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Su JH, Lin DY, Liu XH, Zhang JL, Li ZG, Tao EX, Huang KX. Identifying potential co-expressed genes and molecular mechanisms linking post-COVID-19 and Guillain-Barre syndrome through neutrophil extracellular trap-related genes. Front Neurol 2025; 16:1447725. [PMID: 40433617 PMCID: PMC12109036 DOI: 10.3389/fneur.2025.1447725] [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: 06/12/2024] [Accepted: 03/31/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction Neutrophil extracellular traps (NETs) play a pivotal role in immunity and autoinflammatory disease, leading us to hypothesize that NETs are crucial in Guillain-Barre Syndrome (GBS) after SARS-CoV-2 infection. Methods By collecting six Gene Expression Omnibus (GEO) datasets from the GEO database and dividing them into discovery and validation sets, we screened differentially expressed genes (DEGs) within the discovery set, with further analyses using functional enrichment analysis. Using single-sample gene set enrichment analysis (ssGSEA), we assessed immune cell infiltration in both coronavirus disease 2019 (COVID-19) and GBS datasets. NETs-related genes (NETRGs) were identified through a protein-protein interaction (PPI) network and NETs gene datasets. Finally, candidate drugs were screened using Connectivity Map. Results In this study, a total of 3254 DEGs were identified from the COVID-19 dataset, and 692 DEGs were obtained from the GBS dataset. Among these, 145 co-expressed DEGs were obtained. Bioinformatics functional analysis indicated that co-expressed DEGs were predominantly gathered in immune-related and inflammatory response pathways. Employing various algorithms, we identified MMP9, CAMP, and CASP1 as NETRGs, demonstrating good discriminatory capacity in COVID-19 and GBS. Notably, neutrophils and macrophages were identified as co-upregulated differential immune infiltrating cells significantly associated with both COVID-19 and GBS. Moreover, we identified 10 candidate drugs for patients with post-COVID-19 GBS. Conclusion In conclusion, MMP9, CASP1, and CAMP were identified as promising biomarkers and potential targets for therapy of post-COVID-19 GBS.
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Affiliation(s)
- Jie-Hua Su
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Dan-Yu Lin
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiao-Huan Liu
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie-Li Zhang
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Zhong-Gui Li
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - En-Xiang Tao
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Kai-Xun Huang
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Yeung ST, Damani-Yokota P, Thannickal SA, Bartnicki E, Bernier ED, Barnett CR, Khairallah C, Duerr R, Noval MG, Segal LN, Stapleford KA, Khanna KM. Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling. Immunity 2025; 58:1327-1342.e5. [PMID: 40286790 DOI: 10.1016/j.immuni.2025.04.001] [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: 07/03/2024] [Revised: 12/27/2024] [Accepted: 04/02/2025] [Indexed: 04/29/2025]
Abstract
Despite vaccines, rapidly mutating viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to threaten human health due to an impaired immunoregulatory pathway and a hyperactive immune response. Our understanding of the local immune mechanisms used by tissue-resident macrophages to safeguard the host from excessive inflammation during SARS-CoV-2 infection remains limited. Here, we found that nerve- and airway-associated interstitial macrophages (NAMs) are required to control mouse-adapted SARS-CoV-2 (MA-10) infection. Control mice restricted lung viral distribution and survived infection, whereas NAM depletion enhanced viral spread and inflammation and led to 100% mortality. Mechanistically, type I interferon receptor (IFNAR) signaling by NAMs was critical for limiting inflammation and viral spread, and IFNAR deficiency in CD169+ macrophages mirrored NAM-depleted outcomes and abrogated their expansion. These findings highlight the essential protective role of NAMs in regulating viral spread and inflammation, offering insights into SARS-CoV-2 pathogenesis and underscoring the importance of NAMs in mediating host immunity and disease tolerance.
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Affiliation(s)
- Stephen T Yeung
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Payal Damani-Yokota
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Sara A Thannickal
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Eric Bartnicki
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Eduardo D Bernier
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Clea R Barnett
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Camille Khairallah
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ralf Duerr
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Medicine, Vaccine Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Maria G Noval
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Leopoldo N Segal
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Kenneth A Stapleford
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Kamal M Khanna
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
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3
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Monteiro AHA, Freitas KM, Montuori-Andrade ACM, de Lima EBS, Carvalho AFS, Cardoso C, Lara ES, Oliveira LC, Zaidan I, da Santos FRS, Resende F, Souza-Costa LP, Queiroz-Junior CM, Chaves IDM, Nóbrega NRC, Rabelo MBO, Rocha MP, Campana PRV, Pádua RM, Ferreira RS, Barreto LV, Kronenberger T, Maltarollo VG, de Godoy MO, Oliva G, Guido RVC, Teixeira MM, Costa VV, Sousa LP, Braga FC. Ouratein D, a Biflavanone From Ouratea spectabilis, Alleviates Betacoronavirus Infection by Mitigating Inflammation, Lung Damage and Viral Replication. Phytother Res 2025; 39:2180-2196. [PMID: 40099709 DOI: 10.1002/ptr.8462] [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: 08/19/2024] [Revised: 02/03/2025] [Accepted: 02/08/2025] [Indexed: 03/20/2025]
Abstract
Severe coronavirus outbreaks, including SARS, MERS, and COVID-19, have underscored the urgent need for effective antiviral therapies. This study evaluated the antiviral activity of biflavanones isolated from Ouratea spectabilis-specifically ouratein (Our-) A, B, C, and D-against murine hepatitis virus (MHV-3) and human SARS-CoV-2. Cells infected with MHV-3 or SARS-CoV-2 were treated with ourateins, and viral replication was assessed using plaque assays. Mice infected with MHV-3 were treated with Our-D either orally or intraperitoneally. Key assessments included leukocyte counts, cytokine and chemokine levels, histological analysis, and survival rates. The mechanism of action was explored through in silico and in vitro studies focused on the binding and inhibition of the main protease (Mpro). Our-D significantly inhibited the replication of both viruses, with a selective index of 2.5 for MHV-3 and 14.9 for SARS-CoV-2. In vivo, Our-D reduced leukocyte infiltration in the lungs, decreased CCL2 levels, increased IL-10, and lowered plasma IL-6 and CXCL1 levels. Additionally, Our-D mitigated lung damage, partially restored betacoronavirus-induced lymphopenia, and reduced viral loads in the lungs, heart, and spleen, ultimately improving survival in mice. In silico studies revealed that Our-A and Our-C had strong binding affinity for Mpro, and both significantly inhibited Mpro activity in vitro, unlike Our-D. Our-D protected mice from coronavirus infection by modulating the inflammatory response and reducing viral loads, with minimal effect on Mpro inhibition, suggesting alternative mechanisms for its antiviral activity.
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Affiliation(s)
- Adelson Héric A Monteiro
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Kátia M Freitas
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Clara M Montuori-Andrade
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Erick Bryan Sousa de Lima
- Department of Clinical Analysis and Toxicology, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Antônio Felipe S Carvalho
- Department of Clinical Analysis and Toxicology, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Camila Cardoso
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Edvaldo S Lara
- Department of Clinical Analysis and Toxicology, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Leonardo Camilo Oliveira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Isabella Zaidan
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Felipe Rocha Silva da Santos
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Filipe Resende
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiz Pedro Souza-Costa
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Celso M Queiroz-Junior
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ian de Meira Chaves
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Natália R C Nóbrega
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maria Beatriz O Rabelo
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Marina P Rocha
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Priscilla R V Campana
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Rodrigo M Pádua
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Rafaela S Ferreira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiza V Barreto
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Thales Kronenberger
- Partner-Site Tübingen, German Center for Infection Research (DZIF), Tübingen, Germany
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Vinícius G Maltarollo
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Glaucius Oliva
- Institute of Physics, Universidade de São Paulo, São Carlos, Brazil
| | - Rafael V C Guido
- Institute of Physics, Universidade de São Paulo, São Carlos, Brazil
| | - Mauro M Teixeira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vivian V Costa
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lirlândia P Sousa
- Department of Clinical Analysis and Toxicology, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fernão C Braga
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Cho HK, Kim SH, Jeon CH, Jung JW, Wi YM. KL-6 as a predictor of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) and mortality in critically ill COVID-19 patients: A single-center retrospective cohort study. Med Mycol 2025; 63:myaf032. [PMID: 40194943 DOI: 10.1093/mmy/myaf032] [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: 01/31/2025] [Revised: 03/16/2025] [Accepted: 04/04/2025] [Indexed: 04/09/2025] Open
Abstract
This study evaluated the predictive value of Krebs von den Lungen-6 (KL-6) for the development of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) and its association with mortality in critically ill COVID-19 patients. A retrospective single-center cohort study was conducted on critically ill COVID-19 patients who required high-flow oxygen or mechanical ventilation between January 2021 and June 2023. Serial serum KL-6 levels were measured at admission and weekly thereafter. The predictive performance of initial KL-6 was assessed using ROC curve analysis, and risk factors for CAPA and 30-day mortality were analyzed using multivariable models. Among 238 patients, 25 (10.5%) developed CAPA. Initial KL-6 demonstrated good discriminative ability for CAPA prediction (AUC 0.745; 95% CI: 0.685-0.799), with an optimal cutoff of 270.9 U/ml (sensitivity: 88.0%, specificity: 55.4%). KL-6 ≥ 270.9 U/ml remained independently associated with CAPA (aHR: 9.66; 95% CI: 2.28-40.89) after multivariable analysis. Serial measurements showed a trend toward a greater increase in KL-6 levels among CAPA patients than non-CAPA patients (median difference: 259.9 vs. 73.0 U/ml, P = .053). Additional independent predictors of CAPA included inotropic/vasopressor support, diabetes mellitus, and tocilizumab use. CAPA patients had higher all-cause 30-day mortality (60.8% vs. 45.2%; P = .020), which remained significant after adjustment (aHR: 2.19; 95% CI: 1.08-4.15). Furthermore, KL-6 was independently associated with 30-day mortality (aHR: 1.03 per 100 U/ml; 95% CI: 1.00-1.07). These findings suggest that KL-6 is a promising biomarker for predicting CAPA and mortality in critically ill COVID-19 patients.
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Affiliation(s)
- Hyun Kyu Cho
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-si, Republic of Korea
| | - Si-Ho Kim
- Division of Infectious Diseases, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-si, Republic of Korea
| | - Cheon-Hoo Jeon
- Division of Infectious Diseases, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-si, Republic of Korea
| | - Jae Wan Jung
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-si, Republic of Korea
| | - Yu Mi Wi
- Division of Infectious Diseases, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-si, Republic of Korea
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5
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Hansen CB, Møller MEE, Pérez-Alós L, Israelsen SB, Drici L, Ottenheijm ME, Nielsen AB, Wewer Albrechtsen NJ, Benfield T, Garred P. Differences in biomarker levels and proteomic survival prediction across two COVID-19 cohorts with distinct treatments. iScience 2025; 28:112046. [PMID: 40124495 PMCID: PMC11927729 DOI: 10.1016/j.isci.2025.112046] [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: 09/09/2024] [Revised: 12/07/2024] [Accepted: 02/13/2025] [Indexed: 03/25/2025] Open
Abstract
Prognostic biomarkers have been widely studied in COVID-19, but their levels may be influenced by treatment strategies. This study examined plasma biomarkers and proteomic survival prediction in two unvaccinated hospitalized COVID-19 cohorts receiving different treatments. In a derivation cohort (n = 126) from early 2020, we performed plasma proteomic profiling and evaluated innate and complement system immune markers. A proteomic model based on differentially expressed proteins predicted 30-day mortality with an area under the curve (AUC) of 0.81. The model was tested in a validation cohort (n = 80) from late 2020, where patients received remdesivir and dexamethasone, and performed with an AUC of 0.75. Biomarker levels varied considerably between cohorts, sometimes in opposite directions, highlighting the impact of treatment regimens on biomarker expression. These findings underscore the need to account for treatment effects when developing prognostic models, as treatment differences may limit their generalizability across populations.
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Affiliation(s)
- Cecilie Bo Hansen
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | | | - Laura Pérez-Alós
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Simone Bastrup Israelsen
- Department of Infectious Diseases, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Lylia Drici
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg Hospital, Copenhagen, Denmark
| | - Maud Eline Ottenheijm
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg Hospital, Copenhagen, Denmark
| | - Annelaura Bach Nielsen
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg Hospital, Copenhagen, Denmark
| | - Nicolai J. Wewer Albrechtsen
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Benfield
- Department of Infectious Diseases, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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6
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Ju X, Li J, Huang H, Qing Y, Sandeep B. A meta-analysis of the efficacy and safety of immunomodulators in the treatment of severe COVID-19. J Int Med Res 2025; 53:3000605251317462. [PMID: 40079461 PMCID: PMC11907513 DOI: 10.1177/03000605251317462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 01/13/2025] [Indexed: 03/15/2025] Open
Abstract
ObjectiveTo evaluate the efficacy and adverse events of immunomodulators in the treatment of severe coronavirus disease 2019 (COVID-19).MethodsA literature search for the meta-analysis was performed using PubMed, The Cochrane Library, Embase, Wanfang Data, CNKI, and Web of Science to identify randomized controlled trials assessing the outcomes of patients treated with corticosteroids alone and/or interleukin-6 receptor antagonists for COVID-19. The risk of bias was assessed using the Cochrane method. The protocol was registered with PROSPERO (registry number: CRD42022356904).ResultsCompared with patients receiving standard of care, patients treated with corticosteroids alone had an increased risk of 14-day in-hospital death, whereas those treated with interleukin-6 receptor antagonists alone or in combination with corticosteroids had a lower risk of 14-day in-hospital death. Corticosteroid therapy alone was associated with increased risk of several adverse events, including intensive care unit admission and non-invasive ventilation, whereas interleukin-6 receptor antagonists alone or in combination with corticosteroids were not linked to adverse effects.ConclusionsThe findings supported the safety and efficacy of interleukin-6 receptor antagonists, either alone or together with corticosteroids, in patients with severe COVID-19; evidence supporting the efficacy and safety of corticosteroids monotherapy is lacking.
