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1
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de Brabander J, Michels EHA, Butler JM, Reijnders TDY, van Engelen TSR, Leite GGF, Paling FP, Klarenbeek AM, Sie DLS, Boyer RE, Sweeney TE, Bonten MJM, Timbermont L, Malhotra-Kumar S, Kluytmans JAJW, Peters-Sengers H, van der Poll T. The blood transcriptional response in patients developing intensive care unit-acquired pneumonia. Eur Respir J 2025; 65:2400592. [PMID: 39848701 PMCID: PMC12018758 DOI: 10.1183/13993003.00592-2024] [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: 03/25/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Immune response dysregulation has been implicated in the development of intensive care unit (ICU)-acquired pneumonia. We aimed to determine differences in the longitudinal blood transcriptional response between patients who develop ICU-acquired pneumonia (cases) and those who do not (controls). METHODS We performed a case-cohort study in mechanically ventilated trauma and surgery patients with ICU stays >2 days, enrolled in 30 hospitals across Europe. We collected blood for RNA sequencing at baseline, day 7 and (in cases) the day of pneumonia diagnosis. We performed gene set enrichment analysis and analysed longitudinal gene expression changes using linear mixed models. External validation was performed using an independent trauma cohort. RESULTS We enrolled 113 cases and 115 controls, with similar baseline characteristics. At baseline (median 2 days after ICU admission), cases showed upregulated gene pathways relating to innate immunity, haemostasis and metabolism, and downregulated adaptive immune pathways. These changes persisted at the day of pneumonia diagnosis (median 6 days, compared to day 7 in controls). In the longitudinal comparison, cases exhibited enhanced upregulation of innate immunity, adaptive immunity and haemostasis pathways, along with enhanced downregulation of metabolism pathways, relative to controls (all p<0.00001, except haemostasis p<0.05). These findings were largely externally validated. Cases had higher quantitative sepsis response signature scores (p<0.001), reflective of immune dysregulation. CONCLUSION Patients developing ICU-acquired pneumonia exhibit distinct blood transcriptional responses shortly after ICU admission and in the subsequent path to pneumonia, suggestive of broad immune dysfunction with both immunosuppressive and inflammatory features.
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Affiliation(s)
- Justin de Brabander
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Erik H A Michels
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Joe M Butler
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Tom D Y Reijnders
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Tjitske S R van Engelen
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Giuseppe G F Leite
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Division of Infectious Diseases, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Fleur P Paling
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Augustijn M Klarenbeek
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Daoud L S Sie
- Department of Human Genetics, Amsterdam UMC location Vrije Universiteit, Amsterdam, The Netherlands
| | - Roxane E Boyer
- Department of Human Genetics, Amsterdam UMC location Vrije Universiteit, Amsterdam, The Netherlands
| | | | - Marc J M Bonten
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Leen Timbermont
- Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Surbhi Malhotra-Kumar
- Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Jan A J W Kluytmans
- Department of Medical Microbiology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Hessel Peters-Sengers
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC location Vrije Universiteit, Amsterdam, The Netherlands
| | - Tom van der Poll
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Division of Infectious Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
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Baalaaji M. Pediatric Sepsis - Sailing the Unchartered Waters with Omics. Indian J Crit Care Med 2024; 28:818-819. [PMID: 39360198 PMCID: PMC11443276 DOI: 10.5005/jp-journals-10071-24799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Abstract
How to cite this article: Baalaaji M. Pediatric Sepsis - Sailing the Unchartered Waters with Omics. Indian J Crit Care Med 2024;28(9):818-819.
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Affiliation(s)
- Mullai Baalaaji
- Department of Pediatric Critical Care, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India
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3
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Cajander S, Kox M, Scicluna BP, Weigand MA, Mora RA, Flohé SB, Martin-Loeches I, Lachmann G, Girardis M, Garcia-Salido A, Brunkhorst FM, Bauer M, Torres A, Cossarizza A, Monneret G, Cavaillon JM, Shankar-Hari M, Giamarellos-Bourboulis EJ, Winkler MS, Skirecki T, Osuchowski M, Rubio I, Bermejo-Martin JF, Schefold JC, Venet F. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. THE LANCET. RESPIRATORY MEDICINE 2024; 12:305-322. [PMID: 38142698 DOI: 10.1016/s2213-2600(23)00330-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 08/14/2023] [Accepted: 08/24/2023] [Indexed: 12/26/2023]
Abstract
Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.
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Affiliation(s)
- Sara Cajander
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Matthijs Kox
- Department of Intensive Care Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Brendon P Scicluna
- Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei hospital, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Markus A Weigand
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Raquel Almansa Mora
- Department of Cell Biology, Genetics, Histology and Pharmacology, University of Valladolid, Valladolid, Spain
| | - Stefanie B Flohé
- Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ignacio Martin-Loeches
- St James's Hospital, Dublin, Ireland; Hospital Clinic, Institut D'Investigacions Biomediques August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain
| | - Gunnar Lachmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Operative Intensive Care Medicine, Berlin, Germany
| | - Massimo Girardis
- Department of Intensive Care and Anesthesiology, University Hospital of Modena, Modena, Italy
| | - Alberto Garcia-Salido
- Hospital Infantil Universitario Niño Jesús, Pediatric Critical Care Unit, Madrid, Spain
| | - Frank M Brunkhorst
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Antoni Torres
- Pulmonology Department. Hospital Clinic of Barcelona, University of Barcelona, Ciberes, IDIBAPS, ICREA, Barcelona, Spain
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Guillaume Monneret
- Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon-1, Hôpital E Herriot, Lyon, France
| | | | - Manu Shankar-Hari
- Centre for Inflammation Research, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | | | - Martin Sebastian Winkler
- Department of Anesthesiology and Intensive Care, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Marcin Osuchowski
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
| | - Ignacio Rubio
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Jesus F Bermejo-Martin
- Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain; School of Medicine, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red en Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Joerg C Schefold
- Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Fabienne Venet
- Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Ecole Normale Supeérieure de Lyon, Universiteé Claude Bernard-Lyon 1, Lyon, France.
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Liang P, Wu Y, Qu S, Younis M, Wang W, Wu Z, Huang X. Exploring the biomarkers and potential therapeutic drugs for sepsis via integrated bioinformatic analysis. BMC Infect Dis 2024; 24:32. [PMID: 38166628 PMCID: PMC10763157 DOI: 10.1186/s12879-023-08883-9] [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: 06/01/2023] [Accepted: 12/08/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Sepsis is a life-threatening condition caused by an excessive inflammatory response to an infection, associated with high mortality. However, the regulatory mechanism of sepsis remains unclear. RESULTS In this study, bioinformatics analysis revealed the novel key biomarkers associated with sepsis and potential regulators. Three public datasets (GSE28750, GSE57065 and GSE95233) were employed to recognize the differentially expressed genes (DEGs). Taking the intersection of DEGs from these three datasets, GO and KEGG pathway enrichment analysis revealed 537 shared DEGs and their biological functions and pathways. These genes were mainly enriched in T cell activation, differentiation, lymphocyte differentiation, mononuclear cell differentiation, and regulation of T cell activation based on GO analysis. Further, pathway enrichment analysis revealed that these DEGs were significantly enriched in Th1, Th2 and Th17 cell differentiation. Additionally, five hub immune-related genes (CD3E, HLA-DRA, IL2RB, ITK and LAT) were identified from the protein-protein interaction network, and sepsis patients with higher expression of hub genes had a better prognosis. Besides, 14 drugs targeting these five hub related genes were revealed on the basis of the DrugBank database, which proved advantageous for treating immune-related diseases. CONCLUSIONS These results strengthen the new understanding of sepsis development and provide a fresh perspective into discriminating the candidate biomarkers for predicting sepsis as well as identifying new drugs for treating sepsis.
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Affiliation(s)
- Pingping Liang
- Foshan Fourth People's Hospital, Guangdong Province, Foshan, 528041, China
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Zhuhai, 519000, China
| | - Yongjian Wu
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Zhuhai, 519000, China
| | - Siying Qu
- Department of Clinical Laboratory, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, The Second People's Hospital of Zhuhai, Guangdong Province, Zhuhai, 519020, China
| | - Muhammad Younis
- Foshan Fourth People's Hospital, Guangdong Province, Foshan, 528041, China
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Zhuhai, 519000, China
| | - Wei Wang
- Foshan Fourth People's Hospital, Guangdong Province, Foshan, 528041, China
| | - Zhilong Wu
- Foshan Fourth People's Hospital, Guangdong Province, Foshan, 528041, China.
| | - Xi Huang
- Foshan Fourth People's Hospital, Guangdong Province, Foshan, 528041, China.
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Zhuhai, 519000, China.
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Ghait M, Duduskar SN, Rooney M, Häfner N, Reng L, Göhrig B, Reuken PA, Bloos F, Bauer M, Sponholz C, Bruns T, Rubio I. The non-canonical inflammasome activators Caspase-4 and Caspase-5 are differentially regulated during immunosuppression-associated organ damage. Front Immunol 2023; 14:1239474. [PMID: 38106412 PMCID: PMC10722270 DOI: 10.3389/fimmu.2023.1239474] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
The non-canonical inflammasome, which includes caspase-11 in mice and caspase-4 and caspase-5 in humans, is upregulated during inflammatory processes and activated in response to bacterial infections to carry out pyroptosis. Inadequate activity of the inflammasome has been associated with states of immunosuppression and immunopathological organ damage. However, the regulation of the receptors caspase-4 and caspase-5 during severe states of immunosuppression is largely not understood. We report that CASP4 and CASP5 are differentially regulated during acute-on-chronic liver failure and sepsis-associated immunosuppression, suggesting non-redundant functions in the inflammasome response to infection. While CASP5 remained upregulated and cleaved p20-GSDMD could be detected in sera from critically ill patients, CASP4 was downregulated in critically ill patients who exhibited features of immunosuppression and organ failure. Mechanistically, downregulation of CASP4 correlated with decreased gasdermin D levels and impaired interferon signaling, as reflected by decreased activity of the CASP4 transcriptional activators IRF1 and IRF2. Caspase-4 gene and protein expression inversely correlated with markers of organ dysfunction, including MELD and SOFA scores, and with GSDMD activity, illustrating the association of CASP4 levels with disease severity. Our results document the selective downregulation of the non-canonical inflammasome activator caspase-4 in the context of sepsis-associated immunosuppression and organ damage and provide new insights for the development of biomarkers or novel immunomodulatory therapies for the treatment of severe infections.
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Affiliation(s)
- Mohamed Ghait
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Shivalee N Duduskar
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Michael Rooney
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Norman Häfner
- Department of Gynecology, Jena University Hospital, Jena, Germany
| | - Laura Reng
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Bianca Göhrig
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Frank Bloos
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Christoph Sponholz
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ignacio Rubio
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
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6
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Pelaia TM, Shojaei M, McLean AS. The Role of Transcriptomics in Redefining Critical Illness. Crit Care 2023; 27:89. [PMID: 36941625 PMCID: PMC10027592 DOI: 10.1186/s13054-023-04364-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .
