Todd Jamie L, Weber Jeremy M, Kelly Francine L, Nagler Andrew, McArthur Patrick, Eason Lerin, Rim Jeeyon G, Frankel Courtney W, Belperio John A, Budev Marie, Martinu Tereza, Patel Kunal, Reynolds John M, Shah Pali D, Singer Lianne G, Snyder Laurie D, Tsuang Wayne, Weigt S Sam, Neely Megan L, Palmer Scott M
Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
Duke Clinical Research Institute, Durham, North Carolina.
J Heart Lung Transplant. 2025 Mar;44(3):320-328. doi: 10.1016/j.healun.2024.10.014. Epub 2024 Oct 22.
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.
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.
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.
We identified and validated a precise threshold for BALF HA in the first posttransplant year that distinguishes patients at increased CLAD risk.
用于早期识别慢性肺移植功能障碍（CLAD）风险患者的工具很少。我们之前发现，透明质酸（HA）作为一种调节肺部炎症和纤维化的基质分子，在CLAD患者的支气管肺泡灌洗液（BALF）和血液中会蓄积。我们旨在确定移植后早期HA升高是否能提示CLAD风险。
在5个中心对743名成年肺移植受者移植后第一年收集的3080份BALF样本和1323份血液样本中的HA进行定量分析。使用带有“升高”HA的时间依赖性二元协变量的Cox模型评估BALF或血液中HA与CLAD之间的关系。使用第50百分位数至第85百分位数之间的网格搜索来检查HA升高的潜在阈值。使用拟合统计量确定最佳阈值，并通过迭代重采样对所选阈值与CLAD之间的关联进行内部验证。考虑到其他可能影响CLAD风险的因素，使用所选阈值进行多变量Cox模型以评估HA升高与CLAD的关联。
BALF中HA水平>19.1 ng/ml（第65百分位数）发生CLAD的风险比（HR）最大（HR 1.70，95%置信区间[CI] 1.25 - 1.31；p < 0.001），拟合统计量最佳，且具有很强的可重复性。在多变量模型中，移植后第一年BALF中HA>19.1 ng/ml会使CLAD风险增加66%（调整后HR 1.66，95% CI 1.19 - 2.32；p = 0.003）。血液中HA与CLAD无显著关联。
我们确定并验证了移植后第一年BALF中HA的精确阈值，该阈值可区分CLAD风险增加的患者。
