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.

中文翻译：

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识别和验证移植后早期支气管肺泡液透明质酸的阈值，以区分有慢性肺同种异体移植物功能障碍风险的肺受者。


背景 很少有工具可用于早期识别有慢性肺同种异体移植物功能障碍 （CLAD） 风险的患者。我们之前显示透明质酸 （HA） 是一种调节肺部炎症和纤维化的基质分子，在 CLAD 中积聚在支气管肺泡灌洗液 （BALF） 和血液中。我们旨在确定移植后早期 HA 升高是否会影响 CLAD 风险。方法 对 5 个中心的 743 名成年肺受者移植后第一年收集的 3,080 例 BALF 和 1,323 份血样中定量 HA。使用 Cox 模型评估 BALF 或血液 HA 与 CLAD 之间的关系，该模型具有“升高”HA 的时间依赖性二元协变量。使用第 50 个和第 85 个百分位数之间的网格搜索检查升高 HA 的潜在阈值。使用拟合统计量确定最佳阈值，并通过迭代重采样在内部验证所选阈值与 CLAD 之间的关联。使用所选阈值执行多变量 Cox 模型来评估 HA 升高与 CLAD 的关联，同时考虑可能影响 CLAD 风险的其他因素。结果 BALF HA 水平 >19.1 ng/ml （第 65 个百分位数） 对 CLAD 具有最大的风险比 （HR） （HR 1.70,95% 置信区间 [CI] 1.25-1.31;p < 0.001），优化的拟合统计量，并显示出稳健的可重复性。在多变量模型中，移植后第一年发生 BALF HA >19.1 ng/ml 使 CLAD 的危害增加了 66%（调整后的 HR 1.66,95% CI 1.19-2.32;p = 0.003）。血液 HA 与 CLAD 无显著相关性。结论 我们确定并验证了移植后第一年 BALF HA 的精确阈值，该阈值区分了 CLAD 风险增加的患者。