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Affiliation(s)
- Xuegui Ju
- Department of Nephrology, Chengdu Medical College, School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Jiayao Li
- Department of Nephrology, College of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Haonan Huang
- Department of Nephrology, College of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Yidan Qing
- Department of Nephrology, College of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Bhushan Sandeep
- Department of Cardio-Thoracic Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
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7
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Lu JY, Lu JY, Wang S, Duong KS, Henry S, Fisher MC, Duong TQ. Long term outcomes of patients with chronic kidney disease after COVID-19 in an urban population in the Bronx. Sci Rep 2025; 15:6119. [PMID: 39972044 PMCID: PMC11839904 DOI: 10.1038/s41598-025-90153-6] [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: 10/10/2024] [Accepted: 02/11/2025] [Indexed: 02/21/2025] Open
Abstract
We investigated the long-term kidney and cardiovascular outcomes of patients with chronic kidney disease (CKD) after COVID-19. Our retrospective cohort consisted of 834 CKD patients with COVID-19 and 6,167 CKD patients without COVID-19 between 3/11/2020 to 7/1/2023. Multivariate competing risk regression models were used to estimate risk (as adjusted hazard ratios (aHR) with 95% confidence intervals (CI)) of CKD progression to a more advanced stage (Stage 4 or 5) and major adverse kidney events (MAKE), and risk of major adverse cardiovascular events (MACE) at 6-, 12-, and 24-month follow up. Hospitalized COVID-19 patients at 12 and 24 months (aHR 1.62 95% CI[1.24,2.13] and 1.76 [1.30, 2.40], respectively), but not non-hospitalized COVID-19 patients, were at higher risk of CKD progression compared to those without COVID-19. Both hospitalized and non-hospitalized COVID-19 patients were at higher risk of MAKE at 6-, 12- and 24-months compared to those without COVID-19. Hospitalized COVID-19 patients at 6-, 12- and 24-months (aHR 1.73 [1.21, 2.50], 1.77 [1.34, 2.33], and 1.31 [1.05, 1.64], respectively), but not non-hospitalized COVID-19 patients, were at higher risk of MACE compared to those without COVID-19. COVID-19 increases the risk of long-term CKD progression and cardiovascular events in patients with CKD. These findings highlight the need for close follow up care and therapies that slow CKD progression in this high-risk subgroup.
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Affiliation(s)
- Jason Y Lu
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Justin Y Lu
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Stephen Wang
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
- Department of Surgery, Beth Israel Deaconess Medical Centerand, Harvard Medical School, Boston, MA, USA
| | - Katie S Duong
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Sonya Henry
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Molly C Fisher
- Department of Medicine, Nephrology Division, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tim Q Duong
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
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8
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Naiditch H, Betts MR, Larman HB, Levi M, Rosenberg AZ. Immunologic and inflammatory consequences of SARS-CoV-2 infection and its implications in renal disease. Front Immunol 2025; 15:1376654. [PMID: 40012912 PMCID: PMC11861071 DOI: 10.3389/fimmu.2024.1376654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 12/23/2024] [Indexed: 02/28/2025] Open
Abstract
The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses.
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Affiliation(s)
- Hiam Naiditch
- Department of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Michael R. Betts
- Department of Microbiology and Institute of Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - H. Benjamin Larman
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
| | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
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9
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Vogi V, Haschka D, Forer L, Schwendinger S, Petzer V, Coassin S, Tancevski I, Sonnweber T, Löffler-Ragg J, Puchhammer-Stöckl E, Graninger M, Wolf D, Kronenberg F, Zschocke J, Jukic E, Weiss G. Severe COVID-19 disease is associated with genetic factors affecting plasma ACE2 receptor and CRP concentrations. Sci Rep 2025; 15:4708. [PMID: 39922945 PMCID: PMC11807156 DOI: 10.1038/s41598-025-89306-4] [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: 12/18/2023] [Accepted: 02/04/2025] [Indexed: 02/10/2025] Open
Abstract
A hyperinflammatory state with highly elevated concentrations of inflammatory biomarkers such as C-reactive protein (CRP) is a characteristic feature of severe coronavirus disease 2019 (COVID-19). To examine a potential role of common genetic factors that may influence COVID-19 outcomes, we investigated whether individuals with a polygenic predisposition for a pro-inflammatory response (in the form of Polygenic Scores) are more likely to develop severe COVID-19. The innovative approach of polygenic scores to investigate genetic factors in COVID-19 severity should provide a comprehensive approach beyond single-gene studies. In our cohort of 156 patients of European ancestry, two overlapping Polygenic Scores (PGS) predicting a genetic predisposition to basal CRP concentrations were significantly different between non-severe and severe COVID-19 cases and were associated with less severe COVID-19 outcomes. Furthermore, specific single nucleotide polymorphisms (SNPs) that contribute to either of the two Polygenic Scores predicting basal CRP levels are associated with different traits that represent risk factors for COVID-19 disease initiation (ACE2 receptor, viral replication) and progression (CRP). We suggest that genetically determined enforced CRP formation may contribute to strengthening of innate immune responses and better initial pathogen control thereby reducing the risk of subsequent hyperinflammation and adverse course of COVID-19.
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Affiliation(s)
- Verena Vogi
- Institute of Human Genetics, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - David Haschka
- Department of Internal Medicine II (Infectious Diseases, Immunology, Pneumology and Rheumatology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Lukas Forer
- Institute of Genetic Epidemiology, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Simon Schwendinger
- Institute of Human Genetics, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Verena Petzer
- Department of Internal Medicine V (Hematology and Internistic Oncology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Stefan Coassin
- Institute of Genetic Epidemiology, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Ivan Tancevski
- Department of Internal Medicine II (Infectious Diseases, Immunology, Pneumology and Rheumatology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Thomas Sonnweber
- Department of Internal Medicine II (Infectious Diseases, Immunology, Pneumology and Rheumatology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Judith Löffler-Ragg
- Department of Internal Medicine II (Infectious Diseases, Immunology, Pneumology and Rheumatology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | | | - Marianne Graninger
- Department of Virology, Medical University Vienna, Vienna, 1090, Austria
| | - Dominik Wolf
- Department of Internal Medicine V (Hematology and Internistic Oncology), Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Johannes Zschocke
- Institute of Human Genetics, Medical University Innsbruck, Innsbruck, 6020, Austria
| | - Emina Jukic
- Institute of Human Genetics, Medical University Innsbruck, Innsbruck, 6020, Austria.
| | - Günter Weiss
- Department of Internal Medicine II (Infectious Diseases, Immunology, Pneumology and Rheumatology), Medical University Innsbruck, Innsbruck, 6020, Austria.
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10
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Khan N, Tran KA, Chevre R, Locher V, Richter M, Sun S, Sadeghi M, Pernet E, Herrero-Cervera A, Grant A, Saif A, Downey J, Kaufmann E, Khader SA, Joubert P, Barreiro LB, Yipp BG, Soehnlein O, Divangahi M. β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus. Nat Immunol 2025; 26:174-187. [PMID: 39779870 PMCID: PMC11785525 DOI: 10.1038/s41590-024-02041-2] [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: 08/02/2023] [Accepted: 11/21/2024] [Indexed: 01/11/2025]
Abstract
Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.
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Affiliation(s)
- Nargis Khan
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada.
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - Kim A Tran
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Raphael Chevre
- Institute of Experimental Pathology, Centre of Molecular Biology of Inflammation, Münster, Germany
| | - Veronica Locher
- Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Mathis Richter
- Institute of Experimental Pathology, Centre of Molecular Biology of Inflammation, Münster, Germany
| | - Sarah Sun
- Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Mina Sadeghi
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Erwan Pernet
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Andrea Herrero-Cervera
- Institute of Experimental Pathology, Centre of Molecular Biology of Inflammation, Münster, Germany
| | - Alexandre Grant
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Ahmed Saif
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Jeffrey Downey
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
| | - Eva Kaufmann
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | | | - Philippe Joubert
- Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, Québec, Canada
| | - Luis B Barreiro
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Bryan G Yipp
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Oliver Soehnlein
- Institute of Experimental Pathology, Centre of Molecular Biology of Inflammation, Münster, Germany
| | - Maziar Divangahi
- Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins Christie Laboratories, McGill University, Montréal, Québec, Canada.
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11
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Wigley BR, Stillman EC, Craig‐Atkins E. What Doesn't Kill You Makes You Stronger? Examining Relationships Between Early-Life Stress, Later-Life Inflammation and Mortality Risk in Skeletal Remains. AMERICAN JOURNAL OF BIOLOGICAL ANTHROPOLOGY 2025; 186:e70005. [PMID: 39905993 PMCID: PMC11795231 DOI: 10.1002/ajpa.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 12/27/2024] [Accepted: 01/21/2025] [Indexed: 02/06/2025]
Abstract
OBJECTIVES This paper explores conflicting perspectives on the adaptive significance of phenotypic plasticity during fetal and early postnatal development and the impact that stressors experienced during this critical early-life period have on later-life morbidity and mortality risk. METHODS The sample (n = 216) comprised archeologically-recovered human skeletons. A geometric morphometric (GM) method was employed to evaluate first permanent molar (M1) fluctuating asymmetry (FA) and provide a proxy for early-life stress. Shifts in later-life physiology were inferred through two inflammatory lesions: periosteal new bone formation (PNBF) and periodontal disease (PD). To explore mortality risk, age-at-death was estimated through dental development for skeletally immature individuals (n = 104) and through senescent skeletal changes for mature skeletons (n = 112). RESULTS Significant differences were found in M1 FA between groups, with the immature cohort associated with elevated FA. Within-group analysis revealed age-at-death in the immature group had a significant positive relationship with M1 FA and PD presence. In the mature group, alongside sex and the co-occurrence of PD and PNBF, FA was a significant predictor of a shorter life. Higher FA was also associated with active and bilaterally expressed PNBF. CONCLUSIONS It is theorized that early-life stress, if survived, programmed a hyperinflammatory response to environmentally-mediated physiological perturbations which increased the chances of survival during subsequent development but also elevated later-life mortality risk. Findings demonstrate a complicated relationship between developmental stress and physiological shifts that helps to illustrate the adaptive significance of early-life programming and support the Thrifty Phenotype hypothesis.
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Affiliation(s)
- B. R. Wigley
- School of BiosciencesUniversity of SheffieldSheffieldUK
| | - E. C. Stillman
- School of Mathematical and Physical SciencesUniversity of SheffieldSheffieldUK
| | - E. Craig‐Atkins
- School of History, Philosophy and Digital HumanitiesUniversity of SheffieldSheffieldUK
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12
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Eltayeb A, Redwan EM. T-cell immunobiology and cytokine storm of COVID-19. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2025; 213:1-30. [PMID: 40246342 DOI: 10.1016/bs.pmbts.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
The 2019 coronavirus illness (COVID 2019) first manifests as a newly identified pneumonia and may quickly escalate to acute respiratory distress syndrome, which has caused a global pandemic. Except for individualized supportive care, no curative therapy has been steadfastly advised for COVID-19 up until this point. T cells and virus-specific T lymphocytes are required to guard against viral infection, particularly COVID-19. Delayed immunological reconstitution (IR) and cytokine storm (CS) continue to be significant barriers to COVID-19 cure. While severe COVID-19 patients who survived the disease had considerable lymphopenia and increased neutrophils, especially in the elderly, their T cell numbers gradually recovered. Exhausted T lymphocytes and elevated levels of pro-inflammatory cytokines, including IL6, IL10, IL2, and IL17, are observed in peripheral blood and the lungs. It implies that while convalescent plasma, IL-6 blocking, mesenchymal stem cells, and corticosteroids might decrease CS, Thymosin α1 and adaptive COVID-19-specific T cells could enhance IR. There is an urgent need for more clinical research in this area throughout the world to open the door to COVID-19 treatment in the future.
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Affiliation(s)
- Ahmed Eltayeb
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Elrashdy M Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
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13
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Treon SP, Kotton CN, Park DJ, Moranzoni G, Lemvigh CK, Gathe JC, Varughese TA, Barnett CF, Belenchia JM, Clark NM, Farber CM, Abid MB, Ahmed G, Patterson CJ, Guerrera ML, Soumerai JD, Chea VA, Carulli IP, Southard J, Li S, Wu CJ, Livak KJ, Holmgren E, Kim P, Shi C, Lin H, Ramakrishnan V, Ou Y, Olszewski S, Olsen LR, Keskin DB, Hunter ZR, Tankersley C, Zimmerman T, Dhakal B. A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings. Front Immunol 2025; 15:1369619. [PMID: 39906744 PMCID: PMC11791645 DOI: 10.3389/fimmu.2024.1369619] [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: 01/12/2024] [Accepted: 11/04/2024] [Indexed: 02/06/2025] Open
Abstract
Background Cytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)-related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation BTK inhibitor zanubrutinib in SARS-CoV-2-infected patients with respiratory distress. Method Cohort 1 had a prospective, randomized, double-blind, placebo-controlled design; cohort 2 had a single-arm design. Adults with SARS-CoV-2 requiring hospitalization (without mechanical ventilation) were randomized in cohort 1. Those on mechanical ventilation ≤24 hours were enrolled in cohort 2. Patients were randomized 1:1 to zanubrutinib 320 mg once daily or placebo (cohort 1), or received zanubrutinib 320 mg once daily (cohort 2). Co-primary endpoints were respiratory failure-free survival rate and time to return to breathing room air at 28 days. Corollary studies to assess zanubrutinib's impact on immune response were performed. Results Sixty-three patients in cohort 1 received zanubrutinib (n=30) or placebo (n=33), with median treatment duration of 8.5 and 7.0 days, respectively. The median treatment duration in cohort 2 (n=4) was 13 days; all discontinued treatment early. In cohort 1, respiratory failure-free survival and the estimated rates of not returning to breathing room air by day 28 were not significantly different between treatments. Importantly, serological response to coronavirus disease 2019 (COVID-19) was not impacted by zanubrutinib. Lower levels of granulocyte colony-stimulating factor, interleukin (IL)-10, monocyte chemoattractant protein-1, IL-4, and IL-13 were observed in zanubrutinib-treated patients. Moreover, single-cell transcriptome analysis showed significant downregulation of inflammatory mediators (IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1α, IL-1β) and signaling pathways (JAK1, STAT3, TYK2), and activation of gamma-delta T cells in zanubrutinib-treated patients. Conclusions Marked reduction in inflammatory signaling with preserved SARS-CoV-2 serological response was observed in hospitalized patients with COVID-19 respiratory distress receiving zanubrutinib. Despite these immunological findings, zanubrutinib did not show improvement over placebo in clinical recovery from respiratory distress. Concurrent administration of steroids and antiviral therapy to most patients may have contributed to these results. Investigation of zanubrutinib may be warranted in other settings where cytokine release and immune cell exhaustion are important. Clinical Trial Registration https://www.clinicaltrials.gov/study/NCT04382586, identifier NCT04382586.
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Affiliation(s)
| | | | - David J. Park
- Providence St. Jude Medical Center/Providence Medical Foundation, Fullerton, CA, United States
| | - Giorgia Moranzoni
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Camilla K. Lemvigh
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | | | | | | | | | - Nina M. Clark
- Loyola University Stritch School of Medicine, Chicago, IL, United States
| | | | | | - Gulrayz Ahmed
- Medical College of Wisconsin, Milwaukee, WI, United States
| | | | | | | | | | | | | | - Shuqiang Li
- Dana-Farber Cancer Institute, Boston, MA, United States
| | | | | | | | - Pil Kim
- BeiGene USA, Inc., San Mateo, CA, United States
| | - Carrie Shi
- BeiGene USA, Inc., San Mateo, CA, United States
| | - Holly Lin
- BeiGene USA, Inc., San Mateo, CA, United States
| | | | - Ying Ou
- BeiGene USA, Inc., San Mateo, CA, United States
| | | | - Lars Rønn Olsen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Derin B. Keskin
- Dana-Farber Cancer Institute, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | | | | | | | - Binod Dhakal
- Medical College of Wisconsin, Wauwatosa, WI, United States
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14
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Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L, Xie F, Zhang L, Zhou F. Mucosal immune response in biology, disease prevention and treatment. Signal Transduct Target Ther 2025; 10:7. [PMID: 39774607 PMCID: PMC11707400 DOI: 10.1038/s41392-024-02043-4] [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: 06/01/2024] [Revised: 09/05/2024] [Accepted: 10/27/2024] [Indexed: 01/11/2025] Open
Abstract
The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.
