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

Abstract

PurposeCellular 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.MethodsMulti-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.ResultsA 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.ConclusionsThis 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 registrationThe study was registered with clinicaltrials.gov (NCT02186522).Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5247-0) contains supplementary material, which is available to authorized users.

Immune Profiling Panel: a proof of concept study of a new multiplex molecular tool to assess the immune status of critically-ill patients

“…Similarly, interesting work by Morris et al . based on a 4-hours flow cytometry protocol assessing neutrophil CD88, percentage of regulatory T cells (T regs ), and mHLA-DR expression demonstrated the potential to predict secondary infections in septic patients (6). However, the main challenges that hinder the use of flow cytometry at the bedside, remains that it is mainly operated and interpreted by skilled personnel which makes it hard to standardize, and requires the presence of well-equipped laboratories that work round the clock which is not the case in most hospitals.…”

Immunoparalysis in Septic Shock Patients

“…the CD14/HLA-DR and of heat-shock proteins (HSP) 70 and 90 was present already within 24 hours from the onset of sepsis [5]; in both studies, these alterations were more marked in patients who developed SS later on. More recently, Morris et al [20] in association with raised percentage of regulatory T cells (T reg ) were predictive for infections occurring between 3 and 9 days after ICU admission, and a similar timing has been demonstrated also in another study in which the mortally rate of secondary infection was ~14% [17]. On the basis of these findings, it is reasonable to hypothesize that (a) a combination of cellular and soluble factors able to blunt the immune response is present since the very initial phase of sepsis; (b) their effects on the clinical course, namely, the appearance of secondary infections and/or viral reactivation, can occur within the initial 10 days from the admission; and (c) these are associated with a substantial mortality of patients surviving the initial insult.…”

C5a anaphylatoxin and its role in critical illness‐induced organ dysfunction

“…Ligation of the C5a receptor by C5a leads to internalisation, and hence, several authors have used neutrophil C5a receptor surface expression as a more accurate marker of C5a exposure. Whilst downregulation of neutrophil surface C5a receptor expression may not be caused solely by C5a, at least in vitro, it is a reliable marker of neutrophil phagocytic dysfunction and has been associated with poor outcomes in several cohorts of critically ill patients …”

“…Of key relevance to critical illness is IFX‐1, a monoclonal antibody which has enjoyed success in phase II dose‐escalation trials for early sepsis‐induced organ dysfunction, although full trial results have not yet been reported . Going forward, we suggest that the following points are of critical importance if newer therapeutic options are to be successfully licensed for use in critically ill patients: drug design must be informed by a detailed understanding of the underlying biology in the context of critically ill humans including time courses of responses, the inflammatory signalling network in which the target operates and clinically useable immunophenotyping tools . Understanding of context can facilitate targeted, multi‐pronged pathway blockade, thereby reducing issues related to enzymatic redundancy, as elegantly shown by Skjeflo and colleagues in a porcine model of polymicrobial sepsis .…”