazhuang, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Myasthenia Gravis, Shijiazhuang, China
- Hebei Provincial Clinical Research Center for Myasthenia Gravis, Shijiazhuang, China
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18
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Salman M, Cicin J, Abdul Jabbar AB, El-shaer A, Tauseef A, Asghar N, Mirza M, Aboeata A. Trends in sepsis-associated cardiovascular disease mortality in the United States, 1999 to 2022. Front Cardiovasc Med 2024; 11:1505905. [PMID: 39717445 PMCID: PMC11663846 DOI: 10.3389/fcvm.2024.1505905] [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: 10/03/2024] [Accepted: 11/19/2024] [Indexed: 12/25/2024] Open
Abstract
Purpose Cardiovascular disease (CVD) is the leading cause of death in the United States, and sepsis significantly contributes to hospitalization and mortality. This study aims to assess the trends of sepsis-associated CVD mortality rates and variations in mortality based on demographics and regions in the US. Methods The Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database was used to identify CVD and sepsis-related deaths from 1999 to 2022. Data on gender, race and ethnicity, age groups, region, and state classification were statistically analyzed to obtain crude and age-adjusted mortality rates (AAMR). The Joinpoint Regression Program was used to determine trends in mortality within the study period. Results During the study period, there were a total of 1,842,641 deaths with both CVD and sepsis listed as a cause of death. Sepsis-associated CVD mortality decreased between 1999 and 2013, from AAMR of 65.7 in 1999 to 58.8 in 2013 (APC -1.06*%, 95% CI: -2.12% to -0.26%), then rose to 74.3 in 2022 (APC 3.23*%, 95% CI: 2.18%-5.40%). Throughout the study period, mortality rates were highest in men, NH Black adults, and elderly adults (65+ years old). The Northeast region, which had the highest mortality rate in the initial part of the study period, was the only region to see a decline in mortality, while the Northwest, Midwest, and Southern regions experienced significant increases in mortality rates. Conclusion Sepsis-associated CVD mortality has increased in the US over the past decade, and both this general trend and the demographic disparities have worsened since the onset of the COVID-19 pandemic.
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Affiliation(s)
- Malik Salman
- School of Medicine, Creighton University, Omaha, NE, United States
| | - Jack Cicin
- School of Medicine, Creighton University, Omaha, NE, United States
| | | | - Ahmed El-shaer
- School of Medicine, Creighton University, Omaha, NE, United States
| | - Abubakar Tauseef
- School of Medicine, Creighton University, Omaha, NE, United States
| | - Noureen Asghar
- School of Medicine, Creighton University, Omaha, NE, United States
| | - Mohsin Mirza
- School of Medicine, Creighton University, Omaha, NE, United States
| | - Ahmed Aboeata
- Department of Cardiology, Creighton University Medical Center, Omaha, NE, United States
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19
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Zhu N, Ye R, Liu F, Li D, Lin Y, Li W, Wu G, Zhuang D, Huang X. Comparing clinical and biochemical characteristics of febrile seizures in children with and without COVID-19: a retrospective study. BMC Infect Dis 2024; 24:1389. [PMID: 39639218 PMCID: PMC11622598 DOI: 10.1186/s12879-024-10287-2] [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: 06/28/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Transmission of COVID-19 is now normalized. There is an association between it and increased incidence of febrile seizures in children. Exploring whether COVID-19 has a specific effect on the clinical and biochemical features of febrile seizures is critical for the development of clinical treatment and prevention strategies. This study is to compare the differences in clinical features, hematological features, and cerebrospinal fluid characteristics between COVID-19 and non-COVID-19 children with febrile seizures and to provide a new perspective for further exploring the impact of COVID-19 on the nervous system of children. METHODS This was a retrospective case-control study. The cases included children with COVID-19 and non-COVID-19 febrile seizures admitted to Xiamen Children's Hospital from December 2022 to December 2023. The age, gender, length of hospital stay, peak body temperature, presence or absence of other viral infections, hematological characteristics, and cerebrospinal fluid characteristics were compared between children with COVID-19 febrile seizures and non-COVID-19 febrile seizures. RESULTS A total of 50 COVID-19 children with febrile seizures and 192 non-COVID-19 children with febrile seizures were enrolled in this study. Multivariate analysis showed that age (OR = 0.715, P = 0.031), blood urea nitrogen (OR = 0.454, P = 0.029), platelet count (OR = 0.987, P = 0.009) and magnesium ion concentration (OR = 0.109, P < 0.001) were negatively correlated with COVID-19 febrile seizures. Albumin (OR = 1.840, P < 0.001) was positively correlated. The concentration of potassium ion in cerebrospinal fluid (OR = 0.334, P = 0.012) was negatively correlated with COVID-19 febrile seizures, and the concentration of sodium ion (OR = 4.383, P = 0.022) was positively correlated with COVID-19 febrile seizures. CONCLUSION There were differences in age, blood urea nitrogen, platelet count, magnesium ion concentration, albumin, potassium ion concentration in cerebrospinal fluid, and sodium ion concentration in the cerebrospinal fluid between children with COVID-19 febrile seizures and non-COVID-19 febrile seizures. This study may provide valuable insights into the potential mechanisms of COVID-19 damage to the nervous system in children, and the long-term neurological prognosis of these children requires long-term follow-up.
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Affiliation(s)
- Nanxi Zhu
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Ruming Ye
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Fangyi Liu
- Jinjiang Municipal Hospital, Jinjiang, 362200, China
| | - Dan Li
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Ying Lin
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Wanting Li
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Guanhong Wu
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China
| | - Deyi Zhuang
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China.
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China.
| | - Xianghui Huang
- Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, No. 92-98, Yibin Road, Huli District, Xiamen, 361006, China.
- Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, 361006, China.
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20
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Chen Z, Yang Z, Rao L, Li C, Zang N, Liu E. Human adenovirus type 7 (HAdV-7) infection induces pulmonary vascular endothelial injury through the activation of endothelial autophagy. Respir Res 2024; 25:425. [PMID: 39633448 PMCID: PMC11619570 DOI: 10.1186/s12931-024-03025-4] [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: 05/31/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND HAdV-7 is a prevalent pathogen that can cause severe pneumonia in children. Previous studies have shown a significant increase in serum levels of vascular permeability factor (VPF/VEGF) and viral load in pediatric patients with fatal HAdV-7 infection, suggesting potential damage to the pulmonary vascular endothelium. Further research is necessary to elucidate the underlying mechanism. METHODS The human lung microvascular endothelial cell line-5a and human CD46 mice were used for in vitro and in vivo experiments, respectively. RNA-seq was employed for correlative omics analysis. Viral infection and copy status were examined using transmission electron microscopy to observe virus particles, immunofluorescence to detect the viral protein Hexon, and qPCR to assess HAdV-7 fiber gene copies. Various methods, including ELISAs for VEGF and other injury markers, the CCK8 assay for cell viability, and flow cytometry for endothelium numbers, were employed to evaluate endothelial damage. Acute lung injury severity was evaluated by scoring pathological inflammation and measuring pulmonary vascular permeability. Autophagy activation was assessed by observing autophagosomes and validating marker proteins. RESULTS GSEA analysis showed significant enrichment of gene sets related to endothelial functions (barrier, defense, and regeneration) and ALI in the HAdV-7-infected group. GO analysis indicated an enrichment of autophagy-related pathways linked to cell death. Subsequently, successful signs of HAdV-7 infection and replication were observed in the endothelium, including cytopathic effects, intracellular virions, and increased HAdV-7 fiber gene copies. Endothelial injury, including mitochondrial damage, decreased endothelium, and elevated levels of endothelial injury markers such as VEGF, sICAM-1, sVCAM-1, E-selectin, ESM1, MCP1, and IL1β were observed after HAdV-7 infection. Additionally, evidence of leaky lung blood vessels and ALI was observed, including progressive weight loss, elevated pulmonary vascular permeability, and severe lung consolidation. Furthermore, HAdV-7 infection induced autophagosome formation in the endothelium and triggered complete cell autophagy. Importantly, inhibiting autophagic flux reduced VEGF levels and other endothelial injury markers, decreased viral load, improved cell survival rate, alleviated pulmonary vessel leakage, and mitigated lung inflammation. CONCLUSIONS HAdV-7 successfully infects pulmonary vascular endothelium and replicates effectively, causing injury to the endothelium, high VEGF expression and viral load in the serum, as well as ALI/ARDS. Autophagy inhibitors can alleviate endothelial injury, inhibit viral replication, relieve leakage from the vasculature, and reduce lung inflammation.
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Affiliation(s)
- Zhihe Chen
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China
- Pediatric Department, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Zhongying Yang
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China
| | - Lifen Rao
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China
| | - Changgen Li
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China
| | - Na Zang
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China.
| | - Enmei Liu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, 400014, China.
