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Abdelall EKA, Elshemy HAH, Labib MB, Philoppes JN, Ali FEM, Ahmed AKM. Synthesis of new selective agents with dual anti-inflammatory and SARS-CoV-2 M pro inhibitory activity: Antipyrine-celecoxib hybrid analogues; COX-2, COVID-19 cytokine storm and replication inhibitory activities. Bioorg Chem 2025; 160:108429. [PMID: 40199011 DOI: 10.1016/j.bioorg.2025.108429] [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: 02/01/2025] [Revised: 03/28/2025] [Accepted: 03/30/2025] [Indexed: 04/10/2025]
Abstract
Herein, a great aim to introduce novel pyrazolone derivatives with multiple activities, including selective COX-2 and cytokine inhibition in addition to SARS-CoV-2 Mpro inhibitory effects. All the synthesized compounds 4a-c, 5, 6a,b, 7a-f, 8a,b, 9a,b, 10a,b and 11a-f were evaluated in vitro for investigation of selective COX-2 inhibitory activity. The results introduced the most selective compounds 7a, 7d, 7e, 9a, and 11f that were further screened in vivo to evaluate their anti-inflammatory activity, safety concerning gastric ulcer and myocardial infarction. Compounds 7e, 9a and 11f exhibited % edema inhibition (43.87-54.31) compared to celecoxib (54.17%17 %) at the same time. Histopathological examination of gastric and cardiac tissues proved the safe profiles of compounds 7e and 11 f. The reduction in cardiac biomarkers level (CK-MP, AST, LDH) and the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) ensured the cardiac safety of 7e and 11f. Also, RT-PCR results confirmed the efficacy of compounds 7e and 11f to inhibit gene expression of cytokines responsible for the overwhelming inflammation in COVID-19 infection, including TNF-α, IL-6, IL-2 and IL-1β. Additionally, SARS-CoV-2 Mpro inhibitory assay revealed the potency of the compound 7e against Mpro enzyme (IC50 = 13.24 μM). Furthermore, the proper fitting of 7e inside both COX-2 and Mpro active site through the docking study supported the affinity of 7e to inhibit both enzymes. Therefore, a belief stated that compound 7e is a promising lead compound with a safe profile, acting as a selective COX-2 and cytokine inhibitor. Also, 7e reduces the COVID-19 infection's cytokine storm and inhibits viral replication via targeting the Mpro enzyme.
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Affiliation(s)
- Eman K A Abdelall
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Heba A H Elshemy
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Madlen B Labib
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - John N Philoppes
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Fares E M Ali
- Department of pharmacology and toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Michael Sayegh Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Amira K M Ahmed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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Janevska M, Naessens E, Verhasselt B. Impact of SARS-CoV-2 Wuhan and Omicron Variant Proteins on Type I Interferon Response. Viruses 2025; 17:569. [PMID: 40285011 PMCID: PMC12031613 DOI: 10.3390/v17040569] [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: 03/08/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
SARS-CoV-2 has demonstrated a remarkable capacity for immune evasion. While initial studies focused on the Wuhan variant and adaptive immunity, later emerging strains such as Omicron exhibit mutations that may alter their immune-modulatory properties. We performed a comprehensive review of immune evasion mechanisms associated with SARS-CoV-2 viral proteins to focus on the evolutionary dynamics of immune modulation. We systematically analyzed and compared the impact of all currently known Wuhan and Omicron SARS-CoV-2 proteins on type I interferon (IFN) responses using a dual-luciferase reporter assay carrying an interferon-inducible promoter. Results revealed that Nsp1, Nsp5, Nsp14, and ORF6 are potent type I IFN inhibitors conserved across Wuhan and Omicron strains. Notably, we identified strain-specific differences, with Nsp6 and Spike proteins exhibiting enhanced IFN suppression in Omicron, whereas the Envelope protein largely retained this function. To extend these findings, we investigated selected proteins in primary human endothelial cells and also observed strain-specific differences in immune response with higher type I IFN response in cells expressing the Wuhan strain variant, suggesting that Omicron's adaptational mutations may contribute to a damped type I IFN response in the course of the pandemic's trajectory.
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Affiliation(s)
- Marija Janevska
- Department of Diagnostic Sciences, Ghent University, B9000 Ghent, Belgium;
| | - Evelien Naessens
- Department of Laboratory Medicine, Ghent University Hospital, B9000 Ghent, Belgium;
| | - Bruno Verhasselt
- Department of Diagnostic Sciences, Ghent University, B9000 Ghent, Belgium;
- Department of Laboratory Medicine, Ghent University Hospital, B9000 Ghent, Belgium;
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3
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Stukas S, Goshua G, Conway EM, Lee AYY, Hoiland RL, Sekhon MS, Y. C. Chen L. ABO blood group and COVID-19 severity: Associations with endothelial and adipocyte activation in critically ill patients. PLoS One 2025; 20:e0320251. [PMID: 40173171 PMCID: PMC11964209 DOI: 10.1371/journal.pone.0320251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/14/2025] [Indexed: 04/04/2025] Open
Abstract
BACKGROUND ABO blood group has been implicated both in susceptibility to, and severity of, SARS-CoV-2 infection. The aim of this study was to explore a potential association between ABO blood group and severity of COVID-19 infection in critically ill patients and the following biological mechanisms: inflammatory cytokines, endothelial injury, and adipokines. METHODS We conducted a retrospective study of 128 critically ill COVID-19 patients admitted to Vancouver General Hospital from March 2020-March 2021. Outcomes including 28-day mortality, need for mechanical ventilation and length of intensive care unit (ICU) stay were compared between patients with A & AB blood type vs. B & O blood type. Likewise, serum inflammatory markers, markers of endothelial activation, and adipokines were compared. RESULTS The association between ABO and severity of disease was confirmed. Patients with A&AB blood group had more frequent ventilation requirements compared to patients with blood group B&O (N(%): 35 (71%) vs 41 (52%), p = 0.041), higher total ICU mortality (14 (29%) vs 9 (11%), p = 0.018), longer median ICU stay (days, median [interquartile range]: 10 [6-19], vs 7 [3-14], p = 0.016) and longer median hospital stay (26 [14-36] vs. 17 [10-30] p = 0.034). No association was found between ABO blood group and serum inflammatory cytokines or their receptors [IL-6, IL-1b, IL-10, TNF, sIL-6R, sgp130] measured within the first 10 days of ICU stay. No association was found between ABO and plasma markers of endothelial injury [Thrombomodulin, ADAMTS13, sP-Selectin, Factor IX, Protein C, Protein S, vWF]. Among the plasma adipokines, there were no differences between lipocalin-2, PAI-1 or resistin. Notably, however, median adipsin was higher in patients with A&AB blood group compared to O&B (16.3 [4.2-38.5] x106 pg/mL vs. 9.61 [3.0-20.8] x 106 pg/mL, p = 0.048). CONCLUSIONS This retrospective single-center study confirms an association between A and AB blood type with more severe COVID-19. While an underlying mechanism was not identified, the finding of higher adipsin levels in patients with type A/AB blood warrants further investigation in larger prospective studies.
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Affiliation(s)
- Sophie Stukas
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - George Goshua
- Department of Internal Medicine, Section of Medical Oncology & Hematology, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, United States of America
- Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, United States of America
| | - Edward M. Conway
- Department of Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Agnes Y. Y. Lee
- Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ryan L. Hoiland
- Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Chronic Disease Prevention and Management, University of British Columbia, Kelowna, British Columbia, Canada
| | - Mypinder S. Sekhon
- Division of Critical Care, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Luke Y. C. Chen
- Division of Hematology, Dalhousie University, Halifax, Nova Scotia, Canada
- Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada
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Hiti L, Markovič T, Lainscak M, Farkaš Lainščak J, Pal E, Mlinarič-Raščan I. The immunopathogenesis of a cytokine storm: The key mechanisms underlying severe COVID-19. Cytokine Growth Factor Rev 2025; 82:1-17. [PMID: 39884914 DOI: 10.1016/j.cytogfr.2024.12.003] [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: 10/22/2024] [Revised: 12/18/2024] [Accepted: 12/26/2024] [Indexed: 02/01/2025]
Abstract
A cytokine storm is marked by excessive pro-inflammatory cytokine release, and has emerged as a key factor in severe COVID-19 cases - making it a critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients' immune systems then fail to shift from innate to adaptive immunity, suppressing interferon responses and leading to excessive pyroptosis and neutrophil activation. This amplifies tissue damage and inflammation, creating a pro-inflammatory loop. The result is the disruption of Th1/Th2 and Th17/Treg balances, lymphocyte exhaustion, and extensive blood clotting. Cytokine storm treatments include glucocorticoids to suppress the immune system, monoclonal antibodies to neutralize specific cytokines, and JAK inhibitors to block cytokine receptor signalling. However, the most effective treatment options for mitigating SARS-CoV-2 infection remain vaccines as a preventive measure and antiviral drugs for the early stages of infection. This article synthesizes insights into immune dysregulation in COVID-19, offering a framework to better understand cytokine storms and to improve monitoring, biomarker discovery, and treatment strategies for COVID-19 and other conditions involving cytokine storms.
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Affiliation(s)
- Luka Hiti
- Faculty of Pharmacy, University of Ljubljana, Slovenia
| | | | - Mitja Lainscak
- General Hospital Murska Sobota, Slovenia; Faculty of Medicine, University of Ljubljana, Slovenia
| | | | - Emil Pal
- General Hospital Murska Sobota, Slovenia
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5
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Radwan NA, Gohary HE, Hamed D, Khalil NM, Abdelfatah D, Wahab AA, Elsharkawy MM. MEFV gene variations in COVID-19 pneumonia patients (Pilot study). J Genet Eng Biotechnol 2025; 23:100473. [PMID: 40074447 PMCID: PMC11926684 DOI: 10.1016/j.jgeb.2025.100473] [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: 12/11/2023] [Revised: 12/30/2024] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND The emergence of worldwide pandemic caused by coronavirus 2 (SARS-CoV-2) has caused a radical change in everyday life. Patients diseased with FMF show manifestations and labs highly similar to COVID infected patients. In the current study, we evaluate the presence of variants in exon 10 of MEFV gene and the relation with severity of symptoms in patients with COVID-19 pneumonia. METHOD Thirty-nine COVID-19 infected patients admitted to Kasr Alainy medical school were divided into two groups moderate and severe. Sanger sequencing of exon 10 in MEVF gene was scanned in the 39 subjects. RESULTS We identified variants in 10 out of 39 patients (26 %) with heterozygous variants in 9 patients (23 %) and homozygous in one patient (2.5 %). The most frequent variant found was the silent variant p.(P706 = ) (12.9 %) followed by missense variants p.(A744S) (7.7 %) and p.(V726A) (5.1 %). Striking result was that 90 % of patients with MEFV variants had moderate symptoms and without progression into the severe form of COVID-19 pneumonia. CONCLUSION Our results indicated that the presence of variants in MEFV gene (either benign or of uncertain significance) could have a role in determination of COVID-19 severity.
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Affiliation(s)
- Noha A Radwan
- Departement of Clinical and Chemical Pathology, Kasr Alainy Medical School, Cairo University, Egypt.
| | - Heba El Gohary
- Departement of Clinical and Chemical Pathology, Kasr Alainy Medical School, Cairo University, Egypt
| | - Dalia Hamed
- Departement of Clinical and Chemical Pathology, Kasr Alainy Medical School, Cairo University, Egypt
| | - Noha M Khalil
- Department of Internal Medicine, Kasr Alainy Medical School, Cairo University, Egypt
| | - Dalia Abdelfatah
- Cancer Epidemiology and Biostatistics Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Amal Abdel Wahab
- Departement of Clinical and Chemical Pathology, Kasr Alainy Medical School, Cairo University, Egypt
| | - Marwa Mahmoud Elsharkawy
- Departement of Clinical and Chemical Pathology, Kasr Alainy Medical School, Cairo University, Egypt
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6
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Jadhav P, Liang X, Ansari A, Tan B, Tan H, Li K, Chi X, Ford A, Ruiz FX, Arnold E, Deng X, Wang J. Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates. Nat Commun 2025; 16:1604. [PMID: 39948104 PMCID: PMC11825904 DOI: 10.1038/s41467-025-56902-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PLpro) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70Ub binding site in PLpro, we designed a series of quinoline analogs demonstrating potent PLpro inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70Ub site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PLpro inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.
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Affiliation(s)
- Prakash Jadhav
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Xueying Liang
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Ahmadullah Ansari
- Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
- Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Bin Tan
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Haozhou Tan
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Kan Li
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Xiang Chi
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Alexandra Ford
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Francesc Xavier Ruiz
- Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
- Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
| | - Eddy Arnold
- Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
- Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
| | - Xufang Deng
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA.
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK, USA.
| | - Jun Wang
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
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Goubran M, Spaner C, Stukas S, Zoref-Lorenz A, Shojania K, Beckett M, Li A, Peterson E, Sekhon M, Grey R, Wellington C, Cheng CV, Biggs CM, Mattman A, Jordan MB, Chen LYC, Setiadi A. The role of C-reactive protein and ferritin in the diagnosis of HLH, adult-onset still's disease, and COVID-19 cytokine storm. Sci Rep 2024; 14:31306. [PMID: 39732949 PMCID: PMC11682105 DOI: 10.1038/s41598-024-82760-6] [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: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Cytokine storm syndromes such as hemophagocytic lymphohistiocytosis (HLH), Adult-onset Still's disease (AOSD), and COVID-19 cytokine storm (CCS) are characterized by markedly elevated inflammatory cytokines. However clinical measurement of serum cytokines is not widely available. This study examined the clinical utility of C-reactive protein (CRP) and ferritin, two inexpensive and widely available inflammatory markers, for distinguishing HLH from AOSD and CCS. This single centre retrospective study included 44 secondary HLH patients, 14 AOSD patients, and 13 CCS patients. Baseline CRP and ferritin measured within 72 h of diagnosis and before administration of corticosteroids or other anti-inflammatory therapies were analyzed. The median CRP in HLH patients was lower than AOSD (71 mg/L vs. 172 mg/L, p < 0.001) and CCS (71 mg/L vs. 121 mg/L, p = 0.0095) patients. Serum ferritin levels were lower in CCS compared to HLH (1,386 µg/L vs. 29,019 µg/L, p < 0.001) and AOSD (11,359 µg/L vs. 29,019 µg/L, p = 0.035). A CRP < 130 mg/L when combined with an HScore > 136 improves the specificity of HScore alone for HLH from 85.2 to 96.3%. Adding CRP < 130 mg/L to ferritin > 15,254 µg/L increases specificity for HLH from 88.9 to 100%. This study demonstrates that median CRP is lower in HLH than in AOSD and CCS, and median ferritin is lower in CCS than in HLH or AOSD. This study demonstrates the clinical utility of these widely available inflammatory markers for distinguishing between different cytokine storm syndromes.
