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Polymorphisms in Tumor Necrosis Factor-α Increase Susceptibility to Intra-Abdominal Candida Infection in High-Risk Surgical ICU Patients*

Wójtowicz, Agnieszka PhD1; Tissot, Frederic MD1; Lamoth, Frederic MD1; Orasch, Christina MD1,2; Eggimann, Philippe MD3; Siegemund, Martin MD4; Zimmerli, Stephan MD5; Flueckiger, Ursula Maria MD2,6; Bille, Jacques MD7; Calandra, Thierry MD, PhD1; Marchetti, Oscar MD1; Bochud, Pierre-Yves MD1; the Fungal Infection Network of Switzerland (FUNGINOS)

doi: 10.1097/CCM.0000000000000208
Online Brief Reports

Objectives: To evaluate the influence of genetic polymorphisms on the susceptibility to Candida colonization and intra-abdominal candidiasis, a blood culture–negative life-threatening infection in high-risk surgical ICU patients.

Design: Prospective observational cohort study.

Setting: Surgical ICUs from two University hospitals of the Fungal Infection Network of Switzerland.

Patients: Eighty-nine patients at high risk for intra-abdominal candidiasis (68 with recurrent gastrointestinal perforation and 21 with acute necrotizing pancreatitis).

Measurements and Main Results: Eighteen single-nucleotide polymorphisms in 16 genes previously associated with development of fungal infections were analyzed from patient’s DNA by using an Illumina Veracode genotyping platform. Candida colonization was defined by recovery of Candida species from at least one nonsterile site by twice weekly monitoring of cultures from oropharynx, stools, urine, skin, and/or respiratory tract. A corrected colonization index greater than or equal to 0.4 defined “heavy” colonization. Intra-abdominal candidiasis was defined by the presence of clinical symptoms and signs of peritonitis or intra-abdominal abscess and isolation of Candida species either in pure or mixed culture from intraoperatively collected abdominal samples. Single-nucleotide polymorphisms in three innate immune genes were associated with development of a Candida corrected colonization index greater than or equal to 0.4 (Toll-like receptor rs4986790, hazard ratio = 3.39; 95% CI, 1.45–7.93; p = 0.005) or occurrence of intra-abdominal candidiasis (tumor necrosis factor-α rs1800629, hazard ratio = 4.31; 95% CI, 1.85–10.1; p= 0.0007; β-defensin 1 rs1800972, hazard ratio = 3.21; 95% CI, 1.36–7.59; p = 0.008).

Conclusion: We report a strong association between the promoter rs1800629 single-nucleotide polymorphism in tumor necrosis factor-α and an increased susceptibility to intra-abdominal candidiasis in a homogenous prospective cohort of high-risk surgical ICU patients. This finding highlights the relevance of the tumor necrosis factor-α functional polymorphism in immune response to fungal pathogens. Immunogenetic profiling in patients at clinical high risk followed by targeted antifungal interventions may improve the prevention or preemptive management of this life-threatening infection.

1Infectious Diseases Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

2Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, Basel University Hospital, Basel, Switzerland.

3Adult Intensive Care Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

4Intensive Care Unit, Basel University Hospital, Basel, Switzerland.

5Institute for Infectious Diseases, University of Bern, Bern, Switzerland.

6Division of Infectious Disease, Internal Medicine Centre, Hirslanden Klink, Aarau, Switzerland.

7Institute of Microbiology, Department of Laboratories, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

* See also p. 1019.

Drs. Marchetti and Bochud contributed equally to this work.

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Supported, in part, by research funding from the Leenaards Foundation, the Santos-Suarez Foundation, and the Foundation for the Advancement in Medical Microbiology and Infectious Diseases. The Fungal Infection Network of Switzerland Foundation received unrestricted grant support from (in alphabetical order): Essex Schering-Plough, Gilead, Merck, Sharp and Dohme-Chibret, Novartis, and Pfizer. None of the above funding sources has been involved in study design and conduct, patient recruitment, data collection, analysis, and interpretation; writing of the article; or decision to submit the article for publication.

Dr. Eggimann received support for travel from Astellas, MSD, and Pfizer. He consulted, served as a board member, and lectured for Astellas, MSD, and Pfizer. Dr. Flueckiger’s institution received grant support from Pfizer, Gilead, and MSD (unrestricted grant to Fungal Infection Network of Switzerland [FUNGINOS] Group). Dr. Calandra served as a board member for Pfizer, MSD, and Astellas; consulted for Pfizer, MSD, and Novartis; lectured for bioMerieux and Pfizer; received support for development of educational presentations from MSD and Gilead Sciences; and received support for travel from MSD, Pfizer, and Astellas. Dr. Calandra received grant support from European Union’s Seventh Framework Program (FP7/2007–2013) under grant agreement no. HEALTH-2010–260338 (ALLFUN). Dr. Marchetti’s institution received grant support from the FUNGINOS Foundation, Leenaards Foundation, Foundation for the Advancement in Medical Microbiology and Infectious Diseases, bioMerieux, Bio-Rad, Essex Schering-Plough, Gilead, Merck, Novartis, Pfizer, Roche Diagnostics, Associates of Cape Code, and European Community’s Seventh Framework Program (FP7-2007–2013) under grant agreement no. Health-F2-2010-26033-ALLFUN (peer-reviewed unrestricted research grants); served as board member and consulted for Essex Schering-Plough, Gilead, Merck, Novartis, and Pfizer; and lectured for Essex Schering-Plough, Gilead, Pfizer, and Roche Diagnostics. Dr. Bochud’s institution received grant support from the Leenaards Foundation, Lausanne; National Science Foundation (32003B-127613, 320030-144054); Santos-Suarez Foundation; and European Union’s Seventh Framework Program (FP7/2007–2013) under grant agreement no. HEALTH-2010–260338 (ALLFUN). His institution received payment for lectures and received support for travel from Astellas, Gilead, and MSD (travel grants). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: pierre-yves.bochud@chuv.ch

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins