Bronchiolitis obliterans after allogeneic hematopoietic SCT: further insight—new perspectives?

Abstract

Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHDpatients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L ± 0.7, P ¼ 0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.±0.9 vs 20 p.p.b.±2.1) or healthy controls (25 p.p.b.±2.4, Po0.001). Hypoxia-inducible factor 1 alpha (HIF-1a) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340 ± 61 vs 127 ± 22 vs 140 ± 32, P ¼ 0.02). Calculated 5-year survival was superior in female than in male BO-patients (86 vs 45%, P ¼ 0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia. Keywords: bronchiolitis obliterans; nitric oxide; allogeneic; GVHD; HIF-1a; SCT INTRODUCTION Allogeneic hematopoietic SCT has been shown to provide longterm disease-free survival for otherwise fatal malignant or nonmalignant hematological disorders. With increasing survival rates due to toxicity reduced hematopoietic SCT methods, advanced GVHD-management and improved anti-infectious therapy and prophylaxis, a distinct increment in late transplant related complications can be observed. Pulmonary complications develop in 30-60% of allogeneic hematopoietic SCT recipients and are considered as a major cause of morbidity and mortality. 1,2 Late-onset non-infectious pulmonary complications 3 beginning 3 months after transplantation with an incidence of 10-15% are considered as life-threatening complications significantly limiting the quality of life. 4,5 Although late-onset non-infectious pulmonary complications classification is rather undefined, the most common categorizations include bronchiolitis obliterans (BO), bronchiolitis obliterans organizing pneumonia and interstitial pneumonia. 6,7 According to the NIH consensus criteria, BO is considered to be the only pulmonary manifestation of chronic GVHD. 8 The reported incidence of BO in allogeneic hematopoietic SCT recipients ranges from 2-10% and mortality rates have been assessed between 13 and 23%. 9,10 BO is prevalent in 2-5.5% of hematopoietic SCT recipients and in up to 14% of hematopoietic SCT recipients with chronic GVHD. 11 Patients diagnosed with BO have a 5-year survival rate of only 45% vs 75% in patients without BO. 9 Advanced disease stages at transplantation, preceding GVHD, older donor and recipient age, M...

Extracorporeal photopheresis as a new supportive therapy for bronchiolitis obliterans syndrome after allogeneic stem cell transplantation

“…It occurs in~14% of patients with cGvHD, 1 usually within the first 2 years from transplant (but also several years later), and is characterised by high morbidity and mortality (5-year survival rate of 45 vs 75% in patients without BOS). 2,3 BOS is defined by the onset of progressive airflow obstruction in the absence of respiratory infection, usually correlated with the pathological pattern of obliterative bronchiolitis. At early stages, patients can be asymptomatic; later in the course of disease, respiratory infections or chest constriction due to advanced sclerotic GvHD or intrapulmonary processes may hinder the correct diagnosis.…”

Biopsy-Verified Bronchiolitis Obliterans and Other Noninfectious Lung Pathologies after Allogeneic Hematopoietic Stem Cell Transplantation

“…However, several modifications of the NIH BOS criteria have been applied in different studies [4,5,7,8,15,17,18,[42][43][44][45][46][47], which makes comparison difficult and indicates a need for a more simple and widely accepted classification.…”

“…Lung biopsy is the gold standard for diagnosis but is invasive and not widely used in the daily clinical routine. Instead, multiple diagnostic criteria based on clinical disease manifestations have been applied, which may partly explain the variability in the reported incidence (1.2% to 14.6%) [3][4][5][6][7][8][9][10][11][12][13][14] and mortality (27% to 90%) [3][4][5]7,[10][11][12][13]. To improve the basis for comparative research without running the risks associated with lung biopsy, in 2005 the National Institutes of Health (NIH) published criteria for BO syndrome (BOS), a clinical equivalent of biopsy-verified BO based on pulmonary function (PF) tests and radiology [2].…”

Imaging of Small Airways and Emphysema

“…5C, D). 47,51 EMPHYSEMA Emphysema is a disease characterized by destruction of alveolar and respiratory bronchiolar walls with permanently enlarged airspaces distal to the terminal bronchiole. 14,52 There are 3 main subtypes of emphysema: centrilobular, paraseptal, and panlobular (Fig.…”