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21
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Girish V, Maiwall R. Revisiting septic shock in cirrhosis: a call for personalized management. Expert Rev Gastroenterol Hepatol 2024; 18:795-813. [PMID: 39744868 DOI: 10.1080/17474124.2024.2443813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/14/2024] [Indexed: 01/12/2025]
Abstract
INTRODUCTION Patients with cirrhosis are known to be prone to infections. Infections can trigger organ failures and decompensations in cirrhosis. Septic shock can increase mortality by fourfold and cause hemodynamic imbalances, adding to the already hyperdynamic circulation. Management of septic shock in cirrhosis can be tricky due to this complex interplay of altered hemodynamics, immune function, and coagulation. AREAS COVERED In this review, we explore the pathophysiological basis, screening, monitoring and management of septic shock in cirrhosis. We also explore novel biomarkers, the growing challenge of multidrug-resistant pathogens and novel and adjunctive therapies. Finally, we propose an algorithm for the management of septic shock in cirrhosis. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Cochrane Library using the keywords and MeSH terms like 'septic shock,' 'cirrhosis,' 'liver disease,' 'sepsis' among others. The search was restricted to peer-reviewed articles in English. EXPERT OPINION The difficulties in managing septic shock in cirrhosis are discussed, emphasizing personalized approaches over protocol-driven care. Fluid and vasopressor management, antibiotic timing and selection, the role of adjunctive therapies, the importance of lactate clearance, gut failure, and the need for further research in this population are highlighted.
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Affiliation(s)
- Vishnu Girish
- Department of Hepatology, Institute of liver and biliary sciences, Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of liver and biliary sciences, Delhi, India
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22
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Aksu MD, van der Ent T, Zhang Z, Riza AL, de Nooijer AH, Ricaño-Ponce I, Janssen N, Engel JJ, Streata I, Dijkstra H, Lemmers H, Grondman I, Koeken VACM, Antoniadou E, Antonakos N, van de Veerdonk FL, Li Y, Giamarellos-Bourboulis EJ, Netea MG, Ziogas A. Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis. J Infect 2024; 89:106300. [PMID: 39357572 PMCID: PMC11624491 DOI: 10.1016/j.jinf.2024.106300] [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: 12/17/2023] [Revised: 07/29/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
OBJECTIVES IL-1α/β and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study. METHODS The circulating soluble receptors of TNF (sTNFR1 and sTNFR2) and IL-1α/β (sIL-1R1, sIL-1R2) were evaluated in the plasma of patients with COVID-19, severe bacterial infections, and sepsis and compared with healthy controls. Additionally, IL1R1, IL1R2, TNFRSF1A, and TNFRSF1B expression was evaluated at the single cell level in PBMCs derived from COVID-19 or sepsis patients. RESULTS Plasma concentrations of sIL-1R1, sTNFR1, and sTNFR2 were significantly higher in COVID-19 patients compared to healthy subjects. Notably, sIL-1R1 levels were particularly elevated in ICU COVID-19 patients, and transcriptome analysis indicated heightened IL1R1 expression in PBMCs from severe COVID-19 patients. In severe bacterial infections, only sTNFR1 and sTNFR2 exhibited increased levels compared to healthy controls. Sepsis patients had decreased sIL-1R1 plasma concentrations but elevated sIL-1R2, sTNFR1, and sTNFR2 levels compared to healthy individuals, reflecting the heightened expression due to the increased numbers of monocytes present in sepsis. Finally, elevated concentrations of sIL-1R2, sTNFR1, and sTNFR2 were moderately associated with reduced 28-day survival in sepsis patients. CONCLUSION Our study reveals distinct regulation of plasma concentrations of soluble IL-1 receptors in COVID-19 and sepsis. Moreover, soluble TNF receptors 1 and 2 consistently rise in all conditions and show a positive correlation with disease severity in sepsis.
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Affiliation(s)
- Muhammed D Aksu
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Tijmen van der Ent
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Zhenhua Zhang
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany
| | - Anca L Riza
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Romania; Regional Centre of Medical Genetics Dolj, County Clinical Emergency Hospital Craiova, Romania
| | - Aline H de Nooijer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Isis Ricaño-Ponce
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Nico Janssen
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Job J Engel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Ioana Streata
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Romania; Regional Centre of Medical Genetics Dolj, County Clinical Emergency Hospital Craiova, Romania
| | - Helga Dijkstra
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Heidi Lemmers
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Inge Grondman
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Valerie A C M Koeken
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, the Netherlands
| | - Eleni Antoniadou
- Intensive Care Unit, "G. Gennimatas" Hospital, Thessaloniki, Greece
| | - Nikolaos Antonakos
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Frank L van de Veerdonk
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Yang Li
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany
| | | | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Athanasios Ziogas
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
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Tai Q, Wang Q, Li J, Dou N, Wu H. Application of mathematical models on efficiency evaluation and intervention of medical institutions in China. BMC Health Serv Res 2024; 24:1376. [PMID: 39529103 PMCID: PMC11552179 DOI: 10.1186/s12913-024-11729-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND : The efficiency of medical services directly impacts the economic burden of healthcare, making it crucial to analyze the input-output efficiency of various types of medical institutions. However, while hospitals had been extensively analyzed for their efficiency, other types of medical institutions had received limited attention in this regard. METHODS : In this study, we employed data envelopment analysis (DEA) methods based on time series and internal benchmarks to autonomously assess the efficiency of 18 distinct categories of healthcare facilities in China over the past decade. The verification was conducted through the utilization of the critical incident technique (CIT). Additionally, we utilized the Delphi process (AHP) method to evaluate suppliers of medical consumables, implemented a multi-population genetic algorithm for managing these consumethod and analytic hierarchymables efficiently, and applied stakeholder theory to manage medical personnel efficiency. RESULTS : Our findings indicated that medical institutions capable of providing clinical services exhibited higher levels of efficiency compared to those unable to do so. Multiple indicators suggested redundancy within these institutions. Notably, comprehensive benefit evaluation revealed that clinical laboratory had performed poorly over the past decade. We selected an inefficient medical institution for intervention in reagent management and the work efficiency of medical staff. After implementing the Delphi method and multi-population genetic algorithm for consumable replenishment, the reagent cost was reduced by 40%, 39% and 31% respectively in each of the three experimental groups, compared to the control group. By applying stakeholder theory and process reengineering methods, we were able to shorten quality control management time for medical staff in the experimental group by 41 min per day, reduce clinical service time by 25 min per day, and extend rest time by 70 min per day, while the quality indicators were all meeting the targets. CONCLUSION: By employing various mathematical models as described above, we were able to reduce costs associated with medical consumables and enhance medical personnel work efficiency without compromising quality objectives.
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Affiliation(s)
- Qiwen Tai
- Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, No.188 Shizi road, Suzhou, Jiangsu, China
| | - Qinghua Wang
- Institute of Foreign Languages, China Medical University, No.77 Puhe road, Shenyang, Liaoning, China
| | - Jiang Li
- School of Nursing, China Medical University, No.77 Puhe road, Shenyang, Liaoning, China
| | - Nannan Dou
- Office of General Management, the Forth Affiliated Hospital of China Medical University, No.77 Puhe road, Shenyang, Liaoning, China
| | - Huazhang Wu
- School of Public Health, China Medical University, No.77 Puhe road, Shenyang, Liaoning, China.
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24
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Cai K, Lin S, Gao G, Sagor MLH, Luo Y, Chen Z, Wang J, Yang M, Lian G, Lin Z, Feng S. Transcriptomics changes of calcitonin gene-related peptide in mitigating lipopolysaccharide-induced septic cardiomyopathy. Sci Rep 2024; 14:26385. [PMID: 39487252 PMCID: PMC11530544 DOI: 10.1038/s41598-024-77520-5] [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: 04/17/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024] Open
Abstract
Septic cardiomyopathy (SCM), a complication initiated by sepsis, presents a significant clinical challenge, leading to increased mortality rates. However, the mechanisms of SCM have not been fully uncovered. Our study involved analyzing RNA sequencing (RNA-seq) data from rat heart tissue, along with utilizing molecular docking and molecular dynamics (MD) simulations, to discover key targets and potential pharmacological actions of the calcitonin gene-related peptide (CGRP) against SCM. A lipopolysaccharide-induced SCM model was established in rats (LPS 10 mg/kg, intraperitoneal (i.p.)). Thereafter, the myocardial tissues from the three groups of rats (Ctrl group, LPS group, and CGRP group) (n = 5) were extracted and underwent RNA-seq, followed by bioinformatics analyses. The qPCR-validated hub targets potentially interacting with CGRP were identified. Following this, homology modeling was utilized to obtain the 3D structure of hub targets, and molecular docking was conducted to evaluate the interaction between CGRP and hub targets. MD simulations (300 ns) were performed to confirm the findings further. Our findings demonstrated that CGRP significantly lowered mortality in SCM rats. 633 DEGs were affected by LPS, contrasted with the Ctrl group. 96 DEGs were affected by CGRP compared to the LPS group. In total, ten fully annotated CGRP-triggered hub genes were obtained. The molecular docking and MD simulations indicate that the relationship between CGRP and eight hub genes is extremely strong. This research offers a thorough examination of the possible objectives and fundamental molecular processes of CGRP in combating SCM, laying the groundwork for investigating the potential protective mechanisms of CGRP against SCM.
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Affiliation(s)
- Kexin Cai
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Siming Lin
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Gufeng Gao
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Mohammad Lsmail Hajary Sagor
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Yuqing Luo
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Zhihua Chen
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Jing Wang
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Mengjing Yang
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Guili Lian
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
| | - Zhihong Lin
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Department of Emergency, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, Fujian, China.
| | - Shaodan Feng
- Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Department of Emergency, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, Fujian, China.
