title: Polymorphisms in tumor necrosis factor-α increase susceptibility to intra-abdominal Candida infection in high-risk surgical ICU patients*.
abstract: 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.
  
  
  
  Prospective observational cohort study.
  
  
  
  Surgical ICUs from two University hospitals of the Fungal Infection Network of Switzerland.
  
  
  
  Eighty-nine patients at high risk for intra-abdominal candidiasis (68 with recurrent gastrointestinal perforation and 21 with acute necrotizing pancreatitis).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wójtowicz
authors.forename: Frederic
authors.initials: F
authors.lastname: Tissot
authors.forename: Frederic
authors.initials: F
authors.lastname: Lamoth
authors.forename: Christina
authors.initials: C
authors.lastname: Orasch
authors.forename: Philippe
authors.initials: P
authors.lastname: Eggimann
authors.forename: Martin
authors.initials: M
authors.lastname: Siegemund
authors.forename: Stephan
authors.initials: S
authors.lastname: Zimmerli
authors.forename: Ursula Maria
authors.initials: UM
authors.lastname: Flueckiger
authors.forename: Jacques
authors.initials: J
authors.lastname: Bille
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.forename: Oscar
authors.initials: O
authors.lastname: Marchetti
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002177:Candidiasis / Q000453:epidemiology*; D005260:Female; D005838:Genotype; D006801:Humans; D007362:Intensive Care Units; D059413:Intraabdominal Infections / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000453:epidemiology*; D011446:Prospective Studies; D012737:Sex Factors; D013557:Switzerland; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha