Occurrence of marked sepsis-induced immunosuppression in pediatric septic shock: a pilot study

Solenn Remy, Karine Kolev-Descamps, Morgane Gossez, Fabienne Venet, Julie Demaret, Etienne Javouhey, Guillaume Monneret, Solenn Remy, Karine Kolev-Descamps, Morgane Gossez, Fabienne Venet, Julie Demaret, Etienne Javouhey, Guillaume Monneret

Abstract

Background: While the process of sepsis-induced immunosuppression is now well described in adults, very little information is available on immune functions in pediatric sepsis. The current study investigated this in children with septic shock by performing immunomonitoring, including both innate (monocyte human leukocyte antigen-DR, mHLA-DR, expression) and adaptive immunity (lymphocyte subsets count), as well as cytokine concentrations (IL-6, IL-8, IL-10, IL-1Ra, TNF-α, IFN-γ). Subsequent objectives were to assess the associations between inflammatory response, potential immunosuppression and secondary acquired infection occurrence.

Methods: Single-center prospective observational study, including children aged between 1 month and 18 years admitted to pediatric intensive care unit (PICU) for septic shock. Age-matched controls were children hospitalized for elective surgery without any infectious criteria. Blood was sampled at day 1-2, 3-5, and 7-9 after sepsis onset. mHLA-DR and lymphocyte subsets count were measured by flow cytometry and cytokine concentrations by Luminex technology.

Results: A total of 26 children and 30 controls were included. Patients had lymphopenia, and mHLA-DR levels were significantly lower than controls at each time point (p < 0.0001). All cytokines peaked at day 1-2. Children with secondary acquired infection had lower day 3-5 mHLA-DR and higher pro-inflammatory cytokine concentrations (IL-6, IL-8 and TNF-α) at day 1-2 compared to children without secondary acquired infection.

Conclusions: The higher initial inflammatory cytokine production was, the more innate immunity was altered, while evaluated by low mHLA-DR expression. Children with decreased mHLA-DR expression developed more secondary acquired infections. Upon confirmation in multicenter cohorts, these results pave the way for immunostimulation for the most immunosuppressed children in order to prevent nosocomial infections in PICU. Trial registration PedIRIS study NCT02848144. Retrospectively registered 28 July 2016.

Keywords: Children; Immunosuppression induced; Septic shock.

Figures

Fig. 1
Fig. 1
Flowchart
Fig. 2
Fig. 2
mHLA-DR measurements in pediatric septic shock. a mHLA-DR expression in healthy children: no difference according to age groups (p = 0.35; ANOVA). Dashed line depicts usual threshold to define normal values in adults. b mHLA-DR was significantly decreased at each time point during septic shock, than controls (p < 0.001; Mann–Whitney). c mHLA-DR at day 3–5 was significantly negatively correlated with cumulative vasopressor index, CVI (r = − 0.50; p = 0.031; Spearman). d mHLA-DR was significantly lower in children with secondary acquired infection than those without (p = 0.022; Student t test)
Fig. 3
Fig. 3
Time course of lymphocytes’ subsets during septic shock. a Total lymphocytes, b CD4+ T cells, c CD8+ T cells, d NK cells, e B cells (from a to e, results as cell number/µl), f proportion of regulatory T cells (among CD4 + lymphocytes). *p < 0.05; **p < 0.01; ***p < 0.0001