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Affiliation(s)
- Mariam Goubran
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Caroline Spaner
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Sophie Stukas
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Adi Zoref-Lorenz
- Faculty of Medicine, Hematology Institute, Meir Medical Center, Tel Aviv University, Tel Aviv, Israel
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH, USA
| | - Kamran Shojania
- Division of Rheumatology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Madelaine Beckett
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Amanda Li
- Division of Pediatric Hematology, Oncology, and BMT, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Erica Peterson
- Division of Hematology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Mypinder Sekhon
- Division of Critical Care Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Rebecca Grey
- Division of Critical Care Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Cheryl Wellington
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- International Collaboration On Repair Discoveries, School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Catherine V Cheng
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Catherine M Biggs
- Division of Allergy and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Andre Mattman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Division of Chemistry, St. Paul's Hospital, Vancouver, BC, Canada
| | - Michael B Jordan
- Faculty of Medicine, Hematology Institute, Meir Medical Center, Tel Aviv University, Tel Aviv, Israel
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH, USA
| | - Luke Y C Chen
- Division of Hematology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
- Division of Hematoloy, Department of Medicine, Dalhousie University, Halifax, NS, Canada.
| | - Audi Setiadi
- International Collaboration On Repair Discoveries, School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
- Division of Hematopathology, BC Children's Hospital, Vancouver, BC, Canada.
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8
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Sarmin M, Akter F, Islam AN, Mahfuz M, Das S, Sharifuzzaman, Hasan ST, Bhuiyan TR, Rahman M, Gazi A, Matin FB, Tariqujjaman M, Shahrin L, Islam M, Mahmud AM, Banu S, Chisti MJ, Qadri F, Clemens JD, Ahmed T. Cytokine Storm among Bangladeshi adults with COVID-19: A prospective cohort study. Heliyon 2024; 10:e40532. [PMID: 39654713 PMCID: PMC11625268 DOI: 10.1016/j.heliyon.2024.e40532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 09/24/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024] Open
Abstract
Objective In COVID-19, cytokine storms (CS) result in higher mortality and morbidity. Our study evaluated the rate of cytokine storms among COVID-positive Bangladeshi adults. Methods From October 2020 to March 2022, this cohort study enrolled both COVID-positive and COVID-negative healthy adults. COVID-positive cases were treated in a makeshift COVID unit of icdr,b Dhaka Hospital. CS was defined as having IL-6 >80 pg/mL or any three of the following: high CRP, ferritin, LDH, D-dimer, or low lymphocyte. Stored plasma samples were tested for the cytokines IL-6, IL-1β, and TNF-α. Results This study involved 77 participants, 32 were in the severe-critical group, 30 were in the mild-moderate group, and 14 were COVID-negative. Twelve participants in the severe-critical group had CS. Thus, the rate of CS was 37.5 % (12/32). Compared to COVID-19-negative patients, COVID-19-positive patients had higher IL-6 levels, which decreased at discharge except for those dying. Among the COVID-19-positive patients, nine died. For both the mild-moderate and severe-critical patients, IL-6 increased with increasing CRP (p < 0.001). Conclusion During the COVID-19 pandemic, Bangladeshi adults experienced a surge in cytokine storms. The rate of cytokine storm in Bangladeshi COVID-19-positive adults was 37.5 %.
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Affiliation(s)
- Monira Sarmin
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
- Nutrition Research Division, icddr,b, Bangladesh
| | - Fhameda Akter
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Anika Nawrin Islam
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
| | | | | | - Sharifuzzaman
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
| | | | | | | | - Amran Gazi
- Nutrition Research Division, icddr,b, Bangladesh
| | - Fariha Bushra Matin
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
| | | | - Lubaba Shahrin
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
- Nutrition Research Division, icddr,b, Bangladesh
| | - Mofakharul Islam
- Dhaka Community Medical College & Hospital, Mogbazar, Dhaka, Bangladesh
| | | | - Sayera Banu
- Infectious Diseases Division, icddr,b, Bangladesh
| | - Mohammod Jobayer Chisti
- Clinical and Diagnostic Services, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
- Nutrition Research Division, icddr,b, Bangladesh
| | | | | | - Tahmeed Ahmed
- Nutrition Research Division, icddr,b, Bangladesh
- Office of Executive Director, icddr,b, Bangladesh
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9
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Lourenço C, Moreira F, Igreja R, Martins G. Flexible, Electrochemical Skin-Like Platform for Inflammatory Biomarker Monitoring. Macromol Biosci 2024; 24:e2400287. [PMID: 39292822 DOI: 10.1002/mabi.202400287] [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: 06/19/2024] [Revised: 09/07/2024] [Indexed: 09/20/2024]
Abstract
Addressing global challenges in wound management has greatly encouraged the emergence of home diagnosis and monitoring devices. This technological shift has accelerated the development of new skin patch sensors for continuous health monitoring. A key requirement is the creation of flexible platforms capable of mimicking human skin features. Here, for the first time, an innovative, highly adaptable electrochemical biosensor with molecularly imprinted polymers (MIPs) is customized for the detection of the inflammatory biomarker interleukin-6 (IL-6). The 3-electrode gold pattern is geometrically standardized onto a 6 µm thick polyimide flexible membrane, an optically transparent, and biocompatible polymeric substrate. Subsequently, a biomimetic sensing layer specifically designed for the detection of IL-6 target is produced on these transducers. The obtained MIP biosensor shows a good linear response within the concentration range 50 pg mL-1-50 ng mL-1, with a low limit of detection (8 pg mL-1). X-ray photoelectron spectroscopy, scanning electron microscopy, and Fourier transform infrared spectroscopy characterizations confirm the modifications of the flexible gold transducer. After optimization, the biosensing device shows remarkable potential in terms of sensitivity, selectivity, and reproducibility. Overall, the integration of a low-cost electrochemical sensor on biocompatible flexible polymers opens the way for a new generation of monitoring tools with higher accuracy, less invasiveness, and greater patient comfort.
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Affiliation(s)
- Carolina Lourenço
- BioMark@ISEP, School of Engineering of Polytechnique School of Porto, Porto, 4200-072, Portugal
- CENIMAT|i3N, Department of Materials Science, School of Science and Technology, NOVA University Lisbon and CEMOP/UNINOVA, Caparica, 2829-516, Portugal
| | - Felismina Moreira
- BioMark@ISEP, School of Engineering of Polytechnique School of Porto, Porto, 4200-072, Portugal
- LABBELS/CEB, Centre of Biological Engineering, University of Minho, Braga, 4710-057, Portugal
- LabRISE-CIETI, School of Engineering of Polytechnique School of Porto, Porto, 4200-072, Portugal
| | - Rui Igreja
- CENIMAT|i3N, Department of Materials Science, School of Science and Technology, NOVA University Lisbon and CEMOP/UNINOVA, Caparica, 2829-516, Portugal
| | - Gabriela Martins
- BioMark@ISEP, School of Engineering of Polytechnique School of Porto, Porto, 4200-072, Portugal
- LABBELS/CEB, Centre of Biological Engineering, University of Minho, Braga, 4710-057, Portugal
- LabRISE-CIETI, School of Engineering of Polytechnique School of Porto, Porto, 4200-072, Portugal
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10
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Zhou K, Lu J. Progress in cytokine research for ARDS: A comprehensive review. Open Med (Wars) 2024; 19:20241076. [PMID: 39479463 PMCID: PMC11524396 DOI: 10.1515/med-2024-1076] [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: 05/07/2024] [Revised: 09/16/2024] [Accepted: 10/06/2024] [Indexed: 11/02/2024] Open
Abstract
Introduction Acute respiratory distress syndrome (ARDS) is a critical form of acute respiratory failure characterized by diffuse alveolar damage, refractory hypoxemia, and non-cardiogenic pulmonary edema, resulting in high mortality. Dysregulated inflammation, driven by cytokines, is central to ARDS pathogenesis, progression, and prognosis. Objective This review synthesizes current knowledge on the role of cytokines in ARDS and evaluates their potential as therapeutic targets, offering new insights for clinical management. Methods A comprehensive analysis of recent studies was conducted to explore the roles of pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-8) and anti-inflammatory cytokines (e.g., IL-10, IL-22) in ARDS pathogenesis and to assess current and emerging therapies targeting these cytokines. Results Pro-inflammatory cytokines are crucial in initiating inflammatory responses and lung injury in early ARDS, while anti-inflammatory cytokines help regulate and resolve inflammation. Targeted therapies, such as IL-1 and IL-6 inhibitors, show potential in managing ARDS, particularly in COVID-19, but their clinical efficacy is still debated. Combination therapy strategies may enhance outcomes, but further large-scale, multicenter randomized controlled trials are required to establish their safety and efficacy. Conclusion Understanding cytokine regulation in ARDS could lead to innovative therapeutic approaches. Future research should focus on cytokine roles across ARDS subtypes and stages and develop biomarker-driven, individualized treatments.
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Affiliation(s)
- Kaihuan Zhou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, China
| | - Junyu Lu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, Guangxi 530007, China
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11
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Paranga TG, Mitu I, Pavel-Tanasa M, Rosu MF, Miftode IL, Constantinescu D, Obreja M, Plesca CE, Miftode E. Cytokine Storm in COVID-19: Exploring IL-6 Signaling and Cytokine-Microbiome Interactions as Emerging Therapeutic Approaches. Int J Mol Sci 2024; 25:11411. [PMID: 39518964 PMCID: PMC11547016 DOI: 10.3390/ijms252111411] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-α and IFN-γ has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms. Long COVID-19 patients, as well as those with cytokine storms triggered by other conditions, exhibit distinct laboratory profiles, indicating the need for targeted approaches to diagnosis and management. Growing evidence also highlights the gut microbiota's crucial role in modulating the immune response during COVID-19 by affecting cytokine production, adding further complexity to the disease's immunological landscape. Targeted intervention strategies should focus on specific cytokine cutoffs, though accurate cytokine quantification remains a clinical challenge. Current treatment strategies are increasingly focused on inhibiting IL-6 trans-signaling, which offers promise for more precise therapeutic approaches to manage hyperinflammatory responses in COVID-19. In light of recent discoveries, this review summarizes key research findings on cytokine storms, particularly their role in COVID-19 and other inflammatory conditions. It explores emerging therapeutic strategies targeting cytokines like IL-6, TNF-α, and IFN-γ, while also addressing open questions, such as the need for better biomarkers to detect and manage cytokine storms. Additionally, the review highlights ongoing challenges in developing targeted treatments that mitigate hyperinflammation without compromising immune function, emphasizing the importance of continued research in this field.
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Affiliation(s)
- Tudorita Gabriela Paranga
- Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.G.P.); (I.-L.M.); (M.O.); (C.E.P.); (E.M.)
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
| | - Ivona Mitu
- Department of Morpho-Functional Sciences II, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Mariana Pavel-Tanasa
- Department of Immunology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Laboratory of Immunology, St. Spiridon County Clinical Emergency Hospital, 700101 Iasi, Romania
| | - Manuel Florin Rosu
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
- Department of Preventive Medicine and Interdisciplinarity, Faculty of Medicine, University of Medicine and Pharmacy Grigore. T. Popa, 700115 Iasi, Romania
| | - Ionela-Larisa Miftode
- Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.G.P.); (I.-L.M.); (M.O.); (C.E.P.); (E.M.)
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
| | - Daniela Constantinescu
- Department of Immunology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Laboratory of Immunology, St. Spiridon County Clinical Emergency Hospital, 700101 Iasi, Romania
| | - Maria Obreja
- Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.G.P.); (I.-L.M.); (M.O.); (C.E.P.); (E.M.)
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
| | - Claudia Elena Plesca
- Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.G.P.); (I.-L.M.); (M.O.); (C.E.P.); (E.M.)
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
| | - Egidia Miftode
- Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.G.P.); (I.-L.M.); (M.O.); (C.E.P.); (E.M.)
- St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania
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12
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Singh K, Rubenstein K, Callier V, Shaw-Saliba K, Rupert A, Dewar R, Laverdure S, Highbarger H, Lallemand P, Huang ML, Jerome KR, Sampoleo R, Mills MG, Greninger AL, Juneja K, Porter D, Benson CA, Dempsey W, El Sahly HM, Focht C, Jilg N, Paules CI, Rapaka RR, Uyeki TM, Clifford Lane H, Beigel J, Dodd LE. SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir. J Infect Dis 2024; 230:624-634. [PMID: 38657001 PMCID: PMC11420797 DOI: 10.1093/infdis/jiae198] [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: 10/19/2023] [Revised: 04/09/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy. CLINICAL TRIAL REGISTRATION NCT04280705 (ClinicalTrials.gov).
