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

IF 6.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of Heart and Lung Transplantation Pub Date : 2024-10-22 DOI:10.1016/j.healun.2024.10.014

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

{"title":"Identification and validation of a threshold for early posttransplant bronchoalveolar fluid hyaluronan that distinguishes lung recipients at risk for chronic lung allograft dysfunction","authors":"Jamie L. Todd MD, MHS , Jeremy M. Weber MS , Francine L. Kelly BS , Andrew Nagler BS , Patrick McArthur BS , Lerin Eason BS , Jeeyon G. Rim MD , Courtney W. Frankel PT, MS , John A. Belperio MD , Marie Budev DO, MPH , Tereza Martinu MD, MHS , Kunal Patel MD, PhD , John M. Reynolds MD , Pali D. Shah MD , Lianne G. Singer MD , Laurie D. Snyder MD , Wayne Tsuang MD, MHS , S. Sam Weigt MD , Megan L. Neely PhD , Scott M. Palmer MD, MHS","doi":"10.1016/j.healun.2024.10.014","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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; <em>p</em> < 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; <em>p</em> = 0.003). Blood HA was not significantly associated with CLAD.</div></div><div><h3>Conclusions</h3><div>We identified and validated a precise threshold for BALF HA in the first posttransplant year that distinguishes patients at increased CLAD risk.</div></div>","PeriodicalId":15900,"journal":{"name":"Journal of Heart and Lung Transplantation","volume":"44 3","pages":"Pages 320-328"},"PeriodicalIF":6.4000,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Heart and Lung Transplantation","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1053249824019004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

确定并验证移植后早期支气管肺泡液透明质酸的阈值，以区分有 CLAD 风险的肺部受者。

背景很少有工具可用于早期识别有慢性肺移植功能障碍（CLAD）风险的患者。我们以前研究发现，透明质酸（HA）是一种调节肺部炎症和纤维化的基质分子，会在 CLAD 患者的支气管肺泡灌洗液（BALF）和血液中蓄积。我们的目的是确定移植后早期 HA 升高是否可为 CLAD 风险提供信息。方法对 5 个中心的 743 名成年肺部受者在移植后第一年内采集的 3080 份 BALF 和 1323 份血液样本中的 HA 进行量化。使用Cox模型评估了BALF或血液HA与CLAD之间的关系，HA "升高 "的二元协变量与时间相关。在第 50 个百分位数和第 85 个百分位数之间进行网格搜索，检查了 HA 升高的潜在阈值。使用拟合统计量确定了最佳阈值，并通过迭代重采样对所选阈值与 CLAD 之间的关联进行了内部验证。考虑到可能影响 CLAD 风险的其他因素，使用选定阈值的多变量 Cox 模型评估 HA 升高与 CLAD 的关联。1ng/mL（第 65 百分位数），CLAD 的危险比最大（HR 1.70，95% CI 1.25-1.31；p19.1 ng/mL 在移植后第一年，CLAD 的危险增加 66%（调整后 HR 1.66，95% CI 1.19-2.32；p=0.003）。结论我们确定并验证了移植后第一年BALF HA的精确阈值，该阈值可将CLAD风险增加的患者区分开来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Heart and Lung Transplantation 医学-呼吸系统

CiteScore

10.10

自引率

6.70%

发文量

1667

审稿时长

69 days

期刊介绍： The Journal of Heart and Lung Transplantation, the official publication of the International Society for Heart and Lung Transplantation, brings readers essential scholarly and timely information in the field of cardio-pulmonary transplantation, mechanical and biological support of the failing heart, advanced lung disease (including pulmonary vascular disease) and cell replacement therapy. Importantly, the journal also serves as a medium of communication of pre-clinical sciences in all these rapidly expanding areas.