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Chronic lung transplant rejection: Bronchiolitis obliterans
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Apr 9, 2014.

INTRODUCTION — Chronic allograft rejection has remained a major source of morbidity and mortality following lung transplantation [1]. Survival data from the registry of the International Society for Heart and Lung Transplantation (ISHLT) [2] demonstrate a significant improvement in the early (up to one year) survival of transplant recipients over the past two decades; however, the rate of decline in survival after the first year is unchanged (figure 1).

The clinical syndrome of chronic lung transplant rejection and the infectious complications related to its treatment with intensified immunosuppression are the major sources of late morbidity and mortality after transplantation [3].

The clinical aspects and treatment of chronic rejection appearing in the form of bronchiolitis obliterans (BO) and bronchiolitis obliterans syndrome (BOS) are discussed here. Issues related to acute lung transplant rejection, general transplantation immunobiology, and other causes of bronchiolitis are discussed separately. (See "Evaluation and treatment of acute lung transplant rejection" and "Transplantation immunobiology" and "Bronchiolitis in adults".)

DEFINITIONS — Transplanted lungs are susceptible to several different types of rejection.

Acute cellular rejection – Acute cellular rejection is the predominant type of acute lung allograft rejection and is mediated by T lymphocyte recognition of foreign major histocompatibility complexes (MHC), also known as human leukocyte antigens (HLA), or other antigens in the donor lung [4,5]. (See "Evaluation and treatment of acute lung transplant rejection".)

Humoral rejection – Humoral rejection, which is less common than acute cellular rejection but increasingly recognized, is mediated by antibodies directed against donor HLA epitopes or other antigens. These antibodies may have been present in the recipient at a low level prior to transplant and rise in titer with an amnestic response after transplant, or may develop afterwards (so-called de novo HLA antibodies). Generally, if HLA antibodies are identified in the potential recipient, the corresponding HLA antigens are avoided in a donor (so-called virtual cross-match). Hyperacute rejection is a rare form of humoral rejection that occurs in the first 24 hours following lung transplantation in recipients who have preformed anti-HLA antibodies.

Bronchiolitis obliterans – Bronchiolitis obliterans (BO) is the predominant feature of chronic lung transplant rejection and is manifest pathologically as dense fibrous scar tissue affecting the small airways. Clinically, BO is associated with a progressive decline in forced expiratory volume in one second (FEV1). While BO is felt to be largely a manifestation of chronic lung transplant rejection, several other risk factors have been identified. Less commonly, chronic vascular rejection is also present and manifests pathologically as atherosclerosis in the pulmonary vasculature.

Bronchiolitis obliterans syndrome – When a patient has airflow limitation in the absence of other etiologies, but not histopathology documenting BO, a diagnosis of bronchiolitis obliterans syndrome (BOS) is made.

Restrictive allograft syndrome – Restrictive allograft syndrome (RAS) has been proposed as an additional type of chronic lung allograft dysfunction. In contrast to the obstructive defect characteristic of BO/BOS, RAS is characterized by upper lobe-predominant fibrotic changes and restrictive pulmonary function tests [6]. While not uniformly accepted in the transplant community as a distinct entity, it is sometimes useful to consider this as a form of allograft dysfunction [1].

PATHOLOGY — The pathologic manifestation of chronic lung transplant rejection in the airways is bronchiolitis obliterans (BO, also called obliterative bronchiolitis or OB), and in the pulmonary vasculature it is atherosclerosis [7-9]. The International Society for Heart and Lung Transplantation (ISHLT) has adopted a grading system for the pathologic findings in pulmonary allograft rejection (table 1) [9].

The early lesions of chronic lung allograft rejection are submucosal lymphocytic inflammation and disruption of the epithelium of small airways (picture 1). These are followed by an ingrowth of fibromyxoid granulation tissue into the airway lumen, resulting in partial or complete obstruction (picture 2). Granulation tissue then organizes in a stereotypical cicatricial pattern with resultant obliteration of the lumen of the airway (picture 3). In some instances, the only residual histologic evidence of small airways is found on elastin stains, which demonstrate a ring of circumferential elastin around an otherwise undetectable airway (vanishing airways disease) [10].

