BOS after HCT: Preceding Events, Diagnostic Characteristics, and Natural History of Patients Treated on a Prospective Trial

Bronchiolitis obliterans syndrome (BOS) is a serious late complication of allogeneic hematopoietic cell transplantation (HCT) with poorly characterized risk factors and natural history due to disease rarity. We describe the prevalence of potential risk factors, diagnostic characteristics, and natural history of 36 individuals enrolled on a multicenter prospective trial (NCT01307462) to treat new onset BOS after HSCT. BOS was diagnosed using modified 2005 NIH consensus criteria (FEV₁<75% predicted, FEV₁/VC <0.7, and >10% FEV₁ decline from pre-HCT). Possible risk factors for lung injury included cigarette exposure in 47% (17/36), while history of asthma or chronic obstructive lung disease (6%) and idiopathic pneumonia syndrome (6%) were rare. The most common treatment exposures associated with pulmonary toxicity included cyclophosophamide (69%), fludarabine (44%), busulfan (42%) and radiation (42%). Documented infection potentially associated with pulmonary inflammation prior to BOS diagnosis included respiratory viruses in 12/36 (33%); 4 had CMV viremia. Median time from HCT to BOS diagnosis was 546 days (range 157-4008). The diagnostic workup was prompted by patient-reported symptoms in nearly half of the cohort (17/36, 47%) and by screening pulmonary function tests (PFT) in the remainder (53%), with median FEV₁% predicted of 46.5 (range 26-67). There was a trend toward higher mean FEV₁ in patients with BOS detected by PFT screening, but this was not statistically significant (50.2 vs 43.1, p=0.13). While most evaluations included chest CT (89%), few underwent bronchoscopy (28%) or surgical biopsy (6%). Eye (68 %), skin (56%) and mouth (56%) were the most common concurrent manifestations of chronic graft-versus-host disease (cGVHD); 3 (9%) did not have extrapulmonary cGVHD signs at onset of BOS. Eleven (31%) subjects required supplemental oxygen after BOS diagnosis and 5 (14%) currently use oxygen. Twenty (56%) subjects were hospitalized after their diagnosis of BOS at least once, most commonly for pneumonia and dyspnea. Twenty-one (56%) had one or more respiratory tract infections treated with antimicrobials, most often due to Pseudomonas spp (n=7), Aspergillus spp (n=5), influenza (n=4) and parainfluenza (n=4). Overall survival of the cohort was 72% with a median follow-up of 16 months (range 3-32). The primary causes of death in 8 subjects were complications of cGVHD (n=5) including BOS, relapse (n=2), and infection (n=1). These data suggest the following: there may be exposures that are risk factors for BOS after HCT, lung function loss is moderately severe at diagnosis whether prompted by symptoms or PFT, and patients with BOS have high morbidity and mortality directly associated with cGVHD of the lung, even when treated early after diagnosis.

Figure. Kaplan-Meier Survival Estimate, n=36