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Affiliation(s)
- Kanal Singh
- National Institute of Allergy and Infectious Diseases, Bethesda
| | - Kevin Rubenstein
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research
| | - Viviane Callier
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research
| | | | - Adam Rupert
- National Laboratory for Cancer Research, Frederick, Maryland
| | - Robin Dewar
- National Laboratory for Cancer Research, Frederick, Maryland
| | | | | | | | - Meei-Li Huang
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington
| | - Keith R Jerome
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington
- Fred Hutchinson Cancer Center, Seattle, Washington
| | - Reigran Sampoleo
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington
| | - Margaret G Mills
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington
| | - Alexander L Greninger
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington
| | | | | | | | - Walla Dempsey
- National Institute of Allergy and Infectious Diseases, Bethesda
| | - Hana M El Sahly
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | | | - Nikolaus Jilg
- Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston
| | - Catharine I Paules
- Division of Infectious Diseases, Milton S. Hershey Medical Center, Penn State Health, Hershey, Pennsylvania
| | - Rekha R Rapaka
- Center for Vaccine Development and Global Health, School of Medicine, University of Maryland, Baltimore
| | - Timothy M Uyeki
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - H Clifford Lane
- National Institute of Allergy and Infectious Diseases, Bethesda
| | - John Beigel
- National Institute of Allergy and Infectious Diseases, Bethesda
| | - Lori E Dodd
- National Institute of Allergy and Infectious Diseases, Bethesda
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13
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Timofeeva AM, Nikitin AO, Nevinsky GA. Circulating miRNAs in the Plasma of Post-COVID-19 Patients with Typical Recovery and Those with Long-COVID Symptoms: Regulation of Immune Response-Associated Pathways. Noncoding RNA 2024; 10:48. [PMID: 39311385 PMCID: PMC11417918 DOI: 10.3390/ncrna10050048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Following the acute phase of SARS-CoV-2 infection, certain individuals experience persistent symptoms referred to as long COVID. This study analyzed the patients categorized into three distinct groups: (1) individuals presenting rheumatological symptoms associated with long COVID, (2) patients who have successfully recovered from COVID-19, and (3) donors who have never contracted COVID-19. A notable decline in the expression of miR-200c-3p, miR-766-3p, and miR-142-3p was identified among patients exhibiting rheumatological symptoms of long COVID. The highest concentration of miR-142-3p was found in healthy donors. One potential way to reduce miRNA concentrations is through antibody-mediated hydrolysis. Not only can antibodies possessing RNA-hydrolyzing activity recognize the miRNA substrate specifically, but they also catalyze its hydrolysis. The analysis of the catalytic activity of plasma antibodies revealed that antibodies from patients with long COVID demonstrated lower hydrolysis activity against five fluorescently labeled oligonucleotide sequences corresponding to the Flu-miR-146b-5p, Flu-miR-766-3p, Flu-miR-4742-3p, and Flu-miR-142-3p miRNAs and increased activity against the Flu-miR-378a-3p miRNA compared to other patient groups. The changes in miRNA concentrations and antibody-mediated hydrolysis of miRNAs are assumed to have a complex regulatory mechanism that is linked to gene pathways associated with the immune system. We demonstrate that all six miRNAs under analysis are associated with a large number of signaling pathways associated with immune response-associated pathways.
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Affiliation(s)
- Anna M. Timofeeva
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Artem O. Nikitin
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
| | - Georgy A. Nevinsky
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
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14
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Das A, Pathak S, Premkumar M, Sarpparajan CV, Balaji ER, Duttaroy AK, Banerjee A. A brief overview of SARS-CoV-2 infection and its management strategies: a recent update. Mol Cell Biochem 2024; 479:2195-2215. [PMID: 37742314 PMCID: PMC11371863 DOI: 10.1007/s11010-023-04848-3] [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: 06/20/2023] [Accepted: 09/02/2023] [Indexed: 09/26/2023]
Abstract
The COVID-19 pandemic has become a global health crisis, inflicting substantial morbidity and mortality worldwide. A diverse range of symptoms, including fever, cough, dyspnea, and fatigue, characterizes COVID-19. A cytokine surge can exacerbate the disease's severity. This phenomenon involves an increased immune response, marked by the excessive release of inflammatory cytokines like IL-6, IL-8, TNF-α, and IFNγ, leading to tissue damage and organ dysfunction. Efforts to reduce the cytokine surge and its associated complications have garnered significant attention. Standardized management protocols have incorporated treatment strategies, with corticosteroids, chloroquine, and intravenous immunoglobulin taking the forefront. The recent therapeutic intervention has also assisted in novel strategies like repurposing existing medications and the utilization of in vitro drug screening methods to choose effective molecules against viral infections. Beyond acute management, the significance of comprehensive post-COVID-19 management strategies, like remedial measures including nutritional guidance, multidisciplinary care, and follow-up, has become increasingly evident. As the understanding of COVID-19 pathogenesis deepens, it is becoming increasingly evident that a tailored approach to therapy is imperative. This review focuses on effective treatment measures aimed at mitigating COVID-19 severity and highlights the significance of comprehensive COVID-19 management strategies that show promise in the battle against COVID-19.
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Affiliation(s)
- Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Madhavi Premkumar
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Chitra Veena Sarpparajan
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Esther Raichel Balaji
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Asim K Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India.
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15
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Molinero M, Perez-Pons M, González J, Barbé F, de Gonzalo-Calvo D. Decoding viral and host microRNA signatures in airway-derived biosamples: Insights for biomarker discovery in viral respiratory infections. Biomed Pharmacother 2024; 177:116984. [PMID: 38908203 DOI: 10.1016/j.biopha.2024.116984] [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: 03/05/2024] [Revised: 06/12/2024] [Accepted: 06/15/2024] [Indexed: 06/24/2024] Open
Abstract
The global public health crisis caused by the COVID-19 pandemic has intensified the global concern regarding viral respiratory tract infections. Despite their considerable impact on health, society and the economy, effective management of these conditions remains a significant challenge. Integrating high-throughput analyses is pivotal for early detection, prognostication of adverse outcomes, elucidating pathogenetic pathways and developing therapeutic approaches. In recent years, microRNAs (miRNAs), a subset of small noncoding RNAs (ncRNAs), have emerged as promising tools for molecular phenotyping. Current evidence suggests that miRNAs could serve as innovative biological markers, aiding in informed medical decision-making. The cost-effective quantification of miRNAs in standardized samples using techniques routinely employed in clinical laboratories has become feasible. In this context, samples obtained from the airways represent a valuable source of information due to their direct exposure to the infectious agent and host response within the respiratory tract. This review explores viral and host miRNA profiling in airway-derived biosamples as a source of molecular information to guide patient management, with a specific emphasis on SARS-CoV-2 infection.
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Affiliation(s)
- Marta Molinero
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Manel Perez-Pons
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Jessica González
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Ferran Barbé
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain.
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16
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Kanth SM, Huapaya JA, Gairhe S, Wang H, Tian X, Demirkale CY, Hou C, Ma J, Kuhns DB, Fink DL, Malayeri A, Turkbey E, Harmon SA, Chen MY, Regenold D, Lynch NF, Ramelli S, Li W, Krack J, Kuruppu J, Lionakis MS, Strich JR, Davey R, Childs R, Chertow DS, Kovacs JA, Parizi PT, Suffredini AF. Longitudinal analysis of the lung proteome reveals persistent repair months after mild to moderate COVID-19. Cell Rep Med 2024; 5:101642. [PMID: 38981485 PMCID: PMC11293333 DOI: 10.1016/j.xcrm.2024.101642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/23/2024] [Accepted: 06/13/2024] [Indexed: 07/11/2024]
Abstract
In order to assess homeostatic mechanisms in the lung after COVID-19, changes in the protein signature of bronchoalveolar lavage from 45 patients with mild to moderate disease at three phases (acute, recovery, and convalescent) are evaluated over a year. During the acute phase, inflamed and uninflamed phenotypes are characterized by the expression of tissue repair and host defense response molecules. With recovery, inflammatory and fibrogenic mediators decline and clinical symptoms abate. However, at 9 months, quantified radiographic abnormalities resolve in the majority of patients, and yet compared to healthy persons, all showed ongoing activation of cellular repair processes and depression of the renin-kallikrein-kinin, coagulation, and complement systems. This dissociation of prolonged reparative processes from symptom and radiographic resolution suggests that occult ongoing disruption of the lung proteome is underrecognized and may be relevant to recovery from other serious viral pneumonias.
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Affiliation(s)
- Shreya M Kanth
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Julio A Huapaya
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Salina Gairhe
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Honghui Wang
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xin Tian
- Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cumhur Y Demirkale
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chunyan Hou
- Mass Spectrometry and Analytical Pharmacology Shared Resource, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC 20057, USA
| | - Junfeng Ma
- Mass Spectrometry and Analytical Pharmacology Shared Resource, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC 20057, USA
| | - Douglas B Kuhns
- Neutrophil Monitoring Lab, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA
| | - Danielle L Fink
- Neutrophil Monitoring Lab, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA
| | - Ashkan Malayeri
- Radiology and Imaging Sciences, Clinical Center (CC), National Institutes of Health, Bethesda, MD 20892, USA
| | - Evrim Turkbey
- Radiology and Imaging Sciences, Clinical Center (CC), National Institutes of Health, Bethesda, MD 20892, USA
| | - Stephanie A Harmon
- Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Marcus Y Chen
- Cardiovascular Branch, National Institute of Heart, Lung, and Blood, National Institutes of Health, Bethesda, MD 20892, USA
| | - David Regenold
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicolas F Lynch
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sabrina Ramelli
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Willy Li
- Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Janell Krack
- Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Janaki Kuruppu
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michail S Lionakis
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeffrey R Strich
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard Davey
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard Childs
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Daniel S Chertow
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Joseph A Kovacs
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Parizad Torabi- Parizi
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Anthony F Suffredini
- Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
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17
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Deng X, Tang K, Wang Z, He S, Luo Z. Impacts of Inflammatory Cytokines Variants on Systemic Inflammatory Profile and COVID-19 Severity. J Epidemiol Glob Health 2024; 14:363-378. [PMID: 38376765 PMCID: PMC11176143 DOI: 10.1007/s44197-024-00204-w] [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: 07/03/2023] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Cytokine storm is known to impact the prognosis of coronavirus disease 2019 (COVID-19), since pro-inflammatory cytokine variants are associated with cytokine storm. It is tempting to speculate that pro-inflammatory cytokines variants may impact COVID-19 outcomes by modulating cytokine storm. Here, we verified this hypothesis via a comprehensive analysis. METHODS PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until December 15, 2023. Case-control or cohort studies that investigated the impacts of rs1800795 or rs1800629 on COVID-19 susceptibility, severity, mortality, IL-6, TNF-α, or CRP levels were included after an anonymous review by two independent reviewers and consultations of disagreement by a third independent reviewer. RESULTS 47 studies (8305 COVID-19 individuals and 17,846 non-COVID-19 individuals) were analyzed. The rs1800629 A allele (adenine at the -308 position of the promoter was encoded by the A allele) was associated with higher levels of tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). In contrast, the rs1800795 C allele (cytosine at the -174 position of the promoter was encoded by the C allele) was linked to higher levels of interleukin-6 (IL-6) and CRP. In addition, the A allele of rs1800629 increased the severity and mortality of COVID-19. However, the C allele of rs1800795 only increased COVID-19 susceptibility. CONCLUSIONS rs1800629 and rs1800795 variants of pro-inflammatory cytokines have significant impacts on systemic inflammatory profile and COVID-19 clinical outcomes. rs1800629 may serve as a genetic marker for severe COVID-19.
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Affiliation(s)
- XueJun Deng
- Department of Cardiology, Suining Central Hospital, Suining, 629000, Sichuan, China
| | - Kai Tang
- Department of Cardiology, Suining Central Hospital, Suining, 629000, Sichuan, China
| | - Zhiqiang Wang
- Orthopedic Center 1 Department of Orthopedic Trauma, Suining Central Hospital, Suining, Sichuan, China.
| | - Suyu He
- The Fourth Department of Digestive Disease Center, Suining Central Hospital, Suining, 629000, Sichuan, China.
| | - Zhi Luo
- Department of Cardiology, Suining Central Hospital, Suining, 629000, Sichuan, China.
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18
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Wang X, Zhu Y, Liu D, Zhu L, Tong J, Zheng C. Can COVID-19 Increase Platelet in Adult Immune Thrombocytopenia During the TPO-RA Administration? A Real-World Observational Study. J Blood Med 2024; 15:217-225. [PMID: 38737581 PMCID: PMC11088401 DOI: 10.2147/jbm.s457545] [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: 02/08/2024] [Accepted: 04/27/2024] [Indexed: 05/14/2024] Open
Abstract
Introduction COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection. Materials and Methods A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study. Results In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2-207) ×109/L at the last visit before infection and 108 (19-453) ×109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14-235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040). Conclusion This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.
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Affiliation(s)
- Xiaoyu Wang
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Yingqiao Zhu
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Dan Liu
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Lijun Zhu
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Juan Tong
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
| | - Changcheng Zheng
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China
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19
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Stakišaitis D, Kapočius L, Tatarūnas V, Gečys D, Mickienė A, Tamošuitis T, Ugenskienė R, Vaitkevičius A, Balnytė I, Lesauskaitė V. Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences. Pharmaceutics 2024; 16:409. [PMID: 38543303 PMCID: PMC10974540 DOI: 10.3390/pharmaceutics16030409] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/06/2024] [Accepted: 03/13/2024] [Indexed: 12/10/2024] Open
Abstract
The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA-VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA-VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA-VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA-VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females.
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Affiliation(s)
- Donatas Stakišaitis
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (I.B.)
- Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania
| | - Linas Kapočius
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (I.B.)
| | - Vacis Tatarūnas
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (V.T.); (D.G.); (V.L.)
| | - Dovydas Gečys
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (V.T.); (D.G.); (V.L.)
| | - Auksė Mickienė
- Department of Infectious Diseases, Lithuanian University of Health Sciences, 47116 Kaunas, Lithuania;
| | - Tomas Tamošuitis
- Department of Intensive Care Medicine, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
| | - Rasa Ugenskienė
- Department of Genetics and Molecular Medicine, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
| | - Arūnas Vaitkevičius
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University Hospital Santaros Klinikos, Vilnius University, 08661 Vilnius, Lithuania;
| | - Ingrida Balnytė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (I.B.)
| | - Vaiva Lesauskaitė
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (V.T.); (D.G.); (V.L.)
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20
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Yan H, Liu Y, Li X, Yu B, He J, Mao X, Yu J, Huang Z, Luo Y, Luo J, Wu A, Chen D. Leucine alleviates cytokine storm syndrome by regulating macrophage polarization via the mTORC1/LXRα signaling pathway. eLife 2024; 12:RP89750. [PMID: 38442142 PMCID: PMC10942637 DOI: 10.7554/elife.89750] [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] [Indexed: 03/07/2024] Open
Abstract
Cytokine storms are associated with severe pathological damage and death in some diseases. Excessive activation of M1 macrophages and the subsequent secretion of pro-inflammatory cytokines are a major cause of cytokine storms. Therefore, promoting the polarization of M2 macrophages to restore immune balance is a promising therapeutic strategy for treating cytokine storm syndrome (CSS). This study was aimed at investigating the potential protective effects of leucine on lipopolysaccharide (LPS)-induced CSS in mice and exploring the underlying mechanisms. CSS was induced by LPS administration in mice, which were concurrently administered leucine orally. In vitro, bone marrow derived macrophages (BMDMs) were polarized to M1 and M2 phenotypes with LPS and interleukin-4 (IL-4), respectively, and treated with leucine. Leucine decreased mortality in mice treated with lethal doses of LPS. Specifically, leucine decreased M1 polarization and promoted M2 polarization, thus diminishing pro-inflammatory cytokine levels and ameliorating CSS in mice. Further studies revealed that leucine-induced macrophage polarization through the mechanistic target of rapamycin complex 1 (mTORC1)/liver X receptor α (LXRα) pathway, which synergistically enhanced the expression of the IL-4-induced M2 marker Arg1 and subsequent M2 polarization. In summary, this study revealed that leucine ameliorates CSS in LPS mice by promoting M2 polarization through the mTORC1/LXRα/Arg1 signaling pathway. Our findings indicate that a fundamental link between metabolism and immunity contributes to the resolution of inflammation and the repair of damaged tissues.
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Affiliation(s)
- Hui Yan
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Yao Liu
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Xipeng Li
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Bing Yu
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Jun He
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Xiangbing Mao
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Jie Yu
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Zhiqing Huang
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Yuheng Luo
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Junqiu Luo
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Aimin Wu
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
| | - Daiwen Chen
- Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural UniversityChengduChina
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21
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Dongoran RA, Mardiana M, Huang CY, Situmorang JH. Boosting NAD+ levels through fasting to aid in COVID-19 recovery. Front Immunol 2024; 15:1319106. [PMID: 38420124 PMCID: PMC10899445 DOI: 10.3389/fimmu.2024.1319106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 02/01/2024] [Indexed: 03/02/2024] Open
Affiliation(s)
- Rachmad Anres Dongoran
- Directorate of Drug Registration, Indonesian Food and Drug Authority, Jakarta, Indonesia
- Center for Chinese Studies, National Central Library, Taipei, Taiwan
| | - Meity Mardiana
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
| | - Jiro Hasegawa Situmorang
- Cardiovascular and Mitochondrial Related Disease Research Center, Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center for Biomedical Research, National Research and Innovation Agency (BRIN), Cibinong, Indonesia
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22
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Ashok D, Liu T, Criscione J, Prakash M, Kim B, Chow J, Craney M, Papanicolaou KN, Sidor A, Brian Foster D, Pekosz A, Villano J, Kim DH, O'Rourke B. Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.05.574280. [PMID: 38260287 PMCID: PMC10802485 DOI: 10.1101/2024.01.05.574280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. Methods Radiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection. Results COVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca 2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant. Conclusions The findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.
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23
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Chiu KHY, Yip CCY, Poon RWS, Leung KH, Li X, Hung IFN, To KKW, Cheng VCC, Yuen KY. Correlations of Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in the nasopharyngeal specimens with the diagnosis and severity of SARS-CoV-2 infections. Emerg Microbes Infect 2023; 12:2157338. [PMID: 36482706 PMCID: PMC9809351 DOI: 10.1080/22221751.2022.2157338] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, p < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10-3 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, p = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.
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Affiliation(s)
- Kelvin Hei-Yeung Chiu
- Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China
| | - Cyril Chik-Yan Yip
- Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China,State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China
| | - Rosana Wing-Shan Poon
- Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China,State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China
| | - Kit-Hang Leung
- State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China,Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China
| | - Xin Li
- State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China,Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China
| | - Ivan Fan-Ngai Hung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China,Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China
| | - Kelvin Kai-Wang To
- State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China,Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China,Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China,Centre for Virology, Vaccinology and Therapeutics, , Hong Kong Science and Technology Park, Pak Shek Kok, Hong Kong Special Administrative Region, China
| | - Vincent Chi-Chung Cheng
- Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China
| | - Kwok-Yung Yuen
- State Key Laboratory for Emerging Infectious Disease, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China,Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China,Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China,Centre for Virology, Vaccinology and Therapeutics, , Hong Kong Science and Technology Park, Pak Shek Kok, Hong Kong Special Administrative Region, China, Kwok-Yung Yuen
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24
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García-Esquinas E, Carballo-Casla A, Ortolá R, Sotos-Prieto M, Olmedo P, Gil F, Plans-Beriso E, Fernández-Navarro P, Pastor-Barriuso R, Rodríguez-Artalejo F. Blood Selenium Concentrations Are Inversely Associated with the Risk of Undernutrition in Older Adults. Nutrients 2023; 15:4750. [PMID: 38004143 PMCID: PMC10674362 DOI: 10.3390/nu15224750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/13/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Selenium is an essential trace element with an antioxidant and anti-inflammatory capacity that has been associated in experimental studies with beneficial effects on appetite control, the regulation of the gut microbiota, and control of the anabolic-catabolic balance. The main aim of the present study was to evaluate the association between circulating selenium concentrations and the risk of developing undernutrition in older adults. METHODS This was a cohort study with 1398 well-nourished community-dwelling individuals aged ≥ 65 years residing in Spain in 2017, who were followed for a mean of 2.3 years. Whole blood selenium was measured at baseline using inductively coupled plasma-mass spectrometry. Undernutrition was assessed at baseline and at follow-up, and defined as having at least one of the three GLIM phenotypic criteria (involuntary weight loss, a low body mass index, and a reduced muscle mass) and at least one of the two etiologic criteria (reduced food consumption or nutrient assimilation and inflammation/disease burden). RESULTS During the follow-up, 142 participants (11%) developed moderate undernutrition and 113 (8.8%) severe undernutrition. The standardized relative risks of moderate and severe undernutrition at the 75th percentile of Se levels versus the 25th were 0.90 and 0.70, respectively. In dose-response analyses, the risk of severe undernutrition decreased linearly with increasing selenium concentrations. This association was independent of protein intake or diet quality and was stronger among participants with a diagnosis of a musculoskeletal disorder. CONCLUSIONS The results suggest that an adequate dietary selenium status is needed to prevent undernutrition in older adults. Also, this may open the door for clinical trials with selenium supplementation, at doses considered as safe, to prevent undernutrition.
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Affiliation(s)
- Esther García-Esquinas
- Department of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain; (E.P.-B.); (P.F.-N.); (R.P.-B.)
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
| | - Adrián Carballo-Casla
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society Karolinska Institutet & Stockholm University, 141 86 Stockholm, Sweden
| | - Rosario Ortolá
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
- Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Mercedes Sotos-Prieto
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
- Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- IMDEA Food Institute, CEI UAM+CSIC, 28049 Madrid, Spain
| | - Pablo Olmedo
- Department of Legal Medicine, Toxicology, and Physical Anthropology, School of Medicine, University of Granada, 18071 Granada, Spain; (P.O.); (F.G.)
| | - Fernando Gil
- Department of Legal Medicine, Toxicology, and Physical Anthropology, School of Medicine, University of Granada, 18071 Granada, Spain; (P.O.); (F.G.)
| | - Elena Plans-Beriso
- Department of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain; (E.P.-B.); (P.F.-N.); (R.P.-B.)
| | - Pablo Fernández-Navarro
- Department of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain; (E.P.-B.); (P.F.-N.); (R.P.-B.)
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
| | - Roberto Pastor-Barriuso
- Department of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain; (E.P.-B.); (P.F.-N.); (R.P.-B.)
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
| | - Fernando Rodríguez-Artalejo
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), 28029 Madrid, Spain; (A.C.-C.); (R.O.); (M.S.-P.); (F.R.-A.)
- Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- IMDEA Food Institute, CEI UAM+CSIC, 28049 Madrid, Spain
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25
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Esper Treml R, Caldonazo T, Filho PHA, Mori AL, Carvalho AS, Serrano JSF, Dall-Aglio PAT, Radermacher P, Manoel JS. Effect of restrictive cumulative fluid balance on 28-day survival in invasively ventilated patients with moderate to severe ARDS due to COVID-19. Sci Rep 2023; 13:18504. [PMID: 37898681 PMCID: PMC10613222 DOI: 10.1038/s41598-023-45483-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/19/2023] [Indexed: 10/30/2023] Open
Abstract
This study aimed to evaluate the effect of two restrictive cumulative fluid balance (CFB) trends on survival and on major clinical outcomes in invasively ventilated patients with moderate to severe respiratory distress syndrome (ARDS) due to SARS-CoV-2. Prospective data collection was conducted on patients in the intensive care unit (ICU) originating from a tertiary university hospital. The primary outcomes were the risk association between the CFB trend during D0 to D7 and 28-day survival. The secondary outcomes were ICU mortality, in-hospital mortality, the need for invasive ventilation at D28, administration of vasoactive drugs at D7, time on invasive ventilation after D7, and length of ICU and hospital stay. 171 patients were enrolled in the study and divided according to their CFB trends during seven days of follow-up using model-based clustering [median CFB negative trend (n = 89) - 279 ml (- 664 to 203) and (n = 82) median CFB positive trend 1362 ml (619-2026)]. The group with CFB negative trend showed a higher chance of surviving 28-day in the ICU (HR: 0.62, 95% CI 0.41-0.94, p = 0.038). Moreover, this group had a reduced length of stay in the ICU, 11 (8-19) days versus 16.5 (9-29) days p = 0.004 and presented lower rates (OR = 0.22; 95% CI 0.09-0.52) of invasive ventilation after 28-days in the ICU. In patients invasively ventilated with moderate to severe ARDS due to COVID-19, the collective who showed a negative trend in the CFB after seven days of invasive ventilation had a higher chance of surviving 28 days in the ICU and lower length of stay in the ICU.
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Affiliation(s)
- Ricardo Esper Treml
- Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University, Jena, Germany
- Postgraduate Program, Department of Anesthesiology, University of São Paulo, Av. Dr. Arnaldo, 455, Cerqueira Cesar, São Paulo, SP, 01246-903, Brazil
| | - Tulio Caldonazo
- Department of Cardiothoracic Surgery, Friedrich-Schiller-University, Jena, Germany
| | - Pedro Hilton A Filho
- Department of Anesthesiology, Servidor Público Estadual Hospital, São Paulo, Brazil
| | - Andréia L Mori
- Department of Anesthesiology, Servidor Público Estadual Hospital, São Paulo, Brazil
| | - André S Carvalho
- Department of Anesthesiology, Servidor Público Estadual Hospital, São Paulo, Brazil
| | - Juliana S F Serrano
- Department of Anesthesiology, Servidor Público Estadual Hospital, São Paulo, Brazil
| | - Pedro A T Dall-Aglio
- Department of Anesthesiology, Servidor Público Estadual Hospital, São Paulo, Brazil
| | - Peter Radermacher
- Institute for Anesthesiological Pathophysiology and Process Development, Ulm University Hospital, Ulm, Germany
| | - João Silva Manoel
- Postgraduate Program, Department of Anesthesiology, University of São Paulo, Av. Dr. Arnaldo, 455, Cerqueira Cesar, São Paulo, SP, 01246-903, Brazil.
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Ganda IJ, Putri TKE, Rauf S, Laompo A, Pelupessy NM, Lawang SA, Ridha NR, Fikri B, Massi MN. IL-6 serum level, ARDS, and AKI as risk factors for the COVID-19 infection's mortality in children. PLoS One 2023; 18:e0293639. [PMID: 37889917 PMCID: PMC10610523 DOI: 10.1371/journal.pone.0293639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
INTRODUCTION Dysregulated immune responses are developed in Coronavirus disease-2019 (COVID-19) and Interleukin-6 (IL-6) levels are reflecting the severity of the clinical presentation. This study aimed to analyze IL-6 serum level, Acute Respiratory Distress Syndrome (ARDS), and Acute Kidney Injury (AKI) as risk factors for mortality in children with COVID-19. METHODS This prospective cohort study was conducted on children with COVID-19 infection confirmed by Real Time Polymerase Chain Reaction (RT-PCR) who were admitted to infection center at Dr. Wahidin Sudirohusodo Hospital from September 2021 to September 2022. Subjects were selected using the consecutive sampling method. RESULTS A total of 2,060 COVID-19 RT-PCR tests were performed, and 1,065 children were confirmed positive. There were 291 cases that met the inclusion criteria, with 28.52 percent non-survives and 71.48% survives. The risk factors for mortality were IL-6, ARDS, AKI, Prothrombin Time / Activated Partial Thromboplastin Time (PT/aPTT), oxygen saturation, Absolut lymphocyte count (ALC), leukocytes, Length of Stay (LOS), and nutritional status (p<0.05). IL-6 levels increased in all patients (23.48-252.58 pq/ml). COVID-19 patients with AKI, ARDS, low oxygen saturation and thrombocytopenia had the highest levels of IL-6 (p 0.05). The IL-6 cut-off point was >80.97 pg/ml with 93% sensitivity and 90% specificity. Area Under Curve was 0.981 (95% CI), 0.960-1.000). A multivariate analysis showed IL-6 levels with OR 18.570 (95% CI 5.320-64.803), ARDS with Odds Ratio (OR) 10.177, (95% Confidence Interval (CI) 1.310-9.040), and AKI with OR 3.220 (95% CI 1.070-10.362). A combination of increased IL-6, ARDS, and AKI can predict a mortality probability as high as 98.3%. CONCLUSION IL-6, ARDS, and AKI are risk factors for mortality in children with COVID-19. IL-6 level was the highest mortality risk factor.
