Pulmonary Clinicopathological Correlation In Long Term Survivors Following Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series

Pulmonary complications are a significant cause of morbidity and mortality following Hematopoietic Stem Cell Transplantation (HSCT). It is estimated that they occur in 40-60% of patients, causing 10-40% of transplant-related deaths and resulting in diminished quality of life in those who survive. The wide spectrum of pulmonary complications is believed to be multifactorial, including pretransplant chemoradiation, infection, and graft-versus-host disease (GVHD). The histological spectrum of pulmonary GVHD features interstitial injury, airway injury (including bronchiolitis obliterans), and vascular disease (including veno-occlusive disease). The objective of this study was to compare ante mortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort.

All patients who underwent allogeneic HSCT at our institution (n=1854) between January 1, 2000 and June 30th 2010 were reviewed. To date we have completed the review of all autopsies (38) in patients who died of any cause greater than one year following HSCT. Presence of pulmonary GVHD was assessed by a pathologist blinded to the autopsy report, according to the categories of injury previously described by Yousem (1995). Lymphocytic infiltration and structural remodeling was scored separately for the airways, vasculature, and interstitium. Cases with extensive lung involvement by infection, malignancy, or other defined process (i.e. aspiration injury) were excluded from analysis. We evaluated the following clinical predictors for an association with development of airway disease and pulmonary vascular disease: patient gender, male patient with female donor, baseline FEV₁%, peripheral blood stem cell source, myeloablative conditioning regimen, busulfan based conditioning regimen, patient CMV status, donor CMV status, related donor, matched donor, presence of acute GVHD, presence of chronic GVHD, and donor age. Each predictor was evaluated for significance between cases and controls. Two-sided Fisher’s exact test was used to compare categorical variables between groups, and a 2-sided Wilcoxon Rank-Sum test was used to compare continuous variables. All statistical analyses were performed using SAS9.3.

A total of 35 (92%) patients had evaluable pathology and were reviewed. Pulmonary complications were felt to contribute to death in 17 (49%) cases, and 28 (80%) of the patients had a diagnosis of chronic GVHD prior to death. Airway disease, interstitial disease, and vascular disease were all clinically under recognized compared to the number of cases detected on autopsy (table 1). Varying degrees of pathological changes were detected (table 2); including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-oclussive disease (PVOD). Of the patients with PVOD, 12 (86%) also had airway disease (p=0.07). In a univariate analysis, a positive cytomegalovirus (CMV) serology status in the patient was associated with the presence of airway disease (p=<0.002), and ablative conditioning (p=<0.01) and the presence of acute GVHD (p=<0.04) was associated with the presence of vascular disease.

Pulmonary manifestations of chronic GVHD, particularly BO, were clinically under recognized in our allogeneic HSCT population. Our results also suggest that pulmonary VOD, which has traditionally been considered a rare complication, may be clinically and histologically under recognized. A positive CMV serology status in patients was associated with the occurrence of airway disease. Ablative conditioning and the presence of acute GVHD was associated with the occurrence of vascular disease.

No relevant conflicts of interest to declare.