Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study

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Abstract

Purpose

Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients.

Methods

Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (T _regs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections.

Results

A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of T _regs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00–4.74), 3.44 (1.58–7.47) and 2.41 (1.14–5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9.

Conclusions

This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies.

Trial registration

The study was registered with clinicaltrials.gov (NCT02186522).

Electronic supplementary material

The online version of this article (10.1007/s00134-018-5247-0) contains supplementary material, which is available to authorized users.

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Most cited references 31

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Index for rating diagnostic tests

W. J. Youden, Michele Teng, Matthew Taliaferro … (1951)

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International study of the prevalence and outcomes of infection in intensive care units.

Jean-Louis Vincent (2009)

Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14,414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13,796 adult (>18 years) patients. On the day of the study, 7087 of 13,796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P < .001), as was the hospital mortality rate (33% [2201/6659] vs 15% [ 942/6352], respectively; P < .001) (adjusted odds ratio for risk of hospital mortality, 1.51; 95% confidence interval, 1.36-1.68; P < .001). Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.

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Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

Christian Meisel, Joerg Schefold, Rene Pschowski … (2009)

Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).

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Author and article information

Contributors

Andrew Conway Morris:

ORCID: http://orcid.org/0000-0002-3211-3216

+44 (0)1223 217889 , mozza@doctors.org.uk

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 7 June 2018

Publication date PMC-release: 7 June 2018

Publication date (Print): 2018

Volume: 44

Issue: 5

Pages: 627-635

Affiliations

[1 ]ISNI 0000000121885934, GRID grid.5335.0, University Division of Anaesthesia, Department of Medicine, Addenbrooke’s Hospital, , University of Cambridge, ; Box 93, Hills Road, Cambridge, CB2 0QQ England UK

[2 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, MRC Centre for Inflammation Research, , University of Edinburgh, ; 47 Little France Crescent, Edinburgh, Scotland UK

[3 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Edinburgh Critical Care Research Group, , University of Edinburgh School of Clinical Sciences, ; Edinburgh, Scotland UK

[4 ]GRID grid.420545.2, Intensive Care Unit, , Guy’s and St Thomas’ Hospital NHS Foundation Trust, ; London, England UK

[5 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, , University of Edinburgh, ; Edinburgh, Scotland UK

[6 ]ISNI 0000 0004 0624 9907, GRID grid.417068.c, Intensive Care Unit, , Western General Hospital, ; Crewe Road South, Edinburgh, Scotland UK

[7 ]ISNI 0000 0004 0543 6807, GRID grid.420052.1, BD Biosciences, ; San Jose, CA USA

[8 ]IncellDx, Menlo Park, CA USA

[9 ]Applied Cytometry, Sheffield, England UK

[10 ]GRID grid.425213.3, Vascular Immunology Research Laboratory, Rayne Institute (King’s College London), , St Thomas’ Hospital, ; London, England UK

[11 ]ISNI 0000 0004 0399 9059, GRID grid.416726.0, Integrated Critical Care Unit, , Sunderland Royal Hospital, ; Sunderland, England UK

[12 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Flow Cytometry Core Facility Laboratory, Faculty of Medical Sciences, Centre for Life, , Newcastle University, ; Newcastle, England UK

[13 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Institute of Cellular Medicine, , Newcastle University, ; Newcastle upon Tyne, England UK

Author information

Andrew Conway Morris http://orcid.org/0000-0002-3211-3216

Article

Publisher ID: 5247

DOI: 10.1007/s00134-018-5247-0

PMC ID: 6006236

PubMed ID: 29915941

SO-VID: b180b35b-07b7-4faf-9fd7-b1f2a87e86e9

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 11 January 2018

Date accepted : 16 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100006041, Innovate UK;

Award ID: 101193

Funded by: FundRef http://dx.doi.org/10.13039/100011095, BD Biosciences;

Funded by: FundRef http://dx.doi.org/10.13039/501100000349, National Institute for Academic Anaesthesia;

Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;

Award ID: WT 2055214/Z/16/Z

Award Recipient : Andrew Conway Morris

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: cross infection,immunoparesis,immunophenotyping,monocytes,neutrophils,t-lymphocytes, regulatory

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: cross infection, immunoparesis, immunophenotyping, monocytes, neutrophils, t-lymphocytes, regulatory

Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study

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Abstract

Purpose

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Conclusions

Trial registration

Electronic supplementary material

Related collections

UCL: UN SDG 03 Good Health and Well-Being

Most cited references 31

Index for rating diagnostic tests

International study of the prevalence and outcomes of infection in intensive care units.

Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

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