The Use of Early Spirometric Changes and IGF-1 Levels for the Detection of Patients At Risk for BOS

Introduction: Bronchiolitis Obliterans Syndrome (BOS) is the manifestation of chronic GVHD (cGVHD) of the lung, it affects approximately 10% of patients surviving one year post transplantation (2), and the survival at 5 years is only about 10% (3).  A timely diagnosis could improve the outcome of this potentially fatal disease. Methods: Using a lung transplantation scoring system (4), we retrospectively evaluated 23 consecutive BOS patients to determine whether an FEV1<90% and FEF25-75<75% (stage BOS 0p), would have contributed to earlier detection.  Additionally, we assessed IGF-1 (insulin growth factor 1) levels, a profibrogenic mediator (1), in serum samples of patients at onset of cGVHD (n=57),  including 13/23 patients with a diagnosis of BOS. A retrospective chart review was performed to identify patients meeting the NIH Consensus clinical definition of chronic GVHD of the lung (BOS) between 2007 and 2011.  The criteria included: 1) FEV1<0.8 2) FEV1/FVC <0.75 and RV> 120% and 3)no evidence of infection on most recent imaging or BAL at time of diagnosis. The dates with an observed FEV1 < 90% or FEF 25-75 < 75% were recorded, and compared to the recorded date of BOS diagnosis.  Fisher’s exact test was applied to determine statistical significance where applicable. Results: For all BOS patients, the mean time from transplantation to diagnosis of BOS was 478 days (95% CI 357-599d) compared to a mean time of 169 days (95% CI 100-238d) when patients had either an FEV1<90% or FEF25-75 <75%.  The mean difference was 298 days (95% CI 176-420d, p=0.00003).  Patients with cGVHD and no BOS had similar decline in PFT in only 22/44 patients, compared to 100% of those with BOS. Serum IGF-1 values were > 4,000 (25^th percentile) in 12 of 13 patients with BOS (p=0.04).  Overall, 12 of 13 patients had biomarkers elevation prior to spirometric diagnosis of BOS. Conclusions: Application of the BOS 0-p criteria to HSCT patients may identify patients at risk for BOS at an earlier time point. The use of the IGF 1 as a serum biomarker may also contribute to identify patients at risk, although further studies are needed to investigate whether this marker can differentiate between patients with BOS and those with other lung diseases.