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Gottlieb J, Verleden GM, Perchl M, et al. Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction-A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial. PLoS One. 2021;16(12):e0260881doi: 10.1371/journal.pone.0260881.
Gottlieb, J., Verleden, G. M., Perchl, M., Valtin, C., Vallee, A., Brugière, O., & Bravo, C. (2021). Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction-A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial. PloS one, 16(12), e0260881. https://doi.org/10.1371/journal.pone.0260881
Gottlieb, Jens, et al. "Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction-A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial." PloS one vol. 16,12 (2021): e0260881. doi: https://doi.org/10.1371/journal.pone.0260881
Gottlieb J, Verleden GM, Perchl M, Valtin C, Vallee A, Brugière O, Bravo C. Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction-A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial. PLoS One. 2021 Dec 23;16(12):e0260881. doi: 10.1371/journal.pone.0260881. eCollection 2021. PMID: 34941934.
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PLoS One. 2021 Dec 23;16(12):e0260881. doi: 10.1371/journal.pone.0260881. eCollection 2021.

Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction-A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial.

PloS one

Jens Gottlieb, Geert M Verleden, Michael Perchl, Christina Valtin, Alexander Vallee, Olivier Brugière, Carlos Bravo

Affiliations

  1. Dept. of Respir. Medicine OE 6870, Hannover Medical School, Hannover, Germany.
  2. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
  3. Dept Respir. Med, Lung Transplant Unit, University Hospital Gasthuisberg, Leuven, Belgium.
  4. Department of Cardiology, Section for Lung transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  5. Délégation à la Recherche Clinique et à l'Innovation, Hôpital Foch, Suresnes, France.
  6. Service de Transplantation Pulmonaire et Centre de compétence de la Mucoviscidose, Hôpital Foch, Suresnes, France.
  7. Servei de Pneumologia, Hospital Universitari Val d'Hebron, Barcelona, Spain.

PMID: 34941934 DOI: 10.1371/journal.pone.0260881

Abstract

BACKGROUND: Chronic Lung Allograft Dysfunction (CLAD) is a major obstacle for long term survival after lung transplantation (LTx). Besides Bronchiolitis Obliterans Syndrome, two other phenotypes of CLAD, restrictive allograft syndrome (RAS) and mixed phenotype, have been described. Trials to test in these conditions are desperately needed and analyzing natural outcome to plan such trials is essential.

METHODS: We performed a retrospective analysis of functional outcome in bilateral LTx recipients with RAS and mixed phenotype, transplanted between 2009 and 2018 in five large European centers with follow- up spirometry up to 12 months after diagnosis. Based on these data, sample size and power calculations for randomized therapeutic trial was estimated using two imputation methods for missing values.

RESULTS: Seventy patients were included (39 RAS and 31 mixed phenotype), median 3.1 years after LTx when CLAD was diagnosed. Eight, 13 and 25 patients died within 6, 9 and 12 months after diagnosis and a two patients underwent re-transplantation within 12 months leading to a graft survival of 89, 79 and 61% six, nine and 12 months after diagnosis, respectively. Observed FEV1 decline was 451 ml at 6 months and stabilized at 9 and 12 months, while FVC showed continuous decline. Using two methods of imputation, a progressive further decline after 6 months for FEV1 was noted.

CONCLUSION: The poor outcome of these two specific CLAD phenotypes suggests the urgent need for future therapeutic randomized trials. The number of missing values in a potential trial seems to be high and most frequently attributed to death. Survival may be used as an endpoint in clinical trials in these distinct phenotypes and imputation techniques are relevant if graft function is used as a surrogate of disease progression in future trials.

Conflict of interest statement

The authors have declared that no competing interests exist.

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