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 2023 EHA Congress 2023 ASCO Annual Meeting
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
Annals of Intensive Care
Published in: Annals of Intensive Care 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Annals of Intensive Care | Issue 1/2018

Login to get access

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
Appendix
Available only for authorised users
Literature
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.CrossRefPubMed
2.
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.CrossRefPubMed
3.
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):260–8.CrossRefPubMedPubMedCentral
4.
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):477–83.CrossRefPubMedPubMedCentral
5.
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):1859–66.CrossRefPubMed
6.
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):1175–83.CrossRefPubMed
7.
Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–74.CrossRefPubMedPubMedCentral
8.
Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med. 2014;371(4):380–3.CrossRefPubMed
9.
10.
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):640–8.CrossRefPubMed
11.
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):525–32.CrossRefPubMed
12.
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):313–21.CrossRef
13.
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;33:84–9.CrossRefPubMed
14.
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.CrossRef
15.
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):607–12.CrossRefPubMed
16.
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):224–8.CrossRefPubMed
17.
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.CrossRefPubMed
18.
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.
19.
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):973–80.CrossRefPubMed
20.
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):278–85.CrossRefPubMed
21.
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.CrossRef
22.
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):2210–7.CrossRefPubMedPubMedCentral
23.
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):309–32.CrossRefPubMed
24.
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.CrossRefPubMed
25.
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):358–63.CrossRef
26.
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.CrossRefPubMedPubMedCentral
27.
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):133–9.PubMedPubMedCentral
28.
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):2341–7.CrossRefPubMed
29.
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):276–82.CrossRefPubMedPubMedCentral
30.
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.CrossRefPubMedPubMedCentral
31.
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.CrossRef
32.
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):427–32.CrossRefPubMed
33.
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):1288–95.CrossRef
34.
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):2068–71.CrossRefPubMed
35.
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.CrossRef
36.
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.CrossRef
37.
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.CrossRefPubMed
38.
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):147–55.CrossRefPubMed
39.
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):550–8.CrossRefPubMed
40.
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.CrossRefPubMedPubMedCentral
41.
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):53–7.
42.
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):1182–6.CrossRefPubMedPubMedCentral
43.
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.CrossRefPubMedPubMedCentral
Metadata
Title
Occurrence of marked sepsis-induced immunosuppression in pediatric septic shock: a pilot study
Authors
Solenn Remy
Karine Kolev-Descamps
Morgane Gossez
Fabienne Venet
Julie Demaret
Etienne Javouhey
Guillaume Monneret
Publication date
01-12-2018
Publisher
Springer International Publishing
Published in
Annals of Intensive Care / Issue 1/2018
Electronic ISSN: 2110-5820
DOI
https://doi.org/10.1186/s13613-018-0382-x

Other articles of this Issue 1/2018

Annals of Intensive Care 1/2018 Go to the issue

Research

De-escalation of antifungal treatment in critically ill patients with suspected invasive Candida infection: incidence, associated factors, and safety

Research

Evaluation of emotional excitation during standardized endotracheal intubation in simulated conditions

Research

Prediction of chronic kidney disease after acute kidney injury in ICU patients: study protocol for the PREDICT multicenter prospective observational study

Review

The prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Research

Reliability of respiratory pressure measurements in ventilated and non-ventilated patients in ICU: an observational study

Research

When timing and dose of nutrition support were examined, the modified Nutrition Risk in Critically Ill (mNUTRIC) score did not differentiate high-risk patients who would derive the most benefit from nutrition support: a prospective cohort study