Identification and validation of a threshold for early posttransplant bronchoalveolar fluid hyaluronan that distinguishes lung recipients at risk for chronic lung allograft dysfunction

Jamie L Todd; Jeremy M Weber; Francine L Kelly; Andrew Nagler; Patrick McArthur; Lerin Eason; Jeeyon G Rim; Courtney W Frankel; John A Belperio; Marie Budev; Tereza Martinu; Kunal Patel; John M Reynolds; Pali D Shah; Lianne G Singer; Laurie D Snyder; Wayne Tsuang; S Sam Weigt; Megan L Neely; Scott M Palmer

doi:10.1016/j.healun.2024.10.014

Identification and validation of a threshold for early posttransplant bronchoalveolar fluid hyaluronan that distinguishes lung recipients at risk for chronic lung allograft dysfunction

J Heart Lung Transplant. 2024 Oct 22:S1053-2498(24)01900-4. doi: 10.1016/j.healun.2024.10.014. Online ahead of print.

Authors

Jamie L Todd¹, Jeremy M Weber², Francine L Kelly³, Andrew Nagler³, Patrick McArthur³, Lerin Eason³, Jeeyon G Rim³, Courtney W Frankel³, John A Belperio⁴, Marie Budev⁵, Tereza Martinu⁶, Kunal Patel⁷, John M Reynolds³, Pali D Shah⁸, Lianne G Singer⁶, Laurie D Snyder⁹, Wayne Tsuang⁵, S Sam Weigt⁴, Megan L Neely¹⁰, Scott M Palmer⁹

Affiliations

¹ Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina. Electronic address: jamie.todd@duke.edu.
² Duke Clinical Research Institute, Durham, North Carolina.
³ Department of Medicine, Duke University Medical Center, Durham, North Carolina.
⁴ Department of Medicine, University of California Los Angeles, Los Angeles, California.
⁵ Department of Medicine, Cleveland Clinic, Cleveland, Ohio, United States.
⁶ Department of Medicine, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.
⁷ Department of Surgery, Duke University Medical Center, Durham, North Carolina.
⁸ Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
⁹ Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
¹⁰ Duke Clinical Research Institute, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina.

PMID: 39448000
DOI: 10.1016/j.healun.2024.10.014

Abstract

Background: Few tools exist for the early identification of patients at risk for chronic lung allograft dysfunction (CLAD). We previously showed hyaluronan (HA), a matrix molecule that regulates lung inflammation and fibrosis, accumulates in bronchoalveolar lavage fluid (BALF) and blood in CLAD. We aimed to determine if early posttransplant HA elevations inform CLAD risk.

Methods: HA was quantified in 3,080 BALF and 1,323 blood samples collected over the first posttransplant year in 743 adult lung recipients at 5 centers. The relationship between BALF or blood HA and CLAD was assessed using Cox models with a time-dependent binary covariate for "elevated" HA. Potential thresholds for elevated HA were examined using a grid search between the 50th and 85th percentile. The optimal threshold was identified using fit statistics, and the association between the selected threshold and CLAD was internally validated through iterative resampling. A multivariable Cox model using the selected threshold was performed to evaluate the association of elevated HA with CLAD, considering other factors that may influence CLAD risk.

Results: BALF HA levels >19.1 ng/ml (65th percentile) had the largest hazard ratio (HR) for CLAD (HR 1.70, 95% confidence interval [CI] 1.25-1.31; p < 0.001), optimized fit statistics, and demonstrated robust reproducibility. In a multivariable model, the occurrence of BALF HA >19.1 ng/ml in the first posttransplant year conferred a 66% increase in the hazards for CLAD (adjusted HR 1.66, 95% CI 1.19-2.32; p = 0.003). Blood HA was not significantly associated with CLAD.

Conclusions: We identified and validated a precise threshold for BALF HA in the first posttransplant year that distinguishes patients at increased CLAD risk.

Keywords: bronchoalveolar lavage fluid; chronic lung allograft dysfunction; hyaluronan; lung transplantation.