Metatranscriptomic Signatures of Lung Function in Pediatric Hematopoietic Cell Transplant Candidates

Rationale: Impaired baseline lung function is associated with mortality after allogeneic hematopoietic cell transplantation (HCT). Limited knowledge of the molecular pathways that characterize pre-transplant lung function has hindered the development of lung-targeted interventions. Objectives: To elucidate the biologic and microbiologic correlates of impaired lung function in pediatric allogeneic HCT candidates. Methods: Between 2005-2016, 104 patients with malignant and non-malignant disorders ages 4-19 years underwent paired pulmonary function testing (PFT) and bronchoalveolar lavage (BAL) a median of 1-2 weeks prior to allogeneic transplant in Utrecht, the Netherlands. Cryopreserved BAL underwent RNA sequencing followed by alignment to microbial and human reference genomes for microbiome and gene expression analyses. Measurements and Main Results: Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung-injury related mortality after HCT. BAL microbiome depletion of commensal supraglottic taxa such as Haemophilus and enrichment of nasal and skin taxa such as Staphylococcus were associated with worse measures of lung capacity and gas diffusion. In addition, impaired lung capacity and diffusion were also associated with gene expression signatures of alveolar epithelial proliferation, epithelial-mesenchymal transition, and downregulated immunity, suggesting a post-injury pro-fibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT PFTs for the outcome of post-HCT mortality. Conclusions: These findings suggest a novel and potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.