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We hypothesized that a reduced potential for bronchiolar stem-cell (Clara cell)–related repair in the setting of an ever-present risk of small airway injury would increase the risk of bronchiolitis obliterans syndrome (BOS).CCSP A38G gene polymorphism was assessed in both lung donors and recipients in a longitudinal study cohort of 63 consecutive lung transplant recipients (LTR) with a median follow-up of 493 days (range, 26–894). Clara cell secretory protein (CCSP) and interleukin 8 levels were assessed in the bronchoalveolar lavage and plasma at 1, 3, 6, and 12 months after transplantation. CCSP-positive cells were assessed in transbronchial biopsies at 1 and 3 months.Of the 63 LTR, there were 5 early deaths (≤90 days, 8% [95% confidence interval, 4%–21%]), and 20 developed BOS (32%, [95% confidence interval, 21%–45%]). Donor but not recipient CCSP A38G polymorphism was associated with more risk of BOS (relative risk, 8.6 [2.2–33.5], P<0.0001) and decreased overall survival (log-rank test, P=0.011). Bronchoalveolar lavage CCSP and CCSP/interleukin 8 levels were low and decreasing early after transplantation in LTR who developed BOS (P=0.015). CCSP+ve cells in transbronchial biopsies increased at 3 months only in LTR who remained free of BOS (P=0.003).Donor CCSP A38G polymorphism is associated with decreased CCSP levels early after lung transplantation and poor long-term outcomes.