Blood proteomics of paediatric bronchiolitis obliterans syndrome after hematopoietic cell transplant

The molecular determinants for lung graft- versus -host-disease associated bronchiolitis obliterans syndrome are poorly understood and biomarkers in children following hematopoietic stem-cell transplant do not exist. To address this gap, we analysed plasma samples from 21 paediatric stem-cell transplant recipients prior to and at diagnosis of bronchiolitis obliterans syndrome. Participants included three cohorts: 7 with bronchiolitis obliterans syndrome; 7 sex-, age- and timepoint-matched with severe graft- versus -host-disease alone; and 7 sex-, age-, and timepoint-matched transplant recipients without bronchiolitis obliterans syndrome or other graft- versus -host-disease. Our proteomic approach evaluated the expression of 190–12 588 protein isoforms, depending on statistical stringency, and distinguished the three cohorts of paediatric patients prior to and at the time of BOS diagnosis. Differences included proteins that regulate chromatin modification, acute phase signalling, complement, fibrosis, hypoxia, serine protease inhibition, vitamin transport, glucocorticoid receptor transactivation, and blood coagulation pathways. A subset of newly discovered proteins were cross-platform validated by ELISA in a larger cohort of paediatric patients 14 (n=107), 30 (n=108), 60 (n=108), and 100 (n=134) days post-transplant. Pathways analysis highlighted potential therapeutics including Azithromycin, statins, Pazopanib, and Cediranib. Our strategy offers a potential for early diagnosis and the identification of interventions for paediatric stem-cell transplant associated graft- versus host disease and bronchiolitis obliterans syndrome.