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01.12.2018 | Letter | Ausgabe 1/2018 Open Access

Critical Care 1/2018

Soluble programmed cell death protein-1 and programmed cell death ligand-1 in sepsis

Zeitschrift:
Critical Care > Ausgabe 1/2018
Autoren:
Debasree Banerjee, Sean Monaghan, Runping Zhao, Thomas Walsh, Amy Palmisciano, Gary S. Phillips, Steven Opal, Mitchell M. Levy
Abbreviations
ICU
Intensive care unit
IFN
Interferon
IL
Interleukin
PD-1
Programmed cell death protein-1
PD-L1
Programmed cell death ligand-1
ROC
Receiver operator characteristic
TNF
Tumor necrosis factor
Immunotherapy targeting the programmed cell death protein-1 (PD-1)–programmed cell death ligand-1 (PDL-1) axis in sepsis is poised for clinical trials, although optimal inclusion criteria and predictors of response are not well characterized.
We evaluated the kinetics of soluble (s)PD-1 and sPD-L1 in 30 septic intensive care unit (ICU) patients and 30 nonseptic ICU patients (Table 1). sPD-1 and sPD-L1 were significantly elevated among the septic cohort compared with the nonseptic ICU patients at enrollment (17.7 pg/ml vs. 4.5 pg/ml, p = 0.002; and 29.9 pg/ml vs. 11.3 pg/ml, p = 0.02; respectively) and were associated with sepsis (Fig.  1). Higher sPD-L1 on day 3 was associated with mortality among septic patients (16.7 pg/ml vs. 3.0 pg/ml, p = 0.054) and also in the total ICU cohort (14.9 pg/ml vs. 2.7 pg/ml, p = 0.026). Soluble PD-L1 regressed on interleukin (IL)-6 and interferon (IFN)γ levels were significantly associated in the total ICU cohort and septic patients, possibly pointing to upstream triggers for post-transcriptional modifications. Tumor necrosis factor (TNF)α regressed on sPD-1 and sPD-L1 was significant in all populations including septic survivors, revealing possible downstream effects of sPD-1 and sPD-L1. Initial sPD-1 levels correlated with a drop in lymphocyte count to < 1 × 10 9/L (area under the receiver operating characteristic (ROC) curve 0.72, p = 0.006) and to < 0.6 × 10 9/L (area under the ROC curve 0.68, p = 0.02). sPD-L1 also correlated with lymphocyte count drop to < 1 × 10 9/L during the hospital stay. The correlation between the two immune checkpoint molecules, sPD-1 and sPD-L1, was also significant on enrollment, and at days 1 and 3 ( p < 0.001, p < 0.001, p = 0.004, respectively; Fig.  2).
Table 1
Patient characteristics
Variables
Septic patients ( n = 30)
Control subjects ( n = 30)
 Age (years), median (IQR)
63.3 (49.3–74.1)
58.6 (52.8–64.6)
 Male, n (%)
11 (36)
19 (63)
 White, n (%)
23 (76)
25 (83)
Past medical history
 COPD/asthma/fibrosis, n (%)
11 (36)
2 (7)
 CAD/MI, CHF, AF, n (%)
16 (53)
7 (23)
 Diabetes mellitus, n (%)
5 (17)
10 (33)
 Malignancy, n (%)
8 (27)
6 (20)
 CKD/ESRD, n (%)
5 (17)
1 (3)
 Cirrhosis, n (%)
0 (0)
4 (13)
 Connective tissue disease, n (%)
3 (10)
0
 Arthritis, n (%)
3 (10)
3 (10)
Clinical assessment
 WBC (×10 −9/L), median (IQR)
12.8 (6.9–19.1)
9.1 (7.6–10.9)
 SOFA score, median (IQR)
7 (5–9)
2 (1–4)
 Shock, n (%)
24 (80)
2 (6)
Site of infection in septic patients ( n)
 Pneumonia
13
 
 Genitourinary tract infection
11
 
 Abdominal infection
2
 
 Meningitis
1
 
 Multiple sites of infection
1
 
 Bacteremia
9
 
 Unknown
1
 
Organism of infection if known in septic patients ( n)
Escherichia coli not extended-spectrum β-lactamase producer
4
 
Escherichia coli extended-spectrum β-lactamase producer
2
 
 Enterobacter
1
 
Enterococcus faecalis
1
 
Acinetobacter baumannii
1
 
Pseudomonas aeruginosa
1
 
 Methicillin-resistant Staphylococcus aureus
1
 
 Methicillin-sensitive Staphylococcus aureus
1
 
Candida albicans
1
 
Haemophilus influenzae
1
 
 Bacillus species not anthracis
2
 
Klebsiella pneumoniae
1
 
AF atrial fibrillation, COPD chronic obstructive pulmonary disease, CAD coronary artery disease, CHF congestive heart Failure, CKD chronic kidney disease, ESRD end-stage renal disease, IQR interquartile range, MI myocardial infarction, SOFA sequential organ function assessment, WBC white blood cell
sPD-1 and sPD-L1 are easily sampled, making them advantageous biomarkers in sepsis. A recent study demonstrated elevated sPD-1 among patients with infected pancreatitis [ 1]. sPD-1 may serve as an indicator of severity of sepsis among emergency room patients [ 2]. Lange et al. [ 3] reported that sPD-1 levels did not differ significantly between septic and nonseptic critically ill patients and had no association with outcome among septic patients. Our results may stem from sampling a different population to Lange and colleagues. Our controls, while critically ill, had lower severity of illness and mortality. Additionally, we excluded patients with immunocompromise, malignancy, and organ transplantation due to possible iatrogenic skewing of sPD-1 and sPD-L1. Approximately half of the control group in Lange et al. developed infections; thus, observations comparing sepsis versus nonseptic groups were limited to initial measurement only.
sPD-1 and sPD-L1 are point-of-care tests that might eventually guide personalized medicine in sepsis. These soluble immune checkpoints can risk-stratify patients for immunotherapy in sepsis and may potentially serve as targets themselves.

Acknowledgements

We would like to thank all the participants in this study.

Funding

This work was funded in part by the National Institute of General Medical Sciences (GR5223260.1001). GSP received funding to support statistical analyses for this project from Rhode Island Hospital.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the Rhode Island Hospital IRB 4159-14. All participants consented prior to enrollment.

Competing interests

The authors declare that they have no competing interests.

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Open AccessThis 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. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
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