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Observational Study
. 2018 May;44(5):627-635.
doi: 10.1007/s00134-018-5247-0. Epub 2018 Jun 7.

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

Andrew Conway Morris  1   2 , Deepankar Datta  3   4 , Manu Shankar-Hari  5 , Jacqueline Stephen  6 , Christopher J Weir  6 , Jillian Rennie  3 , Jean Antonelli  6 , Anthony Bateman  7 , Noel Warner  8 , Kevin Judge  8 , Jim Keenan  8 , Alice Wang  8   9 , Tony Burpee  10 , K Alun Brown  11 , Sion M Lewis  11 , Tracey Mare  11 , Alistair I Roy  12 , Gillian Hulme  13 , Ian Dimmick  13 , Adriano G Rossi  3 , A John Simpson  14 , Timothy S Walsh  3   4
Affiliations
Observational Study

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

Andrew Conway Morris et al. Intensive Care Med. 2018 May.

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 (Tregs)] 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 Tregs 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).

Keywords: Cross infection; Immunoparesis; Immunophenotyping; Monocytes; Neutrophils; T-lymphocytes, regulatory.

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Conflict of interest statement

NW, KJ, JK and AW were all employees of BD biosciences whilst this work was being undertaken, and NW and KJ remain employees to date. All four authors hold stock in BD Biosciences. All other authors declare they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Survival curves for patients dichotomised by markers at the cut-offs shown. a Neutrophil CD88 expression, b total monocyte HLA-DR expression, c Tregs as a  percentage of all CD4+ cells. d Additive combination of markers p value by log-rank test (panels a–c) and log-rank test for trend (panel d). Hazard ratios for combined markers are shown in Table 3
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