Other histopathologic findings in BO may include bronchiectasis, organizing pneumonia, various degrees of acute cellular rejection, and interstitial fibrosis [11].

EPIDEMIOLOGY — Chronic rejection is a major source of long-term morbidity after lung transplantation, as it is with heart-lung transplantation. The exact prevalence is uncertain, in part because of inconsistent definitions used among the various reports and different lengths of follow-up. Because the occurrence of BO increases over time, centers with a longer experience report higher prevalence rates, particularly in their later publications. The largest experience, from the International Society for Heart and Lung Transplant (ISHLT) registry, reports that 48 percent of recipients develop BO or BOS by five years after lung transplant and 76 percent after ten years (figure 2) [12].

ETIOLOGY AND RISK FACTORS — The etiology of BO remains to be defined. Some evidence suggests that BO is a manifestation of a chronic alloimmune response and airway-centered rejection. However, events other than chronic rejection may also contribute. It may be more accurate to view BO as the final common pathway of a number of insults, including some that are not immunologically mediated.

Many possible risk factors for the development of BO following lung transplantation have been proposed [13-18]. A panel of experts organized by the International Society for Heart and Lung Transplantation and subsequent studies have categorized various risk factors as probable or possible (table 2) [13,16,17,19,20]. Medication noncompliance is listed as risk factor, although the mechanism is likely via increased acute or chronic rejection. The following factors are considered probable or potential contributors to bronchiolitis obliterans syndrome (BOS):

Chronic rejection – Evidence suggesting that BO is a manifestation of chronic rejection comes from a number of observations. Donor-specific alloreactive T-cells and increased levels of class II antigen have been found within the alveolar walls and airway epithelium in recipients diagnosed with BO [21]. In addition, an oligoclonal CD4+ T-cell expansion is seen in the peripheral blood of patients with BO, but not in control transplant recipients without BO [22].

Reactivity of recipient lymphocytes to donor antigen-specific class I antigens has been documented by primed lymphocyte testing (PLT) and other assays in patients with BO [23-25]. The development of anti-HLA class I antibodies may precede the development of BO, and the progressive increase in anti-HLA antibodies correlates with the loss of pulmonary function [26]. An increasing number of HLA mismatches between graft and host, particularly mismatches at the HLA-A locus, are associated with an enhanced risk of BO [14,27-30].

Finally, the histopathology and clinical presentation of BO in lung transplant recipients closely resembles the lung manifestations of graft versus host disease after bone marrow transplantation, both histologically and clinically [31]. (See "Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease", section on 'Lung'.)

Acute rejection – Episodes of acute rejection have been identified as a risk factor for BO. In particular, recurrent episodes of acute rejection have been identified as a major risk factor in a number of retrospective epidemiologic analyses [8,13,19,32]. Other studies have found that more severe episodes of acute rejection, and those episodes manifesting with lymphocytic bronchiolitis are associated with particularly high risk for BO [33,34]. Even a single episode of mild rejection has been associated with an increased risk of BOS [35]. Development of donor-specific HLA antibodies after transplantation has also been associated with an increased risk of BOS [36]. (See "Evaluation and treatment of acute lung transplant rejection".)

Viral infection – In the nontransplant setting, BO is a well-described result of viral infection and cytomegalovirus infection (CMV) has been described as a cause of nontransplant BO. Retrospective analyses have demonstrated that CMV may be a risk factor for BO in lung transplant recipients [27,29,37]. At a single center, 231 lung transplant recipients who received CMV-prophylaxis for the first 4 to 14 weeks posttransplant were prospectively followed for development of CMV pneumonitis and BOS [38]. Development of CMV pneumonitis within the first six months was associated with a significantly increased risk of BOS (hazard ratio 2.19; 95% CI 1.36-3.51). However, this association has not been confirmed in other studies [39]. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

Other viruses, such as herpes virus 6 and Epstein Barr virus have been associated with an increased risk of BOS in some, but not all studies [40-42].