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Affiliation(s)
- Tiana M Pelaia
- Department of Intensive Care Medicine, Nepean Hospital, Kingswood, NSW, Australia.
| | - Maryam Shojaei
- Department of Intensive Care Medicine, Nepean Hospital, Kingswood, NSW, Australia
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Anthony S McLean
- Department of Intensive Care Medicine, Nepean Hospital, Kingswood, NSW, Australia
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Liu S, Luo W, Szatmary P, Zhang X, Lin JW, Chen L, Liu D, Sutton R, Xia Q, Jin T, Liu T, Huang W. Monocytic HLA-DR Expression in Immune Responses of Acute Pancreatitis and COVID-19. Int J Mol Sci 2023; 24:3246. [PMID: 36834656 PMCID: PMC9964039 DOI: 10.3390/ijms24043246] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Acute pancreatitis is a common gastrointestinal disease with increasing incidence worldwide. COVID-19 is a potentially life-threatening contagious disease spread throughout the world, caused by severe acute respiratory syndrome coronavirus 2. More severe forms of both diseases exhibit commonalities with dysregulated immune responses resulting in amplified inflammation and susceptibility to infection. Human leucocyte antigen (HLA)-DR, expressed on antigen-presenting cells, acts as an indicator of immune function. Research advances have highlighted the predictive values of monocytic HLA-DR (mHLA-DR) expression for disease severity and infectious complications in both acute pancreatitis and COVID-19 patients. While the regulatory mechanism of altered mHLA-DR expression remains unclear, HLA-DR-/low monocytic myeloid-derived suppressor cells are potent drivers of immunosuppression and poor outcomes in these diseases. Future studies with mHLA-DR-guided enrollment or targeted immunotherapy are warranted in more severe cases of patients with acute pancreatitis and COVID-19.
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Affiliation(s)
- Shiyu Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenjuan Luo
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peter Szatmary
- Liverpool Pancreatitis Research Group, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BE, UK
| | - Xiaoying Zhang
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing-Wen Lin
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Lu Chen
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Dan Liu
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Robert Sutton
- Liverpool Pancreatitis Research Group, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BE, UK
| | - Qing Xia
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Jin
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tingting Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wei Huang
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China
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8
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Zanza C, Caputo G, Tornatore G, Romenskaya T, Piccioni A, Franceschi F, Artico M, Taurone S, Savioli G, Longhitano Y. Cellular Immuno-Profile in Septic Human Host: A Scoping Review. BIOLOGY 2022; 11:1626. [PMID: 36358327 PMCID: PMC9687154 DOI: 10.3390/biology11111626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022]
Abstract
Innate and adaptive immune system cells play a critical role in the host response to sepsis. Sepsis is a life-threatening disease characterized by apoptosis-induced depletion of immune cells and immunodepression, which contribute to morbidity and mortality. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of circulating leukocytes. The impact on cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. We conducted a systematic review using Pubmed/Medline, Ovid/Willey, the Cochrane Library, the Cochrane Controlled Trials Register, and EMBASE, combining key terms related to immunological function in sepsis and selected the most relevant clinical trials and review articles (excluding case reports) published in the last 50 years. The most important alteration in neutrophils during sepsis is that they activate an anti-apoptotic survival program. In septic monocytes, a reduced characteristic expression of HLA-DR is observed, but their role does not seem to be significantly altered in sepsis. As regards adaptive immunity, sepsis leads to lymphopenia and immunosuppression in patients with septic shock; this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, which retain their function. Several promising therapies that target the host immune response are currently under evaluation. During the worldwide pandemic caused by SARS-CoV-2, it was useful to study the "cytokine storm" to find additional treatments, such as the oXiris® filter. This therapy can decrease the concentration of inflammatory markers that affect the severity of the disease.
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Affiliation(s)
- Christian Zanza
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Giorgia Caputo
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Gilda Tornatore
- Department of Anesthesia and Intensive Care Medicine, University of Milan-Bicocca, 20126 Milan, Italy
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Andrea Piccioni
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Marco Artico
- Department of Sensory Organs, Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy
| | - Samanta Taurone
- Department of Movement, Human and Health Sciences—Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
| | - Gabriele Savioli
- Department of Emergency Medicine, Polyclinic IRCCS S. Matteo, University of Pavia, 27100 Pavia, Italy
| | - Yaroslava Longhitano
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
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9
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Kalantar KL, Neyton L, Abdelghany M, Mick E, Jauregui A, Caldera S, Serpa PH, Ghale R, Albright J, Sarma A, Tsitsiklis A, Leligdowicz A, Christenson SA, Liu K, Kangelaris KN, Hendrickson C, Sinha P, Gomez A, Neff N, Pisco A, Doernberg SB, Derisi JL, Matthay MA, Calfee CS, Langelier CR. Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults. Nat Microbiol 2022; 7:1805-1816. [PMID: 36266337 PMCID: PMC9613463 DOI: 10.1038/s41564-022-01237-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022]
Abstract
We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a transcriptional signature of sepsis with several genes previously reported as sepsis biomarkers, and a bSVM sepsis diagnostic classifier (AUC = 0.97 training set; AUC = 0.77 validation set). Pathogen detection performance of plasma mNGS varied on the basis of pathogen and site of infection. To improve detection of virus, we developed a secondary transcriptomic classifier (AUC = 0.94 training set; AUC = 0.96 validation set). We combined host and microbial features to develop an integrated sepsis diagnostic model that identified 99% of microbiologically confirmed sepsis cases, and predicted sepsis in 74% of suspected and 89% of indeterminate sepsis cases. In summary, we suggest that integrating host transcriptional profiling and broad-range metagenomic pathogen detection from nucleic acid is a promising tool for sepsis diagnosis.
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Affiliation(s)
| | - Lucile Neyton
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Mazin Abdelghany
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Eran Mick
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Alejandra Jauregui
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Saharai Caldera
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Paula Hayakawa Serpa
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Rajani Ghale
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Jack Albright
- Department of Critical Care Medicine, Western University, London, Ontario, Canada
| | - Aartik Sarma
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Alexandra Tsitsiklis
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | | | - Stephanie A Christenson
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Kathleen Liu
- Department of Medicine, Division of Nephrology, University of California San Francisco, San Francisco, CA, USA
| | - Kirsten N Kangelaris
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Carolyn Hendrickson
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Pratik Sinha
- Washington University, St Louis, St. Louis, MO, USA
| | - Antonio Gomez
- Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA
| | - Norma Neff
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | | | - Sarah B Doernberg
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - Joseph L Derisi
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Michael A Matthay
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Carolyn S Calfee
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Charles R Langelier
- Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA.
- Chan Zuckerberg Biohub, San Francisco, CA, USA.
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10
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Chiscano-Camón L, Plata-Menchaca E, Ruiz-Rodríguez JC, Ferrer R. Fisiopatología del shock séptico. Med Intensiva 2022. [DOI: 10.1016/j.medin.2022.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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11
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Chiscano-Camón L, Plata-Menchaca E, Ruiz-Rodríguez JC, Ferrer R. [Pathophysiology of septic shock]. Med Intensiva 2022; 46 Suppl 1:1-13. [PMID: 38341256 DOI: 10.1016/j.medine.2022.03.010] [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: 02/01/2022] [Accepted: 03/20/2022] [Indexed: 02/12/2024]
Abstract
Sepsis and septic shock result from an inadequate host response to an infection, which causes organ dysfunction. The progression of this condition is manifested by the occurrence of successive clinical stages, resulting from the systemic inflammatory response secondary to the activation of different inflammatory mediators, leading to organ dysfunction. There is a high burden of evidence on the role of endotoxin in the pathogenesis of sepsis and its crucial role in triggering the inflammatory response in sepsis caused by gram-negative bacteria. The coagulation cascade activation in sepsis patients is part of the host's adaptive immune response to infection. The endothelium is the main target in sepsis, which is metabolically active and can.
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Affiliation(s)
- Luis Chiscano-Camón
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España
| | - Erika Plata-Menchaca
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España
| | - Juan Carlos Ruiz-Rodríguez
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España
| | - Ricard Ferrer
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España.
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12
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LaFavers K. Disruption of Kidney-Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health. Int J Mol Sci 2022; 23:1702. [PMID: 35163625 PMCID: PMC8835938 DOI: 10.3390/ijms23031702] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 02/07/2023] Open
Abstract
In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney-immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney-immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury.
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Affiliation(s)
- Kaice LaFavers
- Division of Nephrology and Hypertension, Department of Medicine, Indiana University School of Medicine, Evansville, IN 47708, USA
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13
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Ruiz-Rodriguez JC, Plata-Menchaca EP, Chiscano-Camón L, Ruiz-Sanmartin A, Pérez-Carrasco M, Palmada C, Ribas V, Martínez-Gallo M, Hernández-González M, Gonzalez-Lopez JJ, Larrosa N, Ferrer R. Precision medicine in sepsis and septic shock: From omics to clinical tools. World J Crit Care Med 2022; 11:1-21. [PMID: 35433311 PMCID: PMC8788206 DOI: 10.5492/wjccm.v11.i1.1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/23/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes. As it is associated with an increased risk of death, patients with this condition are candidates for receipt of a very well-structured and protocolized treatment. All patients should receive the fundamental pillars of sepsis management, which are infection control, initial resuscitation, and multiorgan support. However, specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms. Herein, we will review the framework for identifying subpopulations of patients with sepsis, septic shock, and multiorgan dysfunction who may benefit from specific therapies. Some of these approaches are still in the early stages of research, while others are already in routine use in clinical practice, but together will help in the effective generation and safe implementation of precision medicine in sepsis.