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25
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Zhang K, Shi Y, Huang MX. Further Insight into the Association of Long-Term Particulate Matter Exposure and Mortality in Hospitalized Patients with COVID-19. Ann Am Thorac Soc 2024; 21:1630. [PMID: 39255501 PMCID: PMC11568510 DOI: 10.1513/annalsats.202406-655le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/05/2024] [Indexed: 09/12/2024] Open
Affiliation(s)
- Kai Zhang
- Second Hospital of Jilin UniversityChangchun, China
| | - Yu Shi
- Second Hospital of Jilin UniversityChangchun, China
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26
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Zhang J, Song C, Hu Z. The value of D-dimer-albumin ratio as a prognostic biomarker in critically ill patients with sepsis: A retrospective single-center study. Heliyon 2024; 10:e39057. [PMID: 39640745 PMCID: PMC11620166 DOI: 10.1016/j.heliyon.2024.e39057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/21/2024] [Accepted: 10/07/2024] [Indexed: 12/07/2024] Open
Abstract
Background This study aimed to examine the potential prognostic significance of the D-dimer-albumin ratio (DAR) in critically ill patients with sepsis. Methods A retrospective cohort study was carried out at the Affiliated Hospital of Jiangsu University, involving 1123 patients diagnosed with sepsis from January 2015 to November 2023. The patients were categorized into four groups (Q1-Q4) based on their DAR levels. The primary outcomes measured were in-hospital mortality and ICU mortality. Survival analysis was conducted using Kaplan-Meier survival curves and the log-rank test. Additionally, Cox proportional hazards regression models were utilized to investigate the relationship between the DAR and all-cause mortality. Results The study population had a median age of 75 years (interquartile range: 65-84), and the median DAR was 0.15 (interquartile range: 0.08-0.32). The rates of hospital mortality and ICU mortality were 33.7 % and 31.9 % respectively. There was an observed increase in the cumulative incidence of 30-/60-day mortality with higher DAR levels (log-rank test, P < 0.001). After accounting for other variables, the results from multivariable Cox proportional hazards analyses demonstrated that DAR independently predicted hospital death [HR (95%CI): 1.419 (1.205-1.670); P < 0.001] and ICU death [HR (95%CI): 1.437 (1.219-1.693); P < 0.001]. Conclusions The DAR was found to be an independent predictor of all-cause mortality in critically ill patients with sepsis.
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Affiliation(s)
- Jinhui Zhang
- Department of Critical Care Medicine, The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, 212001, China
| | - Chao Song
- Department of Emergency Medicine, The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, 212001, China
| | - Zhenkui Hu
- Department of Emergency Medicine, The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, 212001, China
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27
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Rinawati W, Machin A, Aryati A. A Single-Center Retrospective Study of Bacterial Infections After Acute Ischemic Stroke: The Prevalence Before and During the COVID-19 Pandemic. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1755. [PMID: 39596940 PMCID: PMC11596060 DOI: 10.3390/medicina60111755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024]
Abstract
Background and Objectives: The management of ischemic stroke involves care that is integrated and comprehensive, including the prevention of infection complications. This study aimed to investigate the prevalence and profile of bacterial infections after acute ischemic stroke both before and during the coronavirus disease 2019 (COVID-19) pandemic. Materials and Methods: A retrospective cross-sectional study examined the medical records of hospitalized acute ischemic stroke patients who had microbiological cultures taken at the National Brain Center Hospital Prof. Dr. dr. Mahar Mardjono, Jakarta, Indonesia, from 1 January 2018 to 31 December 2021. The percentage of positive bacterial growth in the microbiological cultures was used to determine the prevalence of bacterial infection after acute ischemic stroke. Results: A total of 519 patients met the study criteria, including 48 and 471 patients with infections before and during the COVID-19 pandemic. The prevalence of bacterial infection after acute ischemic stroke was 17.9%. There were significant differences in the prevalence of bacterial infection after acute ischemic stroke before and during the COVID-19 pandemic (87.5% vs. 10.8%). Staphylococcus sp. and Klebsiella sp. were the most frequently observed. The risk factors that influenced bacterial infection after acute ischemic stroke were intensive care stay (OR 0.22; 95%CI 0.13-0.39, p-value < 0.001), sepsis (OR 1.99; 95%CI 1.12-3.53, p-value = 0.019), COVID-19 infection (OR 4.81; 95%CI 2.64-8.76, p-value < 0.001), the use of steroids (OR 0.31; 95%CI 0.14-0.67, p-value = 0.003), and the use of TPN (OR 0.34; 95%CI 0.13-0.86, p-value = 0.022). Conclusions: Following the start of the COVID-19 pandemic, there was a decrease in the prevalence of bacterial infections after AIS. Patients with bacterial infections had different profiles before and during the COVID-19 pandemic.
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Affiliation(s)
- Weny Rinawati
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia;
- Department of Clinical Pathology, Laboratory and Blood Bank, National Brain Center Hospital Prof. Dr. dr. Mahar Mardjono, Jakarta 13630, Indonesia
| | - Abdulloh Machin
- Department of Neurology, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
- Airlangga University Hospital, Surabaya 60132, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya 60132, Indonesia
| | - Aryati Aryati
- Dr. Soetomo General Academic Hospital, Surabaya 60132, Indonesia
- Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
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Booth JS, Wahid R, Bruder D, Salerno-Goncalves R. Editorial: The synthesis of secretory immunoglobulin A in mucosal tissue: mucosal-associated invariant T, T follicular helper, and B cells. Front Immunol 2024; 15:1504432. [PMID: 39483477 PMCID: PMC11525977 DOI: 10.3389/fimmu.2024.1504432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Affiliation(s)
- Jayaum S. Booth
- Center for Vaccine Development, University of Maryland, Baltimore, MD, United States
| | - Rezwanul Wahid
- Center for Vaccine Development, University of Maryland, Baltimore, MD, United States
| | - Dunja Bruder
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Immune Regulation Group, Helmholtz Center for Infection Research, Braunschweig, Germany
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Jaishwal P, Jha K, Singh SP. Revisiting the dimensions of universal vaccine with special focus on COVID-19: Efficacy versus methods of designing. Int J Biol Macromol 2024; 277:134012. [PMID: 39048013 DOI: 10.1016/j.ijbiomac.2024.134012] [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: 10/28/2023] [Revised: 05/28/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024]
Abstract
Even though the use of SARS-CoV-2 vaccines during the COVID-19 pandemic showed unprecedented success in a short time, it also exposed a flaw in the current vaccine design strategy to offer broad protection against emerging variants of concern. However, developing broad-spectrum vaccines is still a challenge for immunologists. The development of universal vaccines against emerging pathogens and their variants appears to be a practical solution to mitigate the economic and physical effects of the pandemic on society. Very few reports are available to explain the basic concept of universal vaccine design and development. This review provides an overview of the innate and adaptive immune responses generated against vaccination and essential insight into immune mechanisms helpful in designing universal vaccines targeting influenza viruses and coronaviruses. In addition, the characteristics, safety, and factors affecting the efficacy of universal vaccines have been discussed. Furthermore, several advancements in methods worthy of designing universal vaccines are described, including chimeric immunogens, heterologous prime-boost vaccines, reverse vaccinology, structure-based antigen design, pan-reactive antibody vaccines, conserved neutralizing epitope-based vaccines, mosaic nanoparticle-based vaccines, etc. In addition to the several advantages, significant potential constraints, such as defocusing the immune response and subdominance, are also discussed.
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Affiliation(s)
- Puja Jaishwal
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, India
| | - Kisalay Jha
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, India
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Liu Y, Xu J, Wei C, Xu Y, Lyu C, Sun M, Zheng Y, Cao B. Detection of H1N1 Influenza Virus in the Bile of a Severe Influenza Mouse Model. Influenza Other Respir Viruses 2024; 18:e70012. [PMID: 39449559 PMCID: PMC11502934 DOI: 10.1111/irv.70012] [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: 05/09/2024] [Revised: 08/24/2024] [Accepted: 09/09/2024] [Indexed: 10/26/2024] Open
Abstract
AIMS Influenza virus infection may lead to fatal complications including multi-organ failure and sepsis. The influenza virus was detected in various extra-pulmonary organs in autopsy studies during the 2009 pandemic. However, limited research has been conducted on the presence of viral particle or viral components in the peripheral blood. METHODS AND RESULTS We established a mouse model for severe H1N1 influenza. The bile and blood samples were collected over time and inoculated into embryonated chicken eggs. We detected live influenza virus in bile and blood samples in early infection. Immunofluorescence showed influenza viral components in the liver tissue. No live virus was isolated in the bile in mice intragastrically administered with influenza virus, indicating that the virus was spread from the blood stream. Targeted metabolomics analysis of bile acid and liver tissues showed that a secondary bile acid (3-dehydrocholic acid) was decreased after influenza H1N1 infection. Genes related with fatty acid metabolism and bile secretion pathways were down-regulated in liver after influenza virus infection. CONCLUSION Our study indicated that influenza virus viremia is present in severe influenza, and that the liver is a target organ for influenza viral sepsis.
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Affiliation(s)
- Yan Liu
- State Key Laboratory of Respiratory Health and MultimorbidityNational Center for Respiratory MedicineChina
- National Clinical Research Center for Respiratory Diseases; Institute of Respiratory MedicineChinese Academy of Medical SciencesChina
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory MedicineChina‐Japan Friendship Hospital, Capital Medical UniversityBeijingChina
- Department of Critical Care MedicineYantai Affiliated Hospital of Binzhou Medical UniversityYantaiShandongChina
| | - Jiuyang Xu
- State Key Laboratory of Respiratory Health and MultimorbidityNational Center for Respiratory MedicineChina
- National Clinical Research Center for Respiratory Diseases; Institute of Respiratory MedicineChinese Academy of Medical SciencesChina
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory MedicineChina‐Japan Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Cheng Wei
- Peking University China‐Japan Friendship School of Clinical MedicineBeijingChina
| | - Yitian Xu
- Peking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Chen Lyu
- Peking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Mingzhi Sun
- Tsinghua University School of MedicineBeijingChina
| | - Ying Zheng
- Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Bin Cao
- State Key Laboratory of Respiratory Health and MultimorbidityNational Center for Respiratory MedicineChina
- National Clinical Research Center for Respiratory Diseases; Institute of Respiratory MedicineChinese Academy of Medical SciencesChina
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory MedicineChina‐Japan Friendship Hospital, Capital Medical UniversityBeijingChina
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Siew LY, Lee ZY, Yunos NM, Atan R, Cove ME, Lumlertgul N, Srisawat N, Hasan MS. Outcomes of extracorporeal blood purification with oXiris® membrane in critically ill patients: A systematic review and meta-analysis. J Crit Care 2024; 83:154844. [PMID: 38901069 DOI: 10.1016/j.jcrc.2024.154844] [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: 11/02/2023] [Revised: 04/26/2024] [Accepted: 06/08/2024] [Indexed: 06/22/2024]
Abstract
PURPOSE To evaluate the efficacy of the novel oXiris® membrane in critically ill adult patients. METHODS We systematically searched MEDLINE, EMBASE, and CENTRAL from inception to 01/06/2023 for relevant randomised controlled trials (RCTs) and non-randomised studies of intervention (NRSI). The primary outcome was overall mortality. Random effect meta-analyses were conducted in RevMan 5.4.1. Study quality was evaluated using Cochrane's risk of bias tool. (PROSPERO: CRD42023389198). RESULTS Ten studies (2 RCTs and 8 NRSIs) with 481 patients were included. None had low risk of bias. Treatment using oXiris® was associated with reduced overall mortality (RR 0.78, 95%CI 0.62-0.98; p = 0.03; 6 NRSI). One RCT reported 28-day mortality, finding no significant difference between groups. Besides, pooled NRSIs results showed significant reductions in SOFA scores, norepinephrine dosage, and several inflammatory biomarkers (C-reactive protein [CRP], lactate, and interleukin-6 [IL-6]) post oXiris® treatment. However, other clinical outcomes (ICU and hospital length of stay, mechanical ventilation duration) were similar between groups. CONCLUSION In critically ill patients, the use of oXiris® membrane was associated with reduced overall mortality, norepinephrine dosage, CRP, IL-6, lactate levels, along with improved organ function. However, the certainty of evidence was very low, necessitating high-quality RCTs to further evaluate its efficacy in this population.
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Affiliation(s)
- Li Ying Siew
- Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Zheng-Yii Lee
- Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Department of Cardiac Anesthesiology & Intensive Care Medicine, Charité Berlin, Germany
| | - Nor'azim Mohd Yunos
- Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Department of Anaesthesiology, Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Rafidah Atan
- Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Department of Anaesthesiology, Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Matthew Edward Cove
- Division of Respiratory and Critical Care Medicine, Department of Medicine, National University Hospital, National University Health System, Singapore, Singapore
| | - Nuttha Lumlertgul
- Division of Nephrology, Excellence Centre for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Faculty of Medicine, Centre of Excellence in Critical Care Nephrology, Chulalongkorn University, Bangkok, Thailand
| | - Nattachai Srisawat
- Division of Nephrology, Excellence Centre for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Faculty of Medicine, Centre of Excellence in Critical Care Nephrology, Chulalongkorn University, Bangkok, Thailand
| | - M Shahnaz Hasan
- Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Department of Anaesthesiology, Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia.
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Barbosa Bomfim CC, Génin H, Cottoignies-Callamarte A, Gallois-Montbrun S, Murigneux E, Sams A, Rosenberg AR, Belouzard S, Dubuisson J, Kosminder O, Pène F, Terrier B, Bomsel M, Ganor Y. CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells, and its pulmonary levels correlate with viral clearance in critical COVID-19 patients. J Virol 2024; 98:e0012824. [PMID: 39162434 PMCID: PMC11406896 DOI: 10.1128/jvi.00128-24] [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: 01/18/2024] [Accepted: 07/14/2024] [Indexed: 08/21/2024] Open
Abstract
Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage, and cytokine storm. One unexplored component in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients and restored to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analog SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatments with CGRP and/or SAX are enough to block SARS-CoV-2 productive infection of Calu-3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of both SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients by directly inhibiting SARS-CoV-2 propagation. Hence, CGRP-based interventions could be harnessed for management of COVID-19.IMPORTANCEThe neuropeptide CGRP is highly abundant in the airways. Due to its immunomodulatory, vasodilatory, and anti-viral functions, CGRP could affect multiple aspects of COVID-19-related pulmonary pathophysiology. Yet, the interplay between CGRP and SARS-CoV-2 during COVID-19 remains elusive. Herein, we show that pulmonary levels of CGRP are increased in critical COVID-19 patients, at an early stage of their disease when patients are SARS-CoV-2-positive. Upon subsequent viral clearance, CGRP levels are restored to baseline in SARS-CoV-2-negative patients. We further show that pre- and post-infection treatments with CGRP directly inhibit infection of Calu-3 bronchial epithelial cells with SARS -CoV-2, via activation of the CGRP receptor leading to decreased expression of both SARS-CoV-2 entry receptors. Together, we propose that increased pulmonary CGRP is beneficial in COVID-19, as CGRP-mediated inhibition of SARS-CoV-2 infection could contribute to viral clearance in critical COVID-19 patients. Accordingly, CGRP-based formulations could be useful for COVID-19 management.
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Affiliation(s)
- Caio César Barbosa Bomfim
- Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
| | - Hugo Génin
- Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
| | - Andréa Cottoignies-Callamarte
- Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
| | - Sarah Gallois-Montbrun
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Host-Virus Interactions, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
| | - Emilie Murigneux
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Host-Virus Interactions, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
| | - Anette Sams
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Epoqe Pharma, Copenhagen, Denmark
| | - Arielle R. Rosenberg
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Service of Virology, AP-HP Hôpital Cochin, Paris, France
| | - Sandrine Belouzard
- Molecular and Cellular Virology of Coronavirus, Infection and Immunity Center of Lille, Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHRU, Lille, France
| | - Jean Dubuisson
- Molecular and Cellular Virology of Coronavirus, Infection and Immunity Center of Lille, Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHRU, Lille, France
| | - Olivier Kosminder
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Service of Biological Hematology, AP-HP Hôpitaux Universitaires Paris Centre, Paris, France
| | - Frédéric Pène
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Service of Intensive Medicine and Reanimation, AP-HP Hôpital Cochin, Paris, France
| | - Benjamin Terrier
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
- Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP Hôpital Cochin, Paris, France
| | - Morgane Bomsel
- Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
| | - Yonatan Ganor
- Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
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Atif M, Alsrhani A, Naz F, Ullah S, Abdalla AE, Ullah MI, Mazhari BBZ, Eltayeb LB, Hamad I, Ejaz H. Adenosine A2AR in viral immune evasion and therapy: unveiling new avenues for treating COVID-19 and AIDS. Mol Biol Rep 2024; 51:894. [PMID: 39115571 DOI: 10.1007/s11033-024-09839-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 07/31/2024] [Indexed: 02/06/2025]
Abstract
Adenosine is a neuro- and immunomodulator that functions via G protein-coupled cell surface receptors. Several microbes, including viruses, use the adenosine signaling pathway to escape from host defense systems. Since the recent research developments in its role in health and disease, adenosine and its signaling pathway have attracted attention for targeting to treat many diseases. The therapeutic role of adenosine has been extensively studied for neurological, cardiovascular, and inflammatory disorders and bacterial pathophysiology, but published data on the role of adenosine in viral infections are lacking. Therefore, the purpose of this review article was to explain in detail the therapeutic role of adenosine signaling against viral infections, particularly COVID-19 and HIV. Several therapeutic approaches targeting A2AR-mediated pathways are in development and have shown encouraging results in decreasing the intensity of inflammatory reaction. The hypoxia-adenosinergic mechanism provides protection from inflammation-mediated tissue injury during COVID-19. A2AR expression increased remarkably in CD39 + and CD8 + T cells harvested from HIV patients in comparison to healthy subjects. A combined in vitro treatment performed by blocking PD-1 and CD39/adenosine signaling produced a synergistic outcome in restoring the CD8 + T cells funstion in HIV patients. We suggest that A2AR is an ideal target for pharmacological interventions against viral infections because it reduces inflammation, prevents disease progression, and ultimately improves patient survival.
