Monocyte HLA-DR Assessment by a Novel Point-of-Care Device Is Feasible for Early Identification of ICU Patients With Complicated Courses-A Proof-of-Principle Study

Abstract

Background: Critically ill patients, especially following trauma or extensive surgery, experience a systemic immune response, consisting of a pro-inflammatory as well as a counterbalancing anti-inflammatory response. Pro-inflammation is necessary for the initiation of homeostatic control and wound healing of the organism. However, when the counterbalancing mechanisms dominate, a condition of secondary immunodeficiency occurs, which renders the patient susceptible for opportunistic or secondary infections. However, the incidence of this condition is yet illusive. Methods: For a period of 3 months (May to July 2017), 110 consecutive patients admitted to the surgical ICU of the Heidelberg University Hospital, a tertiary university hospital, were enrolled in the study. Monocyte HLA-DR (mHLA-DR), a long-known surrogate of monocyte function, was assessed quantitatively once on admission utilizing a novel point-of-care flow cytometer with single-use cartridges (Accelix system). Patients were followed up for further 28 days and data on ICU stay, antibiotic therapy, microbiological findings, and mechanical ventilation were recorded. Statistical analysis was performed to evaluate the incidence of immunosuppression-defined by different thresholds-as well as its consequence in terms of outcome and clinical course. Results: Depending on the HLA-DR threshold applied for stratification (≤8,000/≤5,000/≤2,000 molecules/cell), a large group of patients (85.5/68.2/40.0%) already presented with a robust decrease of HLA-DR on admission, independent of the cause for critical illness. Analyzed for survival, neither threshold was able to stratify patients with a higher mortality. However, both thresholds of 2,000 and 5,000 were able to discriminate patients with longer ICU stay, ventilation time and duration of antibiotic therapy, as well as higher count of microbiological findings. Moreover, a mHLA-DR value ≤2,000 molecules/cell was associated with higher incidence of overall antibiotic therapy. Conclusion: Single assessment of mHLA-DR using a novel point-of-care flow cytometer is able to stratify patients according to their risk of a complicated course. Therefore, this device overcomes the technical boundaries for measuring cellular biomarkers and paves the way for future studies involving personalized immunotherapy to patients with a high immunological risk profile independent of their background. Trial Registration: German Clinical Trials Register; ID: DRKS00012348.

Keywords: CARS; SIRS; immunosuppression; infection; personalized medicine; precision medicine; sepsis; tolerance.

Figure 1

(A) Study flowchart according to STROBE and (B) distribution of HLA-DR measurements in the analyzed study cohort of 110 patients. Dashed horizontal lines depict threshold values indicated in earlier studies.

Figure 2

Analysis of patient survival over 28 days stratified according to HLA-DR thresholds of (A) 2,000, (B) 5,000, or (C) 8,000. Dashed line always indicates subgroup above corresponding threshold, whereas solid line indicates the group of patients below. Number in brackets equal subgroup size, a total of 110 patients has been analyzed. Group comparison was performed using logrank test and calculated p-values are given within the subpanels.

Figure 3

Group comparisons of clinical variables between different HLA-DR thresholds. (A) Length of ICU stay, (B) Ventilation time, (C) Time under antibiotic therapy (all 3 in days), and (D) Cumulative microbiological findings are shown. A total of 110 patients has been analyzed. Box edges represent quartiles with median given as horizontal line within, whiskers span the 95% confidence interval. Open circles and diamonds indicate outliers. Group comparisons were performed by Mann-Whitney U-test and p-values are given above the compared groups. Bold type indicates a p ≤0.05, assumed as significant.

Figure 4

Cumulative incidence of antibiotic therapy over 28 days stratified according to HLA-DR thresholds of (A) 2,000, (B) 5,000, or (C) 8,000. Dashed line always indicates subgroup above corresponding threshold, whereas solid line indicates the group of patients below. Number in brackets equal subgroup size, a total of 110 patients has been analyzed. Group comparison was performed using logrank test and calculated p-values are given within the subpanels. Bold type indicates a p ≤0.05, assumed as significant.