Background We aimed to identify data-driven FEV1 trajectory phenotypes post-chronic lung allograft dysfunction (CLAD), relate these phenotypes to patient factors and future graft loss, and develop a classification approach for prospective patients.

Methods We studied adult first lung recipients with probable CLAD from two prospective multicenter cohorts: CTOT-20 (n=206) and LTOG (n=1418). FEV1 trajectories over the first nine months post-CLAD were characterized using joint latent class mixed models, jointly modelling time-to-graft loss to account for informative censoring. Models were fit independently in both cohorts and also only among LTOG bilateral recipients. A classification and regression tree (CART) model was derived in LTOG bilateral recipients and applied to CTOT-20 bilateral recipients.

Findings Four distinct early FEV1 trajectory classes were identified in CTOT-20, with large differences in nine-month graft loss (72·3%, 31·1%, 2·2%, 0%). In LTOG, similar trajectory patterns were reproduced, with an additional class demonstrating early post-CLAD FEV1 improvement. Among bilateral recipients, trajectory classes showed a clear risk gradient, including a high-risk class with 100% graft loss and a low-risk class with no early graft loss. A CART model incorporating clinical and spirometric variables demonstrated good discrimination in LTOG bilateral recipients (multiclass AUC 0·85) and consistent class assignment and trajectory patterns when applied to CTOT-20.

Interpretation We identified reproducible, clinically meaningful early post-CLAD FEV1 trajectory phenotypes with differential graft loss risk. These phenotypes and a pragmatic classification tool may support risk stratification, trial enrichment, and improved prognostication for patients and clinicians.

Funding National Institutes of Health, Cystic Fibrosis Foundation

Neely: Support for the present manuscript from 5U01-HL145435, 5R21-AI168582, CF Foundation CTOT-20 Extension (Palmer 19AB0); Grants or contracts from 5U01-AI163099, 1U24-HL163122, Boehringer Ingelheim IPF/ILD-PRO Registries; Payment or honoraria from NC State University, Journal of Heart and Lung Transplantation; nothing else to disclose. Wojdyla: To be collected Hong: Support for the present manuscript from NIH R21AI168582; nothing else to disclose. Wang: Nothing to disclose. Anderson: To be collected. Arroyo: Nothing to disclose. Belperio: Nothing to disclose. Benvenuto: To be collected. Budev: To be collected. Combs: To be collected. Dhillon: Grants or contracts from NHLBI, CF Foundation; nothing else to disclose. Hsu: Support for the present manuscript from U01-HL145435; Leadership or fiduciary role for National Kidney Foundation, Public Library of Science, American Medical Association; nothing else to disclose. Kalman: Support for the present manuscript from NIH; nothing else to disclose. Martinu: To be collected. McDyer: To be collected. Oyster: To be collected. Pandya: To be collected. Reynolds: To be collected. Rim: Nothing to disclose. Roe: Nothing to disclose. Shah: To be collected. J. Singer: Grants or contracts from U01-HL145435-06; nothing else to disclose. L. Singer: Grants or contracts from Sanofi; Payment or honoraria from Sanofi; Participation on a data safety monitoring board or advisory board for Renovion, Zambon; nothing else to disclose. Snyder: To be collected. Tsuang: Nothing to disclose. Weigt: Support for the present manuscript from National Institute of Allergy and Infectious Diseases (U01AI113315), Cystic Fibrosis Foundation (PALMER19AB0); Grants or contracts from CareDx, Zambon; Consulting fees from Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi Pharmaceuticals; Payment or honoraria from Boehringer Ingelheim Pharmaceuticals, Inc., CareDx; Patents planned, issued or pending for U.S.Provisional Patent Application No. 63/862,482 entitled BIOMARKER FOR ALLOGRAFT INJURY OR REJECTION; nothing else to disclose. Christie: Support for the present manuscript from NIH/NHLBI; Grants or contracts from NIH/NHLBI, CF Foundation; Consulting fees from GSK, United Health Care; Support for attending meetings and/or travel from International Society of Heart and Lung Transplantation; Participation on a data safety monitoring board or advisory board for NIH PETALnet, NHLBI; Other financial or non-financial interests include consulting as an expert witness in asbestos litigation for various law firms; nothing else to disclose. Palmer: Grants or contracts from Sanofi, Veloxis, Bristol Myers Squibb, CareDx, Boehringer Ingelheim Pharmaceuticals, Inc.; Royalties or licenses from Up to Date; Consulting fees from Abbvie, Sanofi, Mallinckrodt Pharmaceuticals, Variant Bio, Incyte; Payment or honoraria from Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc.; nothing else to disclose. Todd: Support for the present manuscript from NIH/NHLBI, NIH/NIAID, Cystic Fibrosis Foundation; Grants or contracts from NIH, Boehringer Ingelheim, Cystic Fibrosis Foundation, Sanofi; Consulting fees from Sanofi; Participation on a data safety monitoring board or advisory board from Sanofi, Avalyn; nothing else to disclose.

National Institutes of Health-National Heart Lung and Blood Institute grant U01-HL145435-06. National Institutes of Health-National Institute of Allergy and Infectious Disease awards R21AI168582, U01AI113315 and UM2AI117870. Cystic Fibrosis Foundation award PALMER19AB0.

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The study was approved by the Duke Institutional Review Board (Pro00113359).

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