Inflammatory markers and microbiome dysbiosis in hematopoietic cell transplant recipients with lung graft-versus-host disease.

Abstract

Bronchiolitis obliterans (BOS) is a manifestation of pulmonary chronic graft versus host disease (cGVHD) and is a devastating complication of allogenic hematopoietic stem cell transplantation (HCT). Early detection and treatment of BOS may improve outcomes, but biomarkers which accurately identify BOS early are lacking. We aimed to determine whether certain validated cGVHD markers could also accurately diagnose BOS as compared to patients without BOS and with or without extrapulmonary cGVHD. In addition, we sought to determine whether dysbiosis of gut or oral microbiomes was associated with BOS or with inflammatory biomarkers. We enrolled 43 allogenic HCT recipients, of whom 16 had BOS. For each patient, we obtained pulmonary function tests, measured the levels of nine serum biomarkers utilizing enzyme linked immunosorbent assays, and analyzed both the oral and gut microbiome using microbial DNA amplification and sequencing. We compared biomarker levels to lung function, both at baseline and over time, as well as to microbiome diversity. Higher IL1RL1 (p = 0.002) and IL-17 (p = 0.041) at enrollment were negatively correlated with FEV1% lung function over time. Increases in IL1RL1 (p = 0.035), IL-17 (p = 0.009), and WFDC2 (p = 0.045) levels over time were associated with worsened lung function/FEV1% over time. There were minimal correlations between gut microbiome diversity and lung function or serum biomarkers. Oral microbiome alpha diversity was lower in subjects with BOS than without (p = 0.00057), and oral beta diversity was associated with FEV1% and with levels of several biomarkers. Our pilot study suggests that certain serum cGVHD markers may identify allogeneic HCT recipients at higher risk for pulmonary impairment over time, and should be followed with robust, controlled studies.