Over the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischemia–reperfusion injury and infections have contributed to increase the 1-year patient survival after lung transplantation to 70–80% (1). However, long-term survival is threatened by bronchiolitis obliterans, which is thought to be a form of chronic allograft rejection. Bronchiolitis obliterans after lung transplantation was first described in 1984 at Stanford University in heart–lung transplant recipients who showed a progressive decline in FEV1 (2). Lung biopsies from these patients showed intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar. Obliteration of the small airways by these lesions produces progressive airflow obstruction, often accompanied by recurrent lower respiratory tract infection.
Bronchiolitis obliterans, and its clinical correlate bronchiolitis obliterans syndrome, affect up to 50–60% of patients who survive 5 years after transplantation (3). In most patients, bronchiolitis obliterans is a progressive process that responds poorly to augmented immunosuppression, and it accounts for more than 30% of all deaths occurring after the third postoperative year (1). Survival at 5 years after the onset of bronchiolitis obliterans is only 30–40%, and survival at 5 years after transplantation is 20–40% lower in patients with than in patients without bronchiolitis obliterans (4). In this review, we present current concepts regarding post-transplant bronchiolitis obliterans, including: (1) the recently updated classification system for bronchiolitis obliterans syndrome (BOS), (2) an overview of current concepts regarding its pathogenesis and risk factors, (3) potential surrogate markers that may contribute to early detection, and (4) approaches to the management of this devastating complication.
The diagnosis of bronchiolitis obliterans is based on histology, but histologic proof is often difficult to obtain using transbronchial lung biopsies. Therefore, in 1993, a committee sponsored by the International Society for Heart and Lung Transplantation (ISHLT) proposed a clinical description of bronchiolitis obliterans, termed BOS, which is based on changes in FEV1 (5). For each patient, a stable post-transplant baseline FEV1 is defined as BOS stage 0; in patients who experience a decrease in FEV1, progressive stages of BOS, from 1 to 3, are defined according to the magnitude of the decrease (Table 1)
|BOS 0||FEV1 80% or more of baseline||FEV1 > 90% of baseline and FEF25–75 > 75% of baseline||BOS 0|
|FEV1 81–90% of baseline and/or FEF25–75 ⩽ 75% of baseline||BOS 0p|
|BOS 1||FEV1 66–80% of baseline||FEV1 66–80% of baseline||BOS 1|
|BOS 2||FEV1 51–65% of baseline||FEV1 51–65% of baseline||BOS 2|
|BOS 3||FEV1 ⩽ 50% of baseline||FEV1 ⩽ 50% of baseline||BOS 3|
Although this classification system has been adopted by transplant centers worldwide as a useful descriptor of chronic allograft dysfunction, concern has been raised regarding its ability to detect small changes in pulmonary function. This concern recently led to formulation of a revised classification system for BOS (6), which includes a new “potential-BOS” stage (BOS 0-p) defined as a decrease in midexpiratory flow rates (FEF25–75) and/or FEV1 (Table 1). The rationale for including FEF25–75 comes from studies in heart–lung and bilateral lung recipients, which showed that this variable deteriorates before FEV1 at the onset of BOS (7). The new BOS 0-p stage is meant to alert the physician and to indicate the need for close functional monitoring and for in-depth assessment using surrogate markers for BOS. However, the usefulness of stage BOS 0-p in recipients of single lungs, in particular those with emphysema, still needs to be established.
The histopathologic features of bronchiolitis obliterans suggest that injury and inflammation of epithelial cells and subepithelial structures of small airways lead to excessive fibroproliferation due to ineffective epithelial regeneration and aberrant tissue repair (8). In parallel with the concept of “injury response” that has been proposed to explain chronic dysfunction of other organ allografts, airway injury may occur via alloimmune-dependent and -independent mechanisms acting alone or in combination (9). The evolving concept is that bronchiolitis obliterans represents a “final common pathway” lesion, in which various insults can lead to a similar histologic and clinical result. Yet the rarity of this syndrome in untransplanted individuals suggests that alloimmune-dependent mechanisms usually play a pivotal role.
Acute rejection histology, characterized by perivascular and/or peribronchial infiltration of activated lymphocytes into graft tissue, has been identified in many studies as a statistical risk factor for BOS; the risk increases when the acute rejection is histologically severe or when it persists or recurs after treatment (6, 10, 11). However, many patients with acute rejection do not develop BOS, and some patients with BOS have never experienced acute rejection; therefore, the relationship between acute rejection and BOS appears to be complex and may depend on time after transplantation, whether acute rejection histology occurs in a symptomatic or asymptomatic patient, and on the intensity of therapy provided. In a recent study (12), the use of intense induction and maintenance immunosuppression and of aggressive treatment of acute rejection has been suggested to uncouple the association between early acute rejection and BOS.
