Histological Profiles of Lung Allograft Transbronchial Biopsies and Clinical Outcomes After Lung Transplantation
Condition: Lung Transplant Rejection
Study type: Observational

Summary: 
      Lung transplantation is the only curative treatment for individuals with end-stage lung
      disease. Understanding the lung allograft's histological lesions, which is key for the
      patient management, remains difficult because of the multiplicity of lesions associated with
      graft outcome and their interpenetration.

      The goal of this observational study is to identify clusters of histological lesion on
      transbronchial biopsies in Lung transplant recipient prospective cohort.

      The main question[s] it aims to answer are:

        -  what are the different pattern of histological lesion?

        -  what are the graft outcome associated with the different clusters?
    

Detailed description: 
      SCIENTIFIC JUSTIFICATION:

      With more than three million deaths per year, the chronic obstructive pulmonary disease is
      currently the third cause of mortality worldwide , and contributes to the growing number of
      individuals with end-stage lung disease, which is now a major issue for world public health.
      Overall, for individuals with end-stage lung disease, lung transplantation (LTx) is the only
      treatment able to increase patient survival and quality of life, with more than 4,500 lung
      transplantations performed each year.

      Despite major progresses made in the last decade regarding organ preservation, procurement
      and short term outcome little improvements have been made on the histological
      characterization of rejection, which remains the main determinant of patient death after lung
      transplantation.

      One of the main limitation of histological analysis is the multiplicity of lesions associated
      with graft outcome and their interpenetration. Historically, the perivascular infiltrate or
      cellular rejection (A lesions), and the lymphocytic bronchiolitis (B lesions) are the first
      histological lesions associated with graft dysfunction and stand as key parameters in patient
      management. In addition to A and B lesions, a wide spectrum of histological lesions of the
      lung allograft is associated with clinical outcomes.

      However, to our best knowledge, only few studies thoroughly investigated the various
      elementary lesions in the broad scope of histological analysis, and their association with
      clinical outcomes. Although informative, those studies usually suffer from a small number of
      patients, convenience clinical samples from registry, and the lack of innovative statistical
      approach. Overall, the wide spectrum of the allograft lesions has not been investigated using
      a large number of transbronchial biopsies with standardized protocol and biopsy reading, and
      a multidimensional approach on deeply phenotyped data.

      The recent use of unsupervised method in organ transplantation has permitted the
      identification of clinically relevant patient clusters and may be a relevant strategy to
      decipher the heterogeneity in histological lesions in lung recipients.

      Therefore, using a deeply phenotyped prospective cohort of lung recipients and consecutive
      transbronchial biopsies with protocolized evaluation and interpretation covering the
      different cases scenario encountered in clinical practice, the investigators aim to identify
      histological clusters based on histological lesions and assess their associations with graft
      and patient outcomes.

      OBJECTIVES:

      Main objective: To identify of histological cluster of lung allograft Transbronchial biopsies

      Secondary objective: To evaluate association of each cluster with baseline clinical data and
      anti HLA donor specific antibody and graft outcome

      INTERVENTIONS:

      This is an observational study that involves only minimal risk and constraints. The
      intervention consists in the evaluation of parameters measured as part of the standard of
      care at the time of post-transplant allograft biopsy.

      No medicinal product is under investigation in this protocol.

      EXPECTED BENEFITS for the participants and for society:

      There will be no immediate individual benefit for the patient to participate in the study.

      This study will provide us with data of Lung transplant patients that may allow the
      improvement of clinical decisions and the long-term lung allograft management.

      MINIMAL RISKS AND CONSTRAINTS added by the study No additional intervention beyond the
      standard of care will be performed in this study.

      RECRUITING CENTER:

        -  Single center study

        -  Hopital Foch, Suresnes, France
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        This prospective cohort included consecutive lung transplant recipients who were
        transplanted between February 2010 and November 2019 in Foch Hospital and were eligible for
        inclusion.

        Every protocol and for cause transbronchial biopsies (TBBs) identified in the Foch hospital
        database for each patient were analyzed using standardized template. Reports of TBB with
        one or more missing values were excluded. Protocol TBB were performed after transplantation
        with the following scheme : month 1 (M1) at 30 ± 10 days, month 2 (M2): 60 ± 10 days, month
        3 (M3): 90 ± 10 days, month 4 (M4): 120 ± 10 days, month 6 (M6): 180 ± 10 days, month 9
        (M9): 270 ± 10 days and month 12 (M12): 365 ± 10 days. For cause TBB were performed in case
        of graft dysfunction.
      
Keywords: Lung transplantation; Rejection; Transbronchial biopsy; Donor specific Antibody; Cluster analysis