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Affiliation(s)
- Juan Carlos Ruiz-Rodriguez
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Erika P Plata-Menchaca
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Department of Intensive Care, Hospital Clínic de Barcelona, Barcelona 08036, Spain
| | - Luis Chiscano-Camón
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Adolfo Ruiz-Sanmartin
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Marcos Pérez-Carrasco
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Clara Palmada
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Vicent Ribas
- Data Analytics in Medicine, Digital Health Unit, Eurecat, Centre Tecnològic de Catalunya, Barcelona 08005, Spain
| | - Mónica Martínez-Gallo
- Immunology Division, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Diagnostic Immunology Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Manuel Hernández-González
- Immunology Division, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Diagnostic Immunology Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Juan J Gonzalez-Lopez
- Department of Clinical Microbiology, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Department of Microbiology and Genetics, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Nieves Larrosa
- Department of Clinical Microbiology, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Department of Microbiology and Genetics, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
| | - Ricard Ferrer
- Intensive Care Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
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14
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Zhang L, Zhang JP, Liu Y, Wang H, Cheng Y, Wang JH, Zhang WJ, Li ZZ, Guo JR. Plasma Transfusion Promoted Reprogramming CD4 + T Lymphocytes Immune Response in Severe Sepsis Mice Model Through Modulating the Exosome Protein Galectin 9. Cell Transplant 2021; 29:963689720947347. [PMID: 32907380 PMCID: PMC7784505 DOI: 10.1177/0963689720947347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a life-threatening disease that results in excessive stimulation of the host's immune cells. In the animal study, the purpose was to investigate the roles of fresh frozen plasma (FFP) transfusion in shaping the CD4+ T lymphocytes immune response through modulating the secreted exosome protein Galectin-9 in mice with severe sepsis. By using Western blot analysis, we first identified that the protein Galectin-9 is highly accumulated in the blood plasma of severe sepsis mice, and with transmission electron microscopy (TEM) and protein analysis, we found that Galectin-9 is a secreted exosome protein. Thereafter, we treated the severe sepsis mice with the antibiotic Cefuroxime Axetil; one group of mice received FFP transfusion and the other group of mice received normal saline. Surprisingly, the FFP transfusion reduced the secretion of exosome protein Galectin-9 and there was crosstalking between the exosome protein Galectin-9 and CD4+ T lymphocytes in mice with severe sepsis. Results showed that the proliferation of T helper (Th) cells (Th1 and Th17) was promoted, and regulatory T (Treg) cells' maintenance was inhibited in the sepsis mice after receiving FFP transfusion. Correspondingly, this immune reprogrammed activity shaped the inflammatory cytokine secretion with an increase in the interleukin (IL)-1β, IL-6, and interferon-gamma levels, while it decreased IL-10 levels. Taken together, it was suggested that FFP transfusion promoted reprogramming of CD4+ T lymphocytes' immune response through inhibiting the secretion of exosome protein Galectin-9 in mice with severe sepsis to relieve immunosuppression.
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Affiliation(s)
- Lei Zhang
- Department of Burn Surgery, First Hospital, Jilin University, Changchun, Jilin, P. R. China
| | - Jian-Ping Zhang
- Division of Life Sciences and Medicine, Department of Anesthesiology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P. R. China
| | - Yang Liu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China
| | - Huan Wang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Yong Cheng
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Jin-Huo Wang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Wen-Jie Zhang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Zhen-Zhou Li
- Ningxia Medical University, Gongli Hospital of Shanghai Pudong New Area Training Base, Shanghai, P. R. China
| | - Jian-Rong Guo
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China.,Ningxia Medical University, Gongli Hospital of Shanghai Pudong New Area Training Base, Shanghai, P. R. China
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15
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Llitjos JF, Bounab Y, Rousseau C, Dixneuf S, Rimbault B, Chiche JD, Textoris J, Pène F, Védrine C. Assessing the Functional Heterogeneity of Monocytes in Human Septic Shock: a Proof-of-Concept Microfluidic Assay of TNFα Secretion. Front Immunol 2021; 12:686111. [PMID: 34290706 PMCID: PMC8288100 DOI: 10.3389/fimmu.2021.686111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 01/31/2023] Open
Abstract
Objective The development of advanced single-cell technologies to decipher inter-cellular heterogeneity has enabled the dynamic assessment of individual cells behavior over time, overcoming the limitation of traditional assays. Here, we evaluated the feasibility of an advanced microfluidic assay combined to fluorescence microscopy to address the behavior of circulating monocytes from septic shock patients. Methods Seven septic shock patients and ten healthy volunteers were enrolled in the study. Using the proposed microfluidic assay we investigated the production over time of LPS-elicited TNFα by single monocytes encapsulated within droplets. Cellular endocytic activity was assessed by internalization of magnetic nanoparticles. Besides, we assessed HLA-DR membrane expression and LPS-induced TNFα production in monocytes through classical flow cytometry assays. Results Consistent with the flow cytometry results, the total number of TNFα molecules secreted by encapsulated single monocytes was significantly decreased in septic shock patients compared to healthy donors. TNFα production was dampened as soon as 30 and 60 minutes after LPS stimulation in monocytes from septic patients. Furthermore, the microfluidic assay revealed heterogeneous individual behavior of monocytes from septic shock patients. Of note, monocytes from both healthy donors and patients exhibited similar phagocytic activities over time. Conclusion The microfluidic assay highlights the functional heterogeneity of monocytes, and provides in-depth resolution in assessing the hallmark monocyte deactivation encountered in post-septic immunosuppression.
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Affiliation(s)
- Jean-François Llitjos
- Institut Cochin, U1016, CNRS UMR8104, Paris, France
- UMR-S8104, Université de Paris, Paris, France
- Médecine Intensive et Réanimation, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris APHP-CUP, Paris, France
| | - Yacine Bounab
- Bioassays, Microsystems and Optical Engineering, BIOASTER, Lyon, France
| | - Christophe Rousseau
- Institut Cochin, U1016, CNRS UMR8104, Paris, France
- UMR-S8104, Université de Paris, Paris, France
| | - Sophie Dixneuf
- Bioassays, Microsystems and Optical Engineering, BIOASTER, Lyon, France
| | - Blandine Rimbault
- Bioassays, Microsystems and Optical Engineering, BIOASTER, Lyon, France
| | - Jean-Daniel Chiche
- Institut Cochin, U1016, CNRS UMR8104, Paris, France
- UMR-S8104, Université de Paris, Paris, France
- Médecine Intensive et Réanimation, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris APHP-CUP, Paris, France
| | - Julien Textoris
- EA7426 “Pathophysiology of Injury-induced Immunosuppression”, Université Claude Bernard Lyon-1 - HCL- BioMérieux, Lyon, France
- Medical Diagnostic Discovery Department (MD3), bioMérieux S.A., Lyon, France
- Anesthesiology and Critical Care Medicine, HCL, Lyon, France
| | - Frédéric Pène
- Institut Cochin, U1016, CNRS UMR8104, Paris, France
- UMR-S8104, Université de Paris, Paris, France
- Médecine Intensive et Réanimation, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris APHP-CUP, Paris, France
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Albert Vega C, Karakike E, Bartolo F, Mouton W, Cerrato E, Brengel-Pesce K, Giamarellos-Bourboulis EJ, Mallet F, Trouillet-Assant S. Differential response induced by LPS and MPLA in immunocompetent and septic individuals. Clin Immunol 2021; 226:108714. [PMID: 33741504 DOI: 10.1016/j.clim.2021.108714] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/23/2021] [Accepted: 03/13/2021] [Indexed: 11/30/2022]
Abstract
Lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) induce, overall, similar transcriptional profiles in healthy individuals, although LPS has been shown to more potently induce pro-inflammatory cytokines. We explore herein whether MPLA could be considered as a synthetic replacement of LPS in immune functional assays to study anergy of immune cells in septic patients. Ex vivo whole blood stimulation with MPLA revealed a lower induction of the TNFα secreted protein in 20 septic patients (SP) compared to 10 healthy volunteers (HV), in agreement with monocyte anergy. Principal component analysis of the 93-gene molecular response to MPLA and LPS stimulation found that the main variability was driven by stimulation in HV and by pathophysiology in SP. MPLA was a stronger inducer of the HLA family genes than LPS in both populations, arguing for divergent signalling pathways downstream of TLR-4. In addition, MPLA appeared to present a more informative stratification potential within the septic population.
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Affiliation(s)
- Chloé Albert Vega
- Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France.
| | - Eleni Karakike
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece
| | | | - William Mouton
- Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France; Virpath - Université Lyon, CIRI, INSERM U1111, CNRS 5308, ENS, UCBL, Faculté de Médecine Lyon Est, 69372 Lyon, France
| | - Elisabeth Cerrato
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression, PI3, Claude Bernard Lyon 1 University-bioMérieux-Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437 Lyon, France
| | - Karen Brengel-Pesce
- Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France; EA 7426 Pathophysiology of Injury-Induced Immunosuppression, PI3, Claude Bernard Lyon 1 University-bioMérieux-Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437 Lyon, France
| | | | - François Mallet
- Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France; EA 7426 Pathophysiology of Injury-Induced Immunosuppression, PI3, Claude Bernard Lyon 1 University-bioMérieux-Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437 Lyon, France
| | - Sophie Trouillet-Assant
- Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France; Virpath - Université Lyon, CIRI, INSERM U1111, CNRS 5308, ENS, UCBL, Faculté de Médecine Lyon Est, 69372 Lyon, France.
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17
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Abstract
OBJECTIVES Decreased expression of human leukocyte antigen-DR on monocytes (mHLA-DR) is recognized as the most appropriate marker for the monitoring of immune alterations in septic patients and critically ill subjects. Its measurement has been established for years by flow cytometry, but remains under-used due to pre-analytical constraints. The objectives of the present work were to develop a rapid and robust one-step protocol. METHODS A novel, simplified protocol has been developed to measure mHLA-DR in whole blood using flow cytometry. It is a one-step procedure that includes red cell lysis, antibodies, and fixative reagents. It has been compared to the standardized routine protocol in two consecutive cohorts of septic shock patients (n = 37). Finally, the protocol was applied to a few subjects in point-of-care settings, by collecting capillary blood from fingerpricks. RESULTS Strong correlation was observed between the one-step method and routine protocol in 24 patients. After testing several stabilizing agents, the procedure was further optimized by adding a low-dose formaldehyde to the stain and lyse solution. This improved method was tested in a second cohort of 13 patients, and again strongly correlated to the routine protocol. Finally, the fingerprick and venous puncture samples were shown to provide similar results. CONCLUSIONS The present work demonstrates the feasibility of a bedside protocol for flow cytometry measurement of mHLA-DR in critically ill subjects. This helps overcome pre-analytical constraints previously identified, which have limited wider use of this biomarker in intensive care units. In addition, preliminary results from fingerprick samples are promising.
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Inverse Correlation Between Plasma Sphingosine-1-Phosphate and Ceramide Concentrations in Septic Patients and Their Utility in Predicting Mortality. Shock 2020; 51:718-724. [PMID: 30080743 PMCID: PMC6511430 DOI: 10.1097/shk.0000000000001229] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Supplemental Digital Content is available in the text Introduction: The aim of this study was to investigate the correlation between plasma sphingosine-1-phosphate (S1P) and ceramide concentrations in sepsis, and the possible mechanisms for altered expression. Methods: Plasma S1P and ceramide concentrations were measured by HPLC-ESI-MS/MS. HLA-DR (human leukocyte antigen-DR) expression on peripheral blood mononuclear cells was examined by flow cytometry. Platelet sphingosine kinases 1/2 (SphK1/2) mRNA expression, protein content, and enzyme activities were determined by qRT-PCR, western blot, and commercial enzyme assay kits, respectively. Results: Compared with healthy and ICU controls, septic patients had significantly decreased plasma S1P but increased ceramide concentrations (P < 0.05). S1P concentration was negatively associated with the ceramide concentration in the septic patients (r = −0.36, P < 0.05). Linear regression analysis found that plasma S1P and ceramide were linked not only to sequential (sepsis-related) organ failure assessment (SOFA) score but also the HLA-DR expression on circulating monocytes. An receiver operating characteristic analysis, including S1P, ceramide, SOFA score and HLA-DR, showed integrated analysis of S1P and ceramide as the better powerful predictors of septic lethality with area under the curve value of 0.95. More importantly, we found the platelet SphKs activities and the expression levels of SphK1 were significantly decreased in septic patients (P < 0.05). Linear regression analysis revealed platelet SphKs activity was positively associated with the plasma S1P concentration of the septic patients (r = −0.41, P = 0.02). Conclusions: Integrated analysis of plasma S1P and ceramide predict septic mortality with high accuracy. The decreased platelet SphK1 expression and subsequent reduced SphKs activity might be responsible for the decreased plasma S1P levels during sepsis.
