title: BAL neutrophilia in azithromycin-treated lung transplant recipients: Clinical significance.
abstract: BACKGROUND
  Azithromycin decreases airway neutrophilia and can prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). It also can be used to treat lymphocytic bronchiolitis, as it decreases the submucosal infiltrating IL-17 positive lymphocytes. Some patients, while receiving azithromycin, (re)develop increased airway neutrophilia, which we hypothesize to result in worse outcome and to be regulated by an IL-17-independent mechanism.
  
  
  METHODS
  LTx recipients, transplanted between 2001 and 2012, were investigated and categorized in a study group of patients with increased broncho-alveolar lavage (BAL) neutrophilia (≥15%) and a matched control group with low BAL neutrophilia (<15%), both groups while already being on azithromycin treatment. CLAD-free and overall survival were compared between groups. Cell differentials and 33 proteins in BAL were analyzed to identify underlying mechanisms.
  
  
  RESULTS
  The study group (n=72) demonstrated a significantly lower CLAD-free (p=0.015) and overall survival (p=0.041) compared to the control group (n=37). Absolute BAL neutrophils and eosinophils were increased in the study group, which was paralleled by elevated inflammatory cytokines (IL-1β/IL-1Ra, IL-4 and IL-6) and chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL11/eotaxin) concentrations compared to the control group (all p<0.05).
  
  
  CONCLUSIONS
  Patients with elevated airway neutrophilia despite azithromycin, experience worse CLAD-free and overall survival. In these patients, IL-1β might play a central role giving rise to neutrophils, eosinophils, macrophages and B-cells. This provides an opportunity to further investigate the modulation of this pathway.
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Elly
authors.initials: E
authors.lastname: Vandermeulen
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Stijn E
authors.initials: SE
authors.lastname: Verleden
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Ruttens
authors.affiliation: Laboratory of Molecular Immunology, Dept. of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Moelants
authors.affiliation: Laboratory of Molecular Immunology, Dept. of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Mortier
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Jana
authors.initials: J
authors.lastname: Somers
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Bellon
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Davide
authors.initials: D
authors.lastname: Piloni
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Dupont
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Van Raemdonck
authors.affiliation: Laboratory of Molecular Immunology, Dept. of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.affiliation: Laboratory of Virology and Chemotherapy, Dept. of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Robin
authors.initials: R
authors.lastname: Vos
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Geert M
authors.initials: GM
authors.lastname: Verleden
authors.affiliation: University of Leuven, Department of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, KU Leuven, Leuven Belgium.
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
mesh_terms: D017963:Azithromycin / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007960:Leukocyte Disorders / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D015996:Survival Rate
chemical_list: D016207:Cytokines; D017963:Azithromycin
keywords: Azithromycin therapy; BAL neutrophilia; Chronic lung allograft dysfunction; Lung transplantation