Indian Journal of Critical Care Medicine

Register      Login

SEARCH WITHIN CONTENT

FIND ARTICLE

Volume / Issue

Online First

Archive
Volume  28 (2024)
Volume  27 (2023)
Volume  26 (2022)
Volume  25 (2021)
Volume  24 (2020)
Volume  23 (2019)
Volume  22 (2018)
Volume  21 (2017)
Volume  20 (2016)
Volume  19 (2015)
Volume  18 (2014)
Volume  17 (2013)
Volume  16 (2012)
Volume  15 (2011)
Volume  14 (2010)
Volume  13 (2009)
Volume  12 (2008)
Volume  11 (2007)
Volume  10 (2006)
Volume  9 (2005)
Volume  8 (2004)
Related articles

VOLUME 26 , ISSUE 1 ( January, 2022 ) > List of Articles

Original Article

Immune Modulation and Cytomegalovirus Reactivation in Sepsis-induced Immunosuppression: A Pilot Study

Gaurav Lambe, Dia Mansukhani, Shanaz Khodaiji, Anjali Shetty, Camilla Rodrigues, Farhad Kapadia

Keywords : Cytomegalovirus reactivation, Interleukin-10, Interleukin-6, Immunosuppression, Programmed death-1, Sepsis, Tregs

Citation Information : Lambe G, Mansukhani D, Khodaiji S, Shetty A, Rodrigues C, Kapadia F. Immune Modulation and Cytomegalovirus Reactivation in Sepsis-induced Immunosuppression: A Pilot Study. Indian J Crit Care Med 2022; 26 (1):53-61.

DOI: 10.5005/jp-journals-10071-24079

License: CC BY-NC 4.0

Published Online: 17-01-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Abstract

Introduction: Sepsis is a life-threatening condition caused due to dysregulated immune response to an infection and progressive immunosuppression. Reactivation of cytomegalovirus (CMV) occurs frequently in sepsis and is found associated with adverse outcomes. The study objective was to evaluate the association between incidence of CMV reactivation and immune alteration in sepsis-induced immunosuppression in patients with prolonged sepsis. Patients and methods: Patients admitted to intensive care unit (ICU), with severe sepsis and CMV immunoglobulin G (IgG) seropositivity, were prospectively enrolled. Other manifest immune suppression causes were excluded. Samples were collected on enrolment and further once a week until day 21 or death/discharge. CMV viral load was quantified using qPCR. Lymphocyte subset analysis (CD3+, CD4+, CD8+, CD19+, CD16+/CD56+, and CD25+CD127− regulatory T cells), human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes, programmed death-1 (PD-1) expression on T lymphocytes, and proinflammatory (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)), anti-inflammatory cytokines levels (IL-2, IL-4, and IL-10) were analyzed by flow cytometry as markers for immunosuppression. Results: A total of 25 CMV IgG-positive patients and 11 healthy controls were included. CMV reactivation occurred in 20 patients. Patients with CMV reactivation had T-cell lymphopenia. PD-1 expression on CD4+ and CD8+ T cells was markedly elevated (p <0.02) in CMV-reactivated patients compared to nonreactivated patients. HLA-DR expression was significantly low on monocytes in all septic patients (p <0.01) compared to healthy controls. IL-6 levels showed elevation at day 7, whereas IL-10 was found to be significantly higher from day 0 in CMV-reactivated group. Conclusion: Our study concluded that immune suppression markers and cytokine levels in patients with severe sepsis were found to be significantly associated with the incidence of CMV reactivation.