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Insulin resistance in obese adolescents affects the expression of genes associated with immune response. Endocr Regul 2020; 53:71-82. [PMID: 31517622 DOI: 10.2478/enr-2019-0009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes. METHODS The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity. RESULTS It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance. CONCLUSIONS Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.
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Quantification of Immune Dysregulation by Next-generation Polymerase Chain Reaction to Improve Sepsis Diagnosis in Surgical Patients. Ann Surg 2019; 269:545-553. [PMID: 28692472 DOI: 10.1097/sla.0000000000002406] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also aims to evaluate this approach for improving identification of sepsis in these patients. BACKGROUND Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis. METHODS Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin. RESULTS Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysis: LCN2/HLA-DRA: 0.90 (0.85-0.96), MMP8/HLA-DRA: 0.89 (0.84-0.95), procalcitonin: 0.80 (0.73-0.88) (AUROC, confidence interval 95%), and also in the multivariate analysis: LCN2/HLA-DRA: 8.57 (2.25-32.62); MMP8/HLA-DRA: 8.03 (2.10-30.76), procalcitonin: 4.20 (1.15-15.43) [odds ratio (confidence interval 95%)]. Gene expression levels of HLA-DRA were an independent marker of hospital mortality. CONCLUSIONS Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.
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Xu J, Li J, Xiao K, Zou S, Yan P, Xie X, Xie L. Dynamic changes in human HLA-DRA gene expression and Th cell subsets in sepsis: Indications of immunosuppression and associated outcomes. Scand J Immunol 2019; 91:e12813. [PMID: 31386235 DOI: 10.1111/sji.12813] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 07/11/2019] [Accepted: 07/31/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sepsis is a life-threatening disease that is an immune disorder response that causes multiple organ dysfunction. In this study, we investigated the dynamic changes in mRNA expression of HLA-DRA gene and the specific transcription factor of helper T cell subsets to explore long-term immunophenotyping and its relationship with prognosis. METHODS Seventy-eight sepsis patients and twelve healthy controls were recruited in this study. Blood samples were collected at eight-time points during their septic course and were assayed for the gene expression of HLA-DRA and T helper cell subset-specific transcription factors (T-bet: Th1, GATA3: Th2, Foxp3: Treg, RORC: Th17). RESULTS The levels of HLA-DRA in survivors gradually increased but were maintained at lower levels in non-survivors. The specific transcription factor of Th1 and Th2 cells, T-bet and GATA-3 were significantly lower in sepsis patients than in normal controls, and the non-survivors showed significantly lower levels than the survivors (P < .05). RORC and FOXP3, the specific transcription factor of Treg and Th17 were significantly higher in survivors than in non-survivors and normal controls (P < .05). T-bet and GATA-3 had a linear correlation with HLA-DRA expression (P < .01). CONCLUSIONS The dynamic changes in HLA-DRA expression in peripheral blood could accurately reflect the immune status of sepsis patients, and the reduction in HLA-DRA may be an important reason for abnormal T cell differentiation. The sustained low levels of the Th cell subsets (Th1 and Th2) suggest the suppression of adaptive immunity, and this persistent immunosuppression may be the leading cause of death in septic patients.
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Affiliation(s)
- Jianqiao Xu
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Jia Li
- Department of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Kun Xiao
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Sifan Zou
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Peng Yan
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Xiaowei Xie
- Department of Respiratory and Critical Care Medicine, the first affiliated hospital of the Chinese PLA General Hospital, Beijing, China
| | - Lixin Xie
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
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22
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Malewicz NM, Walstein K, Heine T, Engler A, Bick A, Cox L, Dötsch A, Westendorf AM, Horn PA, Lindemann M, Peters J, Schäfer ST. Early suppression of peripheral mononuclear blood cells in sepsis in response to stimulation with cytomegalovirus, OKT3, and pokeweed mitogen. J Appl Physiol (1985) 2019; 127:1539-1547. [PMID: 31545153 DOI: 10.1152/japplphysiol.00438.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Critically ill patients are at risk for sepsis, and immunosuppressive mechanisms may prevail. Whether functional tests are helpful to detect immune alterations is largely unknown. Therefore, we tested the hypotheses that reactivity of peripheral blood mononuclear cells (PBMCs) to secrete interferon-γ (IFNγ) following stimulation in vitro is decreased in patients with early sepsis compared with postoperative patients. IFNγ secretion [enzyme-linked immunospot (ELISpot)] in response to stimulation with cytomegalovirus (CMV), pokeweed mitogen (PWM), muromonab-anti-CD3 (OKT3), and human leukocyte antigen (HLA)-DRA-mRNA expression and serum cytokine concentrations were repeatedly [days 1, 3, 5, and 7 after intensive care unit (ICU) admission] determined in patients with sepsis (n = 7) and patients undergoing major abdominal surgery (radical prostatectomy, cystectomy, n = 10). In a second cohort, HLA-DRA expression was assessed in 80 patients with sepsis, 30 postoperative patients, and 44 healthy volunteers (German clinical trials database no. 00007694). In patients with sepsis, IFNγ secretion (ELISpot) was decreased compared with controls after stimulation with CMV (P = 0.01), OKT3 (P = 0.02), and PWM (P = 0.02 on day 5), whereas unstimulated IFNγ secretion did not differ. HLA-DRA expression was also significantly decreased in patients with sepsis at all time points (P = 0.004) compared with postoperative surgical patients, a finding confirmed in the larger cohort. Reactivity of PBMCs to stimulation with CMV, PWM, and OKT3 as well as HLA-DRA expression was already decreased upon ICU admission in patients with sepsis when compared with postoperative controls, suggesting early depression of acquired immunity. ELISpot assays may help to clinically characterize the time course of immunocompetence in patients with sepsis.NEW & NOTEWORTHY We observed suppression of reactivity to stimulation with cytomegalovirus, muromonab-anti-CD3, and pokeweed mitogen in mononuclear blood cells of patients with early sepsis when compared with postoperative controls. Thus, there is early depression of acquired immunity in sepsis. Enzyme-linked immunospot assays may help to characterize immunocompetence in patients with sepsis.
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Affiliation(s)
- N M Malewicz
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - K Walstein
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - T Heine
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - A Engler
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - A Bick
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - L Cox
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - A Dötsch
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - A M Westendorf
- Institute for Medical Microbiology, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - P A Horn
- Institute for Transfusion Medicine, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - M Lindemann
- Institute for Transfusion Medicine, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - J Peters
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany
| | - S T Schäfer
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum, Essen, Germany.,Department of Anaesthesiology, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
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23
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Hu ZQ, Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, Hong GL, Lu ZQ, Zhao GJ. Partial Depletion of Regulatory T Cells Enhances Host Inflammatory Response Against Acute Pseudomonas aeruginosa Infection After Sepsis. Inflammation 2019; 41:1780-1790. [PMID: 29956070 DOI: 10.1007/s10753-018-0821-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Immune dysfunction contributes to secondary infection and worse outcomes in sepsis. Regulatory T cells (Tregs) have been implicated in sepsis-induced immunosuppression. Nevertheless, the role of Tregs in secondary infection after sepsis remains to be determined. In the present study, a two-hit model which mimics clinical conditions was used and the potential role of Tregs in secondary Pseudomonas aeruginosa infection post-sepsis was investigated. Results showed that mice were susceptible to secondary P. aeruginosa infection 3 days, but not 7 days, post-cecal ligation and puncture (CLP). The levels of IL-17A, IL-1β, and IL-6 remained low in CLP mice after P. aeruginosa infection, while the levels of IL-10 increased significantly. Additionally, increased number of Tregs in both lung and spleen was observed in "two-hit" mice. Injection with PC61 (anti-CD25) mAb reduced the number of Tregs by 50% in spleen and 60% in lung of septic mice. This partial depletion of Tregs elevated IL-17A, IL-1β, and IL-6 production and decreased IL-10 levels in septic mice with P. aeruginosa infection, leading to lower bacterial load, attenuation of lung injury, and improvement of survival. The present findings demonstrate that Tregs play a crucial role in secondary P. aeruginosa infection after sepsis by modulating the inflammatory response.
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Affiliation(s)
- Zhi-Qiang Hu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Intensive Care Unit, Ningbo First Hospital, Ningbo, 315000, China
| | - Yong-Ming Yao
- Burns Institute, First Affiliated Hospital of PLA General Hospital, Beijing, 100048, China
| | - Wei Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jia-Lan Bian
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lin-Jun Zhao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Long-Wang Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Guang-Liang Hong
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhong-Qiu Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,College of Nursing, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Guang-Ju Zhao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Abstract
Immune therapy to ease the burden of sepsis has thus far failed to consistently improve patient outcomes. Advances in cancer immune therapy and awareness that prolonged immune-suppression in sepsis can leave patients vulnerable to secondary infection and death have driven resurgence in the field of sepsis immune-therapy investigation. As we develop and evaluate these novel therapies, we must learn from past experiences where single-mediator targeted immune therapies were blindly delivered to heterogeneous patient cohorts with complex and evolving immune responses. Advances in genomics, proteomics, metabolomics, and point-of-care technology, coupled with a better understanding of sepsis pathogenesis, have meant that personalised immune-therapy is on the horizon. Here, we review the complex immune pathogenesis in sepsis and the contemporary immune therapies that are being investigated to manipulate this response. An outline of the immune biomarkers that may be used to support this approach is also provided.
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Affiliation(s)
- Roger Davies
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Kieran O’Dea
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
| | - Anthony Gordon
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
- Imperial College Healthcare NHS Trust, London, UK
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25
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Minchenko OH, Tsymbal DO, Minchenko DO, Prylutska SV, Hnatiuk OS, Prylutskyy YI, Tsierkezos NG, Ritter U. Single-walled carbon nanotubes affect the expression of genes associated with immune response in normal human astrocytes. Toxicol In Vitro 2018; 52:122-130. [PMID: 29906516 DOI: 10.1016/j.tiv.2018.06.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 06/02/2018] [Accepted: 06/08/2018] [Indexed: 12/11/2022]
Abstract
The effect of single-walled carbon nanotubes (SWCNTs) on the expression of a subset of immune response, apoptosis and cell proliferation -associated genes was studied in normal human astrocytes (line NHA/TS). In the cells treated with SWCNTs (2, 10 and 50 ng/ml of medium for 24 h) we observed a strong dose-dependent down-regulation of the expression of a cell surface glycoproteins HLA-DRA (major histocompatibility complex, class II, DR alpha) and HLA-DRB1. At the same time, the expression of HLA-F (major histocompatibility complex, class I, F), LMNB1 (lamin B1), and HTRA1 (high temperature requirement A1) genes as well as the level of miR-190b and miR-7 was up-regulated in NHA/TS subjected to different concentrations of SWCNTs. After 24 h of treatment with SWCNTs we detected a dose-dependent suppression of PHLDA2 (pleckstrin homology-like domain, family A, member 2) gene expression in these cells. Obtained data show that SWCNTs may affect an immune response, in particular through suppression of HLA-DRA and HLA-DRB1 gene expressions and that miR-190b and miR-7 possibly participated in this suppression. Deregulation of lamin B1 expression indicates the possibility of alterations in genome stability following treatment of astrocytes with SWCNTs. Thus, more caution is needed in biomedical application of SWCNTs.
