Bronchiolitis Obliterans Syndrome: The Achilles' Heel of Lung Transplantation

Weigt, S. Samuel; Derhovanessian, Ariss; Wallace, W. Dean; Lynch, Joseph P.; Belperio, John A.

doi:10.1055/s-0033-1348467

Cited by 84 publications

(20 citation statements)

References 222 publications

(297 reference statements)

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“…Obliterative bronchiolitis (OB) or bronchiolitis obliterans is a rare disorder most often recognized to occur in the setting of lung or heart-lung transplant with chronic allograft rejection (Myer 2016; Weigt et al, 2013) or hematopoietic stem cell transplant with graft versus host disease (Afessa and Peters 2006; Gunn et al, 2008). OB has also been diagnosed following acute exposure to soluble irritant gases and vapors such as ammonia, chlorine, methyl isocyanate, mustard gas, and nitrogen dioxide (King, 2003).…”

Section: Introductionmentioning

confidence: 99%

Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis

Flake

Morgan

2017

Toxicology

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Inhalation of diacetyl vapors by workers has been associated with obliterative bronchiolitis (OB), a poorly understood fibroproliferative disease of the small airways. Significant insights into the pathogenesis of OB have been obtained through the use of a rat model. Inhalation exposure of rats to diacetyl or 2,3-pentanedione, a related flavoring agent, can cause severe injury to the airway epithelium and underlying basement membrane. Repeated exposure to diacetyl or 2,3-pentanedione leads to aberrant repair, fibroproliferation and partial to complete occlusion of the airway lumen. Fibroproliferative lesions in rat airways were found to include both intraluminal polyps and circumferential intramural lesions. Intraluminal polyps have been observed to form secondary attachments spanning the airway lumen causing increasing obstruction. These airway lesions in rats are accompanied by inflammation in the form of peribronchial and perivascular infiltrates of lymphocytes, eosinophils and neutrophils. Diacety-linduced OB lesions in the rat are similar to OB lesions in humans and provide a good model for studying the pathogenesis of this disease.

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Section: Introductionmentioning

confidence: 99%

Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis

Flake

Morgan

2017

Toxicology

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“…(1) The primary obstacle to long-term survival is chronic rejection in the form of bronchiolitis obliterans syndrome (BOS), which affects up to 50% of patients within 5 years, and is characterized histopathologically by obliterative bronchiolitis, a progressive fibro-obliterative process affecting the allograft small airways. (2)…”

Section: Introductionmentioning

confidence: 99%

The Role of TGF-β in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome

Derhovanessian

Weigt

Palchevskiy

et al. 2016

American Journal of Transplantation

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Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on TGF-β's association with acute and chronic inflammatory disorders, we hypothesized that it may play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-β and procollagen collected within 24 hours of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-β and its receptor in early lung biopsies post-transplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-β and procollagen concentrations were elevated during PGD (p<0.01), and associated with increased rates of BOS. Expression of TGF-β and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-β biology.

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“…In macrolide-unresponsive patients, a number of treatment approaches have been reported (including anti-leukotrienes, total lymphoid irradiation, and modulation of/increase in immunosuppression) mainly with immunosuppressive/anti-inflammatory purposes; however, the overall response rate of these strategies remains suboptimal [8]. …”

Section: Introductionmentioning

confidence: 99%

Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre Analysis

et al. 2015

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Background: Extracorporeal photochemotherapy (ECP) for chronic lung allograft dysfunction (CLAD) has been reported as beneficial in a few short-term studies. Objectives: In this retrospective cohort study on 48 CLAD patients treated by ECP (off-line technique) for a period of >8 years (compared to 58 controls), we explored potential predictors of survival and response. Methods: Failures were defined as a decrease in forced expiratory volume in 1 s (FEV₁) of >10% from ECP initiation. Results: ECP patients were enrolled between February 2003 and December 2013; 14 (29.2%) with restrictive allograft syndrome (RAS) and 34 with bronchiolitis obliterans syndrome. Grade 1 severity was indicated in 58.3%, grade 2 in 20.8%, and grade 3 in 20.8% of patients. The median follow-up was 65 months (cumulative 2,284.4 person-months). Twenty (41.7%) patients died, including 17 (85%) CLAD-related deaths. Among the controls, there were 42 deaths (72.4%), of which 32 (76.2%) were CLAD related, over a median of 51 months (cumulative 3,066.5 person-months; p = 0.09). Among ECP patients, the FEV₁ slope flattened out after a decline in the initial months (slope -19 ml/month in months 0-6, +4 in months 36-48 and later; p = 0.001). RAS was associated with poorer survival, whereas a ‘rapid decline in the previous 6 months' was not. No ECP side effects or complications were observed. Conclusion: Long-term ECP for CLAD is safe and reduces FEV₁ decline over time; the RAS phenotype might show a poorer response. ECP deserves to be evaluated in a randomized controlled trial.

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Bronchiolitis Obliterans Syndrome: The Achilles' Heel of Lung Transplantation

Cited by 84 publications

References 222 publications

Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis

Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis

The Role of TGF-β in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome

Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre Analysis

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