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Affiliation(s)
- Xiaoxue Zhou
- School of Medicine, Hangzhou City University, Hangzhou, China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yuchen Wu
- The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhipeng Zhu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Chu Lu
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Chunwu Zhang
- The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Linghui Zeng
- School of Medicine, Hangzhou City University, Hangzhou, China
| | - Feng Xie
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
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15
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Li J, Huang J, Ai G, Zheng X, Chen B, Gong S, Lu X, Su Z, Chen J, Xie Q, Li Y, Yan F. The Protective Effects of Modified Dachaihu Decoction against LPS-induced Acute Lung Injury via Modulating PI3K/Akt Signalling Pathway. Comb Chem High Throughput Screen 2025; 28:755-767. [PMID: 40326256 DOI: 10.2174/0113862073282311240226113714] [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: 11/03/2023] [Revised: 02/04/2024] [Accepted: 02/13/2024] [Indexed: 05/07/2025]
Abstract
BACKGROUND Modified Dachaihu decoction (MDD) is a herbal prescription that has shown promising therapeutic benefits in ameliorating pulmonary diseases in clinical practice. However, the detailed mechanisms remain unclear. OBJECTIVE This study aimed to elucidate the lung-protective effects of MDD against acute lung injury (ALI) and the involvement of underlying mechanisms. METHODS High-performance liquid chromatography (HPLC) was performed to identify the main active ingredients of MDD. Network pharmacological method was adapted to explore the potential mechanisms. Mice were orally administered MDD (11.25, 22.5, and 45 g/kg) once daily for 7 days. H&E staining was performed to evaluate histological changes in the lungs. Levels of inflammatory cytokines and oxidative stress markers were measured to determine the extent of lung injury. Total protein content in bronchoalveolar lavage fluid (BALF) and lung wet/dry weight ratio were measured to assess the severity of pulmonary edema. TUNEL staining and immunohistochemistry analysis were performed to detect apoptosis. RT-qPCR and western blotting were performed to validate the mechanisms involved. RESULTS About 10 main active ingredients of MDD were identified. Notably, treatment with MDD resulted in a remarkable reduction in total protein content in BALF and lung W/D weight ratio, as well as substantial mitigation of the inflammatory response and oxidative stress. Mechanistically, the PI3K/Akt signalling pathway was activated. Moreover, MDD pretreatment downregulated p53 and caspase-9 mRNA expression and decreased the Bax/Bcl-2 ratio to ameliorate lung apoptosis. CONCLUSIONS MDD exhibited pronounced therapeutic effects via attenuating inflammatory response, oxidative stress, and apoptosis. These therapeutic effects could be attributed to the synergistic effect of the main active ingredients and are believed to be associated with the activation of the PI3K/Akt pathway.
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Affiliation(s)
- Jincan Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Jiechun Huang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
- Li Ke and Qi Yu-ru Academic Experience Inheritance Studio, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
- Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
| | - Gaoxiang Ai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Xiaohong Zheng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Baoyi Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Shiting Gong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Xiaowei Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Ziren Su
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Jiannan Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Qingfeng Xie
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
- Li Ke and Qi Yu-ru Academic Experience Inheritance Studio, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
- Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
| | - Yucui Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Fang Yan
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
- Li Ke and Qi Yu-ru Academic Experience Inheritance Studio, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
- Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, PR China
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16
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Alberto RPJ, Benjamin GN, Elizabeth RMJ, Alberto CDL, Eliseo PDB. Understanding COVID-19-related Acute Renal Injury in Elderly Individuals: Preexisting Systemic Inflammation before COVID-19 (SIC). Endocr Metab Immune Disord Drug Targets 2025; 25:300-309. [PMID: 38919086 DOI: 10.2174/0118715303312433240611093855] [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: 02/23/2024] [Revised: 05/14/2024] [Accepted: 05/20/2024] [Indexed: 06/27/2024]
Abstract
In this study, we examined preexisting systemic inflammation before COVID-19 (SIC), as assessed through C-reactive protein (CRP) levels, to gain insights into the origins of acute kidney injury (AKI) in adults with comorbidities affected by COVID-19. Although aging is not categorized as a disease, it is characterized by chronic inflammation, and older individuals typically exhibit higher circulating levels of inflammatory molecules, particularly CRP, compared to younger individuals. Conversely, elevated CRP concentrations in older adults have been linked with the development of comorbidities. Simultaneously, these comorbidities contribute to the production of inflammatory molecules, including CRP. Consequently, older adults with comorbidities have higher CRP concentrations than their counterparts without comorbidities or those with fewer comorbidities. Given that CRP levels are correlated with the development and severity of AKI in non-COVID-19 patients, we hypothesized that individuals with greater SIC are more likely to develop AKI during SARS-CoV-2 infection than those with less SIC.
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Affiliation(s)
- Ruiz-Pacheco Juan Alberto
- Investigador por México-CONAHCYT, Centro de Investigación Biomédica de Occidente, IMSS, Guadalajara, Jalisco, México
| | - Gomez-Navarro Benjamin
- Servicio de Nefrología y Trasplantes, Hospital Country 2000, Guadalajara, Jalisco, México
| | | | - Castillo-Díaz Luis Alberto
- Departamento de Medicina y Ciencias de la Salud, Facultad Interdiciplinaria de Ciencias Biológicas y de la Salud, Universidad de Sonora, Hermosillo, México
| | - Portilla-de Buen Eliseo
- División de Investigación Quirúrgica, Centro de Investigación Biomédica de Occidente, IMSS, Guadalajara, Jalisco, México
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17
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Chavez-Tapia N, Sayeed MA, Luxmi S, Kasper DJ, Xue F, Shen Y, Fan W, Yuan W, Du B. Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial. JOURNAL OF INTENSIVE MEDICINE 2025; 5:70-78. [PMID: 39872839 PMCID: PMC11763862 DOI: 10.1016/j.jointm.2024.07.003] [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: 04/02/2024] [Revised: 06/26/2024] [Accepted: 07/29/2024] [Indexed: 01/30/2025]
Abstract
Background Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Methods This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical efficacy. Results Forty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were ≥ grade 3. Fewer SIR1-365-treated vs. placebo-treated patients experienced TEAEs (30.4% vs. 57.9%) and serious TEAEs (13.0% vs. 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. Compare to placebo, SIR1-365 significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] vs. -24.2 [23.6]; P=0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days vs. [8.6±5.6] days; P=0.0145) and respiratory failure incidence (8.3% vs. 38.1%; two-sided P=0.0291) during the study, and numerically shortened the time to clinical improvement in World Health Organization ordinal scale (median: 5.0 days vs. 9.0 days, P=0.0766). Conclusions SIR1-365 was well tolerated and demonstrated a trend toward quicker recovery than placebo in hospitalized patients with severe COVID-19.Trial Registration ClinicalTrials.gov number: NCT04622332.
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Affiliation(s)
- Norberto Chavez-Tapia
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | - Muneeba Ahsan Sayeed
- Sindh Infectious Diseases Hospital and Research Centre, Dow University of Health Sciences, Karachi, Sindh, Pakistan
| | - Shobha Luxmi
- Sindh Infectious Diseases Hospital and Research Centre, Dow University of Health Sciences, Karachi, Sindh, Pakistan
| | - Douglas J. Kasper
- Department of Medicine, Division of Infectious Disease, University of Illinois School of Medicine, OSF HealthCare System d/b/a Saint Francis Medical Center, Peoria, IL, USA
| | | | | | | | - Wei Yuan
- Sironax USA, Inc., Edison, NJ, USA
| | - Bin Du
- Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
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18
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Changela S, Ashraf S, Lu JY, Duong KE, Henry S, Wang SH, Duong TQ. New-onset gastrointestinal disorders in COVID-19 patients 3.5 years post-infection in the inner-city population in the Bronx. Sci Rep 2024; 14:31850. [PMID: 39738536 PMCID: PMC11685902 DOI: 10.1038/s41598-024-83232-7] [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: 07/22/2024] [Accepted: 12/12/2024] [Indexed: 01/02/2025] Open
Abstract
This study examined the incidence, characteristics, and risk factors of new gastrointestinal disorders (GID) associated with SARS-CoV-2 infection up to 3.5 years post-infection. This retrospective study included 35,102 COVID-19 patients and 682,594 contemporary non-COVID-19 patients without past medical history of GID (controls) from the Montefiore Health System in the Bronx (3/1/2020 to 7/31/2023). Comparisons were made with unmatched and propensity-matched (1:2) controls. The primary outcome was new GID which included peptic ulcer, inflammatory bowel disease, irritable bowel syndrome, diverticulosis, diverticulitis, and biliary disease. Multivariate Cox proportional hazards model analysis was performed with adjustment for covariates. There were 2,228 (6.34%) COVID-19 positive patients who developed new GID compared to 38,928 (5.70%) controls. COVID-19 patients had an elevated risk of developing new GID (adjusted HR = 1.18 (95% CI 1.12-1.25) compared to propensity-matched controls, after adjusting for confounders that included smoking, obesity, diabetes, hypertension. These findings underscore the need for additional research and follow-up of at-risk individuals for developing GID post infection.
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Affiliation(s)
- Sagar Changela
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Samad Ashraf
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Justin Y Lu
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Kevin E Duong
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Sonya Henry
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Stephen H Wang
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Tim Q Duong
- Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
- Center for Health & Data Innovation, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
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19
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Ghosh S, Chatterjee A, Maitra A. An insight into COVID-19 host immunity at single-cell resolution. Int Rev Immunol 2024:1-16. [PMID: 39707914 DOI: 10.1080/08830185.2024.2443420] [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: 07/25/2023] [Revised: 10/09/2024] [Accepted: 12/12/2024] [Indexed: 12/23/2024]
Abstract
Host immunity helps the body to fight against COVID-19. Single-cell transcriptomics has provided the scope of investigating cellular and molecular underpinnings of host immune response against SARS-CoV-2 infection at high resolution. In this review, we have systematically described the virus-induced dysregulation of relative abundance as well as molecular behavior of each innate and adaptive immune cell type and cell state during COVID-19 infection and for different vaccinations, based on single-cell studies published in last three-four years. Identification and characterization of these disease-associated specific cell populations might help to design better, efficient, and targeted therapeutic avenues.
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Affiliation(s)
- Supratim Ghosh
- Biotechnology Research and Innovation Council - National Institute of Biomedical Genomics, Kalyani, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Ankita Chatterjee
- Biotechnology Research and Innovation Council - National Institute of Biomedical Genomics, Kalyani, India
- John C. Martin Center for Liver Research and Innovations, Kolkata, India
| | - Arindam Maitra
- Biotechnology Research and Innovation Council - National Institute of Biomedical Genomics, Kalyani, India
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20
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Ceylan B, Olmuşçelik O, Karaalioğlu B, Ceylan Ş, Şahin M, Aydın S, Yılmaz E, Dumlu R, Kapmaz M, Çiçek Y, Kansu A, Duger M, Mert A. Predicting Severe Respiratory Failure in Patients with COVID-19: A Machine Learning Approach. J Clin Med 2024; 13:7386. [PMID: 39685844 DOI: 10.3390/jcm13237386] [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: 09/18/2024] [Revised: 10/23/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Background/Objectives: Studies attempting to predict the development of severe respiratory failure in patients with a COVID-19 infection using machine learning algorithms have yielded different results due to differences in variable selection. We aimed to predict the development of severe respiratory failure, defined as the need for high-flow oxygen support, continuous positive airway pressure, or mechanical ventilation, in patients with COVID-19, using machine learning algorithms to identify the most important variables in achieving this prediction. Methods: This retrospective, cross-sectional study included COVID-19 patients with mild respiratory failure (mostly receiving oxygen through a mask or nasal cannula). We used XGBoost, support vector machines, multi-layer perceptron, k-nearest neighbor, random forests, decision trees, logistic regression, and naïve Bayes methods to accurately predict severe respiratory failure in these patients. Results: A total of 320 patients (62.1% male; average age, 54.67 ± 15.82 years) were included in this study. During the follow-ups of these cases, 114 patients (35.6%) required high-level oxygen support, 67 (20.9%) required intensive care unit admission, and 43 (13.4%) died. The machine learning algorithms with the highest accuracy values were XGBoost, support vector machines, k-nearest neighbor, logistic regression, and multi-layer perceptron (0.7395, 0.7395, 0.7291, 0.7187, and 0.75, respectively). The method that obtained the highest ROC-AUC value was logistic regression (ROC-AUC = 0.7274). The best predictors of severe respiratory failure were a low lymphocyte count, a high computed tomography score in the right and left upper lung zones, an elevated neutrophil count, a small decrease in CRP levels on the third day of admission, a high Charlson comorbidity index score, and a high serum procalcitonin level. Conclusions: The development of severe respiratory failure in patients with COVID-19 could be successfully predicted using machine learning methods, especially logistic regression, and the best predictors of severe respiratory failure were the lymphocyte count and the degree of upper lung zone involvement.
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Affiliation(s)
- Bahadır Ceylan
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Oktay Olmuşçelik
- Department of Internal Medicine, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Banu Karaalioğlu
- Department of Radiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Şule Ceylan
- Department of Nuclear Medicine, University of Health Science, Gaziosmanpaşa Training ve Research Hospital, Istanbul 34668, Türkyie
| | - Meyha Şahin
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Selda Aydın
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Ezgi Yılmaz
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Rıdvan Dumlu
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Mahir Kapmaz
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Yeliz Çiçek
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Abdullah Kansu
- Department of Chest Diseases, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Mustafa Duger
- Department of Chest Diseases, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
| | - Ali Mert
- Department of Internal Medicine, Medical Faculty, Istanbul Medipol University, Istanbul 34214, Türkyie
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21
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Amarilla-Irusta A, Zenarruzabeitia O, Sevilla A, Sandá V, Lopez-Pardo A, Astarloa-Pando G, Pérez-Garay R, Pérez-Fernández S, Meijide S, Imaz-Ayo N, Arana-Arri E, Amo L, Borrego F. CD151 identifies an NK cell subset that is enriched in COVID-19 patients and correlates with disease severity. J Infect 2024; 89:106304. [PMID: 39374860 DOI: 10.1016/j.jinf.2024.106304] [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: 04/22/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/09/2024]
Abstract
Severe coronavirus disease 2019 (COVID-19) often leads to acute respiratory distress syndrome and multi-organ dysfunction, driven by a dysregulated immune response, including a cytokine storm with elevated proinflammatory cytokine levels. Natural killer (NK) cells are part of the innate immune system with a fundamental role in the defense against viral infections. However, during COVID-19 acute infection, they exhibit an altered phenotype and impaired functionality contributing to the immunopathogenesis of the disease. In this work, we have studied a cohort of patients with COVID-19 (ranging from mild to severe) by analyzing IL-15, TGF-β, PlGF and GDF-15 plasma levels and performing multiparametric flow cytometry studies. Our results revealed that severe COVID-19 patients exhibited high levels of IL-15, PlGF and GDF-15, along with an enrichment of an NK cell subset expressing the CD151 tetraspanin, which correlated with IL-15 plasma levels and disease severity. In patients, these CD151+ NK cells displayed a more activated phenotype characterized by an increased expression of HLA-DR, CD38 and granzyme B, a distinct receptor repertoire, with lower levels of CD160 and CD31 and higher levels of CD55 and, remarkably, a higher expression of tissue-resident markers CD103 and the NK cell decidual marker CD9. Last of all, in individuals with severe disease, we identified an expansion of a CD151brightCD9+ NK cell subset, suggesting that these cells play a specific role in COVID-19. Altogether, our findings suggest that CD151+ NK cells may have a relevant role in COVID-19 immunopathogenesis.
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Affiliation(s)
| | - Olatz Zenarruzabeitia
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Arrate Sevilla
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Víctor Sandá
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Ainara Lopez-Pardo
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain
| | | | - Raquel Pérez-Garay
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Clinical Analysis Service, Cruces University Hospital, OSI Ezkerraldea-Enkarterri-Cruces, Barakaldo, Spain
| | - Silvia Pérez-Fernández
- Scientific Coordination Facility, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Susana Meijide
- Scientific Coordination Facility, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Natale Imaz-Ayo
- Scientific Coordination Facility, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Eunate Arana-Arri
- Scientific Coordination Facility, Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Laura Amo
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Francisco Borrego
- Immunopathology Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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22
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Wu Y, Li Y, Zhou Y, Bai X, Liu Y. Bioinformatics and systems-biology approach to identify common pathogenic mechanisms for COVID-19 and systemic lupus erythematosus. Autoimmunity 2024; 57:2304826. [PMID: 38332666 DOI: 10.1080/08916934.2024.2304826] [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: 07/06/2023] [Accepted: 01/07/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The Coronavirus disease 2019 (COVID-19) pandemic has brought a heavy burden to the world, interestingly, it shares many clinical symptoms with systemic lupus erythematosus (SLE). It is unclear whether there is a similar pathological process between COVID-9 and SLE. In addition, we don't know how to treat SLE patients with COVID-19. In this study, we analyse the potential similar pathogenesis between SLE and COVID-19 and explore their possible drug regimens using bioinformatics and systems biology approaches. METHODS The common differentially expressed genes (DEGs) were extracted from the COVID-19 datasets and the SLE datasets for functional enrichment, pathway analysis and candidate drug analysis. RESULT Based on the two transcriptome datasets between COVID-19 and SLE, 325 common DEGs were selected. Hub genes were identified by protein-protein interaction (PPI) analysis. few found a variety of similar functional changes between COVID-19 and SLE, which may be related to the pathogenesis of COVID-19. Besides, we explored the related regulatory networks. Then, through drug target matching, we found many candidate drugs for patients with COVID-19 only or COVID-19 combined with SLE. CONCLUSION COVID-19 and SLE patients share many common hub genes, related pathways and regulatory networks. Based on these common targets, we found many potential drugs that could be used in treating patient with COVID-19 or COVID-19 combined with SLE.
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Affiliation(s)
- Yinlan Wu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yanhong Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Zhou
- Department of Respiratory and Critical Care Medicine, Chengdu First People's Hospital, Chengdu, China
| | - Xiufeng Bai
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Human Disease and Immunotherapies, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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23
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Singh T, Macintyre AN, Burke TW, Anderson J, Petzold E, Stover EL, French MJ, Oguin TH, Demarco T, McClain MT, Ko ER, Park LP, Denny T, Sempowski GD, Woods CW. Dynamics of cytokine and antibody responses in community versus hospital SARS-CoV-2 infections. Front Immunol 2024; 15:1468871. [PMID: 39650666 PMCID: PMC11621060 DOI: 10.3389/fimmu.2024.1468871] [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: 07/22/2024] [Accepted: 10/17/2024] [Indexed: 12/11/2024] Open
Abstract
Introduction Dysregulated host cytokine responses to SARS-CoV-2 infection are a primary cause of progression to severe disease, whereas early neutralizing antibody responses are considered protective. However, there are gaps in understanding the early temporal dynamics of these immune responses, and the profile of productive immune responses generated by non-hospitalized people with mild infections in the community. Methods Here we conducted a prospective cohort study of people with suspected infections/exposures in the US state of North Carolina, before vaccine availability. We recruited participants not only in hospitals/clinics, but also in their homes. With serial sampling, we compared virologic and immunologic factors in 258 community cases versus 114 hospital cases of COVID-19 to define factors associated with severity. Results We found that high early neutralizing antibodies were associated with lower nasal viral load, but not protection from hospitalization. Cytokine responses were evaluated in 125 cases, with subsets at first versus second week of illness to assess for time-dependent trajectories. The hospital group demonstrated a higher magnitude of serum IL-6, IL-1R antagonist, IP-10, and MIG; prolonged upregulation of IL-17; and lesser downregulation of GROα, IL-1R antagonist, and MCP1, in comparison to the community group suggesting that these factors may contribute to immunopathology. In the second week of illness, 2-fold increases in IL-6, IL-1R antagonist, and IP-10 were associated with 2.2, 1.8, and 10-fold higher odds of hospitalization respectively, whereas a 2-fold increase in IL-10 was associated with 63% reduction in odds of hospitalization (p<0.05). Moreover, antibody responses at 3-6 months post mild SARS-CoV-2 infections in the community revealed long-lasting antiviral IgM and IgA antibodies as well as a stable set point of neutralizing antibodies that were not waning. Discussion Our data provide valuable temporal cytokine benchmarks to track the progression of immunopathology in COVID-19 patients and guide improvements in immunotherapies.
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Affiliation(s)
- Tulika Singh
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
- Duke Global Health Institute, Durham, NC, United States
| | - Andrew N. Macintyre
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Thomas W. Burke
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
| | - Jack Anderson
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
| | - Elizabeth Petzold
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
| | - Erica L. Stover
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Matthew J. French
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Thomas H. Oguin
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Todd Demarco
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Micah T. McClain
- Duke Global Health Institute, Durham, NC, United States
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
- Division of General Internal Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, United States
| | - Emily R. Ko
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
- Division of General Internal Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, United States
| | - Lawrence P. Park
- Duke Global Health Institute, Durham, NC, United States
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Thomas Denny
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Gregory D. Sempowski
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
- RTI International, Research Triangle Park, NC, United States
| | - Christopher W. Woods
- Duke Global Health Institute, Durham, NC, United States
- Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Duke University, Durham, NC, United States
- Division of General Internal Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, United States
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24
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Gao T, Liu J, Huang N, Zhou Y, Li C, Chen Y, Hong Z, Deng X, Liang X. Sangju Cold Granule exerts anti-viral and anti-inflammatory activities against influenza A virus in vitro and in vivo. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118521. [PMID: 38969152 DOI: 10.1016/j.jep.2024.118521] [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: 04/18/2024] [Revised: 06/22/2024] [Accepted: 07/03/2024] [Indexed: 07/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sangju Cold Granule (SJCG) is a classical traditional Chinese medicine (TCM) prescription described in "Item Differentiation of Warm Febrile Diseases". Historically, SJCG was employed to treat respiratory illnesses. Despite its popular usage, the alleviating effect of SJCG on influenza A virus infection and its mechanisms have not been fully elucidated. AIM OF THE STUDY Influenza is a severe respiratory disease that threatens human health. This study aims to assess the therapeutic potential of SJCG and the possible molecular mechanism underlying its activity against influenza A virus in vitro and in vivo. MATERIALS AND METHODS Ultrahigh-performance liquid chromatography (UPLC)-Q-Exactive was used to identify the components of SJCG. The 50% cytotoxic concentration of SJCG in MDCK and A549 cells were determined using the CCK-8 assay. The activity of SJCG against influenza A virus H1N1 was evaluated in vitro using plaque reduction and progeny virus titer reduction assays. RT-qPCR was performed to obtain the expression levels of inflammatory mediators and the transcriptional regulation of RIG-I and MDA5 in H1N1-infected A549 cells. Then, the mechanism of SJCG effect on viral replication and inflammation was further explored by measuring the expressions of proteins of the RIG-I/NF-kB/IFN(I/III) signaling pathway by Western blot. The impact of SJCG was explored in vivo in an intranasally H1N1-infected BALB/c mouse pneumonia model treated with varying doses of SJCG. The protective role of SJCG in this model was evaluated by survival, body weight monitoring, lung viral titers, lung index, lung histological changes, lung inflammatory mediators, and peripheral blood leukocyte count. RESULTS The main SJCG chemical constituents were flavonoids, carbohydrates and glycosides, amino acids, peptides, and derivatives, organic acids and derivatives, alkaloids, fatty acyls, and terpenes. The CC50 of SJCG were 24.43 mg/mL on MDCK cells and 20.54 mg/mL on A549 cells, respectively. In vitro, SJCG significantly inhibited H1N1 replication and reduced the production of TNF-α, IFN-β, IL-6, IL-8, IL-13, IP-10, RANTES, TRAIL, and SOCS1 in infected A549 cells. Intracellularly, SJCG reduced the expression of RIG-I, MDA5, P-NF-κB P65 (P-P65), P-IκBα, P-STAT1, P-STAT2, and IRF9. In vivo, SJCG enhanced the survival rate and decreased body weight loss in H1N1-infected mice. Mice with H1N1-induced pneumonia treated with SJCG showed a lower lung viral load and lung index than untreated mice. SJCG effectively alleviated lung damage and reduced the levels of TNF-α, IFN-β, IL-6, IP-10, RANTES, and SOCS1 in lung tissue. Moreover, SJCG significantly ameliorated H1N1-induced leukocyte changes in peripheral blood. CONCLUSIONS SJCG significantly reduced influenza A virus and virus-mediated inflammation through inhibiting the RIG-I/NF-kB/IFN(I/III) signaling pathway. Thus, SJCG could provide an effective TCM for influenza treatment.
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Affiliation(s)
- Taotao Gao
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jinbing Liu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, China; Department of Ultrasound Medicine, Liwan Central Hospital of Guangzhou, 35 Liwan Road, Guangzhou, 510000, Guangdong, China
| | - Nan Huang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yingxuan Zhou
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Conglin Li
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yintong Chen
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zifan Hong
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xiaoyan Deng
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Xiaoli Liang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, China.
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Horvath A, Habisch H, Prietl B, Pfeifer V, Balazs I, Kovacs G, Foris V, John N, Kleinschek D, Feldbacher N, Grønbæk H, Møller HJ, Žukauskaitė K, Madl T, Stadlbauer V. Alteration of the Gut-Lung Axis After Severe COVID-19 Infection and Modulation Through Probiotics: A Randomized, Controlled Pilot Study. Nutrients 2024; 16:3840. [PMID: 39599626 PMCID: PMC11597208 DOI: 10.3390/nu16223840] [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: 10/07/2024] [Revised: 10/30/2024] [Accepted: 11/02/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The gut-lung axis could be a potential therapeutic target for improving post-acute COVID-19 symptoms, and probiotics have been proposed as possible modulators. AIM We conducted a pilot study to understand alterations in the gut-lung axis and to explore the effects of a probiotic in post-acute COVID-19 disease. METHODS We included patients after severe COVID-19 disease (sCOV, n = 21) in a randomized, placebo-controlled trial to test the effect of a probiotic (Pro-Vi 5, Institute Allergosan, Graz, Austria) in a six-month intervention and used patients after mild disease (mCOV, n = 10) as controls, to compare the intestinal microbiome, metabolome, and patient-reported outcomes and biomarkers along the gut-lung axis at baseline and throughout probiotic intervention. RESULTS Compared to mCOV patients, sCOV patients showed lower microbial richness, which was significantly improved by probiotic intervention. A reorganization of Ruminococcaceae and Lachnospiraceae taxa was observed in sCOV patients but remained unaffected by the intervention. Serum metabolome showed a dysregulation of lipoproteins in accordance with higher BMI and comorbidities in sCOV patients. HDL and LDL fractions/components were temporarily decreased in the probiotic group. Stool metabolome was altered at baseline in sCOV patients and an increase in L-DOPA after 3 months and butyrate after 6 months of intervention could be observed. Probiotics partially improved reduced quality of life and modulated altered immune responses in sCOV patients. Increased intestinal permeability at baseline remained unaffected. CONCLUSION The study provides evidence of long-term alterations of the gut-lung axis after severe COVID-19 infection and suggests that probiotics can modulate the biomarkers of the gut-lung axis.
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Affiliation(s)
- Angela Horvath
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
| | - Hansjörg Habisch
- Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; (H.H.); (T.M.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Barbara Prietl
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division of Endocrinology and Diabetes, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Verena Pfeifer
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division of Endocrinology and Diabetes, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Irina Balazs
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
| | - Gabor Kovacs
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria; (G.K.); (V.F.); (N.J.)
| | - Vasile Foris
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria; (G.K.); (V.F.); (N.J.)
| | - Nikolaus John
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria; (G.K.); (V.F.); (N.J.)
| | - Daniela Kleinschek
- Ludwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, Austria;
| | - Nicole Feldbacher
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
| | - Henning Grønbæk
- Departments of Hepatology and Gastroenterology, Aarhus University Hospital, 8200 Aarhus, Denmark;
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark;
| | - Holger Jon Møller
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark;
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus, Denmark
| | - Kristina Žukauskaitė
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
- Institute of Biosciences, Life Sciences Center, Vilnius University, 01513 Vilnius, Lithuania
| | - Tobias Madl
- Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; (H.H.); (T.M.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Vanessa Stadlbauer
- Center for Biomarker Research in Medicine (CBmed), Division of Translational Precision Medicine, Division of Precision Medicine Technologies, 8010 Graz, Austria; (A.H.); (B.P.); (V.P.); (I.B.); (N.F.)
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
- BioTechMed-Graz, 8010 Graz, Austria
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Alonazi J, Alrasheed N, Aljabr S, Albaqami K, Alshallal K, Alsemairi SA, AlBaqami F, Alnufaie NF, Bin Talib FA. Timing of Dexamethasone Initiation and Its Impact on the Outcome of COVID-19 Patients. Cureus 2024; 16:e72983. [PMID: 39634973 PMCID: PMC11616674 DOI: 10.7759/cureus.72983] [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] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Introduction COVID-19 emerged in Wuhan in December 2019 and was declared a pandemic in March 2020. Severe cases manifest with respiratory distress. Corticosteroids, initially debated, are now recommended for severe cases following the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial findings. The timing of administration impacts outcomes, with earlier use potentially improving mortality and ICU stays. Regional studies on timing in severe cases are lacking, warranting further investigation. Methodology This retrospective cohort study was conducted at the Medical Department of King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Data were extracted from the BestCare database using a customized data collection sheet. Data were cleaned in Excel (Microsoft Corporation, Redmond, WA) and analyzed in IBM SPSS (IBM Corp., Armonk, NY). Results Our study included 791 COVID-19 patients with 43.1% being female (n = 341) and 56.9% being male (n = 450). The mean age was 69.5 years (SD = 16.1). Regarding BMI, 52.4% (n = 414) were obese. Most admissions were from the emergency department (90.6%, n = 717). Dexamethasone was administered to 80.3% (n = 635) of patients, with 53.0% (n = 419) receiving it early. Patients receiving early dexamethasone had significantly higher discharge rates (p < 0.001). Mortality was higher among those receiving late dexamethasone initiation (52.6%, p = 0.256). Moreover, there was an 87.5% death rate for doses >6 mg (p < 0.001). Intravenous administration was associated with higher mortality (62.3%, p < 0.001). Males had a higher likelihood of discharge (OR = 1.426, p = 0.043). Age and ventilation needs were strong mortality predictors (OR = 1.040, p < 0.001 and OR = 17.620, p < 0.001, respectively). Higher BMI slightly reduced mortality risk (OR = 0.978, p = 0.049). Conclusion Our study highlights significant associations between dexamethasone timing, dosage, and route of administration with COVID-19 outcomes. Early dexamethasone use correlated with higher discharge rates, while late initiation and higher doses were linked to increased mortality. Age and ventilation needs were critical predictors, with BMI showing a nuanced effect on mortality risk.
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Affiliation(s)
- Jamila Alonazi
- Department of Internal Medicine, King Abdulaziz Medical City, Riyadh, SAU
| | - Najla Alrasheed
- Department of Internal Medicine, King Abdulaziz Medical City, Riyadh, SAU
| | - Saad Aljabr
- Division of Internal Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
| | - Khalaf Albaqami
- Division of Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
| | - Khalid Alshallal
- Division of Internal Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
| | - Saif A Alsemairi
- Division of Internal Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
| | - Fahad AlBaqami
- Division of Internal Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
| | - Nawaf F Alnufaie
- Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, SAU
| | - Faisal A Bin Talib
- Division of Internal Medicine, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, SAU
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Demir BT, Söğütlügil MRM, Çankal F. Radiological changes in the thymus in patients who have had COVID-19 and in vaccinated persons who have not had COVID-19: a CT study. RADIOLOGIE (HEIDELBERG, GERMANY) 2024; 64:139-144. [PMID: 39259290 DOI: 10.1007/s00117-024-01363-4] [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: 01/29/2024] [Accepted: 07/17/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND There are very few and limited studies on the role of the thymus in COVID-19 infection. It is known that thymus morphology changes in individuals vaccinated against COVID-19 although they do not have active infection. OBJECTIVE Our study aims to evaluate these differences in detail. METHODS This research was conducted in a total of 141 people, 75 women and 66 men. The research consisted of three groups: unvaccinated persons who have had the disease (n = 49), vaccinated persons who have not had the disease (n = 37), and unvaccinated persons who have not had the disease (control group, n = 55). In the study, the thymus volume, structure, and fat content were investigated and the differences between groups were evaluated. RESULTS Thymus volume was greatest (0.43 ± 0.11) in the vaccinated group that had not had the disease and smallest (0.15 ± 0.07) in the unvaccinated group that had had the disease, and a significant difference was found between the groups. Thymus steatosis was seen mostly in the unvaccinated group that had had the disease (72%; p = 0.04). The diffuse nodular pattern was only present in the diseased group. CONCLUSION This research is the first study in the literature to date on the effect of COVID-19 and vaccines on the thymus. In addition to the acute consequences of the virus, the possibility of negative symptoms after COVID-19 should also be kept in mind, especially in unvaccinated people. Further studies are needed to confirm the results reported herein.
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Affiliation(s)
- Berin Tuğtağ Demir
- Departmant of Anatomy, Ankara Medipol University Faculty of Medicine, Ankara, Turkey.
| | | | - Fatih Çankal
- Departmant of Anatomy, Ankara Medipol University Faculty of Medicine, Ankara, Turkey
- Pursaklar Public Hospital, Department of Radiology, Ankara, Turkey
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28
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Zhou Y, Yang Y, Wang Y, Hou D, Song Y. Anticoagulant therapy in adult with COVID-19: a systematic review and meta-analysis of randomized controlled trial. J Thorac Dis 2024; 16:6391-6405. [PMID: 39552875 PMCID: PMC11565368 DOI: 10.21037/jtd-24-744] [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: 05/07/2024] [Accepted: 09/06/2024] [Indexed: 11/19/2024]
Abstract
Background Blood coagulation dysfunction is a risk factor for adverse outcomes in patients with coronavirus disease 2019 (COVID-19), especially in severe cases. The evidence for the effects of anticoagulation therapy on prognosis of COVID-19 patients and its risk of causing bleeding events is accumulating. Here we conducted a meta-analysis to assess the efficacy and safety of anticoagulants in COVID-19 patients of different severity. Methods We searched PubMed, Embase databases, Cochrane Trials, OVID MEDLINE from December 2019 to April 2023. We included randomized controlled trials (RCTs) involving COVID-19 patients over 18 years of age, which explored the effect of anticoagulant and its dose on outcomes including all-cause mortality, bleeding events or thrombotic events. We calculated the risk ratio (RR) and its 95% confidence interval (CI) for each outcome. We also performed subgroup analyses to assess the impact of disease severity, using a fixed-effect model to test for heterogeneity. The risk of bias, publication bias, and the quality of evidence were also evaluated. Results A total of 20 RCTs were included for final analysis. When compared with standard care, anticoagulation treatment reduced all-cause mortality (RR 0.47, 95% CI: 0.29-0.76) and thrombotic events (RR 0.35, 95% CI: 0.15-0.83) in the whole population with COVID-19 (n=2,365), without increase in bleeding events (total: RR 1.47, 95% CI: 0.54-4.00). Most of the studies only enrolled non-severe patients (n=2,329), while the number of severe patients (n=36) was scarce. In RCTs compared therapeutical and prophylactic doses of anticoagulants, no significant difference in on all-cause mortality was found in the whole population and non-severe and severe subgroups (total: RR 1.01, 95% CI: 0.92-1.10; non-severe: RR 1.03, 95% CI: 0.81-1.32; severe: RR 1.00, 95% CI: 0.91-1.11). Therapeutical dose reduced risk of thrombotic events (total: RR 0.59, 95% CI: 0.48-0.73; subtotal of non-severe: RR 0.57, 95% CI: 0.39-0.84; Subtotal of severe: RR 0.61, 95% CI: 0.47-0.78), while risk of bleeding was increased (total: RR 1.98, 95% CI: 1.47-2.66; non-severe: RR 2.38, 95% CI: 1.56-3.62; severe: RR 1.63, 95% CI: 1.07-2.47). Study heterogeneity was found only in the analysis of effects of anticoagulants on risk of thrombotic events. Conclusions Anticoagulant therapy reduces all-cause mortality and risk of thrombosis in non-severe COVID-19 patients. Therapeutic dose of anticoagulant therapy can be considered in both non-severe and severe COVID-19 patients to reduce thrombosis, but may be associated with increased bleeding events.
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Affiliation(s)
- Yanan Zhou
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Yanping Yang
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Ying Wang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongni Hou
- Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuanlin Song
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Respiratory Research Institute, Shanghai, China
- National and Shanghai Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, China
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29
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Bispo ECI, Argañaraz ER, Neves FDAR, de Carvalho JL, Saldanha-Araujo F. Immunomodulatory effect of IFN-γ licensed adipose-mesenchymal stromal cells in an in vitro model of inflammation generated by SARS-CoV-2 antigens. Sci Rep 2024; 14:24235. [PMID: 39415027 PMCID: PMC11484699 DOI: 10.1038/s41598-024-75776-5] [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: 07/25/2024] [Accepted: 10/08/2024] [Indexed: 10/18/2024] Open
Abstract
In recent years, clinical studies have shown positive results of the application of Mesenchymal Stromal Cells (MSCs) in severe cases of COVID-19. However, the mechanisms of immunomodulation of IFN-γ licensed MSCs in SARS-CoV-2 infection are only partially understood. In this study, we first tested the effect of IFN-γ licensing in the MSC immunomodulatory profile. Then, we established an in vitro model of inflammation by exposing Calu-3 lung cells to SARS-CoV-2 nucleocapsid and spike (NS) antigens, and determined the toxicity of SARS-CoV-2 NS antigen and/or IFN-γ stimulation to Calu-3. The conditioned medium (iCM) generated by Calu-3 cells exposed to IFN-γ and SARS-CoV-2 NS antigens was used to stimulate T-cells, which were then co-cultured with IFN-γ-licensed MSCs. The exposure to IFN-γ and SARS-CoV-2 NS antigens compromised the viability of Calu-3 cells and induced the expression of the inflammatory mediators ICAM-1, CXCL-10, and IFN-β by these cells. Importantly, despite initially stimulating T-cell activation, IFN-γ-licensed MSCs dramatically reduced IL-6 and IL-10 levels secreted by T-cells exposed to NS antigens and iCM. Moreover, IFN-γ-licensed MSCs were able to significantly inhibit T-cell apoptosis induced by SARS-CoV-2 NS antigens. Taken together, our data show that, in addition to reducing the level of critical cytokines in COVID-19, IFN-γ-licensed MSCs protect T-cells from SARS-CoV-2 antigen-induced apoptosis. Such observations suggest that MSCs may contribute to COVID-19 management by preventing the lymphopenia and immunodeficiency observed in critical cases of the disease.
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Affiliation(s)
- Elizabete Cristina Iseke Bispo
- Laboratory of Hematology and Stem Cells (LHCT), Faculty of Health Sciences, University of Brasília, Brasília, 70910-900, Brazil
| | - Enrique Roberto Argañaraz
- Laboratory of Molecular NeuroVirology, Faculty of Health Sciences, University of Brasília, Brasília, 70910-900, Brazil
| | | | - Juliana Lott de Carvalho
- Interdisciplinary Laboratory of Bioscience, Faculty of Medicine, University of Brasília, Brasília, 70910-900, Brazil
| | - Felipe Saldanha-Araujo
- Laboratory of Hematology and Stem Cells (LHCT), Faculty of Health Sciences, University of Brasília, Brasília, 70910-900, Brazil.
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Wilar G, Suhandi C, Fukunaga K, Kawahata I. Efficacy and safety of tofacitinib on COVID-19 patients: A systematic review and meta-analysis. Heliyon 2024; 10:e38229. [PMID: 39381111 PMCID: PMC11456853 DOI: 10.1016/j.heliyon.2024.e38229] [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: 07/03/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/10/2024] Open
Abstract
The use of drugs off-label for managing COVID-19 offers a potential approach. Among these potential drugs, tofacitinib, a JAK inhibitor, is strongly implicated in its ability to mitigate mortality by attenuating the cytokine storm syndrome. This study systematically reviewed and quantitatively assessed the effectiveness and safety profile of tofacitinib use through meta-analysis. Through searches of the PubMed, Scopus, and the Cochrane Library databases up to May 31, 2024, six articles meeting inclusion criteria were identified, encompassing 669 patients diagnosed with COVID-19. The review findings indicate that tofacitinib use demonstrates significant clinical efficacy, as evidenced by a reduced risk of mortality (P = 0.003), and a decreased need for invasive mechanical ventilation (P = 0.0002). Furthermore, tofacitinib use is not correlated with an increased risk of adverse drug reactions (P = 0.98), indicating a favorable safety profile. In conclusion, the evidence supports the clinical efficacy of tofacitinib for COVID-19 patients without concomitant risks of adverse effects. Further clinical studies, especially larger-scale randomized controlled trials, are necessary to validate the findings of this study.
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Affiliation(s)
- Gofarana Wilar
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
| | - Cecep Suhandi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
| | - Kohji Fukunaga
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Ichiro Kawahata
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
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Kole C, Stefanou Ε, Karvelas N, Schizas D, Toutouzas KP. Acute and Post-Acute COVID-19 Cardiovascular Complications: A Comprehensive Review. Cardiovasc Drugs Ther 2024; 38:1017-1032. [PMID: 37209261 PMCID: PMC10199303 DOI: 10.1007/s10557-023-07465-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 05/22/2023]
Abstract
PURPOSE OF REVIEW The risk of cardiovascular complications due to SARS-CoV-2 are significantly increased within the first 6 months of the infection. Patients with COVID-19 have an increased risk of death, and there is evidence that many may experience a wide range of post-acute cardiovascular complications. Our work aims to provide an update on current clinical aspects of diagnosis and treatment of cardiovascular manifestations during acute and long-term COVID-19. RECENT FINDINGS SARS-CoV-2 has been shown to be associated with increased incidence of cardiovascular complications such as myocardial injury, heart failure, and dysrhythmias, as well as coagulation abnormalities not only during the acute phase but also beyond the first 30 days of the infection, associated with high mortality and poor outcomes. Cardiovascular complications during long-COVID-19 were found regardless of comorbidities such as age, hypertension, and diabetes; nevertheless, these populations remain at high risk for the worst outcomes during post-acute COVID-19. Emphasis should be given to the management of these patients. Treatment with low-dose oral propranolol, a beta blocker, for heart rate management may be considered, since it was found to significantly attenuate tachycardia and improve symptoms in postural tachycardia syndrome, while for patients on ACE inhibitors or angiotensin-receptor blockers (ARBs), under no circumstances should these medications be withdrawn. In addition, in patients at high risk after hospitalization due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. In this work we provide a comprehensive review on acute and post-acute COVID-19 cardiovascular complications, symptomatology, and pathophysiology mechanisms. We also discuss therapeutic strategies for these patients during acute and long-term care and highlight populations at risk. Our findings suggest that older patients with risk factors such as hypertension, diabetes, and medical history of vascular disease have worse outcomes during acute SARS-CoV-2 infection and are more likely to develop cardiovascular complications during long-COVID-19.
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Affiliation(s)
- Christo Kole
- Cardiology Department, Sismanoglio General Hospital of Attica, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Εleni Stefanou
- Artificial Kidney Unit, General Hospital of Messinia, Kalamata, Greece
| | - Nikolaos Karvelas
- Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
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Sejdic A, Hartling HJ, Gitz Holler J, Klingen Gjærde L, Matovu Dungu A, Engel Møller ME, Svanberg Teglgaard R, Utoft Niemann CU, Brooks PT, Mogensen TH, Weis N, Podlekareva D, Baum Jørgensen ML, Ortved Gang A, Stampe Hersby D, Hald A, Dam Nielsen S, Lebech AM, Helleberg M, Lundgren J, Træholt Franck K, Fischer TK, Harboe ZB, Marquart HV, Rye Ostrowski S, Lindegaard B. Deep immune cell phenotyping and induced immune cell responses at admission stratified by BMI in patients hospitalized with COVID-19: An observational multicenter cohort pilot study. Clin Immunol 2024; 267:110336. [PMID: 39117044 DOI: 10.1016/j.clim.2024.110336] [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: 06/15/2024] [Revised: 07/18/2024] [Accepted: 07/28/2024] [Indexed: 08/10/2024]
Abstract
INTRODUCTION Overweight and obesity are linked to increased hospitalization and mortality in COVID-19 patients. This study aimed to characterize induced immune responses and deep immune cell profiles stratified by BMI in hospitalized COVID-19 patients. METHODS AND RESULTS This observational multicenter cohort pilot study included 122 adult patients with PCR-confirmed COVID-19 in Denmark, stratified by BMI (normal weight, overweight, obese). Inflammation was assessed using TruCulture® and immune cell profiles by flow cytometry with a customized antibody panel (DuraClone®). Patients with obesity had a more pro-inflammatory phenotype with increased TNF-α, IL-8, IL-17, and IL-10 levels post-T cell stimulation, and altered B cell profiles. Patients with obesity showed higher concentrations of naïve, transitional, and non-isotype switched memory B cells, and plasmablasts compared to normal weight patients and healthy controls. CONCLUSIONS Obesity in hospitalized COVID-19 patients may correlate with elevated pro-inflammatory cytokines, anti-inflammatory IL-10, and increased B cell subset activation, highlighting the need for further studies.
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Affiliation(s)
- Adin Sejdic
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Hans Jakob Hartling
- Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jon Gitz Holler
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, Hillerød, Denmark
| | - Lars Klingen Gjærde
- Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Arnold Matovu Dungu
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, Hillerød, Denmark
| | | | | | - Carsten Utoft Utoft Niemann
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Patrick Terrence Brooks
- Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Trine H Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Nina Weis
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Copenhagen, Denmark
| | - Daria Podlekareva
- Department of Respiratory Medicine and Infectious Disease, Copenhagen University Hospital - Bispebjerg, Denmark
| | - Marie Louise Baum Jørgensen
- Department of Respiratory Medicine and Infectious Disease, Copenhagen University Hospital - Bispebjerg, Denmark
| | - Anne Ortved Gang
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Ditte Stampe Hersby
- Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Annemette Hald
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Anne-Mette Lebech
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Marie Helleberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens Lundgren
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | | | - Thea K Fischer
- Department of Clinical Research, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Zitta Barrella Harboe
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hanne Vibeke Marquart
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Lindegaard
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Pereira-Silva GC, Cornélio CKCA, Pacheco G, Rochael NC, Gomes IAB, Cajado AG, Silva KC, Gonçalves BS, Temerozo JR, Bastos RS, Rocha JA, Souza LP, Souza MHLP, Lima-Júnior RCP, Medeiros JVR, Filgueiras MC, Bou-Habib DC, Saraiva EM, Nicolau LAD. Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation. Life Sci 2024; 352:122895. [PMID: 38986896 DOI: 10.1016/j.lfs.2024.122895] [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: 04/12/2024] [Revised: 06/16/2024] [Accepted: 07/03/2024] [Indexed: 07/12/2024]
Abstract
AIMS To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE). MATERIALS AND METHODS Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction. KEY FINDINGS Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling. SIGNIFICANCE Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
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Affiliation(s)
- Gean C Pereira-Silva
- Laboratory on Innate Immunity, Department of Immunology, Institute of Microbiology Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Cassia K C A Cornélio
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Gabriella Pacheco
- Department of Biochemistry and Pharmacology, Health Sciences Center, Universidade Federal do Piauí (UFPI), Teresina, PI, Brazil
| | - Natalia C Rochael
- Laboratory on Innate Immunity, Department of Immunology, Institute of Microbiology Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Isaac A B Gomes
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Aurilene G Cajado
- Department of Physiology and Pharmacology, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil
| | - Katriane C Silva
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | | | - Jairo R Temerozo
- Laboratory on Thymus Research, Oswaldo Cruz Institute (Fiocruz), Rio de Janeiro, RJ, Brazil; National Institute of Science and Technology on Neuroimmunemodulation, Rio de Janeiro, Brazil
| | - Ruan S Bastos
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Jefferson A Rocha
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Leonardo P Souza
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Marcellus H L P Souza
- Department of Physiology and Pharmacology, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil
| | - Roberto C P Lima-Júnior
- Department of Physiology and Pharmacology, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil
| | - Jand V R Medeiros
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil; Department of Biochemistry and Pharmacology, Health Sciences Center, Universidade Federal do Piauí (UFPI), Teresina, PI, Brazil
| | - Marcelo C Filgueiras
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil
| | - Dumith Chequer Bou-Habib
- Laboratory on Thymus Research, Oswaldo Cruz Institute (Fiocruz), Rio de Janeiro, RJ, Brazil; National Institute of Science and Technology on Neuroimmunemodulation, Rio de Janeiro, Brazil
| | - Elvira M Saraiva
- Laboratory on Innate Immunity, Department of Immunology, Institute of Microbiology Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
| | - Lucas A D Nicolau
- Biotechnology and Biodiversity Center Research, Laboratory of Inflammation and Translational Gastroenterology, Universidade Federal do Delta do Parnaíba (UFDPar), Parnaíba, PI, Brazil; Department of Biochemistry and Pharmacology, Health Sciences Center, Universidade Federal do Piauí (UFPI), Teresina, PI, Brazil.
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Ceja-Gálvez HR, Hernández-Ramírez CO, Vega-Magaña AN, Hernández-Bello J, Arellano-Arteaga KJ, Turrubiates-Hernández FJ, Padilla-Borquez DL, Muñoz-Valle JF. Clinical characteristics and severity markers in hospitalized COVID-19 patients from western Mexico: a comparative analysis of Delta and Omicron variants. Front Public Health 2024; 12:1425372. [PMID: 39281077 PMCID: PMC11392767 DOI: 10.3389/fpubh.2024.1425372] [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: 04/29/2024] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Introduction COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus notable for its rapid mutation rate, which has led to the emergence of various variants such as Delta and Omicron, each with potentially different levels of transmissibility and virulence. Therefore, this study aims to compare clinical charactheristics and markers associated with the severity of COVID-19 in hospitalized patients from western Mexico who were infected with the Delta and Omicron variants of SARS-CoV-2. Methods This cross-sectional study involved 66 patients hospitalized for COVID-19, diagnosed by RT-qPCR. SARS-CoV-2 variants were identified through whole genome sequencing using the COVIDseq platform from Illumina. Upon admission, patients underwent a clinical history assessment, blood gas analysis, and blood biometry. Additionally, several tests and markers were measured, including the percentage of neutralizing antibodies, erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), and ferritin. Results and discussion Patients hospitalized with the Omicron were found to be older, compared to those infected with the Delta (64 vs. 54 years, p = 0.006). Additionally, a higher proportion of male patients were observed in the Omicron compared to the Delta (p = 0.029). Both Omicron and Delta variants were associated with lymphopenia, although the lymphocyte count was lower in Omicron (0.9 vs. 0.56 10x3/L; p = 0.007). The COVID-GRAM scale indicated a high risk for severe disease in both groups, but the score was higher in Omicron compared to Delta (157 vs. 128 points; p = 0.0004). Patients infected with Omicron exhibited a lower percentage of neutralizing antibodies than those with Delta (35.99 vs. 81%; p < 0.05), regardless of their vaccination status. Among the markers assessed, globular ESR was found to be lower in Omicron compared to Delta (30.5 vs. 41.5 mm/h; p = 0.001), while ferritin levels were higher in patients infected with the Omicron (1,359 vs. 960.6 μg/L; p = 0.007). In patients with severe COVID-19, markers such as lymphopenia, neutralizing antibody levels, ferritin, and COVID-GRAM scores are elevated in the Omicron variant, while only the leukocyte count and ESR for the Delta variant.
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Affiliation(s)
- Hazael Ramiro Ceja-Gálvez
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Cristian Oswaldo Hernández-Ramírez
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Alejandra Natali Vega-Magaña
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Jorge Hernández-Bello
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | | | - Francisco Javier Turrubiates-Hernández
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Diana Lourdes Padilla-Borquez
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - José Francisco Muñoz-Valle
- Institute of Research in Biomedical Sciences, Centro Universitario de Ciencias de la Salud (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico
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35
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Dumitrescu G, Antovic J, Soutari N, Gran C, Antovic A, Al-Abani K, Grip J, Rooyackers O, Taxiarchis A. The role of complement and extracellular vesicles in the development of pulmonary embolism in severe COVID-19 cases. PLoS One 2024; 19:e0309112. [PMID: 39178205 PMCID: PMC11343408 DOI: 10.1371/journal.pone.0309112] [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] [Received: 05/15/2024] [Accepted: 08/05/2024] [Indexed: 08/25/2024] Open
Abstract
Complement and extracellular vesicles (EVs) association with thrombogenic tendencies is acknowledged, but limited evidence exists for their link to COVID-19 venous thromboembolism. This study aims to examine the relationship between pulmonary embolism and the expression of complement and other proteins related to thrombogenesis in severe Covid-19 patients. We included prospectively 207 severe COVID-19 patients and retrospectively screened for pulmonary embolism (PE). This analysis comprises 20 confirmed PE cases and 20 matched patients without PE. Blood samples taken at the admission in the intensive care unit were analyzed for complement using ELISA. EVs derived from neutrophils, endothelium, or platelets, as well carrying complement or tissue factor were analyzed using flow cytometry. Complement levels were markedly elevated, with a notable increase in C3a and Terminal Complement Complex. The most prevalent EV population was identified as tissue factor (TF)-carrying EVs which peaked in patients with PE during ICU days 4-9. However, for both the complement and analyzed EV populations, no statistically significant differences were found between the patients who developed pulmonary embolism and those who did not. In conclusion, complement factors and EVs expressing tissue factor, along with EVs derived from endothelial cells and platelets, are elevated in severe COVID-19 patients, regardless of the presence of pulmonary embolism. However, the involvement of complement and procoagulant EVs in peripheral plasma in the development of pulmonary embolism is still unclear and requires further investigation.
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Affiliation(s)
- Gabriel Dumitrescu
- Division of Anaesthesia and Intensive Care, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Perioperative and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Jovan Antovic
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Nida Soutari
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Charlotte Gran
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Aleksandra Antovic
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, and Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Kais Al-Abani
- Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Jonathan Grip
- Division of Anaesthesia and Intensive Care, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Perioperative and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Olav Rooyackers
- Division of Anaesthesia and Intensive Care, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Perioperative and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Apostolos Taxiarchis
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
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Goldstein A, Neuberger A, Darawsha YQ, Hussein K, Shafat T, Grupel D, Strahilevitz J, Israel S, Weil A, Ben-Ami R, Elbaz M, Najjar-Debbiny R, Bishara J, Shlomai A, Landes M. Clinical outcomes of immunomodulation therapy in immunocompromised patients with severe Covid-19 and high oxygen requirement. Sci Rep 2024; 14:16985. [PMID: 39044026 PMCID: PMC11266359 DOI: 10.1038/s41598-024-68013-6] [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: 04/10/2024] [Accepted: 07/18/2024] [Indexed: 07/25/2024] Open
Abstract
Covid-19 disease is implicated in increased mortality among immunocompromised patients. The JAK inhibitor, baricitinib (bar), or the IL-6 inhibitor, tocilizumab (toc), demonstrated a survival benefit in patients with severe disease.However, evidence supporting their use in immunocompromised patients with severe Covid-19 is scarce.We aimed to assess clinical outcomes of bar/toc treatment in immunocompromised patients. A multi-center registry of consecutive immunocompromised patients hospitalized due to severe Covid-19 during the Omicron variant dominance period. After excluding patients who did not require high oxygen supply, patients treated with bar/toc were compared to patients treated by standard of care (SOC). Primary outcome was in hospital mortality. Secondary outcomes were 30 and 60 day mortality, super-infection and thromboembolic events. Among an overall 228 immunocompromised patients hospitalized in six Israeli hospitals with severe Covid-19, 112 patients required high oxygen support, of whom 48 (43%) were treated with bar/toc. In-hospital mortality rates were exceptionally high and did not significantly differ between bar/toc and SOC treated patients (62.5% vs. 64.1%, p = 1.0). A logistic regression analysis revealed that advanced age and incomplete vaccination were predictors of in-hospital mortality. Patients treated with bar/toc had no excess of suspected super-infection (62.8% vs. 60.7%, p = 0.84) or thromboembolic events (8.3% vs 3.1%, p = 0.39). In immunocompromised patients with severe Covid-19 and a high oxygen demand, bar/toc therapy was not associated with reduced mortality or with a higher rate of associated complications, compared to SOC. Larger prospective studies should better address efficacy and safety.
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Affiliation(s)
- Avigayil Goldstein
- Department of Internal Medicine D, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.
| | - Ami Neuberger
- Internal Medicine & Infectious Diseases, Rambam Medical center, Haifa, Israel
- Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | | | - Khetam Hussein
- Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Infection Control Unit, Rambam Medical Center, Haifa, Israel
| | - Tali Shafat
- Infectious Disease Institute, Soroka University Medical Center, Beer Sheba, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Daniel Grupel
- Infectious Disease Institute, Soroka University Medical Center, Beer Sheba, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | | | - Sarah Israel
- Hadassah Hebrew University Medical Center, 9112001, Jerusalem, Israel
| | - Ariel Weil
- Faculty of Medicine, Hebrew university, Jerusalem, Israel
| | - Ronen Ben-Ami
- Infectious Disease Unit, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel
| | - Meital Elbaz
- Infectious Disease Unit, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel
| | - Ronza Najjar-Debbiny
- Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Infection Control and Prevention Unit, Lady Davis Carmel Medical Center , Haifa, Israel
| | - Jihad Bishara
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel
| | - Amir Shlomai
- Department of Internal Medicine D, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel
| | - Michal Landes
- Department of Internal Medicine D, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel
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37
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Wu Y, Wang Y, Wang X, Li M, Yan H, Shi H, Shi D, Chen J, Guo L, Feng L. Elevation of IL-8 secretion induced by PEDV infection via NF-κB signaling pathway. Front Cell Infect Microbiol 2024; 14:1422560. [PMID: 39104852 PMCID: PMC11298435 DOI: 10.3389/fcimb.2024.1422560] [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: 04/24/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is associated with severe enteritis, which contributes to high mortality in piglets. The aim of this study was to describe molecular mechanisms associated with proinflammatory cytokine(s) production during PEDV infection. We showed that infection of porcine intestine epithelial cell clone J2 (IPEC-J2) with PEDV induces a gradual increase in interleukin 8 (IL-8) production at different time points, as well as infection of Vero E6 with PEDV. The secretion of IL-8 in these two cell lines infected with PEDV is related to the activation of NF-κB. Furthermore, the cells expressing PEDV M or E protein can induce the upregulation of IL-8. These findings suggest that the IL-8 production can be the initiator of inflammatory response by the host cells upon PEDV infection.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Longjun Guo
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Li Feng
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
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38
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Wang WT, Zhang YY, Li ZR, Li JM, Deng HS, Li YY, Yang HY, Lau CC, Yao YJ, Pan HD, Liu L, Xie Y, Zhou H. Syringic acid attenuates acute lung injury by modulating macrophage polarization in LPS-induced mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155591. [PMID: 38692075 DOI: 10.1016/j.phymed.2024.155591] [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: 04/28/2023] [Revised: 03/15/2024] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, characterized by a syndrome of uncontrolled systemic inflammation that often leads to significant morbidity and death. Anti-inflammatory is one of its treatment methods, but there is no safe and available drug therapy. Syringic acid (SA) is a natural organic compound commonly found in a variety of plants, especially in certain woody plants and fruits. In modern pharmacological studies, SA has anti-inflammatory effects and therefore may be a potentially safe and available compound for the treatment of acute lung injury. PURPOSE This study attempts to reveal the protective mechanism of SA against ALI by affecting the polarization of macrophages and the activation of NF-κB signaling pathway. Trying to find a safer and more effective drug therapy for clinical use. METHODS We constructed the ALI model using C57BL/6 mice by intratracheal instillation of LPS (10 mg/kg). Histological analysis was performed with hematoxylin and eosin (H&E). The wet-dry ratio of the whole lung was measured to evaluate pulmonary edema. The effect of SA on macrophage M1-type was detected by flow cytometry. BCA protein quantification method was used to determine the total protein concentration in bronchoalveolar lavage fluid (BALF). The levels of Interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in BALF were determined by the ELISA kits, and RT-qPCR was used to detect the expression levels of IL-6, IL-1β and TNF-α mRNA of lung tissue. Western blot was used to detect the expression levels of iNOS and COX-2 and the phosphorylation of p65 and IκBα in the NF-κB pathway in lung tissue. In vitro experiments were conducted with RAW267.4 cell inflammation model induced by 100 ng/ml LPS and A549 cell inflammation model induced by 10 μg/ml LPS. The effects of SA on M1-type and M2-type macrophages of RAW267.4 macrophages induced by LPS were detected by flow cytometry. The toxicity of compound SA to A549 cells was detected by MTT method which to determine the safe dose of SA. The expressions of COX-2 and the phosphorylation of p65 and IκBα protein in NF-κB pathway were detected by Western blot. RESULTS We found that the pre-treatment of SA significantly reduced the degree of lung injury, and the infiltration of neutrophils in the lung interstitium and alveolar space of the lung. The formation of transparent membrane in lung tissue and thickening of alveolar septum were significantly reduced compared with the model group, and the wet-dry ratio of the lung was also reduced. ELISA and RT-qPCR results showed that SA could significantly inhibit the production of IL-6, IL-1β, TNF-α. At the same time, SA could significantly inhibit the expression of iNOS and COX-2 proteins, and could inhibit the phosphorylation of p65 and IκBα proteins. in a dose-dependent manner. In vitro experiments, we found that flow cytometry showed that SA could significantly inhibit the polarization of macrophages from M0 type macrophages to M1-type macrophages, while SA could promote the polarization of M1-type macrophages to M2-type macrophages. The results of MTT assay showed that SA had no obvious cytotoxicity to A549 cells when the concentration was not higher than 80 μM, while LPS could promote the proliferation of A549 cells. In the study of anti-inflammatory effect, SA can significantly inhibit the expression of COX-2 and the phosphorylation of p65 and IκBα proteins in LPS-induced A549 cells. CONCLUSION SA has possessed a crucial anti-ALI role in LPS-induced mice. The mechanism was elucidated, suggesting that the inhibition of macrophage polarization to M1-type and the promotion of macrophage polarization to M2-type, as well as the inhibition of NF-κB pathway by SA may be the reasons for its anti-ALI. This finding provides important molecular evidence for the further application of SA in the clinical treatment of ALI.
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Affiliation(s)
- Wei-Ting Wang
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Yan-Yu Zhang
- Henan University of Chinese Medicine, No. 156 Jinshui East Road, Zhengzhou, Henan 450046, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Zi-Rui Li
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Juan-Min Li
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Hai-Shan Deng
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China
| | - Yuan-Yuan Li
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macao, China
| | - Hua-Yi Yang
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macao, China
| | - Chi Chou Lau
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macao, China
| | - Yi-Jing Yao
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macao, China
| | - Hu-Dan Pan
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Liang Liu
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China
| | - Ying Xie
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China.
| | - Hua Zhou
- International Institute for Translational Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, University Town Hospital, No. 55, Neihuan West Road, University Town, Panyu District, Guangzhou, Guangdong 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao In-Depth Cooperation Zone in Hengqin, 519000, China.
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Yan Z, Ji F, Yan R, Jiao J, Wang W, Zhang M, Li F, Zhao Y, Chang Z, Yan S, Li J. Reyanning mixture inhibits M1 macrophage polarization through the glycogen synthesis pathway to improve lipopolysaccharide-induced acute lung injury. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118005. [PMID: 38508433 DOI: 10.1016/j.jep.2024.118005] [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: 01/18/2024] [Revised: 02/23/2024] [Accepted: 03/01/2024] [Indexed: 03/22/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Reyanning (RYN) mixture is a traditional Chinese medicine composed of Taraxacum, Polygonum cuspidatum, Scutellariae Barbatae and Patrinia villosa and is used for the treatment of acute respiratory system diseases with significant clinical efficacy. AIM OF THE STUDY Acute lung injury (ALI) is a common clinical disease characterized by acute respiratory failure. This study was conducted to evaluate the therapeutic effects of RYN on ALI and to explore its mechanism of action. MATERIALS AND METHODS Ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical components of RYN. 7.5 mg/kg LPS was administered to induce ALI in rats. RYN was administered by gavage at doses of 2 ml/kg, 4 ml/kg or 8 ml/kg every 8 h for a total of 6 doses. Observations included lung histomorphology, lung wet/dry (W/D) weight ratio, lung permeability index (LPI), HE staining, Wright-Giemsa staining. ELISA was performed to detect the levels of TNF-α, IL-6, IL-10, Arg-1,UDPG. Immunohistochemical staining detected IL-6, F4/80 expression. ROS, MDA, SOD, GSH/GSSG were detected in liver tissues. Multiple omics techniques were used to predict the potential mechanism of action of RYN, which was verified by in vivo closure experiments. Immunofluorescence staining detected the co-expression of CD86 and CD206, CD86 and P2Y14, CD86 and UGP2 in liver tissues. qRT-PCR detected the mRNA levels of UGP2, P2Y14 and STAT1, and immunoblotting detected the protein expression of UGP2, P2Y14, STAT1, p-STAT1. RESULTS RYN was detected to contain 1366 metabolites, some of the metabolites with high levels have anti-inflammatory, antibacterial, antiviral and antioxidant properties. RYN (2, 4, and 8 ml/kg) exerted dose-dependent therapeutic effects on the ALI rats, by reducing inflammatory cell infiltration and oxidative stress damage, inhibiting CD86 expression, decreasing TNF-α and IL-6 levels, and increasing IL-10 and Arg-1 levels. Transcriptomics and proteomics showed that glucose metabolism provided the pathway for the anti-ALI properties of RYN and that RYN inhibited lung glycogen production and distribution. Immunofluorescence co-staining showed that RYN inhibited CD86 and UGP2 expressions. In vivo blocking experiments revealed that blocking glycogen synthesis reduced UDPG content, inhibited P2Y14 and CD86 expressions, decreased P2Y14 and STAT1 mRNA and protein expressions, reduced STAT1 protein phosphorylation expression, and had the same therapeutic effect as RYN. CONCLUSION RYN inhibits M1 macrophage polarization to alleviate ALI. Blocking glycogen synthesis and inhibiting the UDPG/P2Y14/STAT1 signaling pathway may be its molecular mechanism.
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Affiliation(s)
- Zhipeng Yan
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China
| | - Fanpu Ji
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Ruijuan Yan
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China; Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China
| | - Junzhe Jiao
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China; Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China
| | - Wenba Wang
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China
| | - Miaomiao Zhang
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China
| | - Fenhong Li
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China
| | - Yunyu Zhao
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Zhanjie Chang
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China; Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China
| | - Shuguang Yan
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China; Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China.
| | - Jingtao Li
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China; Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China.
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Wu J, Zheng Y, Zhang LN, Gu CL, Chen WL, Chang MQ. Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis. World J Clin Cases 2024; 12:2704-2712. [PMID: 38899301 PMCID: PMC11185334 DOI: 10.12998/wjcc.v12.i16.2704] [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: 12/24/2023] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024] Open
Abstract
Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases. Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019 (COVID-19) infection. COVID-19 causes pulmonary embolisms, thus new therapeutic options are required to target thrombosis, as conventional treatment options are either not effective due to the complexity of the immune-thrombosis pathophysiology. In this review, we discuss regulation of immune response in respiratory diseases especially COVID-19. We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles, which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases. We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways, and thus can be recommended to treat respiratory infectious diseases.
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Affiliation(s)
- Jie Wu
- Department of Respiratory and Oncology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
| | - Ying Zheng
- Department of Respiratory and Oncology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
| | - Li-Na Zhang
- Department of Respiratory and Oncology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
| | - Cai-Li Gu
- Department of Respiratory and Oncology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
| | - Wang-Li Chen
- Department of Respiratory and Oncology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
| | - Min-Qiang Chang
- Department of Otorhinolaryngology, 72nd Group Army Hospital of PLA, Huzhou 313000, Zhejiang Province, China
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Niehaus C, Klein S, Strunz B, Freyer E, Maasoumy B, Wedemeyer H, Björkström NK, Kraft ARM, Cornberg M. CXCR6 +CD69 + CD8 + T cells in ascites are associated with disease severity in patients with cirrhosis. JHEP Rep 2024; 6:101074. [PMID: 38882602 PMCID: PMC11179582 DOI: 10.1016/j.jhepr.2024.101074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 03/16/2024] [Accepted: 03/20/2024] [Indexed: 06/18/2024] Open
Abstract
Background & Aims Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and may eventually lead to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we analyzed the role of CD8+ T cells in the ascites immune compartment. Methods Peripheral blood and ascites fluid were collected from 50 patients with decompensated cirrhosis. Phenotype and functional responses of CD8+ T cells were analyzed, and obtained data were compared with each other as well as with healthy controls and patients with compensated cirrhosis. Results High-dimensional flow cytometry revealed that CD8+ T cells are abundant in the ascites of patients with cirrhosis and exhibit a chronically activated bystander phenotype with innate-like functions. Indeed, we identified distinct CXCR6+CD69+ clusters of late effector memory CD8+ T cells that were rarely found in blood and correlated with clinical parameters of disease severity. Moreover, this CD8+ T-cell population was hyperresponsive to innate cytokines and exhibited cytokine-mediated bystander activation. Interestingly, the Janus kinase (JAK) inhibitor tofacitinib was able to effectively block bystander-activated CXCR6+CD69+ CD8+ T cells and significantly suppress effector molecule production. Conclusions The results indicate that CXCR6+CD69+ CD8+ T cells in ascites are associated with disease severity and may contribute to inflammation in patients with decompensated cirrhosis, suggesting that targeted inhibition of this immune cell subset may be a viable therapeutic option. Impact and Implications Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and eventually leads to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we demonstrate that CXCR6+CD69+ CD8+ T cells are abundant in the ascites of patients with cirrhosis, exhibit a chronically activated bystander phenotype, and correlate with clinical parameters of disease severity. Moreover, we show that the Janus kinase (JAK) inhibitor tofacitinib can effectively block these bystander-activated CXCR6+CD69+ CD8+ T cells, suggesting that targeted inhibition of this immune cell subset may be a potential therapeutic strategy. Clinical trial number Prospective registry: INFEKTA (DRKS00010664).
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Affiliation(s)
- Christian Niehaus
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Twincore, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Sebastian Klein
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Twincore, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School, Hannover, Germany
- CAIMed - Center for AI in Medicine, Joint Venture of Leibniz University Hannover and Hannover Medical School, Hannover, Germany
| | - Benedikt Strunz
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Erich Freyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Twincore, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Twincore, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Twincore, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- German Center for Infection Research, HepNet Study-House German Liver Foundation, Hannover, Germany
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Gugo K, Tandara L, Juricic G, Pavicic Ivelja M, Rumora L. Effects of Hypoxia and Inflammation on Hepcidin Concentration in Non-Anaemic COVID-19 Patients. J Clin Med 2024; 13:3201. [PMID: 38892911 PMCID: PMC11173117 DOI: 10.3390/jcm13113201] [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: 04/22/2024] [Revised: 05/20/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Background/Objectives: This study aimed to explore the influence of hypoxia, inflammation, and erythropoiesis on hepcidin and other iron status parameters in non-anaemic COVID-19 patients admitted to the emergency unit before the introduction of therapeutic interventions. Methods: Ninety-six COVID-19 patients and 47 healthy subjects were recruited. Patients were subdivided into hypoxic or normoxic groups and, after follow-up, into mild and moderate, severe or critical disease severity groups. Iron, unsaturated iron-binding capacity (UIBC), ferritin, C-reactive protein (CRP), and interleukin 6 (IL-6) were measured on automatic analysers. ELISA kits were used for hepcidin and erythropoietin (EPO) determination. We calculated total iron-binding capacity (TIBC) and ratios of hepcidin with parameters of iron metabolism (ferritin/hepcidin, hepcidin/iron), inflammation (hepcidin/CRP, hepcidin/IL-6), and erythropoietic activity (hepcidin/EPO). Results: Hepcidin, ferritin, EPO, CRP, IL-6, ferritin/hepcidin, and hepcidin/iron were increased, while UIBC, TIBC, hepcidin/CRP, and hepcidin/IL-6 were decreased in hypoxic compared to normoxic patients as well as in patients with severe or critical disease compared to those with mild and moderate COVID-19. Regarding predictive parameters of critical COVID-19 occurrence, in multivariable logistic regression analysis, a combination of EPO and ferritin/hepcidin showed very good diagnostic performances and correctly classified 88% of cases, with an AUC of 0.838 (0.749-0.906). Conclusions: The hypoxic signal in our group of patients was not strong enough to overcome the stimulating effect of inflammation on hepcidin expression. EPO and ferritin/hepcidin might help to identify on-admission COVID-19 patients at risk of developing a critical form of the disease.
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Affiliation(s)
- Katarina Gugo
- Medical Laboratory Diagnostic Division, University Hospital of Split, Soltanska 1, 21000 Split, Croatia;
- Department of Health Studies, University of Split, Rudera Boskovica 35, 21000 Split, Croatia;
| | - Leida Tandara
- Medical Laboratory Diagnostic Division, University Hospital of Split, Soltanska 1, 21000 Split, Croatia;
- Department of Medical Chemistry and Biochemistry, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Gordana Juricic
- Department of Laboratory Diagnostics, General Hospital Pula, Santoriova 24a, 52100 Pula, Croatia;
| | - Mirela Pavicic Ivelja
- Department of Health Studies, University of Split, Rudera Boskovica 35, 21000 Split, Croatia;
- Department of Infectious Diseases, University Hospital of Split, Soltanska 1, 21000 Split, Croatia
| | - Lada Rumora
- Department of Medical Biochemistry and Haematology, University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovacica 1, 10000 Zagreb, Croatia;
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Çakmak R, Yüce S, Ay M, Uyar MH, Kılıç Mİ, Bektaş M. Intravenous high-dose anakinra drops venous thrombosis and acute coronary syndrome in severe and critical COVID-19 patients: a propensity score matched study. Sci Rep 2024; 14:12369. [PMID: 38811592 PMCID: PMC11137068 DOI: 10.1038/s41598-024-62079-y] [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: 02/27/2024] [Accepted: 05/13/2024] [Indexed: 05/31/2024] Open
Abstract
In our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as diabetes mellitus, hypertension, and coronary heart disease of the patients were determined as the variables to be matched. We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR 4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR 5.1) were lower in the Anakinra group than SoC. No patient experienced cerebrovascular accident and/or clinically evident deep venous thrombosis both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and acute coronary syndrome (ACS) were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as ACS. In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with severe and critical COVID-19.