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Affiliation(s)
- Oleksandr H Minchenko
- Department of Molecular Biology, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovycha Str, Kyiv 01601, Ukraine.
| | - Dariia O Tsymbal
- Department of Molecular Biology, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovycha Str, Kyiv 01601, Ukraine
| | - Dmytro O Minchenko
- Department of Molecular Biology, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovycha Str, Kyiv 01601, Ukraine; Department of Pediatrics, Bohomolets National Medical University, 13 Taras Shevchenko Blvd., Kyiv 01601, Ukraine
| | - Svitlana V Prylutska
- Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str, 01601 Kyiv, Ukraine
| | - Oksana S Hnatiuk
- Department of Molecular Biology, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovycha Str, Kyiv 01601, Ukraine
| | - Yuriy I Prylutskyy
- Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str, 01601 Kyiv, Ukraine
| | - Nikos G Tsierkezos
- Technische Universität Ilmenau, Institut für Chemie und Biotechnik, 25 Weimarer Str., 98693 Ilmenau, Germany.
| | - Uwe Ritter
- Technische Universität Ilmenau, Institut für Chemie und Biotechnik, 25 Weimarer Str., 98693 Ilmenau, Germany
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26
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Siegler BH, Uhle F, Lichtenstern C, Arens C, Bartkuhn M, Weigand MA, Weiterer S. Impact of human sepsis on CCCTC-binding factor associated monocyte transcriptional response of Major Histocompatibility Complex II components. PLoS One 2018; 13:e0204168. [PMID: 30212590 PMCID: PMC6136812 DOI: 10.1371/journal.pone.0204168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022] Open
Abstract
Background Antigen presentation on monocyte surface to T-cells by Major Histocompatibility Complex, Class II (MHC-II) molecules is fundamental for pathogen recognition and efficient host response. Accordingly, loss of Major Histocompatibility Complex, Class II, DR (HLA-DR) surface expression indicates impaired monocyte functionality in patients suffering from sepsis-induced immunosuppression. Besides the impact of Class II Major Histocompatibility Complex Transactivator (CIITA) on MHC-II gene expression, X box-like (XL) sequences have been proposed as further regulatory elements. These elements are bound by the DNA-binding protein CCCTC-Binding Factor (CTCF), a superordinate modulator of gene transcription. Here, we hypothesized a differential interaction of CTCF with the MHC-II locus contributing to an altered monocyte response in immunocompromised septic patients. Methods We collected blood from six patients diagnosed with sepsis and six healthy controls. Flow cytometric analysis was used to identify sepsis-induced immune suppression, while inflammatory cytokine levels in blood were determined via ELISA. Isolation of CD14++ CD16—monocytes was followed by (i) RNA extraction for gene expression analysis and (ii) chromatin immunoprecipitation to assess the distribution of CTCF and chromatin modifications in selected MHC-II regions. Results Compared to healthy controls, CD14++ CD16—monocytes from septic patients with immune suppression displayed an increased binding of CTCF within the MHC-II locus combined with decreased transcription of CIITA gene. In detail, enhanced CTCF enrichment was detected on the intergenic sequence XL9 separating two subregions coding for MHC-II genes. Depending on the relative localisation to XL9, gene expression of both regions was differentially affected in patients with sepsis. Conclusion Our experiments demonstrate for the first time that differential CTCF binding at XL9 is accompanied by uncoupled MHC-II expression as well as transcriptional and epigenetic alterations of the MHC-II regulator CIITA in septic patients. Overall, our findings indicate a sepsis-induced enhancer blockade mediated by variation of CTCF at the intergenic sequence XL9 in altered monocytes during immunosuppression.
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Affiliation(s)
- Benedikt Hermann Siegler
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
| | - Florian Uhle
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
| | - Christoph Lichtenstern
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
| | - Christoph Arens
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
| | - Marek Bartkuhn
- Institute for Genetics, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58–62, Giessen, Hessen, Germany
| | - Markus Alexander Weigand
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
| | - Sebastian Weiterer
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg, Germany
- * E-mail:
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Combined quantification of procalcitonin and HLA-DR improves sepsis detection in surgical patients. Sci Rep 2018; 8:11999. [PMID: 30097607 PMCID: PMC6086887 DOI: 10.1038/s41598-018-30505-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/31/2018] [Indexed: 01/09/2023] Open
Abstract
Early recognition of sepsis is a key factor to improve survival to this disease in surgical patients, since it allows prompt control of the infectious source. Combining pro-inflammatory and immunosupression biomarkers could represent a good strategy to improve sepsis detection. Here we evaluated the combination of procalcitonin (PCT) with gene expression levels of HLA-DRA to detect sepsis in a cohort of 154 surgical patients (101 with sepsis and 53 with no infection). HLA-DRA expression was quantified using droplet digital PCR, a next-generation PCR technology. Area under the receiver operating curve analysis (AUROC) showed that the PCT/HLA-DRA ratio outperformed PCT to detect sepsis (AUROC [CI95%], p): PCT: 0.80 [0.73–0.88], <0.001; PCT/HLA-DRA: 0.85 [0.78–0.91], <0.001. In the multivariate analysis, the ratio showed a superior ability to predict sepsis compared to that of PCT (OR [CI 95%], p): PCT/HLA-DRA: 7.66 [1.82–32.29], 0.006; PCT: 4.21 [1.15–15.43] 0.030. Multivariate analysis was confirmed using a new surgical cohort with 74 sepsis patients and 21 controls: PCT/HLA-DRA: 34.86 [1.22–995.08], 0.038; PCT: 5.52 [0.40–75.78], 0.201. In conclusion, the combination of PCT with HLA-DRA is a promising strategy for improving sepsis detection in surgical patients.
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28
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Meydan C, Bekenstein U, Soreq H. Molecular Regulatory Pathways Link Sepsis With Metabolic Syndrome: Non-coding RNA Elements Underlying the Sepsis/Metabolic Cross-Talk. Front Mol Neurosci 2018; 11:189. [PMID: 29922126 PMCID: PMC5996041 DOI: 10.3389/fnmol.2018.00189] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/15/2018] [Indexed: 01/04/2023] Open
Abstract
Sepsis and metabolic syndrome (MetS) are both inflammation-related entities with high impact for human health and the consequences of concussions. Both represent imbalanced parasympathetic/cholinergic response to insulting triggers and variably uncontrolled inflammation that indicates shared upstream regulators, including short microRNAs (miRs) and long non-coding RNAs (lncRNAs). These may cross talk across multiple systems, leading to complex molecular and clinical outcomes. Notably, biomedical and RNA-sequencing based analyses both highlight new links between the acquired and inherited pathogenic, cardiac and inflammatory traits of sepsis/MetS. Those include the HOTAIR and MIAT lncRNAs and their targets, such as miR-122, −150, −155, −182, −197, −375, −608 and HLA-DRA. Implicating non-coding RNA regulators in sepsis and MetS may delineate novel high-value biomarkers and targets for intervention.
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Affiliation(s)
- Chanan Meydan
- Department of Internal Medicine, Mayanei Hayeshua Medical Center, Bnei Brak, Israel
| | - Uriya Bekenstein
- The Department of Biological Chemistry, The Edmond and Lilly Safra Center for Brain Sciences, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hermona Soreq
- The Department of Biological Chemistry, The Edmond and Lilly Safra Center for Brain Sciences, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Rasmussen G, Cajander S, Bäckman A, Källman J, Söderquist B, Strålin K. Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteremia. Microbiol Immunol 2018; 61:442-451. [PMID: 28862321 DOI: 10.1111/1348-0421.12533] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/23/2017] [Accepted: 08/25/2017] [Indexed: 01/16/2023]
Abstract
To improve management of Staphylococcus aureus bacteremia (SAB), better understanding of host-pathogen interactions is needed. In vitro studies have shown that S. aureus bacteria induce dose-dependent immunosuppression that is evidenced by reduced expression of major histocompatibility complex (MHC) class II on antigen presenting cells. Thus, the aim of this study was to determine whether expression of the MHC class II-related genes HLA-DRA and CD74 is more greatly reduced in complicated SAB, with its probable higher loads of S. aureus, than in uncomplicated SAB. Adult patients with SAB were prospectively included and blood samples taken on the day of confirmation of SAB (Day 1) and on Days 2, 3, 5 and 7. HLA-DRA and CD74 mRNA expression was determined by quantitative reverse transcription PCR. Sepsis was defined according to the Sepsis-3 classification and SAB was categorized as complicated in patients with deep-seated infection and/or hematogenous seeding. Twenty patients with SAB were enrolled and samples obtained on all assessment days. HLA-DRA and CD74 expression did not differ significantly between patients with SAB and sepsis (n = 13) and those without sepsis (n = 7) on any assessment day. However, patients with complicated SAB (n = 14) had significantly weaker HLA-DRA expression on all five assessment days than patients with uncomplicated SAB (n = 6). Additionally, they tended to have weaker CD74 expressions. Neutrophil, monocyte and leukocyte counts did not differ significantly between complicated and uncomplicated SAB. In conclusion, patients with complicated SAB show weaker HLA-DRA expression than those with uncomplicated SAB during the first week of bacteremia.
