Lung-transplant Bronchiolitis Obliterans
Improved survival after lung transplantation continues at an accelerated rate while post lung-transplantation fibrotic constrictive obliterative bronchiolitis continues to be a major lifethreatening complication.[37,38] The surgical group from the University of Virginia (VA, USA) reported a 1-year survival rate of 86%, a 3-year rate of 71% and a 5-year rate of 55%. They found no difference in survival rate between those over or under 60 years of age for single lung transplantation. There has been an explosion of research in the obliterative bronchiolitis lesion, with 853 publications from 1990 to 2005 , and more than 1000 publications by the end of 2006.
The histological findings of post lung-transplant lesions indicate the fibrotic CB obliterans lesion. A clinical system based on FEV1 for the clinical diagnosis of bronchiolitis obliterans has been established for two major reasons : the disease is common among post-transplant recipients (affecting up to 50-60% of patients who survive 5 years after transplantation); and an invasive procedure is needed to established a definitive diagnosis because the lesion is so patchy that transbronchial biopsies are of limited value. The current accepted criteria include a five-stage classification ( Table 1 ).
As bronchiolitis obliterans syndrome (BOS) is a clinical diagnosis and probably has a mix of the fibrotic and inflammatory bronchiolar lesions, studies are needed to determine its usefulness. A 2005 study of the potential BOS stage 0 (BOS 0-p) concluded that the FEV1 criterion of 81-90% of baseline provides useful predictive information for the risk of developing BOS or death in single-lung-transplant recipients. Among patients who met the BOS 0-p criterion, 81% developed BOS or died within 3 years. Martinu reviewed the histological findings of the explanted lung in 12 patients who had undergone pulmonary retransplantation for BOS and found a good correlation between fibrotic CB obliterans and BOS. Even though the explanted lungs showed some degree of epithelial fibrosis and inflammation, not all had severe fibrotic changes and four had other findings that resulted in the classification. These findings included two with interstitial fibrosis, one with focal invasive aspergillosis and one with chronic vascular rejection.
Risk factors for lung-transplant obliterative bronchiolitis continue to evolve with the expansion of extensive research. The group at Stanford University (CA, USA) initially described the disorder in 1984. In 2006, among 77 heart-lung-transplant recipients and 51 double-lung-transplant recipients, these researchers demonstrated the same rates of BOS for both groups, confirming heart-lung-transplant recipients are not protected from developing BOS. Acute rejection is the "single most important risk factor" for bronchiolitis obliterans. The Stanford group found that risk factors among their heart-lung and double-lung recipients also included non-use of cardiopulmonary bypass (p = 0.001) and use of muromonab (OKT3)-induction therapy (p = 0.0001).
Primary graft dysfunction has now been established as a well-defined syndrome occurring during the initial post-transplant phase and is an important risk factor for the development of bronchiolitis obliterans.[44,45,46] The syndrome is characterized by diffuse infiltrates considered to be reperfusion edema and in severe situations represents acute respiratory distress syndrome. Reperfusion edema has been associated with high perioperative mortality, but also with poor long-term survival and more rapid progression to BOS. The International Society for Heart and Lung Transplantation has proposed a standard definition of primary graft dysfunction based on chest x-ray appearance and the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) ratio ( Table 2 ).
Daud and colleagues found that among 334 lung-transplant recipients, 130 (39%) had grade 1 primary graft dysfunction, 69 (20%) had grade 2, and 70 (21%) had grade 3. All grades of primary graft dysfunction were associated with increased risk of BOS stage 1 with increasing risk with increase grades of primary graft dysfunction from a risk ratio of 1.73 for grade 1 to 2.53 for grade 3. This risk was independent of acute rejection and there was no association between primary graft dysfunction and acute rejection.
The pathogenesis and mechanism of lung-transplant-related bronchiolitis obliterans begins with injury and inflammation of bronchiolar airway epithelial cells causing excessive fibroproliferation because of ineffective epithelial regeneration and aberrant tissue repair. Acute rejection is one of the major factors causing the injury by inducing immunologic injuries directed toward epithelial and endothelial cells, especially if the acute rejection is severe and recurrent. Others factors causing injury include HLA mismatch, Cytomegalovirus infections, other lung infections and gastroesophageal reflux. Acute vascular injury from acute rejection is also linked to chronic bronchiolar airway disease. A 2006 study demonstrated that a decrease in microvascular supply to the small airways precedes bronchiolitis obliterans, and onset of the fibrotic airway disease was associated with an increased number of smaller vessels, suggesting neovascularization. Exhaled nitric oxide has been proposed as a noninvasive marker of small airway reaction, yet the ability of expired nitric oxide to predict BOS in an individual patient has not been established. An exhaled breath condensate pH study of patients with allograft rejection after lung transplantation showed the condensate pH was significantly decreased in patients with BOS.
Management of BOS begins with prevention and early detection, which includes not limiting the use of cardiopulmonary bypass, and using the least toxic induction and post-transplant therapies. Current immune-suppressive regimens generally include a calcineurin inhibitor, a purine synthesis inhibitor and a corticosteroid. The calcineurin inhibitor tacrolimus has emerged as an alternative to cyclosporine for patients with recurrent acute rejection; although there have been no convincing studies indicating that this agent is more effective in preventing BOS. Calcineurin induces IL-2 and, therefore, cyclosporine and tacrolimus decrease cytokine IL-2 levels, leading to a decreased inflammatory response. In some centers, mycophenolate mofetil is replacing azathioprine as the purine synthesis inhibitor of choice.
Treatment of established BOS consists of augmenting immunosuppression by changing medications within therapeutic classes, by adding medications or by applying immune-modulating therapies. As BOS represents a heterogeneous syndrome with alloimmune and nonalloimmune mechanisms, vigorous efforts to identify and treat infections are needed during exacerbations.
Macrolides, such as clarythromycin and azithromycin, are being evaluated for the treatment of BOS. The macrolide's anti-inflammatory action has been used successfully for the treatment of suppurative and inflammatory lung disorders. The macrolides were shown to be very effective for the treatment of inflammatory disorder diffuse pan-bronchiolitis many years ago, improving the 10-year survival in patients with Pseudomonas aeruginosa infection from less than 15% to more than 90% among these patients. As the BOOP lesion is an inflammatory process, macrolides appear to be effective in patients with this disorder. Whether macrolides will be effective for the fibrotic lesion of lung-transplantation CB obliterans is not known. It would be anticipated that results will be variable because BOS is a clinically based diagnosis that probably includes patients with the nonresponsive fibrotic CB obliterans lesion and the responsive inflammatory proliferative polypoid bronchiolitis obliterans lesion. For example, Shitrit and colleagues in Israel found short-term improvement in lung function in five out of six lung-transplant recipients with BOS. For example, Shitrit and colleagues in Israel found 10 months of azithromycin treatment had no effect in 11 patients whose mean FEV1 was 40% at initiation of treatment and 38% after 10 months. Yet, in a successful study, Yates and colleagues in England found low-dose macrolides reversed declining lung function in patients with BOS. The San Antonio and Johns Hopkins lung-transplant groups urge a prospective, mulitcenter, randomized trial of azithromycin to make the determination. In 2007, Vanaudenaerde and colleagues found that macrolides inhibit airway cellular IL-8 production, while corticosteroids, tacrolimus, cyclosporine and rapamycin do not.
Rapamycin (sirolimus) may be useful for stabilizing or improving pulmonary function in patients with BOS, yet the adverse effects, such as infections and myelosuppression, must be considered. Pirfenidone may be an effective antifibrotic agent for the treatment of the fibrotic CB obliterans lesions, although no clinical trials have been undertaken.
Expert Rev Resp Med. 2007;1(1):139-147. © 2007 Future Drugs Ltd.
Cite this: Constrictive Bronchiolitis Obliterans: The Fibrotic Airway Disorder - Medscape - Aug 01, 2007.