References

    1. Schlapbach LJ, Straney L, Alexander J, MacLaren G, Festa M, Schibler A, et al. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study. Lancet Infect Dis. 2015;15(1):46–54. doi: 10.1016/S1473-3099(14)71003-5.
    1. Bilgin K, Yaramiş A, Haspolat K, Taş MA, Günbey S, Derman O. A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics. 2001;107(1):36–41. doi: 10.1542/peds.107.1.36.
    1. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13(3):260–268. doi: 10.1016/S1473-3099(13)70001-X.
    1. Venet F, Lukaszewicz A-C, Payen D, Hotchkiss R, Monneret G. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol. 2013;25(4):477–483. doi: 10.1016/j.coi.2013.05.006.
    1. Landelle C, Lepape A, Voirin N, Tognet E, Venet F, Bohé J, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36(11):1859–1866. doi: 10.1007/s00134-010-1962-x.
    1. Monneret G, Lepape A, Voirin N, Bohé J, Venet F, Debard A-L, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32(8):1175–1183. doi: 10.1007/s00134-006-0204-8.
    1. 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.
    1. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med. 2014;371(4):380–383. doi: 10.1056/NEJMcibr1404664.
    1. Delano MJ, Ward PA. The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunol Rev. 2016;274(1):330–353. doi: 10.1111/imr.12499.
    1. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180(7):640–648. doi: 10.1164/rccm.200903-0363OC.
    1. Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37(3):525–532. doi: 10.1007/s00134-010-2088-x.
    1. Muszynski JA, Nofziger R, Greathouse K, Nateri J, Hanson-Huber L, Steele L, et al. Innate immune function predicts the development of nosocomial infection in critically injured children. Shock (Augusta Ga.) 2014;42(4):313–321. doi: 10.1097/SHK.0000000000000217.
    1. Manzoli TF, Troster EJ, Ferranti JF, Sales MM. Prolonged suppression of monocytic human leukocyte antigen-DR expression correlates with mortality in pediatric septic patients in a pediatric tertiary Intensive Care Unit. J Crit Care. 2016;33:84–89. doi: 10.1016/j.jcrc.2016.01.027.
    1. Muszynski JA, Nofziger R, Greathouse K, Steele L, Hanson-Huber L, Nateri J, et al. Early adaptive immune suppression in children with septic shock: a prospective observational study. Crit Care Lond Engl. 2014;18(4):R145. doi: 10.1186/cc13980.
    1. Wisgrill L, Groschopf A, Herndl E, Sadeghi K, Spittler A, Berger A, et al. Reduced TNF-α response in preterm neonates is associated with impaired nonclassic monocyte function. J Leukoc Biol. 2016;100(3):607–612. doi: 10.1189/jlb.4A0116-001RR.
    1. Genel F, Atlihan F, Ozsu E, Ozbek E. Monocyte HLA-DR expression as predictor of poor outcome in neonates with late onset neonatal sepsis. J Infect. 2010;60(3):224–228. doi: 10.1016/j.jinf.2009.12.004.
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228. doi: 10.1007/s00134-012-2769-8.
    1. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2005;6(1):2–8.
    1. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS clinical trials group P1009 study. J Allergy Clin Immunol. 2003;112(5):973–980. doi: 10.1016/j.jaci.2003.07.003.
    1. Slater A, Shann F, Pearson G, Paediatric Index of Mortality (PIM) Study Group PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Med. 2003;29(2):278–285. doi: 10.1007/s00134-002-1601-2.
    1. Leteurtre S, Duhamel A, Deken V, Lacroix J, Leclerc F, Groupe Francophone de Réanimation et Urgences Pédiatriques Daily estimation of the severity of organ dysfunctions in critically ill children by using the PELOD-2 score. Crit Care Lond Engl. 2015;19:324. doi: 10.1186/s13054-015-1054-y.
    1. Trzeciak S, McCoy JV, Phillip Dellinger R, Arnold RC, Rizzuto M, Abate NL, et al. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med. 2008;34(12):2210–2217. doi: 10.1007/s00134-008-1193-6.
    1. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309–332. doi: 10.1016/j.ajic.2008.03.002.
    1. Demaret J, Walencik A, Jacob M-C, Timsit J-F, Venet F, Lepape A, et al. Inter-laboratory assessment of flow cytometric monocyte HLA-DR expression in clinical samples. Cytometry B Clin Cytom. 2013;84(1):59–62. doi: 10.1002/cyto.b.21043.