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Affiliation(s)
- Gunlög Rasmussen
- Department of Infectious Diseases, Örebro University Hospital, Örebro University, Örebro.,Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro
| | - Sara Cajander
- Department of Infectious Diseases, Örebro University Hospital, Örebro University, Örebro.,Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro
| | - Anders Bäckman
- Faculty of Medicine and Health, Department of Clinical Research Laboratory, Örebro University, Örebro
| | - Jan Källman
- Department of Infectious Diseases, Örebro University Hospital, Örebro University, Örebro.,Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro
| | - Bo Söderquist
- Department of Infectious Diseases, Örebro University Hospital, Örebro University, Örebro.,Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro
| | - Kristoffer Strålin
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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Cajander S, Rasmussen G, Tina E, Magnuson A, Söderquist B, Källman J, Strålin K. Dynamics of monocytic HLA-DR expression differs between bacterial etiologies during the course of bloodstream infection. PLoS One 2018; 13:e0192883. [PMID: 29466395 PMCID: PMC5821339 DOI: 10.1371/journal.pone.0192883] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/31/2018] [Indexed: 12/26/2022] Open
Abstract
Objective In the pathogenesis of sepsis, activation of both pro- and anti-inflammatory responses are key components, but knowledge is lacking on the association between bacterial etiology and development of dysregulated responses with sustained immunosuppression. The aim of this study was to evaluate how the immunosupression marker HLA-DR on monocytes (mHLA-DR) is associated with bacterial etiology and markers of inflammation during the clinical trajectory of bloodstream infection (BSI). Methods Ninety-one adults, predominantly non-ICU patients, with BSI caused by Streptococcus pneumoniae (n = 27), Staphylococcus aureus (n = 22), Escherichia coli/Klebsiella pneumoniae (n = 23), and other species (n = 19) were prospectively included, and sampled on admission (day 0) and on days 1–2, 3, 7±1, 14±2, and 28±4. Results The dynamics of mHLA-DR, measured by flow cytometry, differed significantly between etiology groups (p<0.001). Patients with S. pneumoniae and S. aureus BSI demonstrated low initial mHLA-DR, with the S. aureus group showing delayed recovery over time. Eleven patients (55% S. aureus) had negative outcome (secondary bacteremia or death) and they demonstrated sustained C-reactive protein elevation, neutrophilia, lymphocytopenia, and loss of mHLA-DR. Conclusions Dynamics of mHLA-DR varied according to the bacterial etiology of infection, with delayed recovery in patients with S. aureus BSI. Patients with negative outcome showed sustained CRP elevation, neutrophilia, lymphocytopenia, and low levels of mHLA-DR, supporting the theory of a dysregulated host response with persistent inflammation and immunosuppression in late stages of deleterious sepsis.
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Affiliation(s)
- Sara Cajander
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- * E-mail:
| | - Gunlög Rasmussen
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Elisabet Tina
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Anders Magnuson
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Bo Söderquist
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jan Källman
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Kristoffer Strålin
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
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31
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Sharma D, Jakkampudi A, Reddy R, Reddy PB, Patil A, Murthy HVV, Rao GV, Reddy DN, Talukdar R. Association of Systemic Inflammatory and Anti-inflammatory Responses with Adverse Outcomes in Acute Pancreatitis: Preliminary Results of an Ongoing Study. Dig Dis Sci 2017; 62:3468-3478. [PMID: 29080144 DOI: 10.1007/s10620-017-4813-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 10/16/2017] [Indexed: 12/12/2022]
Abstract
INTRODUCTION This paper reports preliminary data of an ongoing study that evaluates the association of systemic inflammatory response (SIRS) with early severe acute pancreatitis (ESAP) and compensatory anti-inflammatory response syndrome (characterized by HLA-DR down-regulation) with infected pancreatic necrosis (IPN). METHODS Consecutive patients presenting within 72 h of symptom onset with organ dysfunction and/or local complications were included. Following parameters were recorded: demographics, etiology, SIRS, APACHE II, creatinine, BUN. Circulating IL-8, IL-6, IL-10, TNF-alpha concentrations and expression of HLA-DR and IL-10 by qRT-PCR in PBMCs were measured. Strength of associations of cytokine concentration and HLA-DR/IL-10 expression with outcomes was expressed as Hedges' G and relative risk (95% CI). RESULTS Twenty-eight patients (10 MSAP; 18 SAP) fulfilled inclusion criteria. Twelve patients had ESAP and eight presented with organ failure. Admission SIRS worsened in eight (28.6%) patients over 48 h. Sixteen (57.1%) patients developed primary IPN. Twenty-one (75%) patients had HLA-DR down-regulation during the first week, which persisted to the second week in 12 (42.9%) patients. IL-8, IL-6, and TNF-α progressively increased from healthy controls to MAP to MSAP to SAP. IL-6 and TNF-α was higher in the patients who developed ESAP (p = 0.01 and 0.05, respectively). Patients who died within the first week also had a significantly elevated concentration of IL-6 and TNF-α (p = 0.02 and 0.01, respectively). The relative risk (95% CI) of developing primary IPN with persistent HLA-DR down-regulation till the second week of illness was 11.3 (1.6-82.4; p = 0.01). CONCLUSIONS Our study objectively demonstrates significant association of ESAP and early mortality with primary cytokine response, and development of IPN with persistent HLA-DR down-regulation.
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Affiliation(s)
- Deepesh Sharma
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661 Somajiguda, Hyderabad, Telangana, 500082, India
| | - Aparna Jakkampudi
- Division of Basic and Translational Sciences, Asian Healthcare Foundation, Hyderabad, India
- Wellcome DBT India Alliance Laboratories, Asian Healthcare Foundation, Hyderabad, India
| | - Ratnakar Reddy
- Division of Basic and Translational Sciences, Asian Healthcare Foundation, Hyderabad, India
| | | | - Aasish Patil
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661 Somajiguda, Hyderabad, Telangana, 500082, India
| | - H V V Murthy
- Department of Biostatistics, Asian Institute of Gastroenterology, Hyderabad, India
| | - G Venkat Rao
- Department of Surgical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661 Somajiguda, Hyderabad, Telangana, 500082, India
| | - Rupjyoti Talukdar
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661 Somajiguda, Hyderabad, Telangana, 500082, India.
- Division of Basic and Translational Sciences, Asian Healthcare Foundation, Hyderabad, India.
- Wellcome DBT India Alliance Laboratories, Asian Healthcare Foundation, Hyderabad, India.
- Pancreas Research Group, Asian Healthcare Foundation, 6-3-661 Somajiguda, Hyderabad, Telangana, 500082, India.
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Pfortmueller CA, Meisel C, Fux M, Schefold JC. Assessment of immune organ dysfunction in critical illness: utility of innate immune response markers. Intensive Care Med Exp 2017; 5:49. [PMID: 29063386 PMCID: PMC5653680 DOI: 10.1186/s40635-017-0163-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/12/2017] [Indexed: 12/15/2022] Open
Abstract
In critically ill patients, organ dysfunctions are routinely assessed, monitored, and treated. Mounting data show that substantial critical illness-induced changes in the immune system can be observed in most ICU patients and that not only "hyper-inflammation" but also persistence of an anti-inflammatory phenotype (as in sepsis-associated immunosuppression) is associated with increased morbidity and mortality. Despite common perception, changes in functional immunity cannot be adequately assessed by routine inflammatory biomarkers such as C-reactive protein, procalcitonin, or numerical analysis of leukocyte (sub)-counts. Cytokines appear also not suited due to their short half-life and pleiotropy, their unexclusive origin from immune cells, and their potential to undergo antagonization by circulating inactivating molecules. Thus, beyond leukocyte quantification and use of routine biomarkers, direct assessment of immune cell function seems required to characterize the immune systems' status. This may include determination of, e.g., ex vivo cellular cytokine release, phagocytosis activity, and/or antigen-presenting capacity. In this regard, standardized flow-cytometric assessment of the major histocompatibility-II complex human leukocyte antigen (-D related) (HLA-DR) has gained particular interest. Monocytic HLA-DR (mHLA-DR) controls the interplay between innate and adaptive immunity and may serve as a "global" biomarker of injury-associated immunosuppression, and its decreased expression is associated with adverse clinical outcomes (e.g., secondary infection risk, mortality). Importantly, recent data demonstrate that injury-associated immunosuppression can be reversed-opening up new therapeutic avenues in affected patients. Here we discuss the potential scientific and clinical value of assessment of functional immunity with a focus on monocytes/macrophages and review the current state of knowledge and potential perspectives for affected critically ill patients.
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Affiliation(s)
- Carmen Andrea Pfortmueller
- Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 10, 3010, Bern, Switzerland
| | - Christian Meisel
- Department of Medical Immunology, Charité University Hospital Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Department of Immunology, Labor Berlin Charité Vivantes, Sylter Strasse 2, 13353, Berlin, Germany
| | - Michaela Fux
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Joerg C Schefold
- Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 10, 3010, Bern, Switzerland.
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Smoking, Gender, and Overweight Are Important Influencing Factors on Monocytic HLA-DR before and after Major Cancer Surgery. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5216562. [PMID: 29104871 PMCID: PMC5591895 DOI: 10.1155/2017/5216562] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 05/24/2017] [Accepted: 07/09/2017] [Indexed: 12/30/2022]
Abstract
Background Monocytic human leukocyte antigen D related (mHLA-DR) is essential for antigen-presentation. Downregulation of mHLA-DR emerged as a general biomarker of impaired immunity seen in patients with sepsis and pneumonia and after major surgery. Influencing factors of mHLA-DR such as age, overweight, diabetes, smoking, and gender remain unclear. Methods We analyzed 20 patients after esophageal or pancreatic resection of a prospective, randomized, placebo-controlled, double-blind trial (placebo group). mHLA-DR was determined from day of surgery (od) until postoperative day (pod) 5. Statistical analyses were performed using multivariate generalized estimating equation analyses (GEE), nonparametric multivariate analysis of longitudinal data, and univariate post hoc nonparametric Mann–Whitney tests. Results In GEE, smoking and gender were confirmed as significant influencing factors over time. Univariate analyses of mHLA-DR between smokers and nonsmokers showed lower preoperative levels (p = 0.010) and a trend towards lower levels on pod5 (p = 0.056) in smokers. Lower mHLA-DR was seen in men on pod3 (p = 0.038) and on pod5 (p = 0.026). Overweight patients (BMI > 25 kg/m2) had lower levels of mHLA-DR on pod3 (p = 0.039) and pod4 (p = 0.047). Conclusion Smoking is an important influencing factor on pre- and postoperative immune function while postoperative immune function was influenced by gender and overweight. Clinical trial registered with ISRCTN27114642.
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Timmermans K, Leijte GP, Kox M, Scheffer GJ, Blijlevens NMA, Pickkers PP. Release of Danger-Associated Molecular Patterns following Chemotherapy Does Not Induce Immunoparalysis in Leukemia Patients. Acta Haematol 2017; 138:39-43. [PMID: 28723682 DOI: 10.1159/000477530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/13/2017] [Indexed: 11/19/2022]
Abstract
Chemotherapy may result in the release of danger-associated molecular patterns (DAMPs), which can cause immunoparalysis (deactivation of the immune system). We investigated DAMPs following chemotherapy and their relationship with markers of immunoparalysis in leukemia patients. In 6 patients with acute myeloid leukemia or myelodysplastic syndrome and 12 healthy subjects, DAMPs, cytokines, and markers of immunoparalysis were determined before and during the first week after chemotherapy initiation. In the patients, plasma levels of nuclear DNA (a marker of general DAMP release) were profoundly increased before chemotherapy and further increased 4-6 h afterwards, while the specific DAMP mitochondrial DNA showed only a trend towards increase. Circulating cytokine levels did not change following chemotherapy. Leukocyte cytokine production capacity and HLA-DR expression were similar in patients and healthy controls until day 4 when leukocytes were found to be virtually absent. In conclusion, in the early phase following chemotherapy in leukemia patients, increased DAMP release does not induce immunoparalysis.
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Affiliation(s)
- Kim Timmermans
- Department of Intensive Care Medicine, Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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35
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Borken F, Markwart R, Requardt RP, Schubert K, Spacek M, Verner M, Rückriem S, Scherag A, Oehmichen F, Brunkhorst FM, Rubio I. Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response. THE JOURNAL OF IMMUNOLOGY 2017; 198:4781-4791. [DOI: 10.4049/jimmunol.1700142] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 04/10/2017] [Indexed: 12/15/2022]
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Cajander S, Tina E, Bäckman A, Magnuson A, Strålin K, Söderquist B, Källman J. Quantitative Real-Time Polymerase Chain Reaction Measurement of HLA-DRA Gene Expression in Whole Blood Is Highly Reproducible and Shows Changes That Reflect Dynamic Shifts in Monocyte Surface HLA-DR Expression during the Course of Sepsis. PLoS One 2016; 11:e0154690. [PMID: 27144640 PMCID: PMC4856385 DOI: 10.1371/journal.pone.0154690] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 04/18/2016] [Indexed: 12/21/2022] Open
Abstract
Introduction A decrease in the expression of monocyte surface protein HLA-DR (mHLA-DR), measured by flow cytometry (FCM), has been suggested as a marker of immunosuppression and negative outcome in severe sepsis. However, FCM is not always available due to sample preparation that limits its use to laboratory operational hours. In this prospective study we evaluated dynamic changes in mHLA-DR expression during sepsis in relation to changes in HLA-DRA gene expression and Class II transactivator (CIITA), measured by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Aims The aims of this study were: 1. to validate the robustness of qRT-PCR measurement of HLA-DRA- and CIITA–mRNA expression, in terms of reproducibility; and 2. to see if changes in expression of these genes reflect changes in mHLA-DR expression during the course of severe and non-severe bacteraemic sepsis. Methods and Findings Blood samples were collected from 60 patients with bacteraemic sepsis on up to five occasions during Days 1–28 after hospital admission. We found the reproducibility of the qRT-PCR method to be high by demonstrating low threshold variations (<0.11 standard deviation (SD)) of the qRT-PCR system, low intra-assay variation of Ct-values within triplicates (≤0.15 SD) and low inter-assay variations (12%) of the calculated target gene ratios. Our results also revealed dynamic HLA-DRA expression patterns during the course of sepsis that reflected those of mHLA-DR measured by FCM. Furthermore, HLA-DRA and mHLA-DR recovery slopes in patients with non-severe sepsis differed from those in patients with severe sepsis, shown by mixed model for repeated measurements (p<0.05). However, during the first seven days of sepsis, PCR-measurements showed a higher magnitude of difference between the two sepsis groups. Mean differences (95% CI) between severe sepsis (n = 20) and non-severe sepsis (n = 40) were; on day 1–2, HLA-DRA 0.40 (0.28–0.59) p<0.001, CIITA 0.48 (0.32–0.72) p = 0.005, mHLA-DR 0.63 (0.45–1.00) p = 0.04, day 7 HLA-DRA 0.59 (0.46–0.77) p<0.001, CIITA 0.56 (0.41–0.76) p<0.001, mHLA-DR 0.81 (0.66–1.00) p = 0.28. Conclusion We conclude that qRT-PCR measurement of HLA-DRA expression is robust, and that this method appears to be preferable to FCM in identifying patients with severe sepsis that may benefit from immunostimulation.
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Affiliation(s)
- Sara Cajander
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, SE 70182 Örebro, Sweden
- * E-mail:
| | - Elisabet Tina
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Anders Bäckman
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Anders Magnuson
- Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Kristoffer Strålin
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Bo Söderquist
- Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jan Källman
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, SE 70182 Örebro, Sweden
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Bermejo-Martin JF, Andaluz-Ojeda D, Almansa R, Gandía F, Gómez-Herreras JI, Gomez-Sanchez E, Heredia-Rodríguez M, Eiros JM, Kelvin DJ, Tamayo E. Defining immunological dysfunction in sepsis: A requisite tool for precision medicine. J Infect 2016; 72:525-36. [PMID: 26850357 DOI: 10.1016/j.jinf.2016.01.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 01/24/2016] [Accepted: 01/26/2016] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs. METHODS Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity. RESULTS Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of [antigen presentation](FID1), [T and B lymphocytes] (FID2), [natural killer cells] (FID3), [relative increase in T regulatory cells] (FID4), [increased expression of PD-1 and PD-ligand1](FID5), [low levels of immunoglobulins](FID6), [low circulating counts of neutrophils and/or increased immature forms in non survivors](FID7), [hyper-cytokinemia] (FID8), [complement consumption] (FID9), [defective bacterial killing by neutrophil extracellular traps](FID10). CONCLUSIONS This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs.
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Affiliation(s)
- Jesús F Bermejo-Martin
- Infection and Immunity Medical Investigation Unit (IMI), Hospital Clínico Universitario de Valladolid, SACYL/IECSCYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - David Andaluz-Ojeda
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Medicina Intensiva, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Raquel Almansa
- Infection and Immunity Medical Investigation Unit (IMI), Hospital Clínico Universitario de Valladolid, SACYL/IECSCYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Francisco Gandía
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Medicina Intensiva, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Jose Ignacio Gómez-Herreras
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Esther Gomez-Sanchez
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - María Heredia-Rodríguez
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Jose Maria Eiros
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - David J Kelvin
- Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada; Sezione di Microbiologia Sperimentale e Clinica, Dipartimento di Scienze Biomediche, Universita' degli Studi di Sassari, Piazza Università, 21, 07100 Sassari SS, Italy; International Institute of Infection and Immunity, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong Province, PR China.
| | - Eduardo Tamayo
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
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Timmermans K, Kox M, Vaneker M, van den Berg M, John A, van Laarhoven A, van der Hoeven H, Scheffer GJ, Pickkers P. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med 2016; 42:551-561. [PMID: 26912315 PMCID: PMC5413532 DOI: 10.1007/s00134-015-4205-3] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/24/2015] [Indexed: 01/08/2023]
Abstract
PURPOSE Danger-associated molecular patterns (DAMPs) released of trauma could contribute to an immune suppressed state that renders patients vulnerable towards nosocomial infections. We investigated DAMP release in trauma patients, starting in the prehospital phase, and assessed its relationship with immune suppression and nosocomial infections. METHODS Blood was obtained from 166 adult trauma patients at the trauma scene, emergency room (ER), and serially afterwards. Circulating levels of DAMPs and cytokines were determined. Immune suppression was investigated by determination of HLA-DRA gene expression and ex vivo lipopolysaccharide-stimulated cytokine production. RESULTS Compared with healthy controls, plasma levels of nuclear DNA (nDNA) and heat shock protein-70 (HSP70) but not mitochondrial DNA were profoundly increased immediately following trauma and remained elevated for 10 days. Plasma cytokines were increased at the ER, and levels of anti-inflammatory IL-10 but not of pro-inflammatory cytokines peaked at this early time-point. HLA-DRA expression was attenuated directly after trauma and did not recover during the follow-up period. Plasma nDNA (r = -0.24, p = 0.006) and HSP70 (r = -0.38, p < 0.0001) levels correlated negatively with HLA-DRA expression. Ex vivo cytokine production revealed an anti-inflammatory phenotype already at the trauma scene which persisted in the following days, characterized by attenuated TNF-α and IL-6, and increased IL-10 production. Finally, higher concentrations of nDNA and a further decrease of HLA-DRA expression were associated with infections. CONCLUSIONS Plasma levels of DAMPs are associated with immune suppression, which is apparent within minutes/hours following trauma. Furthermore, aggravated immune suppression during the initial phase following trauma is associated with increased susceptibility towards infections.
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Affiliation(s)
- Kim Timmermans
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Department of Anesthesiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Matthijs Kox
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Department of Anesthesiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michiel Vaneker
- Department of Anesthesiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Helicopter Emergency Medical Service, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten van den Berg
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Aaron John
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Department of Anesthesiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Arjan van Laarhoven
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans van der Hoeven
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Gert Jan Scheffer
- Department of Anesthesiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Internal Mail 710, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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Galbraith N, Walker S, Galandiuk S, Gardner S, Polk HC. The Significance and Challenges of Monocyte Impairment: For the Ill Patient and the Surgeon. Surg Infect (Larchmt) 2016; 17:303-12. [PMID: 26958709 DOI: 10.1089/sur.2015.245] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Trauma, major elective surgery, and overt sepsis can lead to a cascade of immunological change. A subset of these patients will have a degree of immune suppression that leads to hyporesponsive innate defenses, increasing the risk of infective co-morbidity and death. This article is an overview of monocyte impairment in the high-risk surgical patient. Specifically, our primary focus is on observations made pertaining to monocyte function and pathophysiological mechanisms underpinning this impairment. Clinical factors influencing monocyte function are also discussed. METHODS A Pubmed search was conducted to review aspects of monocyte impairment in the surgical patient. Search terms included "monocyte impairment," "immunoparalysis," and "endotoxin tolerance" cross-referenced against terms including "trauma," "major surgery," and "sepsis." RESULTS Findings revealed a broad variety of monocyte defects reported in surgical patients. They ranged from altered cytokine responses, particularly ex vivo TNF-α production, to impaired antigen presentation such as depressed HLA-DR expression. The latter is the most commonly described marker of secondary infection and death. Studies of underlying mechanisms have commonly utilized a model of endotoxin tolerance with in vitro monocytes, revealing a complex array of dysregulated pathways. For our purposes, endotoxin tolerance and monocyte impairment are sufficiently similar entities to permit further study as a single subject. In the high risk patient, microRNAs (also referred to as miRNA or miR) are emerging as potential biomarkers that may modify such pathways. Creation of a reliable impaired human monocyte model could be important to all such considerations. CONCLUSION Impairment of monocyte function continues to be predictive of nosocomial infection, multi-organ failure, and death in some surgical patients. However, the optimal marker that could identify a patient as high risk early enough, and whether it might guide potential therapy, still is yet to be proven.
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Affiliation(s)
- Norman Galbraith
- Department of Surgery, University of Louisville School of Medicine , Louisville, Kentucky
| | - Samuel Walker
- Department of Surgery, University of Louisville School of Medicine , Louisville, Kentucky
| | - Susan Galandiuk
- Department of Surgery, University of Louisville School of Medicine , Louisville, Kentucky
| | - Sarah Gardner
- Department of Surgery, University of Louisville School of Medicine , Louisville, Kentucky
| | - Hiram C Polk
- Department of Surgery, University of Louisville School of Medicine , Louisville, Kentucky
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Rimmelé T, Payen D, Cantaluppi V, Marshall J, Gomez H, Gomez A, Murray P, Kellum JA. IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS. Shock 2016; 45:282-91. [PMID: 26529661 PMCID: PMC4752878 DOI: 10.1097/shk.0000000000000495] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.
