title: Clinical implications and molecular mechanisms of immunoparalysis after cardiopulmonary bypass.
abstract: OBJECTIVE
  We used a whole blood assay to characterize the immune system's response after cardiopulmonary bypass (CPB) in children to identify the risk for postoperative infections. We assessed the impact of CPB on histone methylation as a potential mechanism for altering gene expression necessary for the immune system's capacity to defend against infections.
  
  
  METHODS
  We prospectively enrolled patients less than 18 years old undergoing heart surgery requiring CPB at C.S. Mott Children's Hospital. Blood was obtained from patients before CPB, on CPB, and on postoperative days 1, 3, and 5. Ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha production measured the capacity of the immune system. Serum cytokines were measured using a multiplex assay. Chromatin immunoprecipitation to detect histone modifications at the interleukin (IL) 10 promoter was performed on circulating mononuclear cells from a subgroup of patients.
  
  
  RESULTS
  We enrolled 92 patients, and postoperative day 1 samples identified a subpopulation of immunocompetent patients at low risk for infections with a specificity of 93% (confidence interval [CI], 83%-98%) and a negative predictive value of 88% (CI, 77%-95%; P = .006). Patients classified as immunoparalyzed had serum IL-10 levels 2.4-fold higher than the immunocompetent group (mean, 14.3 ± 18.3 pg/mL vs 6.0 ± 5.0 pg/mL; P = .01). In a subgroup of patients, we identified a greater percent of the "gene on" epigenetic signature, H3K4me3, associated with the IL-10 promoter after CPB.
  
  
  CONCLUSIONS
  Our data demonstrate that immunophenotyping patients after CPB can predict their risk for the development of postoperative infections. Novel mechanistic data suggest that CPB affects epigenetic alterations in IL-10 gene regulation.
authors: Division of Critical Care Medicine, C.S. Mott Children’s Hospital, F-6882, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0243, USA. ttcornel@med.umich.edu
authors: Timothy T
authors: TT
authors: Cornell
authors: Lei
authors: L
authors: Sun
authors: Mark W
authors: MW
authors: Hall
authors: James G
authors: JG
authors: Gurney
authors: Matthew J
authors: MJ
authors: Ashbrook
authors: Richard G
authors: RG
authors: Ohye
authors: Thomas P
authors: TP
authors: Shanley
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D047369:Chromatin Immunoprecipitation; D003141:Communicable Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007121:Immunocompetence; D016867:Immunocompromised Host; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D008297:Male; D008745:Methylation; D008824:Michigan; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006657:Histones; C508609:IL10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10