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Affiliation(s)
- Ramazan Çakmak
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istinye University, Istanbul, Turkey
| | - Servet Yüce
- Department of Public Health and Biostatistics, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Mustafa Ay
- Aksaray University, Aksaray Training and Research Hospital, Aksaray, Turkey
| | | | - Muhammed İkbal Kılıç
- Department of Internal Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey
| | - Murat Bektaş
- Division of Rheumatology, Department of Internal Medicine, Aksaray Training and Research Hospital, Yeni Sanayi Street, Merkez, 68200, Aksaray, Turkey.
- Division of Rheumatology, Department of Internal Medicine, Istanbul Aydın University, Istanbul, Turkey.
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Krčmová LK, Javorská L, Matoušová K, Šmahel P, Skála M, Kopecký M, Suwanvecho C, Přívratská N, Turoňová D, Melichar B. Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome. Clin Chem Lab Med 2024; 62:1217-1227. [PMID: 38374668 DOI: 10.1515/cclm-2023-1297] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/06/2024] [Indexed: 02/21/2024]
Abstract
OBJECTIVES Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.
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Affiliation(s)
- Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Lenka Javorská
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Petr Šmahel
- Deparment of Infectious Diseases, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Mikuláš Skála
- Department of Pneumology, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Michal Kopecký
- Department of Pneumology, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Chaweewan Suwanvecho
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Nikola Přívratská
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Dorota Turoňová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic
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Mizuno Y, Nakasone W, Nakamura M, Otaki JM. In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development. Vaccines (Basel) 2024; 12:539. [PMID: 38793790 PMCID: PMC11125730 DOI: 10.3390/vaccines12050539] [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: 04/30/2024] [Revised: 05/12/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Spike protein sequences in SARS-CoV-2 have been employed for vaccine epitopes, but many short constituent sequences (SCSs) in the spike protein are present in the human proteome, suggesting that some anti-spike antibodies induced by infection or vaccination may be autoantibodies against human proteins. To evaluate this possibility of "molecular mimicry" in silico and in vitro, we exhaustively identified common SCSs (cSCSs) found both in spike and human proteins bioinformatically. The commonality of SCSs between the two systems seemed to be coincidental, and only some cSCSs were likely to be relevant to potential self-epitopes based on three-dimensional information. Among three antibodies raised against cSCS-containing spike peptides, only the antibody against EPLDVL showed high affinity for the spike protein and reacted with an EPLDVL-containing peptide from the human unc-80 homolog protein. Western blot analysis revealed that this antibody also reacted with several human proteins expressed mainly in the small intestine, ovary, and stomach. Taken together, these results showed that most cSCSs are likely incapable of inducing autoantibodies but that at least EPLDVL functions as a self-epitope, suggesting a serious possibility of infection-induced or vaccine-induced autoantibodies in humans. High-risk cSCSs, including EPLDVL, should be excluded from vaccine epitopes to prevent potential autoimmune disorders.
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Affiliation(s)
- Yuya Mizuno
- The BCPH Unit of Molecular Physiology, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Senbaru, Nishihara 903-0213, Okinawa, Japan
| | - Wataru Nakasone
- Computer Science and Intelligent Systems Unit, Department of Engineering, Faculty of Engineering, University of the Ryukyus, Senbaru, Nishihara 903-0213, Okinawa, Japan
| | - Morikazu Nakamura
- Computer Science and Intelligent Systems Unit, Department of Engineering, Faculty of Engineering, University of the Ryukyus, Senbaru, Nishihara 903-0213, Okinawa, Japan
| | - Joji M. Otaki
- The BCPH Unit of Molecular Physiology, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Senbaru, Nishihara 903-0213, Okinawa, Japan
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Chen L, Dai X. Venous thromboembolism and severe COVID-19: a Mendelian randomization trial and transcriptomic analysis. Front Immunol 2024; 15:1363598. [PMID: 38742101 PMCID: PMC11089160 DOI: 10.3389/fimmu.2024.1363598] [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: 01/02/2024] [Accepted: 04/16/2024] [Indexed: 05/16/2024] Open
Abstract
Introduction Venous thromboembolism (VTE) is known to be intricately linked to severe COVID-19 (sCOVID-19) occurrence. Herein, we employed univariable Mendelian randomization (MR) and transcriptome analysis to predict the causal association and associated signaling networks between VTE and sCOVID-19. Methods Potential VTE and sCOVID-19 association was assessed using MR-Egger, weighted median, simple mode, weighted mode, and inverse variance weighted (IVW) regression. We conducted independent univariable analyses involving VTE and sCOVID-19. Using heterogeneity, pleiotropy, and the Leave-One-Out examinations, we performed sensitivity analyses. Thereafter, we performed transcriptome analysis of the GSE164805 dataset to identify differentially expressed genes (DEGs) linked to single nucleotide polymorphisms (SNPs). Lastly, we conducted immune analyses. Results Based on our univariable analysis, VTE was a strong indicator of sCOVID-19 development, and it was intricately linked to sCOVID-19. We further conducted sensitivity analysis to demonstrate the reliability of our results. Using differential analysis, we identified 15 major genes, namely, ACSS2, CEP250, CYP4V2, DDB2, EIF6, GBGT1, GSS, MADD, MAPK8IP1, MMP24, YBPC3, NT5DC3, PROCR, SURF6, and YIPF2, which were strongly connected to suppressive adaptive immune as well as augmented inflammatory cells. In addition, we uncovered strong associations with most differential immunologic gene sets, such as, the Major Histocompatibility Complex (MHC), immunoactivators, and immunosuppressors. Conclusion Herein, we demonstrated we strong association between VTE and enhanced sCOVID-19 risk. We also identified 15 DEGs which potentially contribute to the shared immunologic pathogenesis between VTE and sCOVID-19.
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Affiliation(s)
- Liang Chen
- Department of Infectious Diseases, Taikang Xianlin Drum Tower Hospital, Affiliated Hospital of Medical College of Nanjing University, Nanjing, China
| | - Xiaoting Dai
- Department of Infectious Diseases, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
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Hou XY, Danzeng LM, Wu YL, Ma QH, Yu Z, Li MY, Li LS. Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19. World J Stem Cells 2024; 16:353-374. [PMID: 38690515 PMCID: PMC11056634 DOI: 10.4252/wjsc.v16.i4.353] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/17/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.
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Affiliation(s)
- Xiang-Yi Hou
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - La-Mu Danzeng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Yi-Lin Wu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Qian-Hui Ma
- Department of Pharmacy, Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng Yu
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Mei-Ying Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Sha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China.
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Guillen-Sola A, Ramírez C, Nieto S, Duarte E, Tejero M, Grillo C, Bel H, Boza R. Therapeutic approach to dysphagia in post-COVID patients in a rehabilitation unit: a descriptive longitudinal study. Eur J Phys Rehabil Med 2024; 60:373-381. [PMID: 38502558 PMCID: PMC11112509 DOI: 10.23736/s1973-9087.24.08234-0] [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: 09/13/2023] [Revised: 02/06/2024] [Accepted: 02/19/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND A high rate of hospitalized patients for COVID-19 had dysphagia, frequently underdiagnosed, and not treated, inducing a prolonged dysphagia with protracted recovery. Specific treatments and protocols have not been well described yet. AIM Given the potential benefits of respiratory muscle training (IEMT) and neuromuscular stimulation (NMES) in dysphagia treatment, this study aimed to assess the feasibility of the protocol used for treating dysphagia in patients who experienced prolonged hospitalization for COVID-19. DESIGN Observational, descriptive, prospective study. SETTING Department of Physical Medicine and Rehabilitation of a tertiary University hospital. POPULATION Fifty-eight COVID-19 patients were admitted for intensive rehabilitation (March 2020 to October 2021) were prospectively studied. METHODS Dysphagia was diagnosed using videofluoroscopy and treated with a 3-week protocol adapted from neuromuscular stimulation (NMES) in a motor threshold and inspiratory/expiratory muscle strength training (IEMST), five sets of five repetitions three times daily for 3 weeks. Feasibility was assessed with adherence, outcomes achieved, and occurrence of adverse/unexpected events. Respiratory function (peak cough flow, maximal inspiratory/expiratory pressures) and swallow function (Penetration-Aspiration Scale and Bolus Residue Scale measured by videofluoroscopy) were recorded descriptive statistics, Student's t test for numerical data, and Wilcoxon Test for ordinal variables were applied. SPPSS vs28 and STATA version 15.1 (StataCorp, College Station, TX, USA) were used for statistical analysis. P values 0.05 were considered significant. RESULTS Dysphagia was highly prevalent in severe COVID-19 patients (86.6%); all respiratory and swallow parameters improved after a 3-week intervention and 12 of 18 patients dependent on tube feeding resumed a normal diet (66.7%; McNemar P=0.03), and 84.09% attended a no restriction diet at discharge. Adherence to treatment was 85%. No significant adverse events were detected. CONCLUSIONS We conclude that a structured swallowing-exercise training intervention based on IEMT and NMES is feasible and safe in prolonged hospitalization post-COVID patients. CLINICAL REHABILITATION IMPACT To describe rehabilitation protocols used to treat dysphagia in post-COVID patients will help us to optimize the available techniques in each center and to induce a faster recovery avoiding potential complications.
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Affiliation(s)
- Anna Guillen-Sola
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain -
- Rehabilitation Research Group, Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain -
| | - Cindry Ramírez
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
- Rehabilitation Research Group, Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Sonia Nieto
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
| | - Esther Duarte
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
- Rehabilitation Research Group, Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Marta Tejero
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
| | - Christian Grillo
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
| | - Helena Bel
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
| | - Roser Boza
- Department of Physical Medicine and Rehabilitation, Parc de Salut Mar, Barcelona, Spain
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Tan JQE, Dawson JL, Bastiampillai T. Can lithium be used in the setting of clozapine commencement in patients with COVID-19 associated neutropenia: A case report. Clin Case Rep 2024; 12:e8758. [PMID: 38617070 PMCID: PMC11014804 DOI: 10.1002/ccr3.8758] [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: 08/20/2023] [Revised: 03/06/2024] [Accepted: 03/16/2024] [Indexed: 04/16/2024] Open
Abstract
COVID-19 infection may increase the likelihood of neutropenia in patients already on clozapine. In clozapine treated patients experiencing COVID-19 associated neutropenia, adjunct therapy with lithium can be considered.
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Affiliation(s)
- Jin Quan Eugene Tan
- SA Pharmacy, Flinders Medical CentreSouthern Adelaide Local Health NetworkAdelaideSouth AustraliaAustralia
- College of Medicine and Public HealthFlinders UniversityAdelaideSouth AustraliaAustralia
| | - Jessica L. Dawson
- SA Pharmacy, Flinders Medical CentreSouthern Adelaide Local Health NetworkAdelaideSouth AustraliaAustralia
- Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical SciencesMonash UniversityParkvilleVictoriaAustralia
| | - Tarun Bastiampillai
- Discipline of Psychiatry, College of Medicine and Public HealthFlinders UniversityAdelaideSouth AustraliaAustralia
- Department of PsychiatryMonash UniversityClaytonVictoriaAustralia
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Schlosser T, Krasselt M, Elsing L, Hecker M, Holler B, Hoffmeister A. Symptoms and Severity of COVID-19 in Patients with Immune-Mediated Inflammatory Diseases: Experience of a University Medical Center. Autoimmune Dis 2024; 2024:6627035. [PMID: 38571561 PMCID: PMC10990649 DOI: 10.1155/2024/6627035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/31/2024] [Accepted: 02/14/2024] [Indexed: 04/05/2024] Open
Abstract
Background The pandemic situation of the novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) and its associated disease (coronavirus disease 2019 (COVID-19)) represents a challenging condition with a plethora of aspects. The course of COVID-19 in patients with immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD) and rheumatic diseases (RD) is not well known. Our study is one step toward closing this gap by collecting data on vaccination rates, infection-free survival, and individual symptom severity. Methods We conducted a prospective questionnaire-based study between April 2022 and October 2022 at our university hospital. Outward patients over the age of 18 years were screened for participation and reported about their infection/infection-free survival since the start of the pandemic. Results Finally, 156 patients were included in the study, 117 (75.0%) of which had inflammatory bowel disease and 39 (25.0%) patients with rheumatic disease. Altogether, 143 (91.7%) persons had received at least one vaccination against SARS-CoV-2. A total of 153 patients provided information regarding their COVID-19 history: 81 patients (52.0%) self-reported about their SARS-CoV-2 infection. In general, courses of infection were mild: only two patients (2.5% of patients with reported COVID-19) were hospitalized due to COVID-19 with one (1.2%) of the two needing intensive care. Asymptomatic COVID-19 had been described by 7 persons (8.6% of patients with reported COVID-19). Acute COVID-19 was accompanied by fatigue/tiredness in 58 persons (71.6% of patients with history of COVID-19) as the most frequent symptom. Other complaints were common cold (55 patients = 67.9%), cough (51 patients = 63.0%), headache (44 patients = 54.3%), and fever (35 patients = 43.2%). Stratified by vaccination status (unvaccinated vs. at least once vaccinated), the time to infection differed significantly (logrank test: p = 0.04, Chi2 4.1). At least once vaccinated people had a median COVID-19-free survival of 28.5 months (confidence interval (CI): 23.6 months-not reached). Without any vaccination, the estimated time to infection was 25.1 months (CI: 23.6 months-not reached). Conclusion Our IMID patients have a high rate of vaccination against SARS-CoV-2. Data show a significantly longer infection-free survival in vaccinated IMID patients as compared to unvaccinated patients. Discrimination between symptoms of COVID-19 and a concomitant inflammatory disease is difficult as complaints might be overlapping. This trial is registered with DRKS00028880.
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Affiliation(s)
- Tobias Schlosser
- Department of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, Division of Gastroenterology, University Medical Center, Leipzig, Germany
| | - Marco Krasselt
- Department of Endocrinology, Nephrology and Rheumatology, Division of Rheumatology, University Medical Center, Leipzig, Germany
| | - Louis Elsing
- Department of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, Division of Gastroenterology, University Medical Center, Leipzig, Germany
| | - Martin Hecker
- Department of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, Division of Gastroenterology, University Medical Center, Leipzig, Germany
| | - Babett Holler
- Department of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, Division of Gastroenterology, University Medical Center, Leipzig, Germany
| | - Albrecht Hoffmeister
- Department of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, Division of Gastroenterology, University Medical Center, Leipzig, Germany
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