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Affiliation(s)
- Thomas Rimmelé
- Anesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France
| | - Didier Payen
- Department of Anesthesiology & Critical Care and UMR INSERM 1160; Lariboisière Hospital, AP-HP and University Paris 7, Sorbonne Paris Cité, Paris, France
| | - Vincenzo Cantaluppi
- Nephrology, Dialysis and Kidney Transplantation Unit, Department of Medical Sciences, “Citta' della Salute e della Scienza di Torino- Molinette” University Hospital, Torino, Italy
| | - John Marshall
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario Canada
| | - Hernando Gomez
- Center for Critical Care Nephrology; The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alonso Gomez
- Academia Colombiana de Medicina Critica (ACOMEC)
- Division of Critical Care Medicine, Clínica Palermo, Bogotá, Colombia
| | | | - John A. Kellum
- Center for Critical Care Nephrology; The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Bermejo-Martin JF, Andaluz-Ojeda D, Almansa R, Eiros JM, Tamayo E. Preventing sepsis. THE LANCET. INFECTIOUS DISEASES 2015; 15:1259-60. [DOI: 10.1016/s1473-3099(15)00374-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 09/24/2015] [Indexed: 10/22/2022]
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Monneret G, Venet F. Sepsis-induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy. CYTOMETRY PART B-CLINICAL CYTOMETRY 2015; 90:376-86. [PMID: 26130241 DOI: 10.1002/cyto.b.21270] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 06/16/2015] [Accepted: 06/25/2015] [Indexed: 12/20/2022]
Abstract
Septic syndromes remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. While sepsis has, for long, been solely described as inducing a tremendous systemic inflammatory response, novel findings indicate that sepsis indeed initiates a more complex immunologic response that varies over time, with the concomitant occurrence of both pro- and anti-inflammatory mechanisms. As a resultant, after a short proinflammatory phase, septic patients enter a stage of protracted immunosuppression. This is illustrated in those patients by reactivation of dormant viruses (CMV or HSV) or infections due to pathogens, including fungi, which are normally pathogenic solely in immunocompromised hosts. Although mechanisms are not totally understood, these alterations might be directly responsible for worsening outcome in patients who survived initial resuscitation as nearly all immune functions are deeply compromised. Indeed, the magnitude and persistence over time of these dysfunctions have been associated with increased mortality and health-care associated infection rate. Consequently, new promising therapeutic avenues are currently emerging from those recent findings such as adjunctive immunostimulation (IFN-γ, GM-CSF, IL-7, anti-PD1/L1 antibodies) for the most immunosuppressed patients. Nevertheless, as there is no clinical sign of immune dysfunctions, the prerequisite for such therapeutic intervention relies on our capacity in identifying the patients who could benefit from immunostimulation. To date, the most robust biomarkers of sepsis-induced immunosuppression are measured by flow cytometry. Of them, the decreased expression of monocyte HLA-DR appears as a "gold standard." This review reports on the mechanisms sustaining sepsis-induced immunosuppression and its related biomarkers measurable by flow cytometry. The objective is to integrate the most recent facts in an up-to-date account of clinical results, flow cytometry aspects as well as issues in results standardization for multicenter studies. © 2015 International Clinical Cytometry Society.
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Affiliation(s)
- Guillaume Monneret
- Cellular Immunology Laboratory, Hospices Civils De Lyon, Hôpital E Herriot, Lyon, France
- Université Claude Bernard Lyon I, Immunology Department, Lyon, France
- TRIGGERSEP (TRIal Group for Global Evaluation and Research in SEPsis)/F-CRIN Network, France
| | - Fabienne Venet
- Cellular Immunology Laboratory, Hospices Civils De Lyon, Hôpital E Herriot, Lyon, France
- Université Claude Bernard Lyon I, Immunology Department, Lyon, France
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Weiterer S, Uhle F, Lichtenstern C, Siegler BH, Bhuju S, Jarek M, Bartkuhn M, Weigand MA. Sepsis induces specific changes in histone modification patterns in human monocytes. PLoS One 2015; 10:e0121748. [PMID: 25793379 PMCID: PMC4368631 DOI: 10.1371/journal.pone.0121748] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 02/03/2015] [Indexed: 12/16/2022] Open
Abstract
Background Sepsis is a global burden and the primary cause of death in intensive care units worldwide. The pathophysiological changes induced by the host’s systemic inflammatory response to infection are not yet fully understood. During sepsis, the immune system is confronted with a variety of factors, which are integrated within the individual cells and result in changes of their basal state of responsiveness. Epigenetic mechanisms like histone modifications are known to participate in the control of immune reactions, but so far the situation during sepsis is unknown. Methods and Findings In a pilot approach, we performed combined chromatin immunoprecipitation followed by high-throughput sequencing to assess the genome-wide distribution of the chromatin modifications histone 3 lysine 4 and 27 trimethylation and lysine 9 acetylation in monocytes isolated from healthy donors (n = 4) and patients with sepsis (n = 2). Despite different underlying causes for sepsis, a comparison over promoter regions shows a high correlation between the patients for all chromatin marks. These findings hold true also when comparing patients to healthy controls. Despite the global similarity, differential analysis reveals a set of distinct promoters with significant enrichment or depletion of histone marks. Further analysis of overrepresented GO terms show an enrichment of genes involved in immune function. To the most prominent ones belong different members of the HLA family located within the MHC cluster together with the gene coding for the major regulator of this locus—CIITA. Conclusions We are able to show for the first time that sepsis in humans induces selective and precise changes of chromatin modifications in distinct promoter regions of immunologically relevant genes, shedding light on basal regulatory mechanisms that might be contributing to the functional changes occurring in monocytes.
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Affiliation(s)
- Sebastian Weiterer
- Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany
- German Centre for Infection Research (DZIF), partner site Giessen-Marburg-Langen, Giessen, Germany
- * E-mail:
| | - Florian Uhle
- Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Benedikt H. Siegler
- Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabin Bhuju
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Jarek
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Marek Bartkuhn
- Institute for Genetics, Justus-Liebig-University, Giessen, Germany
| | - Markus A. Weigand
- Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany
- German Centre for Infection Research (DZIF), partner site Giessen-Marburg-Langen, Giessen, Germany
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Cajander SC, Tina ET, Bäckman AB, Magnuson AM, Strålin KS, Söderquist BS, Källman JK. Expression of mRNA levels of HLA-DRA in relation to monocyte HLA-DR: a longitudinal sepsis study. Crit Care 2015. [PMCID: PMC4471361 DOI: 10.1186/cc14125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Almansa R, Heredia-Rodríguez M, Gomez-Sanchez E, Andaluz-Ojeda D, Iglesias V, Rico L, Ortega A, Gomez-Pesquera E, Liu P, Aragón M, Eiros JM, Jiménez-Sousa MÁ, Resino S, Gómez-Herreras I, Bermejo-Martín JF, Tamayo E. Transcriptomic correlates of organ failure extent in sepsis. J Infect 2014; 70:445-56. [PMID: 25557485 DOI: 10.1016/j.jinf.2014.12.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/22/2014] [Accepted: 12/23/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVES Sepsis is characterised by the frequent presence of organ failure and marked immunologic alterations. We studied the association between the extent of organ failure and the transcriptomic response of septic patients. METHODS Gene expression profiles in the blood of 74 surgical patients with sepsis were compared with those of 30 surgical patients with no sepsis. Differentially expressed genes were assessed for their correlation with the sequential organ failure (SOFA) score. RESULTS The expression levels of a group of genes participating in the cell cycle (HIST1H1C, CKS2, CCNA2, CDK1, CCNB2, CIT, CCNB1, AURKA, RAD51), neutrophil protease activity (ELANE, ADORA3, MPO, MMP8, CTSG), IL-1R and IL-18R response correlated directly with SOFA and mortality. Genes involved in T cell (LCK, CD3G, CD3D, ZAP70, ICOS, CD3E, CD28, IL2RB, CD8B, CD8A, CD40LG, IL23A, CCL5, SH2D1A, ITK, CD247, TBX21, GATA3, CCR7, LEF1, STAT4) and NK cell immunity (CD244, KLRK1, KLRD1) were inversely associated with SOFA and mortality. CONCLUSIONS The extent of organ failure in sepsis correlates directly with the existence of imbalanced innate and adaptive responses at the transcriptomic level. Quantification of the expression levels of the genes identified here could contribute to the simultaneous assessment of disease severity and immunological alterations in sepsis.
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Affiliation(s)
- Raquel Almansa
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad Apoyo a la Investigación, Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - María Heredia-Rodríguez
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Esther Gomez-Sanchez
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - David Andaluz-Ojeda
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Medicina Intensiva, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Verónica Iglesias
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad Apoyo a la Investigación, Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Lucia Rico
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad Apoyo a la Investigación, Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Alicia Ortega
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad Apoyo a la Investigación, Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Estefanía Gomez-Pesquera
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Pilar Liu
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Marta Aragón
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Jose Maria Eiros
- Dpto de Microbiología, Universidad de Valladolid, Avenida Ramón y Cajal, 7, 47005 Valladolid, Spain.
| | - Maria Ángeles Jiménez-Sousa
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología - Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo km. 2, Majadahonda, 28220 Madrid, Spain.
| | - Salvador Resino
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología - Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo km. 2, Majadahonda, 28220 Madrid, Spain.
| | - Ignacio Gómez-Herreras
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Jesús F Bermejo-Martín
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Unidad Apoyo a la Investigación, Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
| | - Eduardo Tamayo
- Grupo de Investigación Biomédica en Cuidados Críticos (BioCritic), Hospital Clínico Universitario de Valladolid, SACYL/IECSYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain; Servicio de Anestesiología, Hospital Clínico Universitario de Valladolid, SACYL, Avenida Ramón y Cajal, 3, 47005 Valladolid, Spain.
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de Montmollin E, Annane D. Year in review 2013: Critical Care--sepsis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:578. [PMID: 25673430 PMCID: PMC4331148 DOI: 10.1186/s13054-014-0578-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This review presents key publications from the research field of sepsis published in Critical Care and other relevant journals during 2013. The results of these experimental studies and clinical trials are discussed in the context of current scientific and clinical background. The discussion highlights and summarises articles on four main topics: sepsis pathogenesis, diagnostic and prognostic biomarkers, potential new therapies, and epidemiologic and outcome studies.
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Tamayo E, Almansa R, Carrasco E, Ávila-Alonso A, Rodríguez-Fernández A, Wain J, Heredia M, Gomez-Sanchez E, Soria S, Rico L, Iglesias V, Martínez-Martínez A, Andaluz-Ojeda D, Herreras JIG, Eiros JM, Bermejo-Martin JF. Quantification of IgM molecular response by droplet digital PCR as a potential tool for the early diagnosis of sepsis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:433. [PMID: 25043844 PMCID: PMC4075261 DOI: 10.1186/cc13910] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Monneret G, Venet F. Monocyte HLA-DR in sepsis: shall we stop following the flow? CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:102. [PMID: 24393356 PMCID: PMC4056426 DOI: 10.1186/cc13179] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The best marker for the monitoring of immune alterations in critically ill patients (sepsis, trauma, pancreatitis, surgery, burns) so far remains decreased HLA-DR expression on monocytes measured by flow cytometry as it regularly provides valuable information in terms of mortality prediction or evaluation of risk for secondary infections. As shown by Cajander and colleagues in a recent issue of Critical Care, some promising tools-based molecular biology may circumvent some drawbacks related to flow cytometry. Herein, issues and perspectives about this alternative are discussed.
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