In some cases, patients with acute rejection, especially when histologically severe or refractory to treatment, experience an irreversible reduction in pulmonary function and progressive BOS without a long intervening time period, suggesting that acute rejection may lead directly to airway fibrosis. This concept is also supported by the evolution of histologic changes in rodent heterotopic tracheal transplant models of bronchiolitis obliterans, in which untreated acute rejection leads directly to airway obliteration (13).
Several lines of evidence support the concept that alloreactivity directed toward HLA antigens is involved in the pathogenesis of BOS. Ciliated bronchial epithelial cells express class II HLA antigens, and this expression is upregulated during chronic rejection (14–16). In addition, reactivity of bronchoalveolar lymphocytes in patients with BOS is directed generally toward donor-specific class I HLA antigens (17), and the presence of anti-HLA antibodies directed toward these antigens is associated with, or may even precede, the development of BOS (18). Despite these observations and single-center reports of an association between HLA mismatching and BOS (19), a recent review of the published literature does not provide a clear consensus that HLA mismatching is a risk factor for chronic rejection (11).
The lung allograft is particularly susceptible to infection, and bacterial and fungal pneumonias may contribute to development of bronchiectasis in alloimmune-damaged large airways (20–22). However, bacterial infections are not known to contribute directly to the pathogenesis of BOS. In contrast, cytomegalovirus (CMV)-related illness has been implicated in chronic vascular rejection of nonpulmonary solid organ allografts, and in some studies, CMV pneumonitis has correlated with development of BOS (23). Non-CMV viral infections, including respiratory syncytial virus, parainfluenza virus, adenovirus, and influenza A and B, occur frequently in lung transplant recipients. Although these viruses have not been unequivocally associated causally with BOS (24), their involvement cannot be totally excluded in view of their known, if infrequent, association with chronic airway dysfunction in nontransplant patients.
Finally, the role of airway ischemia in the pathogenesis of BOS is uncertain. Ischemia may occur as a result of two mechanisms: first, chronic ischemia due to interruption of the bronchial artery supply after reimplantation of the graft is a potential, but unproven, facilitator of subsequent small airway injury. Second, “cold ischemia,” which occurs during the time interval between organ procurement and organ transplantation has been shown to increase the risk of death and chronic graft dysfunction after lung transplantation. The effect on post-transplant mortality is magnified as donor age increases, and the effect on the incidence of BOS is magnified as recipient age increases, suggesting that the susceptibility to ischemic injury at the time of organ procurement is dependent on additional intrinsic donor and recipient factors (1, 25).
The inference that airway inflammation and injury result in bronchiolitis obliterans has led to a search for inflammatory and profibrotic mediators in the airways. Activated airway epithelial cells produce several chemokines, including interleukin (IL)-8 and monocyte chemoattractant protein-1, which promote persistent recruitment of neutrophils and monocytes. These chemokines and cells have been identified in the airways and bronchoalveolar lavage (BAL) fluid before or concurrently with the development of BOS (26–28). The neutrophils secrete proteases (29) and reactive oxygen species (30), which lead to excessive oxidative stress and may cause substantial damage to bronchial tissue. Alveolar macrophages typically produce profibrotic cytokines, including platelet-derived growth factor, transforming growth factor-β, and insulin-like growth factor-1, which elicit attraction and proliferation of fibroblasts, leading to extracellular matrix deposition, proliferation of smooth muscle cells, angiogenesis, and excessive fibroproliferation (26–28, 31–35). The detection of increased levels of several of these cytokines in the BAL may predate the decline of lung function.
Although informative, these studies of individual genes and proteins are only able to provide a limited view of the complex symphony of transcriptional and translational events that likely characterize the development of bronchiolar fibrosis. The evolving technologies of functional genomics and proteomics, which allow simultaneous comparisons of large numbers of mRNA or protein species between individuals or over time in a single individual, will likely yield a more comprehensive and informative view of this process.
To the extent that current therapies work to stop or slow down the progression of BOS, they do so mostly by an antiinflammatory and not an antifibrotic effect. Therefore, they are more likely to be effective in the early stage of BOS. For this reason, various parameters have been evaluated to determine whether they may be useful as early markers of a fall in graft performance.
Several studies have shown that surveillance transbronchial biopsies performed during the first postoperative months may show acute rejection histology in 22–73% of clinically and physiologically stable patients (12, 36, 37). Similarly, a recent study that used home monitoring of FEV1 and FEF25–75 via the internet to detect acute rejection (and infection) found that the sensitivity of home spirometry was only 63% (38). So the performance of surveillance transbronchial biopsies in the first months after surgery provides a means to detect and treat clinically silent rejection episodes, and may dictate the use of a more intense maintenance immunosuppression. This strategy may eventually prove useful to uncouple the association between acute rejection and BOS (12).
A potential limitation of the staging system proposed by the ISHLT is that hospital spirometry may be performed infrequently, especially in patients who live at great distances from transplant centers. This limitation, however, may be overcome by the use of home spirometry with telemetric transmission of functional data to the transplant center (39). Alterations in the distribution of ventilation in peripheral airways may also contribute to the early detection of BOS. Two recent prospective studies in heart–lung and bilateral lung recipients have shown that the slope of the alveolar plateau for nitrogen or helium obtained during single-breath washouts may increase up to several months before the criteria for BOS 0-p are met (7, 40). Finally, the presence of nonspecific bronchial hyperreactivity may also precede BOS; in a recent longitudinal study that included 111 patients undergoing bilateral lung transplantation, a positive methacholine challenge at 3 months after transplantation was associated with the development of BOS, with a positive predictive value of 72% (41). This observation may be related to the fact that in transplanted subjects, metacholine-induced bronchoconstriction involves the small airways (42).
Neutrophilic airway inflammation, evidenced by increased neutrophil count in endobronchial biopsies and BAL fluid, may be seen in stable lung transplant recipients and is probably related to ongoing subclinical allogeneic stimulation (43, 44). With the development of BOS, BAL neutrophilia increases further (40, 44). Several reports have shown that BAL neutrophilia may predate the spirometric criteria defining BOS 1, but whether BAL neutrophilia is an early marker of BOS or whether it reflects ongoing infection is still debated. The overlap of cytokine concentrations found in the BAL of patients with and without BOS limits the predictive value of these markers in individual patients. In addition, measurements of these markers are not currently available at most transplant centers.
Exhaled nitric oxide (eNO) concentration, which has been proposed as a noninvasive marker of airway inflammation, may be useful in the early detection of BOS. In patients with BOS, eNO concentrations are greater than in stable patients, in particular at the onset of the functional deterioration, and they correlate with the expression of inducible NO synthase in the bronchial epithelium, and with the percentage of neutrophils in BAL (45). These data indicate that eNO reflects the degree of airway inflammation in lung transplant recipients (46), but the extent to which eNO may predict the development of BOS in an individual patient remains to be established.
The presence of air trapping on expiratory high-resolution computed tomography (CT) is an accurate indicator of the bronchiolar obliteration underlying BOS. In patients with BOS, the pulmonary lobules that have normal airways increase in density during the expiratory phase, whereas areas with obstructed airways cannot empty and remain radiolucent. Studies in adults and children have shown that the sensitivity of air trapping for enabling the diagnosis of BOS and bronchiolitis obliterans ranges from 74–91%, whereas the specificity ranges from 67–94% (47, 48). This variability may be accounted for by differences in the technique used to quantify the extent of air trapping, and by the fact that some studies included both heart–lung or bilateral lung recipients and single-lung recipients (48); the sensitivity and specificity of air trapping for the diagnosis of BOS may be lower in the latter. Interestingly, in the study by Bankier and coworkers (47), five of the six patients with initial false-positive findings (with significant air trapping but FEV1 > 80% of baseline) later developed BOS, which suggests that expiratory CT may contribute to the early detection of the condition. Conversely, air trapping has a very high negative predictive value (> 90%), i.e., a low score of air trapping in a patient with declining lung function makes the diagnosis of BOS very unlikely.
Current immune suppressive regimens generally include a calcineurin inhibitor, a purine synthesis inhibitor, and a corticosteroid. At present, there is not convincing evidence that the choice of calcineurin inhibitor at the time of transplantation influences the probability of developing BOS. However, several studies have confirmed the utility of substituting tacrolimus for cyclosporine A in patients with refractory acute rejection (49), which could conceivably help prevent the subsequent development of BOS. Two purine synthesis inhibitors, azathioprine and mycophenolate mofetil, are widely prescribed for lung transplant recipients. Preliminary results from a European multicenter randomized study in 317 patients have shown no difference between mycophenolate and azathioprine in the rate of acute rejection during the first postoperative year (50); because this trial is still ongoing, no data are available regarding the efficacy of the two drugs for the prevention of BOS.
Current treatment consists primarily of augmenting immunosuppression by changing medications within therapeutic classes, by adding medications, or by applying nonmedicinal immune-modulating therapies. Although each of these approaches has some support, the majority of reports are limited by small numbers of patients treated, retrospective study design, short duration of follow-up after treatment, and/or absence of a control group.
Small case series indicate that patients who develop BOS while taking cyclosporine A may become more stable after switching to tacrolimus (51). Although encouraging, these results are limited by the fact that the rate of loss of lung function in many obstructive lung diseases is nonlinear, with the rate of decline of FEV1 decreasing as airflow obstruction becomes more severe; therefore, the possibility exists that the same results might have been observed without changing medications. In addition, the change from cyclosporin A to tacrolimus may have been accompanied by additional medication changes in at least some of the patients analyzed; therefore, the stabilization of pulmonary function may not be entirely attributable to the change of calcineurin inhibitor.
