The INFECT Study: Cell surface signatures of immune dysfunction risk stratify critically ill patients

EJRC Article Review

Background

In critically ill patients, immune activation is often accompanied by a state of immune depression. The persistence of this is associated with a complicated intensive care unit (ICU) course, including the development of nosocomial infections¹.

Objective

The aim of the ImmuNe FailurE in Critical Therapy (INFECT) study was to confirm the ability of previously identified cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients².

Method

In this multicentre, prospective observational cohort study of critically ill patients in 4 UK intensive care units, serial blood samples were taken, and 3 cell surface markers associated with immune cell dysfunction were assayed on site using standardised flow cytometric measures. These included neutrophil CD88 (nCD88), monocyte Human Leukocyte Antigen-DR (HLA-DR) and percentage of regulatory T-cells (Tregs).

Population

Adult patients admitted to ICU and receiving either invasive mechanical ventilation or two or more other organ systems support, who were predicted to remain in ICU for at least 48 hours were included.

Intervention

Blood samples for flow cytometry were obtained on the day of study enrolment, and then at 2-day intervals until day 12 with patients being followed for determination of infection to day 16. The ability of the immune dysfunction measurements to predict subsequent infection, ICU length of stay and duration of organ support were investigated.

Optimum cut-offs from ROC analysis were used for their ability to predict subsequent nosocomial infections when measured at baseline, and days 2- 4, 6-8 and 10-12 post study enrolment were calculated. The number of dysfunctions were summed to give a cumulative total (range 0-3).

Outcome

Data on 138 patients were available for analysis. In total, 51 (37%) patients developed secondary infections after study entry. None of the clinical or demographic variables were significant independent predictors of subsequent infection.

All three tests demonstrated high intra- and inter-rater reliability. Reduced nCD88, reduced mHLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection when applying optimal ROC cut-offs.

Baseline marker values did not predict subsequent infection, with or without adjustment for clinical variables. In contrast, the sample taken between study days 2-4 had potentially useful discriminant value for patients at low and high risk of subsequent secondary infection. This predictive ability was also found at days 6-8. The median time to infection from a positive test on the day 2-4 sample was 5 days.

An increase in the number of immune dysfunctions was associated with a progressive increase in the risk of subsequent infection. Using the combined markers, the area under ROC curve (AUC ROC) was 0.72 (95% CI 0.62-0.81). Patients who developed secondary infections demonstrated an impaired recovery in both monocyte HLA-DR and nCD88 relative to those who did not develop infections, suggesting that persistence of dysfunction is an important risk factor for subsequent infection.

Limitation

At present the assays need a high degree of machine standardisation and external validation is required from other centres and patient populations.

Conclusion

This is the first report of multicentre, multi-parametric immunophenotyping for the determination of immune dysfunction amongst critically ill adults and one of only two studies to examine multiple markers over time. Using this approach may allow targeting of immunomodulatory therapies to patients who might have greatest risk-benefit balance from these therapies for reduction in secondary infections.

Future work

The use and timing of immunomodulatory among ICU patients at high risk of secondary infections needs to be determined by future randomised controlled trials

Article review prepared and submitted by EJRC member Nish Arulkumaran, MD (Centre for Intensive Care Medicine, University College London, London, UK).

References

1. Vanzant EL, Lopez CM, Ozrazgat-Baslanti T, et al. Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. The Journal of Trauma and Acute Care Surgery. Jan 2014;76(1):21-29; discussion 29-30.
2. Conway Morris A, et al. Cell surface signatures of immune dysfunction risk stratify critically ill patients: INFECT Study. Intensive Care Medicine. 2018. May 2018, Volume 44, Issue 5, pp 627–635