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Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit*

Henckaerts, Liesbet MD, PhD; Nielsen, Kaspar R. MD; Steffensen, Rudi PhD; Van Steen, Kristel PhD; Mathieu, Chantal MD, PhD; Giulietti, Annapaula PhD; Wouters, Pieter J. MSc; Milants, Ilse RN; Vanhorebeek, Ilse PhD; Langouche, Lies PhD; Vermeire, Séverine MD, PhD; Rutgeerts, Paul MD, PhD, FRCP; Thiel, Steffen PhD; Wilmer, Alexander MD, PhD; Hansen, Troels Krarup MD, PhD; Van den Berghe, Greet MD, PhD

doi: 10.1097/CCM.0b013e31819263d8
Clinical Investigations
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Objective: Critically ill patients are at risk of sepsis, organ failure, and death. Studying the impact of genetic determinants may improve our understanding of the pathophysiology and allow identification of patients who would benefit from specific treatments. Our aim was to study the influence of single nucleotide polymorphisms in selected genes involved in innate immunity on the development of bacteremia or risk of death in patients admitted to a medical intensive care unit.

Design, Setting, and Patients: DNA was available from 774 medical intensive care unit patients. We selected 31 single nucleotide polymorphisms in 14 genes involved in host innate immune defense. Serum levels of MASP2 and chemotactic capacity, phagocytosis, and killing capacity of monocytes at admission were quantified. Univariate Kaplan-Meier estimates with log-rank analysis and multivariate logistic regression were performed. Bootstrap resampling technique and ten-fold cross-validation were used to assess replication stability, prognostic importance of the variables, and repeatability of the final regression model.

Main Results: Patients with at least one NOD2 variant were shown to have a reduced phagocytosis by monocytes (p = 0.03) and a higher risk of bacteremia than wild-type patients (p = 0.02). The NOD2/TLR4 combination was associated with bacteremia using survival analyses (time to bacteremia development, log-rank p < 0.0001), univariate regression (p = 0.0003), and multivariate regression analysis (odds ratio [OR] 4.26, 95% confidence interval [CI] 1.85–9.81; p = 0.0006). Similarly, the same combination was associated with hospital mortality using survival analysis (log-rank p = 0.03), univariate regression (p = 0.02), and multivariate regression analysis (OR 2.27, 95% CI 1.09–4.74; p = 0.03). Also variants in the MASP2 gene were significantly associated with hospital mortality (survival analysis log-rank-p = 0.003; univariate regression p = 0.02; multivariate regression analysis OR 2.35, 95% CI 1.38–3.99; p = 0.002).

Conclusions: Functional polymorphisms in genes involved in innate immunity predispose to severe infections and death, and may become part of a risk model, allowing identification of patients at risk, who could benefit from early introduction of specific preventive or therapeutic interventions.

From the Departments of Medicine (LH, SV, PR), and Intensive Care Medicine (PJW, IM, IV, LL, GVdB) Catholic University of Leuven, Leuven, Belgium; Department of Clinical Immunology (KRN, RS), Aalborg Hospital, Aalborg, Denmark; Department of Applied Mathematics and Computer Science (KVS), Ghent University, Ghent, Belgium; Department of Experimental Medicine (CM, AG), Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven, Leuven, Belgium; Department of Medical Microbiology and Immunology (ST), University of Aarhus, Aarhus, Denmark; Department of Medicine (AW), Medical Intensive Care Unit, Catholic University of Leuven, Leuven, Belgium; and Immunoendocrine Research Unit (TKH), Medical Department M, Aarhus University Hospital, Aarhus, Denmark.

Supported, in part, by the Research Fund of the Catholic University of Leuven (GOA/2007/14 to GVdB, IV and LL), by Det Obelske Familyfund, Aalborg, Denmark, the SparNord Foundation, Aalborg, Denmark and the Danish Medical Research Council (22-03-0174 to TKH). L. Henckaerts is a doctoral fellow, L. Langouche and I. Vanhorebeek are postdoctoral fellows; and S. Vermeire is a clinical researcher of the Fund for Scientific Research (FWO), Flanders, Belgium. The funding sources had no role in study design, collection, analysis, and interpretation of data, writing of the report, or the decision to submit the paper for publication.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: greet.vandenberghe@med.kuleuven.be

Supplementary text and tables can be viewed online at http://www.ccmjournal.org.

© 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins