Chronic rejection/Bronchiolitis Obliterans Syndrome

Obliterative bronchiolitis or bronchiolitis obliterans syndrome (BOS) is now regarded as a manifestation of chronic rejection.47 The prevalence of OB in patients surviving more than 3 months after lung transplantation is 68%.52 The actuarial 1, 3, and 5-year freedom from OB were 82%, 42% and 25% respectively.

Several risk factors for the development of OB/BOS have been identified, the predominant being late or recurrent/refractory acute rejections, lymphocytic bron-chitis/bronchiolitis, noncompliance with the immunosuppressive medication, HLA mismatches at the A locus, total human leukocyte antigen mismatches and CMV pneumonitis.54,55

This chronic allograft dysfunction is associated with characteristic clinical, functional, and histologic changes. Obliterative bronchiolitis is consistently characterized by a reduction in pulmonary function parameters, most specifically in FEV1, attributed to progressive airways obstruction. There is no significant reversibility after inhalation of short-acting beta-2 agonists. The onset of symptoms is mostly insidious, with progressive exertional dyspnea and cough. The characteristic his-tologic findings are obliterative bronchiolitis, which consists of dense fibrosis and scar tissue that obliterates the bronchiolar wall and lumen. In the later course of the disease, airway superinfections are frequently seen and colonization with Pseudomonas aeruginosa and Aspergillus fumigatus is common. At this time, high resolution CT scan often reveals bronchiectasis, diminution of peripheral vascular markings, hyperlucency due to air trapping, thickening of septal lines and mosaic phenomena. Once established, BOS may progress to severe airways obstruction with respiratory insufficiency and death. In other patients, progression may be arrested, either spontaneously or in response to treatment.

Although OB is a diagnosis that has to be made by the pathologist, it is often impossible to obtain adequate material on a TBB. The sensitivity of TBB for OB is only 28%, whereas the specificity is 75%. Because of this, in 1993, a committee sponsored by the International Society for Heart and Lung Transplantation proposed a clinical definition, called bronchiolitis obliterans syndrome (BOS). Based on pulmonary function criteria, rather than histology, BOS has been divided in four stages. Within each BOS category, there is a subtype a and b, based on no pathological evidence of OB or no pathological material for evaluation (a) or pathological evidence of OB (b). Recently, a modification to this staging system was proposed which includes a potential-BOS stage (BOS 0-p) that refers to patients with a 10% to 19% fall in FEV1 or a 25% or greater decrease from baseline in midexpiratory flow rate (FEF25-75).56 The purpose of this additional stage is to signal the possible onset of BOS and to prompt closer surveillance, Table 12.7

Unfortunately, therapeutic options for established BOS are limited.48 The current treatment of chronic rejection has been summarized by Trulock and involves augmentation of the immunosuppressive drug regimen with high dose corticosteroids (methylprednisolone 1000 mg/day for 3 days, followed by prednisone 1 mg/kg/d tapering to the pretreatment dose over 2 to 3 weeks). If there is no stabilization in pulmonary function, cytolytic therapy with antilymphocyte agents such

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