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 allogeneic hematopoietic stem cell transplantation (HCT). Early detection and treatment of BOS may improve outcomes, but biomarkers that accurately identify BOS early are lacking. We aimed to determine whether certain validated cGVHD markers could also accurately diagnose BOS as compared with patients without BOS and with or without extrapulmonary cGVHD. In addition, we sought to determine whether dysbiosis of the gut or oral microbiomes was associated with BOS or with inflammatory biomarkers. We enrolled 43 recipients of allogeneic HCT, 16 of whom had BOS. For each patient, we obtained pulmonary function tests, measured the levels of 9 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 = .002) and IL-17 (P = .041) at enrollment were negatively correlated with FEV1% (forced expiratory volume in 1 second) lung function over time. Increases in IL1RL1 (P = .035), IL-17 (P = .009), and WFDC2 (P = .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 = .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 recipients of allogeneic HCT at higher risk for pulmonary impairment over time and that these markers should be followed with robust, controlled studies.

Keywords: Biomarkers; Bronchiolitis obliterates; Chronic graft-versus-host disease; Gut microbiome; Hematopoietic stem cell transplant.