    1. Venet F, Davin F, Guignant C, Larue A, Cazalis M-A, Darbon R, et al. Early assessment of leukocyte alterations at diagnosis of septic shock. Shock (Augusta Ga.) 2010;34(4):358–363. doi: 10.1097/SHK.0b013e3181dc0977.
    1. Saison J, Maucort-Boulch D, Chidiac C, Demaret J, Malcus C, Cotte L, et al. Increased regulatory T-cell percentage contributes to poor CD4(+) lymphocytes recovery: a 2-year prospective study after introduction of antiretroviral therapy. Open Forum Infect Dis. 2015;2(2):ofv063. doi: 10.1093/ofid/ofv063.
    1. de Jager W, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT. Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol. 2003;10(1):133–139.
    1. Döcke W-D, Höflich C, Davis KA, Röttgers K, Meisel C, Kiefer P, et al. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem. 2005;51(12):2341–2347. doi: 10.1373/clinchem.2005.052639.
    1. Wong HR, Cvijanovich N, Wheeler DS, Bigham MT, Monaco M, Odoms K, et al. Interleukin-8 as a stratification tool for interventional trials involving pediatric septic shock. Am J Respir Crit Care Med. 2008;178(3):276–282. doi: 10.1164/rccm.200801-131OC.
    1. Peronnet E, Nguyen K, Cerrato E, Guhadasan R, Venet F, Textoris J, et al. Evaluation of mRNA biomarkers to identify risk of hospital acquired infections in children admitted to paediatric intensive care unit. PLoS ONE. 2016;11(3):e0152388. doi: 10.1371/journal.pone.0152388.
    1. Monserrat J, de Pablo R, Diaz-Martín D, Rodríguez-Zapata M, de la Hera A, Prieto A, et al. Early alterations of B cells in patients with septic shock. Crit Care Lond Engl. 2013;17(3):R105. doi: 10.1186/cc12750.
    1. Halstead ES, Carcillo JA, Schilling B, Greiner RJ, Whiteside TL. Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients. Pediatr Res. 2013;74(4):427–432. doi: 10.1038/pr.2013.121.
    1. von Muller L, Klemm A, Durmus N, Weiss M, Suger-Wiedeck H, Schneider M, et al. Cellular immunity and active human cytomegalovirus infection in patients with septic shock. J Infect Dis. 2007;196(9):1288–1295. doi: 10.1086/522429.
    1. Monneret G, Debard A-L, Venet F, Bohe J, Hequet O, Bienvenu J, et al. Marked elevation of human circulating CD4 + CD25 + regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med. 2003;31(7):2068–2071. doi: 10.1097/01.CCM.0000069345.78884.0F.
    1. Drewry AM, Ablordeppey EA, Murray ET, Beiter ER, Walton AH, Hall MW, et al. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit Care Lond Engl. 2016;20(1):334. doi: 10.1186/s13054-016-1505-0.
    1. Bo L, Wang F, Zhu J, Li J, Deng X. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit Care Lond Engl. 2011;15(1):R58. doi: 10.1186/cc10031.
    1. Gessler P, Pretre R, Bürki C, Rousson V, Frey B, Nadal D. Monocyte function-associated antigen expression during and after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2005;130(1):54–60. doi: 10.1016/j.jtcvs.2005.01.008.
    1. Hoffman JA, Weinberg KI, Azen CG, Horn MV, Dukes L, Starnes VA, et al. Human leukocyte antigen-DR expression on peripheral blood monocytes and the risk of pneumonia in pediatric lung transplant recipients. Transpl Infect Dis. 2004;6(4):147–155. doi: 10.1111/j.1399-3062.2004.00069.x.
    1. Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M. Potentially inadvertent immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med. 2016;194(5):550–558. doi: 10.1164/rccm.201604-0862CP.
    1. Gouel-Chéron A, Allaouchiche B, Guignant C, Davin F, Floccard B, Monneret G, et al. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. PLoS ONE. 2012;7(3):e33095. doi: 10.1371/journal.pone.0033095.
    1. Field-Ridley A, Dharmar M, Steinhorn D, McDonald C, Marcin JP. ICU-acquired weakness is associated with differences in clinical outcomes in critically ill children. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2016;17(1):53–57.
    1. Carcillo JA, Dean JM, Holubkov R, Berger J, Meert KL, Anand KJS, et al. Inherent risk factors for nosocomial infection in the long stay critically ill child without known baseline immunocompromise: a post hoc analysis of the crisis trial. Pediatr Infect Dis J. 2016;35(11):1182–1186. doi: 10.1097/INF.0000000000001286.
    1. 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(1):49. doi: 10.1186/s40635-017-0163-0.

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