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Published in: Journal of Clinical Immunology 3/2021

01-04-2021 | Nosocomial Infection | Original Article

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage

Authors: Florian Reizine, Mathieu Lesouhaitier, Murielle Gregoire, Kieran Pinceaux, Arnaud Gacouin, Adel Maamar, Benoit Painvin, Christophe Camus, Yves Le Tulzo, Pierre Tattevin, Matthieu Revest, Audrey Le Bot, Alice Ballerie, Berengère Cador-Rousseau, Mathieu Lederlin, Thomas Lebouvier, Yoann Launey, Maelle Latour, Clotilde Verdy, Delphine Rossille, Simon Le Gallou, Joelle Dulong, Caroline Moreau, Claude Bendavid, Mikael Roussel, Michel Cogne, Karin Tarte, Jean-Marc Tadié

Published in: Journal of Clinical Immunology | Issue 3/2021

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Abstract

Purpose

The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients.

Methods

A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission.

Results

We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation.

Conclusions

The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.
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Literature
1.
go back to reference Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA. 2020;323:1574–81.CrossRefPubMedPubMedCentral Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA. 2020;323:1574–81.CrossRefPubMedPubMedCentral
2.
go back to reference Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.CrossRefPubMedPubMedCentral Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.CrossRefPubMedPubMedCentral
3.
go back to reference Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:934–43.CrossRefPubMed Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:934–43.CrossRefPubMed
4.
go back to reference Du RH, Liang LR, Yang CQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020. Du RH, Liang LR, Yang CQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020.
5.
go back to reference Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363–74.CrossRefPubMed Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363–74.CrossRefPubMed
6.
go back to reference Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunologic features in severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9.CrossRefPubMedPubMedCentral Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunologic features in severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9.CrossRefPubMedPubMedCentral
7.
go back to reference Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020.
8.
go back to reference Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181:281–92 e286.PubMedPubMedCentral Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181:281–92 e286.PubMedPubMedCentral
9.
go back to reference Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol. 2019;73:529–57.CrossRefPubMed Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol. 2019;73:529–57.CrossRefPubMed
10.
go back to reference Zhao J, Zhao J, Legge K, Perlman S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest. 2011;121:4921–30.CrossRefPubMedPubMedCentral Zhao J, Zhao J, Legge K, Perlman S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest. 2011;121:4921–30.CrossRefPubMedPubMedCentral
11.
go back to reference Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020.
12.
go back to reference Leijte GP, Rimmele T, Kox M, Bruse N, Monard C, Gossez M, et al. Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes. Crit Care. 2020;24:110.CrossRefPubMedPubMedCentral Leijte GP, Rimmele T, Kox M, Bruse N, Monard C, Gossez M, et al. Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes. Crit Care. 2020;24:110.CrossRefPubMedPubMedCentral
13.
go back to reference Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not Lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201:1299–300.CrossRefPubMedPubMedCentral Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not Lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201:1299–300.CrossRefPubMedPubMedCentral
14.
go back to reference Le Balc'h P, Pinceaux K, Pronier C, Seguin P, Tadie JM, Reizine F. Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients. Crit Care. 2020;24:530.CrossRefPubMedPubMedCentral Le Balc'h P, Pinceaux K, Pronier C, Seguin P, Tadie JM, Reizine F. Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients. Crit Care. 2020;24:530.CrossRefPubMedPubMedCentral
15.
go back to reference Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quinones-Falconi F, Bautista E, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009;361:680–9.CrossRefPubMed Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quinones-Falconi F, Bautista E, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009;361:680–9.CrossRefPubMed
16.
go back to reference Gey A, Tadie JM, Caumont-Prim A, Hauw-Berlemont C, Cynober L, Fagon JY, et al. Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients. Clin Exp Immunol. 2015;180:280–8.CrossRefPubMedPubMedCentral Gey A, Tadie JM, Caumont-Prim A, Hauw-Berlemont C, Cynober L, Fagon JY, et al. Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients. Clin Exp Immunol. 2015;180:280–8.CrossRefPubMedPubMedCentral
17.
go back to reference Uhel F, Azzaoui I, Gregoire M, Pangault C, Dulong J, Tadie JM, 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.CrossRefPubMed Uhel F, Azzaoui I, Gregoire M, Pangault C, Dulong J, Tadie JM, 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.CrossRefPubMed
18.
go back to reference Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol. 2018;14:121–37.CrossRefPubMed Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol. 2018;14:121–37.CrossRefPubMed
20.
go back to reference Dorhoi A, Glaria E, Garcia-Tellez T, Nieuwenhuizen NE, Zelinskyy G, Favier B, et al. MDSCs in infectious diseases: regulation, roles, and readjustment. Cancer Immunol Immunother. 2019;68:673–85.CrossRefPubMed Dorhoi A, Glaria E, Garcia-Tellez T, Nieuwenhuizen NE, Zelinskyy G, Favier B, et al. MDSCs in infectious diseases: regulation, roles, and readjustment. Cancer Immunol Immunother. 2019;68:673–85.CrossRefPubMed
21.
go back to reference Bordoni V, Sacchi A, Cimini E, Notari S, Grassi G, Tartaglia E, et al. An inflammatory profile correlates with decreased frequency of cytotoxic cells in COVID-19. Clin Infect Dis. 2020. Bordoni V, Sacchi A, Cimini E, Notari S, Grassi G, Tartaglia E, et al. An inflammatory profile correlates with decreased frequency of cytotoxic cells in COVID-19. Clin Infect Dis. 2020.
22.
go back to reference Agrati C, Sacchi A, Bordoni V, Cimini E, Notari S, Grassi G, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. 2020;27:3196–207.CrossRefPubMedPubMedCentral Agrati C, Sacchi A, Bordoni V, Cimini E, Notari S, Grassi G, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. 2020;27:3196–207.CrossRefPubMedPubMedCentral
23.
go back to reference Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–33. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–33.
24.
go back to reference Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186:56–64.CrossRefPubMed Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186:56–64.CrossRefPubMed
25.
go back to reference Le Gall JR, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–63.CrossRefPubMed Le Gall JR, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–63.CrossRefPubMed
26.
go back to reference Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019;23:374.CrossRefPubMedPubMedCentral Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019;23:374.CrossRefPubMedPubMedCentral
27.
go back to reference Camus C, Bellissant E, Sebille V, Perrotin D, Garo B, Legras A, et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med. 2005;33:307–14.CrossRefPubMed Camus C, Bellissant E, Sebille V, Perrotin D, Garo B, Legras A, et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med. 2005;33:307–14.CrossRefPubMed
28.
go back to reference Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42 e813.CrossRefPubMedPubMedCentral Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42 e813.CrossRefPubMedPubMedCentral
30.
go back to reference van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19 associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19 associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020.
32.
go back to reference Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020.
33.
go back to reference Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, et al. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat Commun. 2015;6:10224.CrossRefPubMed Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, et al. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat Commun. 2015;6:10224.CrossRefPubMed
34.
go back to reference Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–2.CrossRefPubMedPubMedCentral Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–2.CrossRefPubMedPubMedCentral
36.
37.
go back to reference Remy KE, Mazer M, Striker DA, Ellebedy AH, Walton AH, Unsinger J, et al. Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections. JCI Insight. 2020;5. Remy KE, Mazer M, Striker DA, Ellebedy AH, Walton AH, Unsinger J, et al. Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections. JCI Insight. 2020;5.
38.
go back to reference Luo Y, Mao L, Yuan X, Xue Y, Lin Q, Tang G, et al. Prediction model based on the combination of cytokines and lymphocyte subsets for prognosis of SARS-CoV-2 infection. J Clin Immunol. 2020;40:960–9.CrossRefPubMedPubMedCentral Luo Y, Mao L, Yuan X, Xue Y, Lin Q, Tang G, et al. Prediction model based on the combination of cytokines and lymphocyte subsets for prognosis of SARS-CoV-2 infection. J Clin Immunol. 2020;40:960–9.CrossRefPubMedPubMedCentral
39.
go back to reference Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.CrossRefPubMed Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.CrossRefPubMed
40.
go back to reference Hall MW, Joshi I, Leal L, Ooi EE. Immune modulation in COVID-19: strategic considerations for personalized therapeutic intervention. Clin Infect Dis. 2020. Hall MW, Joshi I, Leal L, Ooi EE. Immune modulation in COVID-19: strategic considerations for personalized therapeutic intervention. Clin Infect Dis. 2020.
41.
go back to reference Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA. 2001;286:944–53.CrossRefPubMed Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA. 2001;286:944–53.CrossRefPubMed
42.
go back to reference Tepaske R, Velthuis H, Oudemans-van Straaten HM, Heisterkamp SH, van Deventer SJ, Ince C, et al. 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.CrossRefPubMed Tepaske R, Velthuis H, Oudemans-van Straaten HM, Heisterkamp SH, van Deventer SJ, Ince C, et al. 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.CrossRefPubMed
43.
go back to reference Rice TW. Immunonutrition in critical illness: limited benefit, potential harm. JAMA. 2014;312:490–1.CrossRefPubMed Rice TW. Immunonutrition in critical illness: limited benefit, potential harm. JAMA. 2014;312:490–1.CrossRefPubMed
Metadata
Title
SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage
Authors
Florian Reizine
Mathieu Lesouhaitier
Murielle Gregoire
Kieran Pinceaux
Arnaud Gacouin
Adel Maamar
Benoit Painvin
Christophe Camus
Yves Le Tulzo
Pierre Tattevin
Matthieu Revest
Audrey Le Bot
Alice Ballerie
Berengère Cador-Rousseau
Mathieu Lederlin
Thomas Lebouvier
Yoann Launey
Maelle Latour
Clotilde Verdy
Delphine Rossille
Simon Le Gallou
Joelle Dulong
Caroline Moreau
Claude Bendavid
Mikael Roussel
Michel Cogne
Karin Tarte
Jean-Marc Tadié
Publication date
01-04-2021
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 3/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-020-00920-5

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