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Affiliation(s)
- Muhammad Atif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia.
| | - Abdullah Alsrhani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Farrah Naz
- Northwestern Polytechnical University, Xian, 710060, China
| | - Sajjad Ullah
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Lahore, 54590, Pakistan
| | - Abualgasim Elgaili Abdalla
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Bi Bi Zainab Mazhari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Qurayyat, 75911, Saudi Arabia
| | - Lienda Bashier Eltayeb
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin AbdulAziz University- Al-Kharj, Riyadh, 11942, Saudi Arabia
| | - Ismail Hamad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia
| | - Hasan Ejaz
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Saudi Arabia.
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Chen X, Zhu Y, Shen L, Zhou D, Feng N, Tong Q. Efficacy and Safety of Nirmatrelvir/Ritonavir in Severe Hospitalized Patients with COVID-19 and in Patients at High Risk for Progression to Critical Illness: A Real-World Study. J Intensive Care Med 2024; 39:742-750. [PMID: 38356292 DOI: 10.1177/08850666241228841] [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] [Indexed: 02/16/2024]
Abstract
Background: Nirmatrelvir/Ritonavir is an orally administered anti-SARS-Cov-2 drug used in mild-to-moderate COVID-19 patients. Our retrospective cohort study aims to evaluate the efficacy and safety of Nirmatrelvir/Ritonavir in severe hospitalized patients with Omicron infection, as well as in patients at high risk for progression to critical illness in real-world settings. Methods: A total of 350 patients received Nirmatrelvir/Ritonavir while 350 matched controls did not. Patients with confirmed COVID-19 were administered Nirmatrelvir 300 mg and Ritonavir 100 mg orally twice a day for 5 days, with the medication initiated on the first day after admission. The primary endpoint of the study was a composite outcome of hospitalization or death from any cause within 28 days. Secondary endpoints included the occurrence of adverse events and the evaluation of serum levels of IL-6 and viral load. Results: We documented the mortality risk from any cause within 28 days, viral load, serum IL-6 levels, and adverse events. Nirmatrelvir/Ritonavir reduced the 28-day risk of all-cause mortality by 86% (P = .011, hazard ratio (HR) = 0.14, 95% confidence interval (CI) = 0.03, 0.64). At baseline, the serum level of IL-6 was significantly higher in the antiviral treatment group compared to the control group (P < .001), but no significant difference (P = .990) was found between the two groups at discharge. In CKD patients undergoing hemodialysis, no significant worsening of renal function was observed in the Nirmatrelvir/Ritonavir treatment group compared to the control group. Conclusion: Nirmatrelvir/Ritonavir may reduce the 28-day risk of all-cause mortality in critically ill patients with COVID-19 and in patients at high risk for critical disease progression.
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Affiliation(s)
- Xiaohua Chen
- Department of Infectious Diseases, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Zhu
- Department of Pulmonary and Critical Care Medicine, 8th Medical Center of Chinese PLA General Hospital General Hospital, Beijing, China
- Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Leer Shen
- Department of Infectious Diseases, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Zhou
- Shanghai Key Laboratory of Medical Epigenetics, Laboratory of Cancer Epigenetics, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Institutes of Biomedical Sciences, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, China
| | - Nannan Feng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Tong
- Department of Rheumatology & Immunology, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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35
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Brujats A, Huerta A, Osuna-Gómez R, Guinart-Cuadra A, Ferrero-Gregori A, Pujol C, Soriano G, Poca M, Fajardo J, Escorsell A, Gallego A, Vidal S, Villanueva C, Alvarado-Tapias E. Immune Response and Risk of Decompensation following SARS-CoV-2 Infection in Outpatients with Advanced Chronic Liver Disease. Int J Mol Sci 2024; 25:8302. [PMID: 39125872 PMCID: PMC11312207 DOI: 10.3390/ijms25158302] [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: 06/26/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.
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Affiliation(s)
- Anna Brujats
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Anna Huerta
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Rubén Osuna-Gómez
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Albert Guinart-Cuadra
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Andreu Ferrero-Gregori
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Clàudia Pujol
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - German Soriano
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria Poca
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier Fajardo
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Angels Escorsell
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Adolfo Gallego
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Silvia Vidal
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Càndid Villanueva
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Edilmar Alvarado-Tapias
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Atencio LA, Quintero IJ, Almanza A, Eskildsen G, Sánchez-Gallego J, Herrera M, Fernández-Marín H, Loaiza JR, Mejía LC. Insights into the Naso-Oropharyngeal Bacterial Composition in Suspected SARS-CoV-2 Cases. Pathogens 2024; 13:615. [PMID: 39204216 PMCID: PMC11357247 DOI: 10.3390/pathogens13080615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 09/03/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. While research on COVID-19 has mainly focused on its epidemiology, pathogenesis, and treatment, studies on the naso-oropharyngeal microbiota have emerged in the last few years as an overlooked area of research. Here, we analyzed the bacterial community composition of the naso-oropharynx in 50 suspected SARS-CoV-2 cases (43 detected, 7 not detected) from Veraguas province (Panama) distributed across five age categories. Statistical analysis revealed no significant differences (p < 0.05) in bacterial alpha and beta diversities between the groups categorized by SARS-CoV-2 test results, age, or patient status. The genera Corynebacterium, Staphylococcus, Prevotella, Streptococcus, and Tepidiphilus were the most abundant in both detected and not-detected SARS-CoV-2 group. The linear discriminant analysis effect size (LEfSe) for biomarker exploration indicated that Veillonella and Prevotella were enriched in detected and hospitalized patients with SARS-CoV-2 relative to non-detected patients, while Thermoanaerobacterium and Haemophilus were enriched in non-detected patients with SARS-CoV-2. The results also indicated that the genus Corynebacterium was found to decrease in patients with detected SARS-CoV-2 relative to those with non-detected SARS-CoV-2. Understanding the naso-oropharyngeal microbiota provides insights into the diversity, composition, and resilience of the microbial community in patients with SARS-CoV-2.
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Affiliation(s)
- Librada A. Atencio
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
| | - Indira J. Quintero
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
| | - Alejandro Almanza
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
| | - Gilberto Eskildsen
- Departamento de Microbiología Humana, Facultad de Medicina, Universidad de Panamá, Panama City 0819-07289, Panama;
| | - Joel Sánchez-Gallego
- Department of Marine Earth and Atmospheric Sciences, North Carolina State University, Raleigh, NC 27695, USA;
- Coiba Scientific Station (COIBA AIP), Gustavo Lara Street, Bld. 145B, City of Knowledge, Clayton, Panama City 0843-01853, Panama
| | | | - Hermógenes Fernández-Marín
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
- Sistema Nacional de Investigación (SNI), Secretaría Nacional de Ciencia, Tecnología, e Innovación (SENACYT), Panama City 0816-02852, Panama
| | - José R. Loaiza
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
- Sistema Nacional de Investigación (SNI), Secretaría Nacional de Ciencia, Tecnología, e Innovación (SENACYT), Panama City 0816-02852, Panama
- Smithsonian Tropical Research Institute, Panama City 0843-03092, Panama
| | - Luis C. Mejía
- Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT), Clayton, Panama City 0843-01103, Panama; (L.A.A.); (I.J.Q.); (A.A.); (H.F.-M.)
- Sistema Nacional de Investigación (SNI), Secretaría Nacional de Ciencia, Tecnología, e Innovación (SENACYT), Panama City 0816-02852, Panama
- Smithsonian Tropical Research Institute, Panama City 0843-03092, Panama
- Departamento de Genética y Biología Molecular, Universidad de Panamá, Estafeta Universitaria Apartado 3366, Zona 4, Panama City 0819-07289, Panama
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Bu J, Zhang M, Zhang R, Sun L, Chen Z, Wu Y. Could Ocular Glands Be Infected by SARS-CoV-2? Diseases 2024; 12:169. [PMID: 39195168 DOI: 10.3390/diseases12080169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/29/2024] Open
Abstract
The aim of the study was to investigate the expression levels of ACE2 in ocular glands and to investigate the effect of S protein on them. Male C57BL/6J mice were used for the experiments. The expression levels of ACE2 are highest in the Meibomian glands, followed by the conjunctiva, the cornea, and the lacrimal glands. Co-immunoprecipitation assays confirmed direct binding between ACE2 and S protein in ocular surface epithelia and Meibomian glands. CD45+ cell infiltration was found in the S protein treatment group, which was accompanied by upregulation of inflammation-related cytokines. There was also prominent cell apoptosis in the S protein treatment group. In conclusion, not only the cornea and the conjunctiva, but also the Meibomian glands express ACE2, and S protein could induce ocular surface epithelial cell and Meibomian gland cell inflammation and apoptosis.
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Affiliation(s)
- Jinghua Bu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Minjie Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Rongrong Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Le Sun
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhenzong Chen
- Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361006, China
| | - Yang Wu
- Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361006, China
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Bhalerao KS, De Silva PIT, Hiniduma K, Grunbaum A, Rozza N, Kremer R, Rusling JF. Microfluidic Immunoarray for Point-of-Care Detection of Cytokines in COVID-19 Patients. ACS OMEGA 2024; 9:29320-29330. [PMID: 39005811 PMCID: PMC11238202 DOI: 10.1021/acsomega.4c00735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/16/2024]
Abstract
The "cytokine storm" often induced in COVID-19 patients contributes to the onset of "acute respiratory distress syndrome" (ARDS) accompanied by lung infection and damage, multiorgan failure, and even death. This large increase in pro-inflammatory cytokines in blood may be related to severity. Rapid, on-demand cytokine analyses can thus be critical to inform treatment plans and improve survival rates. Here, we report a sensitive, low-cost, semiautomated 3D-printed microfluidic immunoarray to detect 2 cytokines and CRP simultaneously in a single 10 μL serum sample in 25 min. Accuracy was validated by analyzing 80 COVID-19 patient serum samples, with results well correlated to a commercial Meso Scale protein immunoassay. Capture antibodies immobilized in detection microwells in a flat well plate-type flow chamber facilitate the immunoassay, with a programmable syringe pump automatically delivering reagents. Chemiluminescence signals were captured in a dark box with a CCD camera integrated for 30 s. This system was optimized to detect inflammation biomarkers IL-6, IFN-γ, and CRP simultaneously in blood serum. Ultralow limits of detection (LODs) of 0.79 fg/mL for IL-6, 4.2 fg/mL for CRP, and 2.7 fg/mL for IFN-γ with dynamic ranges of up to 100 pg/mL were achieved. ROC statistical analyses showed a relatively good diagnostic value related to the samples assigned WHO COVID-19 scores for disease severity, with the best results for IL-6 and CRP. Monitoring these biomarkers for coronavirus severity may allow prediction of disease severity as a basis for critical treatment decisions and better survival rates.
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Affiliation(s)
- Ketki S Bhalerao
- Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
| | - P I Thilini De Silva
- Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Keshani Hiniduma
- Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Ami Grunbaum
- Department of Medicine, McGill University Health Centre, 1001 Decarie Blvd., Montreal, QC H3A 1A1, Canada
| | - Nicholas Rozza
- Department of Medicine, McGill University Health Centre, 1001 Decarie Blvd., Montreal, QC H3A 1A1, Canada
| | - Richard Kremer
- Department of Medicine, McGill University Health Centre, 1001 Decarie Blvd., Montreal, QC H3A 1A1, Canada
| | - James F Rusling
- Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
- Institute of Material Science, University of Connecticut, Storrs, Connecticut 06269, United States
- School of Chemistry, National University of Ireland at Galway, Galway H91 TK33, Ireland
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39
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Kulma M, Šakanović A, Bedina-Zavec A, Caserman S, Omersa N, Šolinc G, Orehek S, Hafner-Bratkovič I, Kuhar U, Slavec B, Krapež U, Ocepek M, Kobayashi T, Kwiatkowska K, Jerala R, Podobnik M, Anderluh G. Sequestration of membrane cholesterol by cholesterol-binding proteins inhibits SARS-CoV-2 entry into Vero E6 cells. Biochem Biophys Res Commun 2024; 716:149954. [PMID: 38704887 DOI: 10.1016/j.bbrc.2024.149954] [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: 02/13/2024] [Revised: 03/26/2024] [Accepted: 04/15/2024] [Indexed: 05/07/2024]
Abstract
Membrane lipids and proteins form dynamic domains crucial for physiological and pathophysiological processes, including viral infection. Many plasma membrane proteins, residing within membrane domains enriched with cholesterol (CHOL) and sphingomyelin (SM), serve as receptors for attachment and entry of viruses into the host cell. Among these, human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use proteins associated with membrane domains for initial binding and internalization. We hypothesized that the interaction of lipid-binding proteins with CHOL in plasma membrane could sequestrate lipids and thus affect the efficiency of virus entry into host cells, preventing the initial steps of viral infection. We have prepared CHOL-binding proteins with high affinities for lipids in the plasma membrane of mammalian cells. Binding of the perfringolysin O domain four (D4) and its variant D4E458L to membrane CHOL impaired the internalization of the receptor-binding domain of the SARS-CoV-2 spike protein and the pseudovirus complemented with the SARS-CoV-2 spike protein. SARS-CoV-2 replication in Vero E6 cells was also decreased. Overall, our results demonstrate that the integrity of CHOL-rich membrane domains and the accessibility of CHOL in the membrane play an essential role in SARS-CoV-2 cell entry.
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Affiliation(s)
- Magdalena Kulma
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Aleksandra Šakanović
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Apolonija Bedina-Zavec
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Simon Caserman
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Neža Omersa
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Gašper Šolinc
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Sara Orehek
- Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
| | - Iva Hafner-Bratkovič
- Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; EN-FIST Centre of Excellence, Trg Osvobodilne Fronte 13, 1000, Ljubljana, Slovenia
| | - Urška Kuhar
- Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia
| | - Brigita Slavec
- Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia
| | - Uroš Krapež
- Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia
| | - Matjaž Ocepek
- Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia
| | - Toshihide Kobayashi
- Lipid Biology Laboratory, RIKEN, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198, Japan; UMR 7021 CNRS, Université de Strasbourg, F-67401, Illkirch, France
| | - Katarzyna Kwiatkowska
- Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland
| | - Roman Jerala
- Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; EN-FIST Centre of Excellence, Trg Osvobodilne Fronte 13, 1000, Ljubljana, Slovenia
| | - Marjetka Podobnik
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia
| | - Gregor Anderluh
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
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40
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Singh M, Verma H, Gera N, Baddipadige R, Choudhary S, Bhandu P, Silakari O. Evaluation of Cordyceps militaris steroids as anti-inflammatory agents to combat the Covid-19 cytokine storm: a bioinformatics and structure-based drug designing approach. J Biomol Struct Dyn 2024; 42:5159-5177. [PMID: 37551029 DOI: 10.1080/07391102.2023.2245039] [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: 11/29/2022] [Accepted: 06/08/2023] [Indexed: 08/09/2023]
Abstract
Since the SARS-CoV-2 epidemic, researchers have been working on figuring out ways to tackle multi-organ failure and hyperinflation, which are brought on by a cytokine storm. Angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike glycoprotein's cellular receptor, is involved in complicated molecular processes that result in hyperinflammation. Cordyceps militaris is one of the traditional Chinese medicines that is used as an immune booster, and it has exhibited efficacy in lowering blood glucose levels, seminal emissions, and infertility. In the current study, we explored the potential of Cordyceps militaris steroids as key agents in managing the anger of cytokine storm in Covid-19 using network ethnopharmacological techniques and structure-based drug designing approaches. The steroids present in Cordyceps militaris were initially screened against the targets involved in inflammatory pathways. The results revealed that out of 16 steroids, 5 may be effective against 17 inflammatory pathways by targeting 11 pathological proteins. Among the five steroids, beta-sitosterol, Cholest-5-en-3β-ol, 3β, and 7α-Dihydroxycholest-5-ene were found to interact with thrombin (F2), an important protein reported to reduce the severity of inflammatory mediators and Cholest-4-en-3-one was found to target Glucocorticoid receptor (NR3C1). The top docked steroid displayed key interactions with both targets, which retained key interactions throughout the 100 ns simulation period. These compounds were also shown high binding free energy scores in water swap studies. Based on obtained results the current study suggests the use of Cordyceps militaris as an add-on therapy that may reduce the progression of inflammatory co-morbidities among patients infected with SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Manmeet Singh
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Himanshu Verma
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Narendra Gera
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Raju Baddipadige
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Shalki Choudhary
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Priyanka Bhandu
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Om Silakari
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
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Mueankwan S, Trongtrakul K, Tajarernmuang P, Niyatiwatchanchai N, Kusirisin P, Narongkiatikhun P. Care Bundles to Improve Hemoperfusion Performance in Patients with Severe COVID-19: A Retrospective Study. J Clin Med 2024; 13:3360. [PMID: 38929889 PMCID: PMC11205105 DOI: 10.3390/jcm13123360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Background/Objectives: Hemoperfusion (HP) is employed to modulate cytokine storms in severe coronavirus disease 2019 (COVID-19) patients, requiring careful attention for success and safety. Therefore, we investigated whether our care bundles could enhance HP performance. Methods: We conducted a retrospective cohort study on adult patients (≥20 years old) with severe COVID-19 pneumonia. In the first wave (Phase I), we identified HP-related issues and addressed them with care bundles in the second wave (Phase II). The care bundles included early temperature control, precise hemodynamic monitoring, and clot prevention measures for the HP membrane. The HP success rate and associated adverse events (AEs) were assessed between the two phases. Results: The study included 60 HP (HA330) sessions from 27 cases (Phase I: 21 sessions from 9 cases; Phase II: 39 sessions from 18 cases). Patient characteristics and treatments for COVID-19 were similar, except for baseline body temperature (BT) and heart rate (HR). Phase II showed a higher success rate (67% vs. 89%, p = 0.19), although it did not reach statistical significance. Phase I recorded a significantly higher frequency of AEs (3 [IQR 1, 4] events/case vs. 1 [IQR 0, 2] events/case, p = 0.014). After implementing the care bundles, hypothermia significantly decreased (78% vs. 33%, p = 0.037), with an adjusted odds ratio of 0.15; 95% CI 0.02-0.95, p = 0.044 for baseline BT. Conclusions: Further exploration with a larger sample size is required to establish the advantages of care bundles. However, the bundles' implementation has significantly improved hypothermia prevention.
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Affiliation(s)
- Sirirat Mueankwan
- Surgical Intensive Care Unit, Division of Nursing Services, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Konlawij Trongtrakul
- Division of Pulmonary, Critical Care, and Allergy, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.T.); (N.N.)
| | - Pattraporn Tajarernmuang
- Division of Pulmonary, Critical Care, and Allergy, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.T.); (N.N.)
| | - Nutchanok Niyatiwatchanchai
- Division of Pulmonary, Critical Care, and Allergy, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.T.); (N.N.)
| | - Prit Kusirisin
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.K.); (P.N.)
| | - Phoom Narongkiatikhun
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.K.); (P.N.)
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42
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Kozłowski P, Leszczyńska A, Ciepiela O. Long COVID Definition, Symptoms, Risk Factors, Epidemiology and Autoimmunity: A Narrative Review. AMERICAN JOURNAL OF MEDICINE OPEN 2024; 11:100068. [PMID: 39034937 PMCID: PMC11256271 DOI: 10.1016/j.ajmo.2024.100068] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 07/23/2024]
Abstract
The virus called SARS-CoV-2 emerged in 2019 and quickly spread worldwide, causing COVID-19. It has greatly impacted on everyday life, healthcare systems, and the global economy. In order to save as many lives as possible, precautions such as social distancing, quarantine, and testing policies were implemented, and effective vaccines were developed. A growing amount of data collected worldwide allowed the characterization of this new disease, which turned out to be more complex than other common respiratory tract infections. An increasing number of convalescents presented with a variety of nonspecific symptoms emerging after the acute infection. This possible new global health problem was identified and labelled as long COVID. Since then, a great effort has been made by clinicians and the scientific community to understand the underlying mechanisms and to develop preventive measures and effective treatment. The role of autoimmunity induced by SARS-CoV-2 infection in the development of long COVID is discussed in this review. We aim to deliver a description of several conditions with an autoimmune background observed in COVID-19 convalescents, including Guillain-Barré syndrome, antiphospholipid syndrome and related thrombosis, and Kawasaki disease highlighting a relationship between SARS-CoV-2 infection and the development of autoimmunity. However, further studies are required to determine its true clinical significance.
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Affiliation(s)
- Paweł Kozłowski
- Central Laboratory, University Clinical Centre of the Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Leszczyńska
- Central Laboratory, University Clinical Centre of the Medical University of Warsaw, Warsaw, Poland
| | - Olga Ciepiela
- Central Laboratory, University Clinical Centre of the Medical University of Warsaw, Warsaw, Poland
- Department of Laboratory Medicine, Medical University of Warsaw, Warsaw, Poland
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43
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Meshref M, Ghaith HS, Hammad MA, Shalaby MMM, Ayasra F, Monib FA, Attia MS, Ebada MA, Elsayed H, Shalash A, Bahbah EI. The Role of RIN3 Gene in Alzheimer's Disease Pathogenesis: a Comprehensive Review. Mol Neurobiol 2024; 61:3528-3544. [PMID: 37995081 PMCID: PMC11087354 DOI: 10.1007/s12035-023-03802-0] [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: 09/08/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023]
Abstract
Alzheimer's disease (AD) is a globally prevalent form of dementia that impacts diverse populations and is characterized by progressive neurodegeneration and impairments in executive memory. Although the exact mechanisms underlying AD pathogenesis remain unclear, it is commonly accepted that the aggregation of misfolded proteins, such as amyloid plaques and neurofibrillary tau tangles, plays a critical role. Additionally, AD is a multifactorial condition influenced by various genetic factors and can manifest as either early-onset AD (EOAD) or late-onset AD (LOAD), each associated with specific gene variants. One gene of particular interest in both EOAD and LOAD is RIN3, a guanine nucleotide exchange factor. This gene plays a multifaceted role in AD pathogenesis. Firstly, upregulation of RIN3 can result in endosomal enlargement and dysfunction, thereby facilitating the accumulation of beta-amyloid (Aβ) peptides in the brain. Secondly, RIN3 has been shown to impact the PICLAM pathway, affecting transcytosis across the blood-brain barrier. Lastly, RIN3 has implications for immune-mediated responses, notably through its influence on the PTK2B gene. This review aims to provide a concise overview of AD and delve into the role of the RIN3 gene in its pathogenesis.
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Affiliation(s)
- Mostafa Meshref
- Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | | | | | - Faris Ayasra
- Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Mohamed S Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | | | - Hanaa Elsayed
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ali Shalash
- Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eshak I Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt.
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44
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Citarella BW, Kartsonaki C, Ibáñez-Prada ED, Gonçalves BP, Baruch J, Escher M, Pritchard MG, Wei J, Philippy F, Dagens A, Hall M, Lee J, Kutsogiannis DJ, Wils EJ, Fernandes MA, Tirupakuzhi Vijayaraghavan BK, Panda PK, Martin-Loeches I, Ohshimo S, Fatoni AZ, Horby P, Dunning J, Rello J, Merson L, Rojek A, Vaillant M, Olliaro P, Reyes LF. Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms. Heliyon 2024; 10:e29591. [PMID: 38779000 PMCID: PMC11109728 DOI: 10.1016/j.heliyon.2024.e29591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 03/21/2024] [Accepted: 04/10/2024] [Indexed: 05/25/2024] Open
Abstract
Background COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83-0.93]). Conclusion Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.
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Affiliation(s)
| | - Christiana Kartsonaki
- MRC Population Health Research Unit, Clinical Trials Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Elsa D. Ibáñez-Prada
- Universidad de La Sabana, Chía, Colombia
- Clínica Universidad de La Sabana, Chía, Colombia
| | | | - Joaquin Baruch
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Martina Escher
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Mark G. Pritchard
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Jia Wei
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Fred Philippy
- Competence Centre for Methodology and Statistics, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Andrew Dagens
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Matthew Hall
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - James Lee
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Demetrios James Kutsogiannis
- Department of Critical Care Medicine, Faculty of Medicine and Dentistry, The University of Alberta, Edmonton, Alberta, Canada
| | - Evert-Jan Wils
- Department of Intensive Care, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Marília Andreia Fernandes
- Department of Internal Medicine, Hospital Curry Cabral, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | | | | | - Ignacio Martin-Loeches
- Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James' Hospital, Dublin, Ireland
| | - Shinichiro Ohshimo
- Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Arie Zainul Fatoni
- Department of Anesthesiology and Intensive Therapy, Saiful Anwar General Hospital, Brawijaya University, Malang, East Java, Indonesia
| | - Peter Horby
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Jake Dunning
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Jordi Rello
- Vall d'Hebrón Institute Research, Barcelona, Spain
- CHU Nîmes, Nîmes, France
| | - Laura Merson
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Amanda Rojek
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
- Royal Melbourne Hospital, Melbourne, Australia
| | - Michel Vaillant
- Competence Centre for Methodology and Statistics, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Piero Olliaro
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Luis Felipe Reyes
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford, UK
- Universidad de La Sabana, Chía, Colombia
- Clínica Universidad de La Sabana, Chía, Colombia
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Bai WH, Yang JJ, Liu Z, Ning WS, Mao Y, Zhou CL, Cheng L. Development and validation of a nomogram for predicting in-hospital survival rates of patients with COVID-19. Heliyon 2024; 10:e31380. [PMID: 38803927 PMCID: PMC11129089 DOI: 10.1016/j.heliyon.2024.e31380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
Objective Our aim was to develop and validate a nomogram for predicting the in-hospital 14-day (14 d) and 28-day (28 d) survival rates of patients with coronavirus disease 2019 (COVID-19). Methods Clinical data of patients with COVID-19 admitted to the Renmin Hospital of Wuhan University from December 2022 to February 2023 and the north campus of Shanghai Ninth People's Hospital from April 2022 to June 2022 were collected. A total of 408 patients from Renmin Hospital of Wuhan University were selected as the training cohort, and 151 patients from Shanghai Ninth People's Hospital were selected as the verification cohort. Independent variables were screened using Cox regression analysis, and a nomogram was constructed using R software. The prediction accuracy of the nomogram was evaluated using the receiver operating characteristic (ROC) curve, C-index, and calibration curve. Decision curve analysis was used to evaluate the clinical application value of the model. The nomogram was externally validated using a validation cohort. Result In total, 559 patients with severe/critical COVID-19 were included in this study, of whom 179 (32.02 %) died. Multivariate Cox regression analysis showed that age >80 years [hazard ratio (HR) = 1.539, 95 % confidence interval (CI): 1.027-2.306, P = 0.037], history of diabetes (HR = 1.741, 95 % CI: 1.253-2.420, P = 0.001), high APACHE II score (HR = 1.083, 95 % CI: 1.042-1.126, P < 0.001), sepsis (HR = 2.387, 95 % CI: 1.707-3.338, P < 0.001), high neutrophil-to-lymphocyte ratio (NLR) (HR = 1.010, 95 % CI: 1.003-1.017, P = 0.007), and high D-dimer level (HR = 1.005, 95 % CI: 1.001-1.009, P = 0.028) were independent risk factors for 14 d and 28 d survival rates, whereas COVID-19 vaccination (HR = 0.625, 95 % CI: 0.440-0.886, P = 0.008) was a protective factor affecting prognosis. ROC curve analysis showed that the area under the curve (AUC) of the 14 d and 28 d hospital survival rates in the training cohort was 0.765 (95 % CI: 0.641-0.923) and 0.814 (95 % CI: 0.702-0.938), respectively, and the AUC of the 14 d and 28 d hospital survival rates in the verification cohort was 0.898 (95 % CI: 0.765-0.962) and 0.875 (95 % CI: 0.741-0.945), respectively. The calibration curves of 14 d and 28 d hospital survival showed that the predicted probability of the model agreed well with the actual probability. Decision curve analysis (DCA) showed that the nomogram has high clinical application value. Conclusion In-hospital survival rates of patients with COVID-19 were predicted using a nomogram, which will help clinicians in make appropriate clinical decisions.