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Affiliation(s)
- Idham Jaya Ganda
- Emergency and Pediatric Intensive Care Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
- Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, Indonesia
| | - Try Kartika Eka Putri
- Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Syarifuddin Rauf
- Nephrology Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Amiruddin Laompo
- Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, Indonesia
- Respirology Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Ninny Meutia Pelupessy
- Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, Indonesia
- Infection & Tropical Disease Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Sitti Aizah Lawang
- Emergency and Pediatric Intensive Care Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Nadirah Rasyid Ridha
- Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, Indonesia
- Hematology-oncology Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Bahrul Fikri
- Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, Indonesia
- Allergy & Immunology Division, Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Muhammad Nasrum Massi
- Department of Microbiology, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
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27
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Cui N, Zhu X, Zhao C, Meng C, Sha J, Zhu D. A Decade of Pathogenesis Advances in Non-Type 2 Inflammatory Endotypes in Chronic Rhinosinusitis: 2012-2022. Int Arch Allergy Immunol 2023; 184:1237-1253. [PMID: 37722364 DOI: 10.1159/000532067] [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: 04/17/2023] [Accepted: 07/12/2023] [Indexed: 09/20/2023] Open
Abstract
Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely, CRS with nasal polyps and CRS without nasal polyps. The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the PubMed and Web of Science databases were searched to conduct a critical analysis of representative literature works on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increase the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied, and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.
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Affiliation(s)
- Na Cui
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China,
| | - Xuewei Zhu
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Chen Zhao
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Cuida Meng
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jichao Sha
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Dongdong Zhu
- Department of Otorhinolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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28
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Madhurantakam S, Karnam JB, Muthukumar S, Prasad S. COVID severity test (CoST sensor)-An electrochemical immunosensing approach to stratify disease severity. Bioeng Transl Med 2023; 8:e10566. [PMID: 37693054 PMCID: PMC10486328 DOI: 10.1002/btm2.10566] [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: 11/22/2022] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 09/12/2023] Open
Abstract
With the evolution of the COVID-19 pandemic, there is now a need for point-of-care devices for the quantification of disease biomarkers toward disease severity assessment. Disease progression has been determined as a multifactor phenomenon and can be treated based on the host immune response within each individual. CoST is an electrochemical immunosensor point-of-care device that can determine disease severity through multiplex measurement and quantification of spike protein, nucleocapsid protein, D-dimer, and IL-2R from 100 μL of plasma samples within a few minutes. The limit of detection was found to be 3 ng/mL and 21 ng/mL for S and N proteins whereas for D-dimer and IL-2R it was 0.0006 ng/mL and 0.242 ng/mL, respectively. Cross-reactivity of all the biomarkers was studied and it was found to be <20%. Inter and intra-assay variability of the CoST sensor was less than <15% confirming its ability to detect the target biomarker in body fluids. In addition, this platform has also been tested to quantify all four biomarkers in 40 patient samples and to predict the severity index. A significant difference was observed between healthy and COVID-19 samples with a p-value of 0.0002 for D-dimer and <0.0001 for other proteins confirming the ability of the COST sensor to be used as a point of care device to assess disease severity at clinical sites. This device platform can be modified to impact a wide range of disease indications where prognostic monitoring of the host response can be critical in modulating therapy.
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Affiliation(s)
- Sasya Madhurantakam
- Department of BioengineeringThe University of Texas at DallasRichardsonTexasUSA
| | | | | | - Shalini Prasad
- Department of BioengineeringThe University of Texas at DallasRichardsonTexasUSA
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29
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Klöditz K, Tewolde E, Nordling Å, Ingelman-Sundberg M. Mechanistic, Functional, and Clinical Aspects of Pro-inflammatory Cytokine Mediated Regulation of ADME Gene Expression in 3D Human Liver Spheroids. Clin Pharmacol Ther 2023; 114:673-685. [PMID: 37307233 DOI: 10.1002/cpt.2969] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/05/2023] [Indexed: 06/14/2023]
Abstract
During systemic inflammation, pro-inflammatory cytokines alter metabolism and transport of drugs affecting the clinical outcome. We used an in vivo like human 3D liver spheroid model to study the effects and mechanisms of pro-inflammatory cytokines on the expression of 9 different genes encoding enzymes responsible for the metabolism of > 90% of clinically used drugs. Treatment of spheroids with pathophysiologically relevant concentrations of IL-1β, IL-6, or TNFα resulted in a pronounced decrease in mRNA expression of CYP3A4 and UGT2B10 within 5 hours. The reduction of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 mRNA expression was less pronounced, whereas the pro-inflammatory cytokines caused increased CYP2E1, and UGT1A3 mRNA expression. The cytokines did not influence expression of key nuclear proteins, nor the activities of specific kinases involved in the regulation of genes encoding drug metabolizing enzymes. However, ruxolitinib, a JAK1/2 inhibitor, inhibited the IL-6 dependent increase in CYP2E1 and the decrease in CYP3A4 and UGT2B10 mRNA expression. We evaluated the effect of TNFα in hepatocytes in 2D plates and found a rapid decrease in drug-metabolizing enzyme mRNA both in the absence or presence of the cytokines. Taken together, these data suggest that pro-inflammatory cytokines regulate multiple gene- and cytokine-specific events seen in in vivo and in 3D but not in 2D liver models. We propose that the 3D spheroid system is suitable for the prediction of drug metabolism under conditions of inflammation and constitutes a versatile system for short- and long-term preclinical and mechanistic studies of cytokine-induced changes in drug metabolism.
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Affiliation(s)
- Katharina Klöditz
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Eida Tewolde
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Åsa Nordling
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Ingelman-Sundberg
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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30
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Woodruff MC, Bonham KS, Anam FA, Walker TA, Faliti CE, Ishii Y, Kaminski CY, Ruunstrom MC, Cooper KR, Truong AD, Dixit AN, Han JE, Ramonell RP, Haddad NS, Rudolph ME, Yalavarthi S, Betin V, Natoli T, Navaz S, Jenks SA, Zuo Y, Knight JS, Khosroshahi A, Lee FEH, Sanz I. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat Commun 2023; 14:4201. [PMID: 37452024 PMCID: PMC10349085 DOI: 10.1038/s41467-023-40012-7] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 07/09/2023] [Indexed: 07/18/2023] Open
Abstract
While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.
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Affiliation(s)
- Matthew C Woodruff
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA.
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
| | - Kevin S Bonham
- Department of Biological Sciences, Wellesley College, Wellesley, MA, USA
| | - Fabliha A Anam
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Tiffany A Walker
- Department of Medicine, Division of General Internal Medicine, Emory University, Atlanta, GA, USA
| | - Caterina E Faliti
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Yusho Ishii
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | | | - Martin C Ruunstrom
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Kelly Rose Cooper
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Alexander D Truong
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Adviteeya N Dixit
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Jenny E Han
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Richard P Ramonell
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | | | | | | | | | | | - Sherwin Navaz
- Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
| | - Scott A Jenks
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Yu Zuo
- Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
| | - Jason S Knight
- Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
| | - Arezou Khosroshahi
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - F Eun-Hyung Lee
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA.
| | - Ignacio Sanz
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA.
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
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31
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Ghosn L, Assi R, Evrenoglou T, Buckley BS, Henschke N, Probyn K, Riveros C, Davidson M, Graña C, Bonnet H, Jarde A, Ávila C, Nejstgaard CH, Menon S, Ferrand G, Kapp P, Breuer C, Schmucker C, Sguassero Y, Nguyen TV, Devane D, Meerpohl JJ, Rada G, Hróbjartsson A, Grasselli G, Tovey D, Ravaud P, Chaimani A, Boutron I. Interleukin-6 blocking agents for treating COVID-19: a living systematic review. Cochrane Database Syst Rev 2023; 6:CD013881. [PMID: 37260086 PMCID: PMC10237088 DOI: 10.1002/14651858.cd013881.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
BACKGROUND It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022. The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies. Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence). The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.
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Affiliation(s)
- Lina Ghosn
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Rouba Assi
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Theodoros Evrenoglou
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | | | | | | | - Carolina Riveros
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Mauricia Davidson
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Carolina Graña
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Hillary Bonnet
- Cochrane France, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Alexander Jarde
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | | | - Camilla Hansen Nejstgaard
- Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
| | | | | | - Philipp Kapp
- Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claudia Breuer
- Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
| | - Christine Schmucker
- Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
| | | | | | - Declan Devane
- Evidence Synthesis Ireland, Galway, Ireland
- Cochrane Ireland and HRB-Trials Methodology Research Network, Galway, Ireland
- University of Galway, Galway, Ireland
| | - Joerg J Meerpohl
- Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
| | - Gabriel Rada
- Epistemonikos Foundation, Santiago, Chile
- UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Asbjørn Hróbjartsson
- Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
| | - Giacomo Grasselli
- Department of Anesthesia, Intensive Care and Emergency Department of Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | | | - Philippe Ravaud
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Anna Chaimani
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Isabelle Boutron
- Cochrane France, Paris, France
- Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel Dieu, F-75004, Paris, France
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
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Jalavu TP, Sigwadhi LN, Kotze MJ, Yalew A, Ngah V, Tamuzi JL, Chapanduka ZC, Allwood BW, Koegelenberg CF, Irusen EM, Lalla U, Matsha TE, Erasmus RT, Zumla A, Zemlin AE, Nyasulu PS. An investigation of the correlation of vitamin D status and management outcomes in patients with severe COVID-19 at a South African tertiary hospital. IJID REGIONS 2023; 8:S2772-7076(23)00063-2. [PMID: 37363198 PMCID: PMC10234344 DOI: 10.1016/j.ijregi.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023]
Abstract
Background Severe COVID-19 has a poor prognosis, and biomarkers may predict disease severity. This study aimed to assess the effect of baseline Vitamin D (VitD) inadequacy on outcome of patients with severe COVID-19 admitted to intensive care unit (ICU) in a tertiary hospital in South Africa. Methods Patients with confirmed SARS-CoV-2 were recruited during wave II of the pandemic in Cape Town. Eighty-six patients were included in the study. They were categorized into three groups "VitD deficient, VitD insufficient and VitD sufficient". We combined the VitD deficient with insufficient group to form "VitD inadequate'' group. Cox regression analysis was done to assess the association between VitD status and mortality. Factors with p< 0.05 in adjusted multivariable cox regression were considered statistically significant. Results The proportion of VitD inadequacy was 64% (55/86), with significantly higher proportion of hypertension (66%; p 0.012). Kaplan Meir curve showed no significant difference in the probability of survival among the COVID-19 patients admitted in the ICU with or without VitD inadequacy. However, patients with elevated serum creatinine were significantly more at risk of dying (Adjusted Hazard Ratio 1.008 (1.002 - 1.030, p<0.017). Conclusion Our study found a high prevalence of VitD inadequacy (combined deficiency and insufficiency) in COVID-19 patients admitted to the ICU. This may indicate a possible risk of severe disease. Whilst there was no statistically significant relationship between VitD status and mortality in this cohort, baseline VitD may be an important prognostic biomarker in COVID-19 patients admitted to the ICU, particularly in those with comorbidities that predispose to VitD deficiency.
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Affiliation(s)
- Thumeka P. Jalavu
- Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and NHLS Tygerberg Hospital, Cape Town, South Africa
| | - Lovemore N. Sigwadhi
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Maritha J. Kotze
- Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and NHLS Tygerberg Hospital, Cape Town, South Africa
| | - Anteneh Yalew
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Vera Ngah
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jacques L. Tamuzi
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Zivanai C. Chapanduka
- Division of Haematological Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and NHLS Tygerberg Hospital, Cape Town, South Africa
| | - Brian W. Allwood
- Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
| | - Coenraad F. Koegelenberg
- Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
| | - Elvis M. Irusen
- Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
| | - Usha Lalla
- Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
| | - Tandi E. Matsha
- Sefako Makgatho Health Sciences University, Ga-Rankuwa, Pretoria, South Africa
- SAMRC/CPUT/Cardiometabolic Health Research Unit, Cape Peninsula University of Technology, Cape Town, South Africa
| | - Rajiv T. Erasmus
- Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and NHLS Tygerberg Hospital, Cape Town, South Africa
| | - Alimmudin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Annalise E. Zemlin
- Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and NHLS Tygerberg Hospital, Cape Town, South Africa
| | - Peter S. Nyasulu
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Kyagambiddwa T, Kintu TM, Miiro E, Nabalamba F, Asiimwe GS, Namutebi AM, Abeya FC, Lumori BA, Ijuka I, Muhindo RK, Mutekanga A, Musinguzi R, Natuhwera F, Ngonzi J, Nuwagira E. Thirty-Day Outcomes of Young and Middle-Aged Adults Admitted with Severe COVID-19 in Uganda: A Retrospective Cohort Study. Infect Drug Resist 2023; 16:2923-2932. [PMID: 37197696 PMCID: PMC10184892 DOI: 10.2147/idr.s405256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/28/2023] [Indexed: 05/19/2023] Open
Abstract
Background There is scarcity of data regarding young and middle-aged adults hospitalized with severe Corona Virus Disease 2019 (COVID-19) in Africa. In this study, we describe the clinical characteristics and 30-day survival among adults aged 18 to 49 years admitted with severe COVID-19 in Uganda. Methods We reviewed treatment records of patients admitted with severe COVID-19 across five COVID-19 treatment units (CTU) in Uganda. We included individuals aged 18 to 49 years, who had a positive test or met the clinical criteria for COVID-19. We defined severe COVID-19 as having an oxygen saturation <94%, lung infiltrates >50% on imaging and presence of a co-morbidity that required admission in the CTU. Our main outcome was the 30-day survival from the time of admission. We used a Cox proportional hazards model to determine the factors associated with 30-day survival at a 5% level of significance. Results Of the 246 patient files reviewed, 50.8% (n = 125) were male, the mean ± (standard deviation) age was 39 ± 8 years, majority presented with cough, 85.8% (n = 211) and median C-reactive protein (interquartile range) was 48 (47.5, 178.8) mg/L. The 30-day mortality was 23.9% (59/246). At admission, anemia (hazard ratio (HR): 3.00, 95% confidence interval (CI), 1.32-6.82; p = 0.009) and altered mental state (GCS <15) (HR: 6.89, 95% CI: 1.48-32.08, p = 0.014) were significant predictors of 30-day mortality. Conclusion There was a high 30-day mortality among young and middle-aged adults with severe COVID-19 in Uganda. Early recognition and targeted management of anemia and altered consciousness are needed to improve clinical outcomes.