Several medications and immune-modulating treatments have been reported to result in stabilization of pulmonary function of patients with BOS; these include polyclonal and monoclonal antilymphocyte antibody preparations (52), methotrexate (53), cyclophosphamide (54), extracorporeal photochemotherapy (photopheresis) (55), and total lymphoid irradiation (56). These findings are somewhat encouraging and suggest that augmented immunosuppression can inhibit disease progression. However, even when effective, many treated patients suffer from the cumulative burden of intense immunosuppression; in addition, reactivation of disease is relatively common after therapy reduction.
As discussed previously, it is likely that BOS represents a heterogeneous syndrome, with alloimmune and nonalloimmune mechanisms predominating to variable degrees in individual patients. To the extent possible, lung transplant physicians should attempt to discern these differences and individualize therapy. In particular, many patients with BOS suffer from recurrent bacterial, viral, and fungal infections which further compromise lung function and often become the proximate cause of death (20–22). Therefore, vigorous efforts to identify and treat infections are warranted during exacerbations of respiratory illness in recipients with BOS. It is also likely, although unproven, that aggressive immunosuppressive treatment of BOS predisposes to intercurrent bronchopulmonary infections; this must be factored into the risk–benefit analysis of augmented immunosuppression in these patients.
Currently employed therapy for BOS is disappointing. Even “successful” therapy is limited to halting the progression of disease without any hope of restoring lost lung function, and many affected recipients eventually develop severe respiratory limitation. Conceptually, pulmonary retransplantation is an attractive option for these individuals; however, retransplantation for BOS has been controversial in light of the very limited availability of donor lungs. Novick and colleagues (57) have reported results of 230 retransplants performed at 47 centers worldwide, 63% of which were performed for patients with BOS. The report indicates that early survival after retransplantation is reduced compared with first transplants, but results of retransplants performed for BOS were not different than those done for other indications. In addition, recurrent BOS has been observed in a frequency similar to that seen after first transplants.
Current therapies, when effective, will necessarily preserve the most lung function if they are employed early in the evolution of the disease process. In this regard, it is possible that lung recipients with risk factors for chronic rejection, such as prior episodes of acute rejection or anti-HLA antibodies, may benefit from intensified immune suppressive therapy, even before observing decreased pulmonary function (12). However, this approach is rarely taken by lung transplant physicians due to the relatively low predictive value of currently recognized risk factors and the known risks of increased immunosuppression. Therefore, an important goal for future research will be to validate the surrogate markers described above in longitudinal studies, and to develop more sensitive and specific noninvasive biomarkers of the risk for progression to BOS.
It is also possible that currently available maintenance immune-suppressive medications would prevent chronic rejection in more recipients if they could be given in higher doses. This has led to the concept of delivering these medications directly to the lower respiratory tract by aerosol inhalation, thereby increasing drug delivery while decreasing systemic drug exposure. In this regard, Iacono and coworkers (58) have reported stablilization of pulmonary function and histologic improvement in seven of nine patients with refractory, “histologically active” obliterative bronchiolitis after treatment with inhaled cyclosporine A. As an extension of this study, a randomized trial using aerosolized cyclosporine A to prevent BOS is in progress. In view of the prominent component of airway inflammation in BOS, it is possible that inhaled corticosteroids would be of benefit. Indeed, in a recent study, inhaled budesonide was found to improve lung function in lung transplant recipients with lymphocytic bronchiolitis (46); confirmation in larger placebo-controlled studies will be necessary before this can be recommended as standard therapy.
Current therapies for BOS are designed to inhibit cell-mediated immunity in an attempt to decrease airway inflammation. However, it is clear that the physiologic abnormalities of BOS are more directly related to airway fibroproliferation; therefore, developing effective antifibroproliferative therapies is an important goal. Rapamycin and related compounds are structural analogs of tacrolimus and bind to the same intracellular target (59). However, unlike tacrolimus, they do not appear to inhibit IL-2 production, but rather inhibit the response of T cells to IL-2 and other cytokines. In addition to its immune-suppressive activity, rapamycin has been shown to induce lymphoid cell apoptosis and to inhibit growth factor–induced endothelial and mesenchymal cell proliferation, implying that it may be useful in prevention and treatment of airway fibrosis in BOS. Rapamycin has been shown to prolong graft survival in several animal transplant models, is capable of reversing ongoing rejection, and reduces fibroproliferation in a murine heterotopic tracheal transplant model (60). Clinical trials are currently in progress to assess the safety and utility of rapamycin and its congener, everolimus, in human lung transplantation.
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