Dynamic Clustering Analysis of Neutrophil to Lymphocyte Ratio Evolution Overtime in Intensive Care Unit Patients
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Abstract
Elevated neutrophil to lymphocyte ratio (NLR) upon ICU admission has been reported to be associated with disease progression, severity, or mortality in critically ill patients. However, the overtime trajectories of NLR after admission and their association with other markers of intensive care units patients’ immuno-inflammatory status have not be evaluated so far. In a cohort of 353 critically ill patients (sepsis, trauma, major surgery), we evaluated the association between NLR trajectories and patients’ deterioration (mortality or occurrence of nosocomial infection) both by a conventional analysis at each time-point and through K-means clustering analysis. Additionally, these trajectories were delineated alongside established markers of hyper-inflammation (e.g., IL-6) or immunosuppression (including HLA-DR expression on monocytes, proportion of immature neutrophils, and plasma IL-10 levels). The results showed that persistently elevated NLR values were associated with an increased risk of patient deterioration, as demonstrated in a multivariate analysis that included usual clinical confounders. Patients belonging to the persistently elevated NLR endotype simultaneously exhibited heightened inflammation and pronounced immunosuppression. In conclusion, by providing integrated information on both hyper-inflammation and immunosuppression, NLR measurement holds significant promise for monitoring the immune status of ICU patients. This straightforward and standardized marker could serve to assess immune organ failure in ICU and assist in guiding potential immunomodulation strategies.
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References
1. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. Feb 24 2012;335(6071):936-941.
2. Rubio I, Osuchowski MF, Shankar-Hari M, et al. Current gaps in sepsis immunology: new opportunities for translational research. Lancet Infect Dis. 2019;In press.
3. van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. Nov 9 2021;54(11):2450-2464.
4. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. Dec 2013;13(12):862-874.
5. Vincent JL, van der Poll T, Marshall JC. The End of "One Size Fits All" Sepsis Therapies: Toward an Individualized Approach. Biomedicines. Sep 12 2022;10(9).
6. Stanski NL, Wong HR. Prognostic and predictive enrichment in sepsis. Nat Rev Nephrol. Jan 2020;16(1):20-31.
7. Sinha P, Meyer NJ, Calfee CS. Biological Phenotyping in Sepsis and Acute Respiratory Distress Syndrome. Annual review of medicine. Jan 27 2023;74:457-471.
8. Cajander S, Kox M, Scicluna BP, et al. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. Lancet Respir Med. Apr 2024;12(4):305-322.
9. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15.
10. Demaret J, Venet F, Friggeri A, et al. Marked alterations of neutrophil functions during sepsis-induced immunosuppression. J Leukoc Biol. Dec 2015;98(6):1081-1090.
11. Finfer S, Venkatesh B, Hotchkiss RS, Sasson SC. Lymphopenia in sepsis-an acquired immunodeficiency? Immunol Cell Biol. Dec 5 2022.
12. Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. Bratislavske lekarske listy. 2001;102(1):5-14.
13. Zahorec R. Neutrophil-to-lymphocyte ratio, past, present and future perspectives. Bratislavske lekarske listy. 2021;122(7):474-488.
14. Firment J, Hulin I. Zahorec index or Neutrophil-to-lymphocyte ratio, valid biomarker of inflammation and immune response to infection, cancer and surgery. Bratislavske lekarske listy. 2024;125(2):75-83.
15. Huang Z, Fu Z, Huang W, Huang K. Prognostic value of neutrophil-to-lymphocyte ratio in sepsis: A meta-analysis. Am J Emerg Med. Mar 2020;38(3):641-647.
16. Dilektasli E, Inaba K, Haltmeier T, et al. The prognostic value of neutrophil-to-lymphocyte ratio on mortality in critically ill trauma patients. J Trauma Acute Care Surg. Nov 2016;81(5):882-888.
17. Younan D, Richman J, Zaky A, Pittet JF. An Increasing Neutrophil-to-Lymphocyte Ratio Trajectory Predicts Organ Failure in Critically-Ill Male Trauma Patients. An Exploratory Study. Healthcare (Basel). Mar 14 2019;7(1).
18. Torres LK, Pickkers P, van der Poll T. Sepsis-Induced Immunosuppression. Annu Rev Physiol. Oct 27 2021.
19. Rol ML, Venet F, Rimmele T, et al. The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients. BMJ Open. Jun 21 2017;7(6):e015734.
20. Venet F, Textoris J, Blein S, et al. Immune Profiling Demonstrates a Common Immune Signature of Delayed Acquired Immunodeficiency in Patients With Various Etiologies of Severe Injury. Crit Care Med. Apr 1 2022;50(4):565-575.
21. Bidar F, Bodinier M, Venet F, et al. Concomitant Assessment of Monocyte HLA-DR Expression and Ex Vivo TNF-alpha Release as Markers of Adverse Outcome after Various Injuries-Insights from the REALISM Study. J Clin Med. Dec 24 2021;11(1).
22. Bodinier M, Peronnet E, Brengel-Pesce K, et al. Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients. Front Immunol. 2021;12:795052.
23. Salciccioli JD, Marshall DC, Pimentel MA, et al. The association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study. Crit Care. 2015;19:13.
24. Roldgaard M, Benfield T, Tingsgard S. Blood neutrophil to lymphocyte ratio is associated with 90-day mortality and 60-day readmission in Gram negative bacteremia: a multi-center cohort study. BMC Infect Dis. Feb 23 2024;24(1):255.
25. Hwang SY, Shin TG, Jo IJ, et al. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically-ill septic patients. Am J Emerg Med. Feb 2017;35(2):234-239.
26. Di Rosa M, Sabbatinelli J, Soraci L, et al. Neutrophil-to-lymphocyte ratio (NLR) predicts mortality in hospitalized geriatric patients independent of the admission diagnosis: a multicenter prospective cohort study. J Transl Med. Nov 21 2023;21(1):835.
27. Coudereau R, Bodinier M, Lukaszewicz AC, et al. Persistent NLRP3 inflammasome activation is associated with delayed immunosuppression in septic patients. J Leukoc Biol. Mar 29 2024;115(4):706-713.
28. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. Mar 2013;13(3):260-268.