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Affiliation(s)
- Tonny Kyagambiddwa
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Timothy Mwanje Kintu
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Emmanuel Miiro
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Franchesca Nabalamba
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Gloria Suubi Asiimwe
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | | | - Fardous C Abeya
- Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Boniface A Lumori
- Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | | | - Rose K Muhindo
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
- Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Andrew Mutekanga
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
- Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | | | | | - Joseph Ngonzi
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
- Department of Obstetrics and Gynecology, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Edwin Nuwagira
- Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
- Tuberculosis Treatment Unit, Mbarara Regional Referral Hospital, Mbarara, Uganda
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De Biasi S, Mattioli M, Meschiari M, Lo Tartaro D, Paolini A, Borella R, Neroni A, Fidanza L, Busani S, Girardis M, Coppi F, Mattioli AV, Guaraldi G, Mussini C, Cossarizza A, Gibellini L. Prognostic immune markers identifying patients with severe COVID-19 who respond to tocilizumab. Front Immunol 2023; 14:1123807. [PMID: 37215114 PMCID: PMC10196248 DOI: 10.3389/fimmu.2023.1123807] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/26/2023] [Indexed: 05/24/2023] Open
Abstract
Introduction A growing number of evidences suggest that the combination of hyperinflammation, dysregulated T and B cell response and cytokine storm play a major role in the immunopathogenesis of severe COVID-19. IL-6 is one of the main pro-inflammatory cytokines and its levels are increased during SARS-CoV-2 infection. Several observational and randomized studies demonstrated that tocilizumab, an IL-6R blocker, improves survival in critically ill patients both in infectious disease and intensive care units. However, despite transforming the treatment options for COVID-19, IL-6R inhibition is still ineffective in a fraction of patients. Methods In the present study, we investigated the impact of two doses of tocilizumab in patients with severe COVID-19 who responded or not to the treatment by analyzing a panel of cytokines, chemokines and other soluble factors, along with the composition of peripheral immune cells, paying a particular attention to T and B lymphocytes. Results We observed that, in comparison with non-responders, those who responded to tocilizumab had different levels of several cytokines and different T and B cells proportions before starting therapy. Moreover, in these patients, tocilizumab was further able to modify the landscape of the aforementioned soluble molecules and cellular markers. Conclusions We found that tocilizumab has pleiotropic effects and that clinical response to this drug remain heterogenous. Our data suggest that it is possible to identify patients who will respond to treatment and that the administration of tocilizumab is able to restore the immune balance through the re-establishment of different cell populations affected by SARS-COV-2 infection, highlighting the importance of temporal examination of the pathological features from the diagnosis.
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Affiliation(s)
- Sara De Biasi
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Marco Mattioli
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Marianna Meschiari
- Infectious Diseases Clinics, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Domenico Lo Tartaro
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Annamaria Paolini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Rebecca Borella
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Anita Neroni
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Lucia Fidanza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Stefano Busani
- Department of Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Girardis
- Department of Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Francesca Coppi
- Department of Metabolic Sciences and Neurosciences, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Anna Vittoria Mattioli
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Giovanni Guaraldi
- Infectious Diseases Clinics, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Cristina Mussini
- Infectious Diseases Clinics, Azienda Ospedaliera Universitaria (AOU) Policlinico and University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
- National Institute for Cardiovascular Research, Bologna, Italy
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
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Cennamo N, Piccirillo A, Bencivenga D, Arcadio F, Annunziata M, Della Ragione F, Guida L, Zeni L, Borriello A. Towards a point-of-care test to cover atto-femto and pico-nano molar concentration ranges in interleukin 6 detection exploiting PMMA-based plasmonic biosensor chips. Talanta 2023; 256:124284. [PMID: 36709711 DOI: 10.1016/j.talanta.2023.124284] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023]
Abstract
Point-of-Care tests based on biomarkers, useful to monitor acute and chronic inflammations, are required for advances in medicine. In this scope, a key role is played by pro-inflammatory cytokines, of which interleukin 6 (IL-6) is generally thought as one of the most relevant. To use IL-6 in real scenarios, detection in ultra-low concentration ranges is required. In this work, two IL-6 biosensors are obtained by exploiting the combination of the same antibody self-assembled monolayer with two different plasmonic probes. This approach has demonstrated, via experimental results, that two different IL-6 concentration ranges can be explored. More specifically, IL-6 in an atto-femto molar range can be detected via polymer-based nanoplasmonic chips. On the other hand, a pico-nano molar range is obtained by a surface plasmon resonance platform in plastic optical fibers. As a proof of concept, the detection of IL-6 at the femto molar range has been obtained in Saliva and Serum. The results show that the proposed sensing approach could be useful in developing Point-of-Care devices based on a general setup with the capability to exploit both the plasmonic biosensor chips to monitor the IL-6 in the concentration range of interest, to provide an important support for the diagnosis and monitoring of oral and systemic diseases.
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Affiliation(s)
- Nunzio Cennamo
- Department of Engineering, University of Campania "Luigi Vanvitelli", 81031, Aversa, Italy
| | - Angelantonio Piccirillo
- Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Debora Bencivenga
- Department of Precision Medicine, University of Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Francesco Arcadio
- Department of Engineering, University of Campania "Luigi Vanvitelli", 81031, Aversa, Italy
| | - Marco Annunziata
- Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Fulvio Della Ragione
- Department of Precision Medicine, University of Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Luigi Guida
- Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
| | - Luigi Zeni
- Department of Engineering, University of Campania "Luigi Vanvitelli", 81031, Aversa, Italy.
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania "L. Vanvitelli", 80138, Naples, Italy.
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Baalbaki N, Duijvelaar E, Said MM, Schippers J, Bet PM, Twisk J, Fritchley S, Longo C, Mahmoud K, Maitland-van der Zee AH, Bogaard HJ, Swart EL, Aman J, Bartelink IH. Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19. Eur J Pharm Sci 2023; 184:106418. [PMID: 36870577 PMCID: PMC9979628 DOI: 10.1016/j.ejps.2023.106418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 02/19/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023]
Abstract
INTRODUCTION In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.
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Affiliation(s)
- Nadia Baalbaki
- Department of Pulmonary Medicine, Amsterdam UMC, location AMC, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Public Health, Amsterdam, the Netherlands.
| | - Erik Duijvelaar
- Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Medhat M Said
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Job Schippers
- Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Pierre M Bet
- Amsterdam Public Health, Amsterdam, the Netherlands; Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Jos Twisk
- Amsterdam Public Health, Amsterdam, the Netherlands; Department of Epidemiology and Data Science, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
| | | | - Cristina Longo
- Department of Pulmonary Medicine, Amsterdam UMC, location AMC, Amsterdam, the Netherlands
| | - Kazien Mahmoud
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
| | - Anke H Maitland-van der Zee
- Department of Pulmonary Medicine, Amsterdam UMC, location AMC, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Public Health, Amsterdam, the Netherlands
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Eleonora L Swart
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Jurjan Aman
- Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Imke H Bartelink
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands.
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Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis. Bioact Mater 2023; 21:531-546. [PMID: 36185750 PMCID: PMC9508173 DOI: 10.1016/j.bioactmat.2022.09.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 08/12/2022] [Accepted: 09/09/2022] [Indexed: 11/29/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction. Inspired by macrophage membranes harbor the receptors with special high affinity for proinflammation cytokines, lipopolysaccharide (LPS)-stimulated macrophage membrane-coated nanoparticles (LMNP) were developed to show strong sponge ability to both IFN-γ and IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo. Besides, LMNP also efficiently alleviated HLH-related symptoms including cytopenia, hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models. Furthermore, its sponge effect also worked well for five human HLH samples in vitro. Altogether, it's firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation, which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.
LMNP functioned better as a multiple-cytokine sponging tool when compared with conventional macrophage coated nanoparticles. LMNP sponged inflammation cytokines and suppressed macrophage overactivation by inhibiting JAK/STAT signaling pathway. LMNP calmed down systematic cytokine storm and dampened HLH in HLH mice models. LMNP also worked well in sponging cytokines in human HLH samples which indicated high potential of clinical transformation.
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Bauer A, Pachl E, Hellmuth JC, Kneidinger N, Heydarian M, Frankenberger M, Stubbe HC, Ryffel B, Petrera A, Hauck SM, Behr J, Kaiser R, Scherer C, Deng L, Teupser D, Ahmidi N, Muenchhoff M, Schubert B, Hilgendorff A. Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166592. [PMID: 36328146 PMCID: PMC9622026 DOI: 10.1016/j.bbadis.2022.166592] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development.
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Affiliation(s)
- Alina Bauer
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany
| | - Elisabeth Pachl
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Fraunhofer IKS, Fraunhofer Institute for Cognitive Systems IKS, 80686 Munich, Germany
| | - Johannes C. Hellmuth
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany,German Cancer Consortium (DKTK), Munich, Germany,COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany
| | - Nikolaus Kneidinger
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany,Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
| | | | - Marion Frankenberger
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany
| | - Hans C. Stubbe
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Bernhard Ryffel
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans and Artimmune, Orléans, France
| | - Agnese Petrera
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, Munich, Germany
| | - Stefanie M. Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, Munich, Germany
| | - Jürgen Behr
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany,Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Rainer Kaiser
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Clemens Scherer
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Li Deng
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Daniel Teupser
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Narges Ahmidi
- Fraunhofer IKS, Fraunhofer Institute for Cognitive Systems IKS, 80686 Munich, Germany
| | - Maximilian Muenchhoff
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, LMU München, Munich, Germany,German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Benjamin Schubert
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Department of Mathematics, Technical University of Munich, 85748 Garching bei München, Germany
| | - Anne Hilgendorff
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany; Center for Comprehensive Developmental Care (CDeC(LMU)) at the Interdisciplinary Social Pediatric Center (iSPZ), LMU Hospital, Munich, Germany.
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Kitsos D, Tzartos J, Korres G, Giannopapas V, Riga M, Stergiou C, Tsoga A, Grigoropoulos C, Paraskevas G, Zompola C, Nikolopoulos T, Giannopoulos S. IL-6 Serum Levels in COVID-19 Patients With Vertigo. Cureus 2023; 15:e35042. [PMID: 36942191 PMCID: PMC10024114 DOI: 10.7759/cureus.35042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2023] [Indexed: 02/18/2023] Open
Abstract
Introduction Dizziness and vertigo represent well-established symptoms of COVID-19. An overexpression of cytokines, a condition often described with the term "cytokine storm" or "hypercytokinemia", is a key characteristic of SARS-Cov-2 infection and plays a pivotal role in disease progression and prognosis. Among them, IL-6 is of major importance. Purpose The purpose of this study is to investigate any probable IL-6 serum titer difference in COVID-19 patients with vertigo (V+) or without vertigo (V-) admitted to the COVID-19 internal medicine departments of Attikon University Hospital, Athens, Greece, within 12 months. Methods The sample consisted of 52 COVID-19 patients who were diagnosed between January 1, 2020, and December 31, 2020. Of those, 31 reported vertigos during their admission (V+), while the remaining 21 COVID-19 patients did not complain of such symptoms (V-). Results Higher IL-6 serum levels post-COVID-19 infections lead to higher incidence rates of vertigo symptoms (p<.005), regardless of gender and age (p.005).
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Affiliation(s)
- Dimitrios Kitsos
- Department of Neurology, Attikon University Hospital, Athens, GRC
| | - John Tzartos
- Department of Neurology, Attikon University Hospital, Athens, GRC
| | - George Korres
- Department of Otolaryngology, National and Kapodistrian University of Athens School of Medicine, Athens, GRC
| | - Vasileios Giannopapas
- Physical Therapy, University of West Attica, Athens, GRC
- Department of Neurology, Attikon University Hospital, Athens, GRC
| | - Maria Riga
- Department of Otorhinolaryngology-Head and Neck Surgery, Dammam Medical Complex, Dammam, SAU
| | | | - Anthi Tsoga
- Department of Neurology, Attikon University Hospital, Athens, GRC
| | | | | | | | - Thomas Nikolopoulos
- Department of Otorhinolaryngology, Attikon University Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, GRC
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Samir A, Altarawy D, Sweed RA, Abdel-Kerim AA. "Sinopharm", "Oxford-AstraZeneca", and "Pfizer-BioNTech" COVID-19 vaccinations: testing efficacy using lung CT-volumetry with comparative analysis of variance (ANOVA). THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2023. [PMCID: PMC9987394 DOI: 10.1186/s43055-023-00999-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
Abstract
Background Several clinical studies tested the efficacy of the different COVID-19 vaccinations while very few radiological researches targeted this issue before.
