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Background: Bronchiolitis obliterans (BO) is the major obstacle to long-term lung allograft viability. Its clinical correlate, BO syndrome (BOS), is defined as a decline of at least 20% in forced expiratory volume in 1 second (FEV(1)) from baseline. BOS is often diagnosed after significant organ dysfunction has occurred. Because BO is a small-airways disease, we hypothesized that a 20% decline in the 25% to 75% forced expiratory flow (FEF(25-75)) from baseline should occur before a decline in FEV(1) and should predict progression to BOS with high sensitivity and specificity., Methods: Pulmonary function tests and records of pediatric lung transplantation patients at Texas Children's Hospital from 2002 to 2007 were reviewed. Declines in FEV(1) and FEF(25-75) from the best post-transplant baseline values were recorded and analyzed. Sensitivity, specificity, and positive and negative predictive values were calculated., Results: Thirty-one patients were eligible for the study. In 11 BOS patients, the mean±standard deviation number of days from transplant until a 20% decline in FEV(1) was 896.5±400 compared with 728.0±475 (p = 0.022) until a 20% decline in FEF(25-75) was reached. The sensitivity, specificity, and positive predictive and negative predictive values of a 20% reduction in FEF(25-75) in determining BOS were 100%, 90.0%, 84.6%, and 100%, respectively., Conclusions: All patients who developed BOS had a decline in FEF(25-75) at or before the decline in FEV(1). The reduction in FEF(25-75) occurred statistically significantly earlier than the decline in FEV(1), by an average of 168.5 days. This decline in FEF(25-75) was also highly sensitive and specific for the diagnosis of BOS., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

KL-6 is a glycoprotein expressed by pulmonary epithelial cells, and its serum level has been used as a marker of disease activity in a variety of respiratory illnesses. Previously, we showed that KL-6 was elevated in lung transplant recipients diagnosed with BOS. In this study, we followed serum KL-6 levels and lung functions prospectively in lung transplant recipients who were within the first five-yr post-transplant and had no evidence of BOS at the time of study entry. Mean peak KL-6 levels were 596.16 ± 309.32 U/mL in the nine recipients who developed BOS compared to 352.41 ± 140.68 in 36 recipients who did not (p = 0.05). Six of the nine patients with BOS had an absolute rise in KL-6 above baseline level >200 U/mL compared to two of the 37 who had the same increase in KL-6 but did not develop BOS. Using the 200 U/mL elevation of KL-6 from baseline as a threshold for a positive test would produce a sensitivity of 67%, specificity of 95%, PPV of 75%, and a NPV of 92%. In addition, mean KL-6 levels of patients during acute rejection were not significantly elevated compared to the prerejection mean KL-6 levels (p = 0.71). We conclude that serum KL-6 is a relatively specific marker of BOS in lung transplant recipients., (© 2010 John Wiley & Sons A/S.)

In adult lung transplantation, a single minimal AR episode is a significant predictor of BOS independent of other factors. However, the significance of single minimal AR episodes in children is unknown. A retrospective, multi-center analysis was performed to determine whether isolated single AR episodes are associated with an increased BOS risk in children. Risk factors for BOS, death, or re-transplantation, and a combined outcome of BOS, death, or re-transplantation were assessed. Original data included 577 patients (<21 yr of age). A total of 383 subjects were eligible for the study. Fifteen percent of patients developed BOS, and 13% of patients either died or underwent re-transplant within one-yr post-transplant. In the multivariable survival model for time to BOS, there was no significant risk to developing BOS after a single minimal AR (A1) episode (HR 1.7, 95% CI 0.64-4.8; p=0.28). Even after a second minimal AR episode, no significant risk for BOS was appreciated. However, a single episode of mild AR (A2) was associated with twice the risk of BOS within one-yr post-transplant. In this select cohort, a single minimal AR episode was not associated with an increased risk for BOS within one yr following lung transplantation, in contrast to previous reports in adults., (Copyright (c) 2010 John Wiley & Sons A/S.)

Bronchiolitis obliterans (BO) is the pathologic manifestation of chronic allograft rejection in lung transplant recipients and specific diagnosis requires invasive tests. BO causes progressive obstruction of the small airways. The term bronchiolitis obliterans syndrome (BOS) is a clinical surrogate for the histopathologic diagnosis of BO and is measured by lung function testing. KL-6 is a glycoprotein expressed on pulmonary epithelial cells and it is present in the serum of normal individuals in small amounts. Serum KL-6 has been shown to be a useful marker of disease activity in interstitial lung diseases. We demonstrated that serum levels of KL-6 are elevated in lung transplant recipients with BOS when compared with those without BOS and healthy controls. Our results indicate that serum KL-6 measurement has the potential to serve as a noninvasive diagnostic test for the detection of BO in lung transplant recipients.