Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2021

01-12-2021 | Nosocomial Infection | Research

Venoarterial extracorporeal membrane oxygenation induces early immune alterations

Authors: Aurélien Frerou, Mathieu Lesouhaitier, Murielle Gregoire, Fabrice Uhel, Arnaud Gacouin, Florian Reizine, Caroline Moreau, Aurélie Loirat, Adel Maamar, Nicolas Nesseler, Amedeo Anselmi, Erwan Flecher, Jean-Philippe Verhoye, Yves Le Tulzo, Michel Cogné, Mikael Roussel, Karin Tarte, Jean-Marc Tadié

Published in: Critical Care | Issue 1/2021

Login to get access

Abstract

Background

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation.

Methods

We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients).

Results

Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine.

Conclusion

VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.
Literature
1.
2.
Grimaldi D, Louis S, Pene F, Sirgo G, Rousseau C, Claessens YE, Vimeux L, Cariou A, Mira JP, Hosmalin A, Chiche JD. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med. 2011;37:1438–46.PubMedCrossRef
3.
Chalk K, Meisel C, Spies C, Volk T, Thuenemann K, Linneweber J, Wernecke KD, Sander M. Dysfunction of alveolar macrophages after cardiac surgery and postoperative pneumonia? An observational study. Crit Care. 2013;17:R285.PubMedPubMedCentralCrossRef
4.
Hadley JS, Wang JE, Michaels LC, Dempsey CM, Foster SJ, Thiemermann C, Hinds CJ. Alterations in inflammatory capacity and TLR expression on monocytes and neutrophils after cardiopulmonary bypass. Shock. 2007;27:466–73.PubMedCrossRef
5.
Gaudriot B, Uhel F, Gregoire M, Gacouin A, Biedermann S, Roisne A, Flecher E, Le Tulzo Y, Tarte K, Tadie JM. Immune dysfunction after cardiac surgery with cardiopulmonary bypass: beneficial effects of maintaining mechanical ventilation. Shock. 2015;44:228–33.PubMedCrossRef
6.
Guglin M, Zucker MJ, Bazan VM, Bozkurt B, El Banayosy A, Estep JD, Gurley J, Nelson K, Malyala R, Panjrath GS, et al. Venoarterial ECMO for adults: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;73:698–716.PubMedCrossRef
7.
Squiers JJ, Lima B, DiMaio JM. Contemporary extracorporeal membrane oxygenation therapy in adults: fundamental principles and systematic review of the evidence. J Thorac Cardiovasc Surg. 2016;152:20–32.PubMedCrossRef
8.
Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. J Am Coll Cardiol. 2014;63:2769–78.PubMedCrossRef
9.
Chang CH, Chen HC, Caffrey JL, Hsu J, Lin JW, Lai MS, Chen YS. Survival analysis after extracorporeal membrane oxygenation in critically ill adults: a nationwide cohort study. Circulation. 2016;133:2423–33.PubMedCrossRef
10.
Burns S, Constantin N, Robles P, Investigators RP. Understanding the long-term sequelae of ECMO survivors. Intensive Care Med. 2018;44:1144–7.PubMedCrossRef
11.
Schmidt M, Brechot N, Hariri S, Guiguet M, Luyt CE, Makri R, Leprince P, Trouillet JL, Pavie A, Chastre J, Combes A. Nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Clin Infect Dis. 2012;55:1633–41.PubMedPubMedCentralCrossRef
12.
Abrams D, Grasselli G, Schmidt M, Mueller T, Brodie D. ECLS-associated infections in adults: what we know and what we don’t yet know. Intensive Care Med. 2020;46:182–91.PubMedCrossRef
13.
Messika J, Schmidt M, Aubry A, Combes A, Ricard JD. Extracorporeal membrane oxygenation-associated infections: carefully consider cannula infections! Crit Care Med. 2018;46:e171–2.PubMedCrossRef
14.
Grasselli G, Scaravilli V, Di Bella S, Biffi S, Bombino M, Patroniti N, Bisi L, Peri AM, Pesenti A, Gori A, Alagna L. Nosocomial infections during extracorporeal membrane oxygenation: incidence, etiology, and impact on patients’ outcome. Crit Care Med. 2017;45:1726–33.PubMedCrossRef
15.
16.
Granja T, Hohenstein K, Schussel P, Fischer C, Prufer T, Schibilsky D, Wendel HP, Jaschonek K, Serna-Higuita L, Schlensak C, et al. Multi-modal characterization of the coagulopathy associated with extracorporeal membrane oxygenation. Crit Care Med. 2020;48:e400–8.PubMedCrossRef
17.
Millar JE, Fanning JP, McDonald CI, McAuley DF, Fraser JF. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care. 2016;20:387.PubMedPubMedCentralCrossRef
18.
19.
20.
Hubner M, Tomasi R, Effinger D, Wu T, Klein G, Bender M, Kilger E, Juchem G, Schwedhelm E, Kreth S. Myeloid-derived suppressor cells mediate immunosuppression after cardiopulmonary bypass. Crit Care Med. 2019;47:e700–9.PubMedCrossRef
21.
Hollen MK, Stortz JA, Darden D, Dirain ML, Nacionales DC, Hawkins RB, Cox MC, Lopez MC, Rincon JC, Ungaro R, et al. Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis. Crit Care. 2019;23:355.PubMedPubMedCentralCrossRef
22.
Waeckel L, Venet F, Gossez M, Monard C, Rimmele T, Monneret G. Delayed persistence of elevated monocytic MDSC associates with deleterious outcomes in septic shock: a retrospective cohort study. Crit Care. 2020;24:132.PubMedPubMedCentralCrossRef
23.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.PubMedCrossRef
24.
Frantz S, Falcao-Pires I, Balligand JL, Bauersachs J, Brutsaert D, Ciccarelli M, Dawson D, de Windt LJ, Giacca M, Hamdani N, et al. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC. Eur J Heart Fail. 2018;20:445–59.PubMedCrossRef
25.
Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, De Zeeuw D, Hostetter TH, Lameire N, Eknoyan G. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67:2089–100.PubMedCrossRef
26.
Spaan AN, Surewaard BG, Nijland R, van Strijp JA. Neutrophils versus Staphylococcus aureus: a biological tug of war. Annu Rev Microbiol. 2013;67:629–50.PubMedCrossRef
27.
28.
Le Tulzo Y, Pangault C, Amiot L, Guilloux V, Tribut O, Arvieux C, Camus C, Fauchet R, Thomas R, Drenou B. Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Am J Respir Crit Care Med. 2004;169:1144–51.PubMedCrossRef
29.
Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, Tattevin P, Thomas R, Fauchet R, Drenou B. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock. 2002;18:487–94.PubMedCrossRef
30.
Uhel F, Azzaoui I, Gregoire M, Pangault C, Dulong J, Tadie JM, Gacouin A, Camus C, Cynober L, Fest T, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in patients with sepsis. Am J Respir Crit Care Med. 2017;196:315–27.PubMedCrossRef
31.
Darcy CJ, Minigo G, Piera KA, Davis JS, McNeil YR, Chen Y, Volkheimer AD, Weinberg JB, Anstey NM, Woodberry T. Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit Care. 2014;18:R163.PubMedPubMedCentralCrossRef
32.
Drifte G, Dunn-Siegrist I, Tissieres P, Pugin J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med. 2013;41:820–32.PubMedCrossRef
33.
Pedersen CC, Borup R, Fischer-Nielsen A, Mora-Jensen H, Fossum A, Cowland JB, Borregaard N. Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans. J Immunol. 2016;197:1989–99.PubMedCrossRef
34.
Guo RF, Riedemann NC, Laudes IJ, Sarma VJ, Kunkel RG, Dilley KA, Paulauskis JD, Ward PA. Altered neutrophil trafficking during sepsis. J Immunol. 2002;169:307–14.PubMedCrossRef
35.
Mekontso-Dessap A, Honore S, Kirsch M, Plonquet A, Fernandez E, Touqui L, Farcet JP, Soussy CJ, Loisance D, Delclaux C. Blood neutrophil bactericidal activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus during cardiac surgery. Shock. 2005;24:109–13.PubMedCrossRef
36.
Tepaske R, Velthuis H, Oudemans-van Straaten HM, Heisterkamp SH, van Deventer SJ, Ince C, Eysman L, Kesecioglu J. Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial. Lancet. 2001;358:696–701.PubMedCrossRef
37.
Sbrana S, Bevilacqua S, Buffa M, Spiller D, Parri MS, Gianetti J, De Filippis R, Clerico A. Post-reperfusion changes of monocyte function in coronary blood after extracorporeal circulation. Cytometry B Clin Cytom. 2005;65:14–21.PubMedCrossRef
38.
Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen CJ, Dunbar PR, Wadley RB, Jeet V, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60.PubMedPubMedCentralCrossRef
39.
Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, von Bernuth H, Benarafa C, Roos D, Skokowa J, Hartl D. Neutrophils: Between host defence, immune modulation, and tissue injury. PLoS Pathog. 2015;11:e1004651.PubMedPubMedCentralCrossRef
40.
41.
Gey A, Tadie JM, Caumont-Prim A, Hauw-Berlemont C, Cynober L, Fagon JY, Terme M, Diehl JL, Delclaux C, Tartour E. Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients. Clin Exp Immunol. 2015;180:280–8.PubMedPubMedCentralCrossRef
42.
43.
Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C, Geilich M, Winkels G, Traggiai E, Casati A, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2010;40:22–35.PubMedCrossRef
44.
Birge RB, Ucker DS. Innate apoptotic immunity: the calming touch of death. Cell Death Differ. 2008;15:1096–102.PubMedCrossRef
45.
Hotchkiss RS, Chang KC, Grayson MH, Tinsley KW, Dunne BS, Davis CG, Osborne DF, Karl IE. Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc Natl Acad Sci U S A. 2003;100:6724–9.PubMedPubMedCentralCrossRef
46.
Rodriguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008;222:180–91.PubMedPubMedCentralCrossRef
47.
48.
Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, McDunn JE, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–79.PubMedCrossRef
49.
Venet F, Foray AP, Villars-Mechin A, Malcus C, Poitevin-Later F, Lepape A, Monneret G. IL-7 restores lymphocyte functions in septic patients. J Immunol. 2012;189:5073–81.PubMedCrossRef
50.
Ouyang W, O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019;50:871–91.PubMedCrossRef
51.
Park MJ, Lee SH, Kim EK, Lee EJ, Baek JA, Park SH, Kwok SK, Cho ML. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. Sci Rep. 2018;8:3753.PubMedPubMedCentralCrossRef
52.
Zhou L, Miao K, Yin B, Li H, Fan J, Zhu Y, Ba H, Zhang Z, Chen F, Wang J, et al. Cardioprotective role of myeloid-derived suppressor cells in heart failure. Circulation. 2018;138:181–97.PubMedCrossRef
53.
Stolk R, van der Pasch E, Naumann F, Schouwstra J, Bressers S, van Herwaarden T, Gerretsen J, Schambergen R, Ruth M, van der Hoeven H, et al. Norepinephrine dysregulates the immune response and compromises host defense during sepsis. Am J Respir Crit Care Med. 2020;202:830–42.PubMedCrossRef
54.
Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.PubMedPubMedCentralCrossRef
Metadata
Title
Venoarterial extracorporeal membrane oxygenation induces early immune alterations
Authors
Aurélien Frerou
Mathieu Lesouhaitier
Murielle Gregoire
Fabrice Uhel
Arnaud Gacouin
Florian Reizine
Caroline Moreau
Aurélie Loirat
Adel Maamar
Nicolas Nesseler
Amedeo Anselmi
Erwan Flecher
Jean-Philippe Verhoye
Yves Le Tulzo
Michel Cogné
Mikael Roussel
Karin Tarte
Jean-Marc Tadié
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2021
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-03444-x

Other articles of this Issue 1/2021

Critical Care 1/2021 Go to the issue

Research

Adverse events associated with administration of vasopressor medications through a peripheral intravenous catheter: a systematic review and meta-analysis

Research

Protective reactive thymus hyperplasia in COVID-19 acute respiratory distress syndrome

Editorial

COVID-19: spot urine rather than bronchoalveolar lavage fluid analysis?

Research

Diaphragm thickening fraction predicts noninvasive ventilation outcome: a preliminary physiological study

Research Letter

Acute cor pulmonale in Covid-19 related acute respiratory distress syndrome

Editorial

Equilibrating SSC guidelines with individualized care