Aim of the work To verify the additive role of lung CT-Volumetry in testing the efficacy of three widely distributed COVID-19 vaccinations; namely the "Sinopharm", "Oxford-AstraZeneca", and "Pfizer-BioNTech" vaccinations, with comparative analysis of variance (ANOVA).
Results This study was retrospectively conducted on 341 COVID-19 patients during the period between June/2021 and March/2022. Based on the immunization status, they were divided into four groups; group (A) included 156/341 (46%) patients who did not receive any vaccination (control group), group (B) included 92/341 (27%) patients who received "Sinopharm" vaccine, group (C) included 55/341 (16%) patients who received "Oxford-AstraZeneca" vaccine, group (D) included 38/341 (11%) patients who received "Pfizer-BioNTech" vaccine. Every group was subdivided based on the medical history into three groups; group (1) patients without comorbidities, group (2) patients with comorbidities, and group (3) immunocompromised patients. Automated CT volumetry was calculated for the pathological lung parenchyma. Five CT-severity scores were provided (score 0 = 0%, score 1 = 1–25%, score 2 = 25–50%, score 3 = 51–75%, and score 4 = 76–100%). Analysis of variance (ANOVA) including Tukey HSD testing was utilized in comparison to the non-immunized patients. The "Phizer-Biontech" vaccine succeeded to eliminate severity in patients without and with comorbidity, and also decreased severity in immunocompromised patients (from 79 to 17%). The "Oxford-AstraZeneca" vaccine and to a lesser extent "Sinopharm" vaccine also decreased the clinical severity in patients with comorbidities and immunocompromised patients (from 15 to 9% & 10% as well as from 79 to 20% & 50% respectively). Significant variance was proved regarding the use of "Sinopharm", "Oxford-AstraZeneca", and "Phizer-Biontech" vaccines in patients without comorbidities (f-ratio averaged 4.0282, 10.8049, and 8.4404 respectively, also p-value averaged 0.04632, 0.001268, and 0.004294). Significant variance was proved regarding the use of "Oxford-AstraZeneca", and "Phizer-Biontech" vaccines in patients with comorbidities and immunocompromised patients (f-ratio averaged 4.7521, and 4.1682 as well as 11.7811, and 15.6 respectively, also p-value averaged 0.03492, and 0.04857, as well as both 0.003177, and 0.0009394 respectively, all < 0.05). No significant variance was proved regarding the use of the "Sinopharm" vaccine. Conclusions In addition to the decline of clinical severity rates & CT severity scores, a significant variance was proved regarding the use of the "Sinopharm", "Oxford-AstraZeneca", and "Phizer-Biontech" vaccines in patients without comorbidities. Significant variance was also proved regarding the use of the "Oxford-AstraZeneca" and "Phizer-Biontech" vaccines in patients with comorbidities and immunocompromised patients. Despite that, no significant variance could be proved regarding the use of the "Sinopharm" vaccine in these patients, it decreases the percentage of clinical severity and CT severity scores.
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Affiliation(s)
- Ahmed Samir
- grid.7155.60000 0001 2260 6941Department of Radio-Diagnosis, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Dina Altarawy
- grid.7155.60000 0001 2260 6941Department of Radio-Diagnosis, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Rania Ahmed Sweed
- grid.7155.60000 0001 2260 6941Department of Chest Diseases, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amr A. Abdel-Kerim
- grid.7155.60000 0001 2260 6941Department of Radio-Diagnosis, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Plocque A, Mitri C, Lefèvre C, Tabary O, Touqui L, Philippart F. Should We Interfere with the Interleukin-6 Receptor During COVID-19: What Do We Know So Far? Drugs 2023; 83:1-36. [PMID: 36508116 PMCID: PMC9743129 DOI: 10.1007/s40265-022-01803-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2022] [Indexed: 12/14/2022]
Abstract
Severe manifestations of COVID-19 consist of acute respiratory distress syndrome due to an initially local reaction leading to a systemic inflammatory response that results in hypoxia. Many therapeutic approaches have been attempted to reduce the clinical consequences of an excessive immune response to viral infection. To date, systemic corticosteroid therapy is still the most effective intervention. More recently, new hope has emerged with the use of interleukin (IL)-6 receptor inhibitors (tocilizumab and sarilumab). However, the great heterogeneity of the methodology and results of published studies obfuscate the true value of this treatment, leading to a confusing synthesis in recent meta-analyses, and the persistence of doubts in terms of patient groups and the appropriate time to treat. Moreover, their effects on the anti-infectious or pro-healing response are still poorly studied. This review aims to clarify the potential role of IL-6 receptor inhibitors in the treatment of severe forms of COVID-19.
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Affiliation(s)
- Alexia Plocque
- Medical and Surgical Intensive Care Unit, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Christie Mitri
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, Inserm, 75012, Paris, France
| | - Charlène Lefèvre
- Medical and Surgical Intensive Care Unit, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Olivier Tabary
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, Inserm, 75012, Paris, France
| | - Lhousseine Touqui
- INSERM U938 Unit, St. Antoine Research Centre, Sorbona University, Paris, France
- Mucoviscidosis and Pulmonary Disease Units, Institute Pasteur, Paris, France
- Cystic fibrosis and Bronchial diseases team-INSERM U938, Institut Pasteur, Paris, France
| | - Francois Philippart
- Medical and Surgical Intensive Care Unit, Groupe Hospitalier Paris Saint Joseph, Paris, France.
- Endotoxins, Structures and Host Response, Department of Microbiology, Institute for Integrative Biology of the Cell, UMR 9891 CNRS-CEA-Paris Saclay University, 98190, Gif-sur-Yvette, France.
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Wang N, Li E, Deng H, Yue L, Zhou L, Su R, He B, Lai C, Li G, Gao Y, Zhou W, Gao Y. Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation. J Pharm Anal 2023; 13:11-23. [PMID: 36313960 PMCID: PMC9595505 DOI: 10.1016/j.jpha.2022.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 02/02/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19 (COVID-19) progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19, but have limited clinical efficacy in severe and critical cases. Nevertheless, the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection. We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin (IL)-6, upregulated anti-inflammatory IL-10, and ameliorated acute inflammatory lung injury caused by multiple infectious agents. Inosine significantly improved survival in mice infected with SARS-CoV-2. It indirectly impeded TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes (STING) and glycogen synthase kinase-3β (GSK3β), inhibited the activation and nuclear translocation of the downstream transcription factors interferon regulatory factor (IRF3) and nuclear factor kappa B (NF-κB), and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide (LPS), H1N1, or SARS-CoV-2. Thus, inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19. Moreover, targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.
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Affiliation(s)
- Ningning Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Entao Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China
| | - Huifang Deng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Lanxin Yue
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Lei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Rina Su
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130022, China
| | - Baokun He
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chengcai Lai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Gaofu Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yuwei Gao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China
- Corresponding author.
| | - Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
- Corresponding author.
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Corresponding author. Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
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Mohamed Atef Refaat M, Ali Elkafrawy L, Elkabarity RH, Hafez AF. Effect of dexmedetomidine vs midazolam on the microcirculation of septic patients who are mechanically ventilated. EGYPTIAN JOURNAL OF ANAESTHESIA 2022. [DOI: 10.1080/11101849.2022.2109826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022] Open
Affiliation(s)
- Mostafa Mohamed Atef Refaat
- Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Laila Ali Elkafrawy
- Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Reem Hamdy Elkabarity
- Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Amr Fouad Hafez
- Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
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Özbek M, Toy HI, Takan I, Asfa S, Arshinchi Bonab R, Karakülah G, Kontou PI, Geronikolou SA, Pavlopoulou A. A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis. Viruses 2022; 15:104. [PMID: 36680144 PMCID: PMC9866184 DOI: 10.3390/v15010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic "cytokine storm". Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies.
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Affiliation(s)
- Melih Özbek
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Halil Ibrahim Toy
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Işil Takan
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Seyedehsadaf Asfa
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Reza Arshinchi Bonab
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | - Gökhan Karakülah
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
| | | | - Styliani A. Geronikolou
- Clinical, Translational and Experimental Surgery Research Centre, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, 11527 Athens, Greece
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Balcova, Izmir 35220, Turkey
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Cognasse F, Hamzeh-Cognasse H, Rosa M, Corseaux D, Bonneaudeau B, Pierre C, Huet J, Arthaud CA, Eyraud MA, Prier A, Duchez AC, Ebermeyer T, Heestermans M, Audoux-Caire E, Philippot Q, Le Voyer T, Hequet O, Fillet AM, Chavarin P, Legrand D, Richard P, Pirenne F, Gallian P, Casanova JL, Susen S, Morel P, Lacombe K, Bastard P, Tiberghien P. Inflammatory markers and auto-Abs to type I IFNs in COVID-19 convalescent plasma cohort study. EBioMedicine 2022; 87:104414. [PMID: 36535107 PMCID: PMC9758484 DOI: 10.1016/j.ebiom.2022.104414] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 11/10/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND COVID-19 convalescent plasma (CCP) contains neutralising anti-SARS-CoV-2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. METHODS CCP (n = 766) was compared to non-convalescent control plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralising auto-Abs to type I IFNs and reported adverse events in the recipients. FINDINGS CCP exhibited a statistically significant increase in IL-6 and TNF-alpha levels (0.531 ± 0.04 vs 0.271 ± 0.04; (95% confidence interval [CI], 0.07371-0.4446; p = 0.0061) and 0.900 ± 0.07 vs 0.283 ± 0.07 pg/mL; (95% [CI], 0.3097-0.9202; p = 0.0000829) and lower IL-10 (0.731 ± 0.07 vs 1.22 ± 0.19 pg/mL; (95% [CI], -0.8180 to -0.1633; p = 0.0034) levels than control plasma. Neutralising auto-Abs against type I IFNs were detected in 14/766 (1.8%) CCPs and were not associated with reported adverse events when transfused. Inflammatory markers and bioactivity in CCP with or without auto-Abs, or in CCP whether or not linked to adverse events in transfused patients, did not differ to a statistically significant extent. INTERPRETATION Overall, CCP exhibited moderately increased inflammatory markers compared to the control plasma with no discernible differences in ex-vivo bioactivity. Auto-Abs to type I IFNs detected in a small fraction of CCP were not associated with reported adverse events or differences in inflammatory markers. Additional studies, including careful clinical evaluation of patients treated with CCP, are required in order to further define the clinical relevance of these findings. FUNDING French National Blood Service-EFS, the Association "Les Amis de Rémi" Savigneux, France, the "Fondation pour la Recherche Médicale (Medical Research Foundation)-REACTing 2020".
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Affiliation(s)
- Fabrice Cognasse
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France,Corresponding author. Etablissement Français du Sang Auvergne-Rhône-Alpes, INSERM U1059, Campus Santé Innovation - 10 rue de la Marandière, 42270, Saint-Priest-en-Jarez, France.
| | - Hind Hamzeh-Cognasse
- Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Mickael Rosa
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1011- EGID, F-59000 Lille, France,Centre National de la Recherche Scientifique (National Scientific Research Centre), Surgical Critical Care, Department of Anaesthesiology and Critical Care, U1019 - Unité Mixte de Recherche 9017 (Mixed Research Unit 9017) – Lille Centre for Infection and Immunity, France
| | - Delphine Corseaux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1011- EGID, F-59000 Lille, France,Centre National de la Recherche Scientifique (National Scientific Research Centre), Surgical Critical Care, Department of Anaesthesiology and Critical Care, U1019 - Unité Mixte de Recherche 9017 (Mixed Research Unit 9017) – Lille Centre for Infection and Immunity, France
| | | | - Chloe Pierre
- Etablissement Français du Sang, La Plaine, St Denis, France
| | - Julie Huet
- Etablissement Français du Sang, La Plaine, St Denis, France
| | - Charles Antoine Arthaud
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Marie Ange Eyraud
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Amélie Prier
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Anne Claire Duchez
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Theo Ebermeyer
- Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Marco Heestermans
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Estelle Audoux-Caire
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France,Univ Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023, Saint-Étienne, France
| | - Quentin Philippot
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163 (National Institute for Health and Medical Research), Necker Hospital for Sick Children, Paris, France,University of Paris, Imagine Institute, Paris, France
| | - Tom Le Voyer
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163 (National Institute for Health and Medical Research), Necker Hospital for Sick Children, Paris, France,University of Paris, Imagine Institute, Paris, France
| | - Olivier Hequet
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France
| | | | - Patricia Chavarin
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France
| | - Dominique Legrand
- Établissement Français du Sang Auvergne-Rhône-Alpes, Saint-Étienne, France
| | | | - France Pirenne
- Univ Paris Est Creteil, INSERM U955, Institut Mondor de Recherche Biomédicale (Mondor Biomedical Research Institute) (IMRB), Creteil, France & Laboratory of Excellence GR-Ex, Paris, France
| | - Pierre Gallian
- Etablissement Français du Sang, La Plaine, St Denis, France,UMR “Unité des Virus Emergents” (Emerging Virus Unit), Aix-Marseille University - IRD 190 - INSERM 1207 - IRBA - EFS - IHU Méditerranée Infection, Marseille, France
| | - Jean Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163 (National Institute for Health and Medical Research), Necker Hospital for Sick Children, Paris, France,University of Paris, Imagine Institute, Paris, France,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA,Howard Hughes Medical Institute, New York, NY, USA
| | - Sophie Susen
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1011- EGID, F-59000 Lille, France,Centre National de la Recherche Scientifique (National Scientific Research Centre), Surgical Critical Care, Department of Anaesthesiology and Critical Care, U1019 - Unité Mixte de Recherche 9017 (Mixed Research Unit 9017) – Lille Centre for Infection and Immunity, France
| | - Pascal Morel
- Etablissement Français du Sang, La Plaine, St Denis, France
| | - Karine Lacombe
- Sorbonne University, Inserm IPLESP, Infectious Diseases Department, Saint-Antoine Hospital, APHP (University Hospital Trust), Paris, France
| | - Paul Bastard
- Etablissement Français du Sang, La Plaine, St Denis, France,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163 (National Institute for Health and Medical Research), Necker Hospital for Sick Children, Paris, France,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Pierre Tiberghien
- Etablissement Français du Sang, La Plaine, St Denis, France,UMR RIGHT U1098, INSERM, Etablissement Français du Sang, University of Franche-Comté, Besançon, France
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Beimdiek J, Janciauskiene S, Wrenger S, Volland S, Rozy A, Fuge J, Olejnicka B, Pink I, Illig T, Popov A, Chorostowska J, Buettner FFR, Welte T. Plasma markers of COVID-19 severity: a pilot study. Respir Res 2022; 23:343. [PMID: 36514048 PMCID: PMC9745704 DOI: 10.1186/s12931-022-02272-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND SARS-CoV-2 infected patients show heterogeneous clinical presentations ranging from mild symptoms to severe respiratory failure and death. Consequently, various markers reflect this wide spectrum of disease presentations. METHODS Our pilot cohort included moderate (n = 10) and severe (n = 10) COVID-19 patients, and 10 healthy controls. We determined plasma levels of nine acute phase proteins (APPs) by nephelometry, and full-length (M65), caspase-cleaved (M30) cytokeratin 18, and ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type-1 motif 13) by ELISA. In addition, we examined whole plasma N-glycosylation by capillary gel electrophoresis coupled to laser-induced fluorescence detection (CGE-LIF). RESULTS When compared to controls, COVID-19 patients had significantly lower concentrations of ADAMTS13 and albumin (ALB) but higher M30, M65, α1-acid glycoprotein (AGP), α1-antitrypsin (AAT), ceruloplasmin (CP), haptoglobin (HP), and high-sensitivity C-reactive protein (hs-CRP). The concentrations of α1-antichymotrypsin (ACT), α2-macroglobulin (A2MG) and serum amyloid A (SAA) proteins did not differ. We found significantly higher levels of AAT and M65 but lower ALB in severe compared to moderate COVID-19 patients. N-glycan analysis of the serum proteome revealed increased levels of oligomannose- and sialylated di-antennary glycans and decreased non-sialylated di-antennary glycan A2G2 in COVID-19 patients compared to controls. CONCLUSIONS COVID-19-associated changes in levels and N-glycosylation of specific plasma proteins highlight complexity of inflammatory process and grant further investigations.
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Affiliation(s)
- Julia Beimdiek
- Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Sabina Janciauskiene
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Sabine Wrenger
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Sonja Volland
- Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Str. 15, 30625 Hannover, Germany
| | - Adriana Rozy
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 26 Plocka St., 01138 Warsaw, Poland
| | - Jan Fuge
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Beata Olejnicka
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Isabell Pink
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Thomas Illig
- Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Str. 15, 30625 Hannover, Germany
| | - Alexander Popov
- Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Str. 15, 30625 Hannover, Germany
| | - Joanna Chorostowska
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 26 Plocka St., 01138 Warsaw, Poland
| | - Falk F. R. Buettner
- Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Tobias Welte
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, BREATH German Center for Lung Research (DZL) Hannover University School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Gedda MR, Danaher P, Shao L, Ongkeko M, Chen L, Dinh A, Thioye Sall M, Reddy OL, Bailey C, Wahba A, Dzekunova I, Somerville R, De Giorgi V, Jin P, West K, Panch SR, Stroncek DF. Longitudinal transcriptional analysis of peripheral blood leukocytes in COVID-19 convalescent donors. J Transl Med 2022; 20:587. [PMID: 36510222 PMCID: PMC9742656 DOI: 10.1186/s12967-022-03751-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 11/03/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND SARS-CoV2 can induce a strong host immune response. Many studies have evaluated antibody response following SARS-CoV2 infections. This study investigated the immune response and T cell receptor diversity in people who had recovered from SARS-CoV2 infection (COVID-19). METHODS Using the nCounter platform, we compared transcriptomic profiles of 162 COVID-19 convalescent donors (CCD) and 40 healthy donors (HD). 69 of the 162 CCDs had two or more time points sampled. RESULTS After eliminating the effects of demographic factors, we found extensive differential gene expression up to 241 days into the convalescent period. The differentially expressed genes were involved in several pathways, including virus-host interaction, interleukin and JAK-STAT signaling, T-cell co-stimulation, and immune exhaustion. A subset of 21 CCD samples was found to be highly "perturbed," characterized by overexpression of PLAU, IL1B, NFKB1, PLEK, LCP2, IRF3, MTOR, IL18BP, RACK1, TGFB1, and others. In addition, one of the clusters, P1 (n = 8) CCD samples, showed enhanced TCR diversity in 7 VJ pairs (TRAV9.1_TCRVA_014.1, TRBV6.8_TCRVB_016.1, TRAV7_TCRVA_008.1, TRGV9_ENST00000444775.1, TRAV18_TCRVA_026.1, TRGV4_ENST00000390345.1, TRAV11_TCRVA_017.1). Multiplexed cytokine analysis revealed anomalies in SCF, SCGF-b, and MCP-1 expression in this subset. CONCLUSIONS Persistent alterations in inflammatory pathways and T-cell activation/exhaustion markers for months after active infection may help shed light on the pathophysiology of a prolonged post-viral syndrome observed following recovery from COVID-19 infection. Future studies may inform the ability to identify druggable targets involving these pathways to mitigate the long-term effects of COVID-19 infection. TRIAL REGISTRATION https://clinicaltrials.gov/ct2/show/NCT04360278 Registered April 24, 2020.
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Affiliation(s)
- Mallikarjuna R. Gedda
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA ,grid.280030.90000 0001 2150 6316Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892 USA
| | - Patrick Danaher
- grid.510973.90000 0004 5375 2863NanoString Technologies, Seattle, WA 98109 USA
| | - Lipei Shao
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Martin Ongkeko
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Leonard Chen
- grid.94365.3d0000 0001 2297 5165Blood Services Section, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Anh Dinh
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Mame Thioye Sall
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Opal L. Reddy
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Christina Bailey
- grid.510973.90000 0004 5375 2863NanoString Technologies, Seattle, WA 98109 USA
| | - Amy Wahba
- grid.510973.90000 0004 5375 2863NanoString Technologies, Seattle, WA 98109 USA
| | - Inna Dzekunova
- grid.510973.90000 0004 5375 2863NanoString Technologies, Seattle, WA 98109 USA
| | - Robert Somerville
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Valeria De Giorgi
- grid.94365.3d0000 0001 2297 5165Infectious Disease Section, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Ping Jin
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Kamille West
- grid.94365.3d0000 0001 2297 5165Blood Services Section, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
| | - Sandhya R. Panch
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA ,grid.34477.330000000122986657Department of Medicine (Hematology Division), University of Washington/Fred Hutchinson Cancer Center, Seattle, WA 98109 USA
| | - David F. Stroncek
- grid.94365.3d0000 0001 2297 5165Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892 USA
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Samir A, Bastawi RA, Baess AI, Sweed RA, Eldin OE. Thymus CT-grading and rebound hyperplasia during COVID-19 infection: a CT volumetric study with multivariate linear regression analysis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2022. [PMCID: PMC9108347 DOI: 10.1186/s43055-022-00784-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Background The importance of thymic CT-grading and presence of thymic rebound hyperplasia during COVID-19 infection were only investigated in a few studies. This multivariate study aims to evaluate the relation between thymus CT-grading and rebound during COVID-19 infection and the following: (1) the patients' age, (2) the patients' blood lymphocytic count, (3) the CT-volumetry of the diseased lung parenchyma, (4) the patient's clinical course and prognosis, and finally (5) the final radiological diagnosis. Results Multicenter retrospective analyses were conducted between March and June 2021 on 325 adult COVID-19 patients with positive PCR results and negative history of malignant or autoimmune diseases. They included 186 males and 139 females (57.2%:42.8%). Their mean age was 40.42 years ± 14.531 SD. Three consulting radiologists performed CT-grading of the thymus gland (grade 0–3) and CT-severity scoring (CT-SS) of the pathological lung changes in consensus. Two consulting pulmonologists correlated the clinical severity and blood lymphocytic count. Pearson correlation coefficient (r) and linear regression analyses were statistically utilized. Sub-involuted thymus (with CT-grade 0:2) was detected in 42/325 patients (12.9%); all of them had a mild clinical course and low CT-SS (0–1). Thymic rebound hyperplasia was the only positive CT-finding in 15/325 patients (4.6%) without pathological lung changes. A weak positive significant correlation was proved between thymic grade and patient's age, clinical course, and CT-SS (r = 0.217, 0.163, and 0.352 with p ≤ 0.0001, < 0.0001, and 0.002, respectively). A weak negative significant correlation was found between thymic grade and lymphocytic count (r = − 0.343 and p ≤ 0.0001). A strong positive significant correlation was encountered between clinical severity against patients' age and CT-SS (r = 0.616 and 0.803 with p ≤ 0.0001). Conclusions The presence of sub-involuted thymus or thymic rebound should not be radiologically overlooked in COVID-19 patients. During COVID-19 infection, the presence of sub-involuted thymus with low CT-grading (0–2) was correlated with young age groups, low CT-severity scoring, mild clinical course, and better prognosis (good prognostic factor). It was seldom seen in old hospitalized patients. Atypically, it was also correlated with normal lymphocytic count or even lymphocytosis. The thymic rebound could be the only positive CT-finding even during the absence of lung involvement.
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Samir A, Gharraf HS, Baess AI, Sweed RA, Matrawy K, Geijer M, Shalabi A, Tarek Y. Splenomegaly versus pathological lung volume during COVID-19 infection with or without cytokine storm; a linear regression analysis using CT volumetry. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2022. [PMCID: PMC9117999 DOI: 10.1186/s43055-022-00793-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Background Due to the paucity of scientific evidence, it is unclear among pulmonologists and physicians in critical care units if and when splenomegaly in novel coronavirus disease (2019) (COVID-19) patients is worrisome. This study aims to evaluate the significance of splenic volume during COVID-19 infection with or without cytokine storm and correlates splenic volume to the volume of pathological lung changes through linear regression analysis. Results A retrospective study collected 509 polymerase chain reaction proved COVID-19 patients (399 males, 110 females; mean age 48 years, age range 24–78 years) between June and November 2021, without a history of splenic pathology. A control group of age and sex-matched 509 healthy subjects was used and analyzed according to the splenic volume. Five consulting radiologists evaluated initial and follow-up computed tomography (CT) examinations using lung CT volumetry and splenic volume calculation in consensus. Three consulting pulmonologists correlated the severity of clinical and laboratory findings, including oxygen requirements and interleukin-6 (IL-6) levels. The T test results for comparison between the COVID-19 patients and the healthy subjects control group regarding the splenic volume were significant (T value was − 4.731452 and p value was 0.00002). There was no significant correlation between the severity of the disease and normal-sized spleen (26% of patients, p = 0.916) or splenomegaly (24% of patients, p = 0.579). On the other hand, all patients with a small spleen or progressive splenomegaly during serial follow-up imaging had clinically severe disease with a statistically significant correlation (p = 0.017 and 0.003, respectively). Ninety-seven percent of patients with clinically mild disease and splenomegaly had 0–20% lung involvement (CT-severity score 1) while all patients with clinically severe disease and splenomegaly had 27–73% lung involvement (CT-severity score 2 and 3) (r = 0.305, p = 0.030). Conclusions Splenomegaly is a non-specific sign that may be found during mild and severe COVID-19 infection, it was not statistically correlated with the clinical severity and a weak positive relationship was found between the splenic size and the CT-severity score of the pathological lung volume. On the other hand, the presence of splenic atrophy or progressive splenomegaly was correlated with severe COVID-19 presentation and “cytokine storm”. Therefore, the splenic volume changes should not be overlooked in COVID-19 serial CT examinations, particularly in severe or critically ill patients with cytokine storms.
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Dutt N, Shishir S, Chauhan NK, Jalandra R, kuwal A, Garg P, Kumar D, Vishwajeet V, Chakraborti A, Deokar K, Asfahan S, Babu A, bajad P, Gupta N, Khurana A, Garg MK. Mortality and Its Predictors in COVID-19 Patients With Pre-existing Interstitial Lung Disease. Cureus 2022; 14:e27759. [PMID: 36106257 PMCID: PMC9448685 DOI: 10.7759/cureus.27759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2022] [Indexed: 11/05/2022] Open
Abstract
Background The data on the impact of coronavirus disease 2019 (COVID-19) on interstitial lung disease (ILD) is still limited. To the best of our knowledge, there has been no study from India to date to assess the impact of COVID-19 in patients with preexisting ILD. We undertook this study to assess the clinical outcome of ILD patients admitted to our hospital with COVID-19. Methods In this retrospective observational study, records of reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients with preexisting ILD who were admitted to the hospital in the period from May 1, 2020, to April 30, 2021, were obtained from the hospital database. The clinical outcomes of the patients were recorded. Univariate analysis was performed to find relation between various predetermined risk factors for mortality and those with significant p values (p<0.05) were subjected to multiple logistic regression to determine independent risk factors. Results In our study of 28 patients, the overall mortality was 35.7%. On comparing the parameters associated with increased mortality, there was no effect of age, gender, comorbidities, type of ILD, CT thorax findings on diagnosis, use of corticosteroids and antifibrotics in the past, spirometric findings on mortality. On multivariate analysis, the significant parameters were interleukin 6 (IL-6), p=0.02, OR=1.020 (1.006-1.043) and D-dimer, p=0.04, OR=2.14 (5.55-1.14). Conclusion COVID-19 in patients with pre-existing ILD has a comparatively higher mortality. D-dimer and IL-6 are significant predictors of mortality in ILD patients infected with COVID-19.
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