HTML PDF Share
  1. Singer M, Deutschman CS, Seymour C, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA–J Am Med Assoc 2016;315(8): 801–810. DOI: 10.1001/jama.2016.0287.
  2. Goodman CW, Brett AS. Gabapentin and pregabalin for pain — is increased prescribing a cause for concern? N Engl J Med 2017; 377(5):411–414. DOI: 10.1056/NEJMp1704633.
  3. Lewis DH, Chan DL, Pinheiro D, Garden OA. Immunopathology of sepsis: review article. J Vet Intern Med 2012;457–482. DOI: 10.1111/j.1939-1676.2012.00905.x.
  4. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA–J Am Med Assoc 2011;306(23):2594–2605. DOI: 10.1001/jama.2011.1829.
  5. Muenzer JT, Davis CG, Chang K, Schmidt RE, Dunne WM, Coopersmith CM, et al. Characterization and modulation of the immunosuppressive phase of sepsis. Infect Immun 2010;78(4):1582–1592. DOI: 10.1128/IAI.01213-09.
  6. Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C, et al. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev 2013;93(3):1247–1288. DOI: 10.1152/physrev.00037.2012.
  7. Muszynski JA, Hall MW. Sepsis-induced innate and adaptive immune suppression. Open Inflamm J 2011;4(1):67–73.
  8. Winkler MS, Rissiek A, Priefler M, Schwedhelm E, Robbe L, Bauer A, et al. Human leukocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNF α response : a diagnostic tool for immunosuppression? PLoS One 2017;12(8):e0182427. DOI: 10.1371/journal.pone.0182427.
  9. Wang J, Li L, Shi S. Expression of monocyte HLA-DR and blood lactic acid level in patients with sepsis and correlation with prognosis. Int J Clin Exp Med 2018;11(5):4905–4911.
  10. Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology 2010;129(4):474–481. DOI: 10.1111/j.1365-2567.2010.03255.x.
  11. Monneret G, Gossez M, Venet F. Sepsis in PD-1 light. Crit Care 2016;20(1):1–2. DOI: 10.1186/s13054-016-1370-x.
  12. De Pablo R, Monserrat J, Prieto A, Alvarez-Mon M. Role of circulating lymphocytes in patients with sepsis. Biomed Res Int 2014;2014:671087. DOI: 10.1155/2014/671087.
  13. Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One 2014;9(6):1–13. DOI: 10.1371/journal.pone.0098819.
  14. Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2014;300(4):413–422. DOI: 10.1001/jama.300.4.413.
  15. Tomino A, Tsuda M, Aoki R, Kajita Y, Hashiba M, Terajima T, et al. Increased PD-1 expression and altered T cell repertoire diversity predict mortality in patients with septic shock: a preliminary study. PLoS One 2017;12(1):1–12. DOI: 10.1371/journal.pone.0169653.
  16. Heininger A, Haeberle H, Fischer I, Beck R, Riessen R, Rohde F, et al. Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit Care 2011;15(2):R77. DOI: 10.1186/cc10069. Available from: http://ccforum.com/content/15/2/R77.
  17. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22(7):707–710. DOI: 10.1007/BF01709751. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8844239.
  18. Kraft CS, Armstrong WS, Caliendo AM. Interpreting quantitative cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis 2012;54(12):1793–1797. DOI: 10.1093/cid/cis212.
  19. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013;13(12):862–874. DOI: 10.1038/nri3552. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24232462%0A. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4077177.
  20. Zhuang Y, Peng H, Chen Y, Zhou S, Chen Y. Dynamic monitoring of monocyte HLA-DR expression for the diagnosis, prognosis, and prediction of sepsis. 3. Sepsis and the immune response : reduced expression of HLA-DR. Front Biosci 2017;301:1344–1354. DOI: 10.2741/4547.
  21. Adrie C, Lugosi M, Sonneville R, Souweine B, Ruckly S, Cartier JC, et al. Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission. Ann Intensive Care 2017;7(1):30. DOI: 10.1186/s13613-017-0242-0.
  22. Drewry A, Samra N, Skrupky L, Fuller B, Compton S, Hotchkiss R. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 2014;42(5):383–391. DOI: 10.1097/SHK.0000000000000234.
  23. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010;236(1):219–242. DOI: 10.1111/j.1600-065X.2010.00923.x.
  24. La Rosa C, Krishnan A, Longmate J, Martinez J, Manchanda P, Lacey SF, et al. Programmed death–1 expression in liver transplant recipients as a prognostic indicator of cytomegalovirus disease. J Infect Dis 2008;197(1):25–33. DOI: 10.1086/523652.
  25. Zhang Y, Li J, Lou J, Zhou Y, Bo L, Zhu J, et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 2011;15(1):1–9. DOI: 10.1186/cc10059.
  26. Choi YJ, Kim SB, Kim JH, Park SH, Park MS, Kim JM, et al. Impaired polyfunctionality of CD8+ T cells in severe sepsis patients with human cytomegalovirus reactivation. Exp Mol Med 2017;49(9):1–8. DOI: 10.1038/emm.2017.146.
  27. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets–an updated view. Mediators Inflamm 2013;2013:165974. DOI: 10.1155/2013/165974.
  28. Clement M, Humphreys IR. Cytokine-mediated induction and regulation of tissue damage during cytomegalovirus infection. Front Immunol 2019;10(1):1–9. DOI: 10.3389/fimmu.2019.00078.
  29. Rojas JM, Avia M, Martín V, Sevilla N. IL-10: a multifunctional cytokine in viral infections. J Immunol Res 2017;2017:6104054. DOI: 10.1155/2017/6104054.
  30. Silva TF, Concato VM, Tomiotto-Pellissier F, Gonçalves MD, Bortoleti BT da S, Tavares ER, et al. Reactivation of cytomegalovirus increases nitric oxide and IL-10 levels in sepsis and is associated with changes in renal parameters and worse clinical outcome. Sci Rep 2019;9(1):1–9. DOI: 10.1038/s41598-019-45390-x.
  31. Matsumoto H, Ogura H, Shimizu K, Ikeda M, Hirose T, Matsuura H, et al. The clinical importance of a cytokine network in the acute phase of sepsis. Sci Rep 2018;8(1):1–4. DOI: 10.1038/s41598-018- 32275-8.
  32. Remy S, Kolev-Descamps K, Gossez M, Venet F, Demaret J, Javouhey E, et al. Occurrence of marked sepsis-induced immunosuppression in pediatric septic shock: a pilot study. Ann Intensive Care 2018;8(1). DOI: 10.1186/s13613-018-0382-x.
  33. Humar A, Louis PS, Mazzulli T, Mcgeer A, Lipton J, Messner H, et al. Elevated serum cytokines are associated with cytomegalovirus infection and disease in bone marrow transplant recipients. J Infect Dis 1999;179(2):484–488. DOI: 10.1086/314602.
  34. Reeves MB, Compton T. Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J Virol 2011;85(23):12750–12758. DOI: 10.1128/JVI.05878-11.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.