Prospective Assessment of Chronic Lung Allograft Dysfunction (CLAD); the Clinical Trials in Organ Transplantation (CTOT) Study Experience
PURPOSE: Diagnosis of CLAD after lung transplantation (LT) requires sustained decline in lung function and exclusion of other etiologies for the decline. The limitations of relying primarily on pulmonary function test (PFT) decline to define CLAD onset for large cohort studies are not well characterized. Using a large, prospective, multicenter cohort of LT recipients, we sought to implement a rigorous approach to identify and confirm CLAD using automated analysis of serial PFT trajectory combined with local site adjudication to rule out exclusionary conditions. METHODS: The CTOT-20 cohort consists of 803 adult first LT recipients enrolled between 2015 and 2018 from 5 North American centers. PFT data transfers occurred monthly from sites to the data coordinating center, which applied an automated process using SAS code to identify potential CLAD in subjects who survived at least 90 days and had at least 5 PFTs. Potential CLAD cases, defined by sustained PFT decline per ISHLT definition, were sent to the local site to either identify alternative reasons for the decline or confirm CLAD. The site adjudication process included systematic assessment of clinical findings, bronchoscopy, microbiology, pathology, and radiographic information. RESULTS: 746 subjects were included in the analysis and had on average 18.9 (range 5-77) PFTs. Potential CLAD was identified a total of 379 times in 195 subjects based on PFT decline. CLAD was confirmed by the local site PI in 108/195 subjects (55.4%) and the mean time to CLAD onset was 14.8 (range 3.6-39.6) months. CLAD was confirmed even less frequently during earlier timepoints (28% in months 0-6, 43% in months 7-12, and 52% in months 13-18). The most frequent concurrent conditions excluding CLAD diagnosis were active infection (34.4%), airways stenosis (16.0%), pleural effusion/disease (14.9%), and acute rejection (14.1%). CONCLUSION: Utilizing an automated approach to identify potential CLAD supplemented by local site adjudication, we found that the majority of potential CLAD qualifying events by PFT decline had evident alternative explanations. Our results indicate that CLAD adjudication utilizing a broad spectrum of clinical information is critical. This approach was used effectively across multiple centers and provides a robust strategy that can be leveraged in future multicenter CLAD studies.
Frankel, CW; Kopetskie, H; Sever, M; Cosgrove, M; Kirchner, J; Robien, M; Williams, N; Reynolds, JM; Arroyo, K; Shah, P; Mathew, J; Budev, MM; Maierson, E; Singer, LG; Islam, A; Belperio, JA; Weigt, SS; Punzalan, E; Neely, M; Todd, JL; Snyder, LD; Palmer, SM
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