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Affiliation(s)
- Wen-Hui Bai
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430200, China
| | - Jing-Jing Yang
- Department of Critical Care Medicine, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430200, China
| | - Zhou Liu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430000, China
| | - Wan-Shan Ning
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Yong Mao
- Department of Vascular Surgery, North Campus of Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201900, China
| | - Chen-Liang Zhou
- Department of Critical Care Medicine, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430200, China
| | - Li Cheng
- Department of Critical Care Medicine, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430200, China
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Lai K, Lin G, Chen C, Xu Y. Development and Validation of a Predictive Model for Acute Kidney Injury in Sepsis Patients Based on Recursive Partition Analysis. J Intensive Care Med 2024; 39:465-476. [PMID: 37964547 DOI: 10.1177/08850666231214243] [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] [Indexed: 11/16/2023]
Abstract
BACKGROUND Sepsis-associated acute kidney injury (SA-AKI) is a critical condition with significant clinical implications, yet there is a need for a predictive model that can reliably assess the risk of its development. This study is undertaken to bridge a gap in healthcare by creating a predictive model for SA-AKI with the goal of empowering healthcare providers with a tool that can revolutionize patient care and ultimately lead to improved outcomes. METHODS A cohort of 615 patients afflicted with sepsis, who were admitted to the intensive care unit, underwent random stratification into 2 groups: a training set (n = 435) and a validation set (n = 180). Subsequently, a multivariate logistic regression model, imbued with nonzero coefficients via LASSO regression, was meticulously devised for the prognostication of SA-AKI. This model was thoughtfully rendered in the form of a nomogram. The salience of individual risk factors was assessed and ranked employing Shapley Additive Interpretation (SHAP). Recursive partition analysis was performed to stratify the risk of patients with sepsis. RESULTS Among the panoply of clinical variables examined, hypertension, diabetes mellitus, C-reactive protein, procalcitonin (PCT), activated partial thromboplastin time, and platelet count emerged as robust and independent determinants of SA-AKI. The receiver operating characteristic curve analysis for SA-AKI risk discrimination in both the training set and validation set yielded an area under the curve estimates of 0.843 (95% CI: 0.805 to 0.882) and 0.834 (95% CI: 0.775 to 0.893), respectively. Notably, PCT exhibited the most conspicuous influence on the model's predictive capacity. Furthermore, statistically significant disparities were observed in the incidence of SA-AKI and the 28-day survival rate across high-risk, medium-risk, and low-risk cohorts (P < .05). CONCLUSION The composite predictive model, amalgamating the quintet of SA-AKI predictors, holds significant promise in facilitating the identification of high-risk patient subsets.
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Affiliation(s)
- Kunmei Lai
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Guo Lin
- Department of Intensive Care Unit, The First Affifiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Caiming Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Singh L, Kumar A, Rai M, Basnet B, Rai N, Khanal P, Lai KS, Cheng WH, Asaad AM, Ansari S. Spectrum of COVID-19 induced liver injury: A review report. World J Hepatol 2024; 16:517-536. [PMID: 38689748 PMCID: PMC11056898 DOI: 10.4254/wjh.v16.i4.517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/20/2024] [Accepted: 02/28/2024] [Indexed: 04/24/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused changes in the global health system, causing significant setbacks in healthcare systems worldwide. This pandemic has also shown resilience, flexibility, and creativity in reacting to the tragedy. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection targets most of the respiratory tract, resulting in a severe sickness called acute respiratory distress syndrome that may be fatal in some individuals. Although the lung is the primary organ targeted by COVID-19 viruses, the clinical aspect of the disease is varied and ranges from asymptomatic to respiratory failure. However, due to an unorganized immune response and several affected mechanisms, the liver may also experience liver cell injury, ischemic liver dysfunction, and drug-induced liver injury, which can result in respiratory failure because of the immune system's disordered response and other compromised processes that can end in multisystem organ failure. Patients with liver cirrhosis or those who have impaired immune systems may be more likely than other groups to experience worse results from the SARS-CoV-2 infection. We thus intend to examine the pathogenesis, current therapy, and consequences of liver damage concerning COVID-19.
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Affiliation(s)
- Lokjan Singh
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Anil Kumar
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Maya Rai
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Bibek Basnet
- Health Sciences, Asian College of Advance Studies, Purbanchal University, Satdobato 24122, Lalitpur, Nepal
| | - Nishant Rai
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India
| | - Pukar Khanal
- Department of Pharmacology & Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, Karnataka, India
| | - Kok-Song Lai
- Division of Health Sciences, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates
| | - Wan-Hee Cheng
- Health and Life Sciences, INTI International University, Nilai 71800, Malaysia
| | - Ahmed Morad Asaad
- Department of Microbiology, College of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Shamshul Ansari
- Division of Health Sciences, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates.
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Yin X, Zhu W, Tang X, Yang G, Zhao X, Zhao K, Jiang L, Li X, Zhao H, Wang X, Yan Y, Xing L, Yu J, Meng X, Zhao H. Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer. BMC Cancer 2024; 24:486. [PMID: 38632501 PMCID: PMC11022442 DOI: 10.1186/s12885-024-12228-3] [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: 11/14/2023] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.
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Affiliation(s)
- Xiaoyan Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Wanqi Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Xiaoyong Tang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, 250117, Jinan, Shandong Province, China
| | - Guangjian Yang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, 250117, Jinan, Shandong Province, China
| | - Xianguang Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Kaikai Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Liyang Jiang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Xiaolin Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Hong Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Xin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Yuanyuan Yan
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, 250117, Jinan, Shandong Province, China
| | - Ligang Xing
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China.
| | - Hanxi Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, Shandong, China.
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Iancu IV, Diaconu CC, Plesa A, Fudulu A, Albulescu A, Neagu AI, Pitica IM, Dragu LD, Bleotu C, Chivu‐Economescu M, Matei L, Mambet C, Nedeianu S, Popescu CP, Sultana C, Ruta SM, Botezatu A. LncRNAs expression profile in a family household cluster of COVID-19 patients. J Cell Mol Med 2024; 28:e18226. [PMID: 38501860 PMCID: PMC10949602 DOI: 10.1111/jcmm.18226] [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: 10/09/2023] [Revised: 02/19/2024] [Accepted: 02/24/2024] [Indexed: 03/20/2024] Open
Abstract
More than 3 years after the start of SARS-CoV-2 pandemic, the molecular mechanisms behind the viral pathogenesis are still not completely understood. Long non-coding RNAs (lncRNAs), well-known players in viral infections, can represent prime candidates for patients' risk stratification. The purpose of the current study was to investigate the lncRNA profile in a family cluster of COVID-19 cases with different disease progression, during the initial wave of the pandemic and to evaluate their potential as biomarkers for COVID-19 evolution. LncRNA expression was investigated in nasopharyngeal swabs routinely collected for diagnosis. Distinct expression patterns of five lncRNAs (HOTAIR, HOTAIRM1, TMEVPG1, NDM29 and snaR) were identified in all the investigated cases, and they were associated with disease severity. Additionally, a significant increase in the expression of GAS5-family and ZFAS1 lncRNAs, which target factors involved in the inflammatory response, was observed in the sample collected from the patient with the most severe disease progression. An lncRNA prognostic signature was defined, opening up novel research avenues in understanding the interactions between lncRNAs and SARS-CoV-2.
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Affiliation(s)
| | | | - Adriana Plesa
- Stefan S Nicolau Institute of VirologyBucharestRomania
| | - Alina Fudulu
- Stefan S Nicolau Institute of VirologyBucharestRomania
| | - Adrian Albulescu
- Stefan S Nicolau Institute of VirologyBucharestRomania
- Department of PharmacologyNational Institute for Chemical Pharmaceutical Research and DevelopmentBucharestRomania
| | - Ana Iulia Neagu
- Stefan S Nicolau Institute of VirologyBucharestRomania
- Carol Davila University of Medicine and PharmacyBucharestRomania
| | | | | | | | | | - Lilia Matei
- Stefan S Nicolau Institute of VirologyBucharestRomania
| | | | | | - Corneliu Petru Popescu
- Carol Davila University of Medicine and PharmacyBucharestRomania
- Dr Victor Babes Infectious and Tropical Diseases Clinical HospitalBucharestRomania
| | - Camelia Sultana
- Stefan S Nicolau Institute of VirologyBucharestRomania
- Carol Davila University of Medicine and PharmacyBucharestRomania
| | - Simona Maria Ruta
- Stefan S Nicolau Institute of VirologyBucharestRomania
- Carol Davila University of Medicine and PharmacyBucharestRomania
| | - Anca Botezatu
- Stefan S Nicolau Institute of VirologyBucharestRomania
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Williams B, Zou L, Pittet JF, Chao W. Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies. Anesth Analg 2024; 138:696-711. [PMID: 38324297 PMCID: PMC10916756 DOI: 10.1213/ane.0000000000006888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 02/08/2024]
Abstract
Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.
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Affiliation(s)
- Brittney Williams
- From the Division of Cardiothoracic Anesthesia, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Lin Zou
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Jean-Francois Pittet
- Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
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