Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

John A. Belperio, MD; Kathleen Lake, PharmD; Henry Tazelaar, MD; Michael P. Keane, MD; Robert M. Strieter, MD; Joseph P. Lynch, III, MD

Disclosures

Semin Respir Crit Care Med. 2003;24(5) 

In This Article

Abstract and Introduction

Abstract

Lung transplantation is a therapeutic option for patients with end stage lung diseases, but long-term survival remains poor, primarily due to chronic allograft rejection. Bronchiolitis obliterans (BO), a fibrotic process resulting in progressive narrowing of bronchiolar lumens and airflow obstruction, is a manifestation of chronic allograft rejection. The term obliterative bronchiolitis (OB) is synonymous. Once bronchiolitis obliterans syndrome (BOS) develops, progressive decline in pulmonary function is typical; most patients die of respiratory failure within 5 years of onset. The diagnosis of BOS is usually made by clinical, physiological, and radiographic parameters. The dominant risk factor for BOS is acute allograft rejection, but additional factors play contributory roles [e.g., infections; human leukocyte antigen (HLA) mismatching; and injury to the allograft or airways]. The pathogenesis of BOS is complex and involves myriad cell types (both immune and nonimmune) and release of diverse cytokines and chemokines. Unfortunately, current therapies for BOS are of unproven value. A greater understanding of the pathogenic mechanisms operative in BOS are critical to developing novel strategies to treat and prevent this devastating complication.

Introduction

Lung transplantation is a therapeutic option for patients with end stage pulmonary disorders,[1,2] but long-term survival remains poor, primarily due to chronic allograft rejection. Five-year survival in lung transplant recipients (LTRs) is < 45%, as compared with > 70% for other solid organs.[1,2,3,4] Surgical complications, graft failure, and infectious complications are the leading causes of death during the first year following transplantation.[4] The major obstacle to prolonged survival following lung transplantation (LT) is chronic allograft rejection, manifesting histologically as bronchiolitis obliterans (BO).[5,6] BO is a cicatricial process affecting the respiratory and terminal bronchioles, resulting in fibrosis and obliteration of airway lumens ("vanishing airways disease").[7] Clinically, severe airflow obstruction, exercise limitation, and, eventually, death result.[5] Although BO is rarely observed within the first year posttransplant, the cumulative incidence of BO at 5 years posttransplant ranges from 50 to 80%.[4,5,6,8,9,10,11] BO (also termed bronchiolitis obliterans syndrome) (BOS) is the major cause of late mortality (> 1 year) following LT.[1,2,12,13,14,15,16,17,18] Five-year survival after the onset of BO is only 30 to 50%.[5,15] In the International Society of Heart and Lung Transplantation (ISHLT) Registry, comprising > 17,000 lung or heart-lung transplant recipients, development of BO within the first year was the single most important risk factor for 5-year mortality among LTRs [odds ratio (OR), 3.67, p < 0.0001].[4] Other risk factors for 5-year mortality included: donor cytomegalovirus (CMV)+/recipient CMV(2) (OR 1.36, p = 0.02); rejection during the first year, OR 1.30, p = 0.005).[4]

Strategies to reduce the risk of BO are essential to improve mortality rates following LT. Augmentation of immunosuppressive therapy is routinely administered in patients with BOS or BO19 but is of unproven value.[18,20] In this review, we initially describe clinical features of BOS, diagnostic criteria, risk factors, and proposed pathogenic mechanisms. We then discuss therapeutic options and options for novel therapeutic targets.

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