Abstract
Background: As mounting numbers of patients receive allogeneic hematopoetic stem cell transplantation (allo-SCT) for hematologic malignancies, focus on survivorship and post-transplant complications is increasing. 30-60% of patients develop pulmonary complications, making the lungs the most affected organ post-transplant. While obstructive lung disease post-allo-SCT has been studied as a manifestation of graft-versus-host-disease (GVHD) in the form of bronchiolitis obliterans syndrome, many patients' post-transplant pulmonary function tests (PFTs) reveal restrictive patterns of disease which have been understudied. The pathophysiology, risk factors, and clinical course of restrictive lung disease (RLD) post-allo-SCT have not been fully elucidated. This retrospective study sought to characterize baseline characteristics, imaging findings, and possible risk factors of patients with RLD post-allo-SCT.
Methods: The study included all patients receiving allo-SCT at our institution between 2005 and 2021 with at least one screening PFT with a restrictive pattern. Restriction is defined as normal forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio and total lung capacity (TLC) less than the lower limit of normal. Data collected via chart review included demographic information; indication for and type of transplant; myeloablative or nonmyeloablative conditioning; pre-existing lung disease; history of lung or chest-wall irradiation; acute post-transplant complications; documented acute or chronic graft-versus-host-disease (GVHD) of the lungs, skin, or other organs; and chest imaging findings on x-ray or computed tomography. For patients with at least two PFTs (n=168), average rate of change of TLC since transplant was calculated. Average monthly change in TLC post-transplant was compared between multiple groups detailed under Results. Analysis of variance or unpaired t-test and linear regression were used for comparison of categorical and continuous variables, respectively. Statistical analyses were completed using BlueSky Statistics 10.3.4, R version 4.1.3.
Results: 234 patients were included. Median age at transplant was 51 years (range 18-74), and 163 (70%) were male. Average BMI at transplant was 29.6 (17.9–51.4). 107 (46.3%) underwent myeloablative conditioning, and 124 (53.2%) underwent reduced intensity or nonmyeloablative regimens. The most common indications for transplant were AML (n=87), MDS (n=41), and ALL (n=40).
Most had no pre-existing lung disease (n=131, 56.2%), and 61 (26.1%) had evidence of restriction on pre-transplant PFTs. About half (n=119, 51.1%) had a history of lung or chest-wall irradiation. Within 30-days post-transplant, 55 (23.5%) had pulmonary complications (pneumonia or other hypoxic respiratory failure). 151 (64.8%) had either acute or chronic skin GVHD; 91 (39.1%) carried diagnoses of pulmonary GVHD. Most common associated imaging findings were infiltrates (n=120), scarring/atelectasis (n=73), pleural effusion (n=62), and air-trapping (n=50).
Mean rate of change in TLC following transplant among all subjects was -0.0473 L/month. Comparative analysis revealed no statistically significant differences in mean values of average change in TLC between those with myeloablative and nonmyeloablative regimens (-0.0733 vs -0.0227 L/month, p = 0.176); pulmonary GVHD or not (-0.0752 vs -0.0203 L/month, p=0.141); GVHD or not (-0.0514 vs -0.0373 L/month, p=0.731); or with or without prior chest irradiation (-0.0234 vs -0.0687 L/month, p=0.226). Women had, on average, positive change in TLC compared to men (+0.00963 vs -0.0709 L/month, p=0.049). Decline in TLC was faster in overweight or obese patients (p=0.006).
Conclusion: Our study establishes and describes a cohort of patients with restrictive lung disease post-allo-SCT, a poorly understood and incompletely characterized, yet highly morbid, set of diverse entities into which our findings provide insight. Based on the descriptive analysis we completed, patients experience decline in TLC due to a variety of processes – infiltrative pathology, pleural effusions, and chest wall weakness/restriction. Rate of decline increases with BMI and male gender. Diagnosis of pulmonary GVHD does not seem related to progression of restriction. As more long-term data is obtained from screening PFTs, examining larger datasets may allow for more granular analysis of the numerous possible etiologies.
