title: Proteomic bronchiolitis obliterans syndrome risk monitoring in lung transplant recipients.
abstract: BACKGROUND
  Obliterative bronchiolitis poses a primary obstacle for long-term survival of lung transplant recipients and manifests clinically as bronchiolitis obliterans syndrome (BOS). Establishing a molecular level screening method to detect BOS-related proteome changes before its diagnosis by forced expiratory volume surrogate marker criteria was the main objective of this study.
  
  
  METHODS
  Bronchoalveolar lavage was performed in 82 lung transplant recipients (48/34 with/without known BOS development) at different time points between 12 and 48 months after lung transplantation. A mass spectrometry-based method was devised to generate bronchoalveolar lavage fluid proteome profiles that were screened for BOS-specific alterations. Statistically significant marker peptides and proteins were identified and validated by in-gel digestion, tandem mass spectrometric sequencing, and quantitative immunoassays.
  
  
  RESULTS
  Among the panel of statistically significant markers were Clara cell protein, calgranulin A, human neutrophil peptides, and the antimicrobial agent histatin. To assess their clinical relevance, a highly sensitive and specific classifier model was developed. Positive BOS classification by monitoring of seven polypeptides correlated strongly with a significant decrease in BOS-free time. Thus, it was possible to detect high-risk patients early on in the pathogenetic process.
  
  
  CONCLUSIONS
  Monitoring the bronchoalveolar lavage fluid levels of seven polypeptides detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows a reliable prediction of early BOS using a Random Forest decision tree-based classifier model. The high accuracy of this robust model and its synergistic potential in combination with established forced expiratory volume-based diagnostics could make it an effective tool to supplement the current diagnostic regime after multicentric validation.
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School (MHH), Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.forename: Tonio
authors.initials: T
authors.lastname: Oumeraci
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.forename: Andreas
authors.initials: A
authors.lastname: Pich
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Nils
authors.initials: N
authors.lastname: von Neuhoff
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000175:diagnosis* / Q000209:etiology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D040501:Calgranulin A / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D054808:Histatins / Q000378:metabolism; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013577:Syndrome; D014598:Uteroglobin / Q000378:metabolism; D023084:alpha-Defensins
chemical_list: D040501:Calgranulin A; D054808:Histatins; D020543:Proteome; C556389:SCGB1A1 protein, human; D023084:alpha-Defensins; D014598:Uteroglobin