Bacterial and fungal infection and colonization – Isolation of pathogens such as Aspergillus fumigatus [43] and Pseudomonas aeruginosa [44-46] have been associated with a higher incidence of chronic lung rejection. While the causal relationship remains to be determined (that is, does early chronic rejection predispose to airway colonization via impaired host defense, or does colonization incite an immune response that contributes to bronchiolitis), these observations suggest that identification and treatment of colonization may be of merit in preventing the progression of chronic rejection, in addition to potentially reducing the risk of invasive distal infection.

Primary graft dysfunction (PGD), a multifactorial injury to the transplanted lung that develops in the first 72 hours after transplantation, is associated with later development of BO, and the severity of initial PGD correlates with the risk of BO [20,47,48]. The mechanism for such an association is hypothesized to be due to oxidative damage, impairment of nitric oxide synthesis by pulmonary endothelial cells, and/or upregulation of HLA class II antigens on the allograft leading to production of anti-donor antibodies [49-52]. (See "Primary lung graft dysfunction" and "Lung transplantation: Donor lung preservation", section on 'Methods of preservation'.)

Gastroesophageal reflux (GER) is common in patients following lung transplantation and may contribute to chronic allograft rejection via acid or alkaline aspiration [53-57]. (See "Physiologic changes following lung transplantation", section on 'Oropharyngeal dysphagia, gastroesophageal reflux, and gastroparesis'.)

The frequency and clinical importance of GER were evaluated in a report of 128 lung transplant recipients at a single institution; 93 (73 percent) had abnormal esophageal acid contact times based upon 24 hour ambulatory pH probe monitoring [53]. From this group, 26 patients met diagnostic criteria for BOS and underwent fundoplication. Following the procedure, 16 had lower BOS scores, and 13 no longer met criteria for the diagnosis of BOS. Long-term follow-up of these patients suggests that early fundoplication may result in a lower incidence of BOS and improved survival [53,57].

The retrospective nature and size of these studies are insufficient to establish a clear causal relationship between GER and BOS. However, the findings suggest that GER should be treated aggressively following lung transplantation. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

Transplant type – Single rather than double lung transplantation may also be a risk factor for BO (at least among patients with COPD). In a retrospective study of 221 patients who received lung transplantation due to end-stage COPD, double lung transplant recipients were more likely to be free from BOS than single lung transplant recipients three years (57 versus 51 percent) and five years (45 versus 18 percent) after transplantation [58].

Autoimmunity and pre-transplant alloimmunity – An emerging theory concerning the pathobiology of bronchiolitis obliterans is that it could result from autoimmunity (in addition to alloimmunity) to usually hidden epitopes of collagen type V that are presumably exposed as a result of ischemia/reperfusion injury or other insults that damage the allograft airway epithelium [15]. Moreover, increasing evidence suggests that patients with pre-existing antibodies to HLA or major histocompatibility complex (MHC) Class I chain-related gene A antigens are associated with a higher risk of developing BOS after transplantation [59].

CLINICAL PRESENTATION — The symptoms associated with the development of BO are nonspecific and include dyspnea on exertion and a nonproductive cough (table 3). Patients may present with a syndrome resembling an upper respiratory tract infection. It is not known whether such a presentation reflects an etiologic role of viral infection or the nonspecific nature of the symptoms. Alternatively, patients may simply present with subtle increases in exertional dyspnea and a decline in spirometry. It is unusual for bronchiolitis obliterans syndrome (BOS) to begin less than three months after transplant, and the onset is typically more indolent than that of acute rejection. In the early stages of BO, the physical examination is typically normal.

The more advanced stages of BO are associated with dyspnea at rest and in some patients, symptoms and signs of bronchiectasis, including a productive cough and an abnormal chest examination with end-inspiratory pops and squeaks (table 3).

EVALUATION FOR BO AND BOS — The evaluation of possible BO/BOS in lung transplant recipients is part of ongoing monitoring of lung transplant recipients and generally includes frequent home spirometry and regular clinical assessment. Typical findings of BO/BOS are summarized in the table (table 3). The exact frequency of follow-up is determined by the individual centers and the clinical stability of the patient. A reasonable protocol is to obtain lab testing and formal spirometry monthly for the first year. For patients who do well, the interval may be extended to every two months in subsequent years. (See "Maintenance immunosuppression following lung transplantation", section on 'Monitoring and adjusting maintenance therapy'.)

Laboratory — No laboratory tests have been identified that are diagnostic for BO/BOS. Generally, when evaluating a patient for possible BO, the patient’s ongoing immunosuppression is assessed by checking drug levels as indicated by the patient’s maintenance immunosuppressive regimen (table 4).

Depending on the clinical suspicion for infection, other tests may be performed such as complete blood count and differential, sputum gram stain and culture, cytomegalovirus assays, other viral cultures/immunoassays, blood culture, and legionella urinary antigen. Screening for de novo HLA antibodies to donor antigens should be performed. (See "Maintenance immunosuppression following lung transplantation", section on 'Monitoring and adjusting maintenance therapy' and "Bacterial infections following lung transplantation".)

Patients with advanced BOS may develop bronchiectasis, and their sputum cultures often grow Pseudomonas. It remains unclear whether Pseudomonas colonization contributes to BOS or merely results from allograft dysfunction and defects in host defense.

Pulmonary function testing — The key feature of BOS is airflow limitation, so pulmonary function testing (PFT), particularly spirometry, is a standard method for monitoring lung transplant recipients. Most centers use routine home spirometry. Additional testing with measurement of lung volumes and diffusing capacity would be guided by the results of spirometry. (See "Overview of pulmonary function testing in adults".)

In order to monitor for new onset airflow limitation, a “baseline value” is ascertained after lung transplantation, by taking the average of the two highest values of forced expiratory volume in one second (FEV1) and forced expiratory flow between 25 and 75 percent (FEF25-75) obtained at least three weeks apart and without preceding bronchodilator inhalation [16]. The values used to compute baseline FEV1 and FEF25-75 may be obtained on different days. If these values improve with a longer postoperative time, the baseline value is recalculated with the higher values.

The spirometric pattern associated with BOS is airflow limitation with a decrease in FEV1 and the FEV1/forced vital capacity (FVC) ratio. The degree of decline in FEV1 determines the stage of BOS (table 5). As BOS represents a persistent otherwise unexplained airflow limitation, patients are not considered to have BOS until two sets of spirometry obtained at least three weeks apart show a significant decrease from baseline. Once the criteria for BOS have been met, the stage of BOS thereafter is determined by the most recent value of FEV1.

Measurement of flow rates in mid-expiration, as assessed by the forced expiratory flow between 25 and 75 percent of the vital capacity (FEF25-75), appears to be an earlier and more sensitive indicator of airflow obstruction than a decline in the FEV1 [16,60-62]. Thus, potential BOS (stage 0-p) is defined as an FEV1 81 to 90 percent of baseline and/or an FEF25-75 ≤75 percent of baseline.

The results of spirometry from single lung transplant recipients may be more difficult to interpret, particularly if the underlying lung disease in the native lung was obstructive (eg, COPD, panbronchiolitis) [3]. By consensus, the determination of BOS is based on a percent (rather than absolute) decline in FEV1 from the highest post-transplant value regardless of whether the patient had a single or bilateral lung transplant.  

Bronchial hyperresponsiveness to methacholine is common following lung transplantation and does not appear to be a useful predictor of the development of BOS [63], although earlier studies suggested otherwise [64]. (See "Bronchoprovocation testing".)

Imaging — Chest imaging studies have a low sensitivity for identification of BO and are not used for screening. On the other hand, virtually all lung transplant recipients who present with new onset or worsening shortness of breath or other respiratory symptoms or signs should have a chest radiograph. In addition, a decline in FEV1 of 10 percent or greater should prompt a chest radiograph.

High resolution computed tomography (HRCT) is typically performed to evaluate abnormalities seen on conventional chest radiography or pulmonary function testing.

In the early stages of BO, the chest radiograph is typically unchanged compared with the post-transplantation baseline. In more advanced disease, the chest radiograph and HRCT demonstrate areas of hyperinflation and possibly bronchiectasis [65,66]. The role of HRCT to identify early BOS is unclear but many transplant pulmonologists obtain HRCT as part of the initial evaluation of obstructive lung disease after transplant.

Bronchoscopy and bronchoalveolar lavage — For patients with spirometric findings suggestive of BOS, bronchoscopy may be useful to exclude other airway abnormalities that can cause airflow limitation on spirometry, such as stenosis at the anastomotic site or endobronchial tumor. In addition, bronchoalveolar lavage (BAL) is typically performed to exclude infection or malignancy as a cause of deteriorating lung function. For patients with a new opacity on chest imaging, BAL is performed in the affected area. When BAL is performed, samples are sent for cell counts and differential, microbiologic stains and cultures, viral testing (eg, nucleic acid or polymerase chain reaction), and cytology. (See "Basic principles and technique of bronchoalveolar lavage".)

The BAL findings in patients with BOS/BO are nonspecific. Among stable lung transplant recipients undergoing routine monitoring BAL and transbronchial biopsy, BAL neutrophilia was noted in those with biopsies showing higher grade lymphocytic bronchiolitis, suggestive of BO [67]. However, a neutrophilic BAL fluid (eg, 25 to 50 percent neutrophils) is common in the first three months following transplantation [67]. The cause of BAL neutrophilia in BO is not known. Possible explanations include gastroesophageal reflux with aspiration, bacterial superinfection in areas of bronchiectasis proximal to the narrowed areas of BO, and neutrophilic infiltration of alveolar or bronchiolar walls.

Role of transbronchial biopsy — In general, our practice is to perform transbronchial biopsy when a diagnosis of BO is suspected on the basis of symptoms, spirometry showing a decline in FEV1 (eg, 10 percent or greater), and chest imaging (algorithm 1). The biopsy is used to exclude other causes of dyspnea and airflow limitation (eg, recurrence of an original lung disease such as sarcoid) and to confirm the diagnosis of BO. However, in a patient with advanced airflow obstruction, the morbidity of the biopsy outweighs its utility, and we do not perform it under these circumstances. (See "Evaluation and treatment of acute lung transplant rejection", section on 'Flexible bronchoscopy'.)

The utility of transbronchial biopsy for definitively establishing the diagnosis of BO has been debated due to the variable yield, as shown in the following studies:

One study of 105 transplant recipients reported a sensitivity of 17 percent and a specificity of 94.5 percent for a single set of transbronchial biopsies [68].

Another study found that transbronchial biopsies confirmed the diagnosis in 82 percent of their patients who developed clinical BOS [19].

In contrast, among 77 patients with chronic lung transplant rejection, the diagnosis was made on the basis of declining FEV1 alone in 40 patients (52 percent) [69]. Only seven patients (9 percent) had diagnostic biopsies without accompanying physiologic abnormalities, while 30 patients (39 percent) had both positive histology and declining spirometry.

A separate study of 16 patients clinically diagnosed with BOS reported a 15 percent rate of histologic confirmation by transbronchial biopsy [60].

Surrogate markers of bronchiolitis obliterans — Other potential markers of early BOS have been suggested. These include:

Neutrophil-predominant bronchoalveolar lavage fluid with increased levels of interleukin (IL)-12 and/or IL-17 [67,70-74]

Evidence of air trapping on chest CT scan [75-78] (see 'Imaging' above)

Elevated exhaled nitric oxide levels [79-81]

Soluble CD 30 levels [82]

An increase in circulating fibrocytes detected by flow cytometry [83]

Although these findings should alert physicians to the possibility of early BOS, none of these modalities is sensitive or specific enough to be used outside of well-designed trials [16].

DIAGNOSIS — The diagnosis of chronic rejection in lung transplant recipients can be made conditionally without histopathology (bronchiolitis obliterans syndrome or BOS) or definitively with histopathology (BO). For the majority of patients, the diagnosis of chronic lung transplant rejection is based on the demonstration of persistent airflow obstruction without an alternative cause and without histopathologic confirmation (that is, BOS). The usual approach to a patient presenting with declining spirometry with or without associated dyspnea is summarized in the figure (algorithm 1). For patients presenting with an acute illness suggestive of infection or with new opacities on chest imaging, additional studies (eg, blood and sputum cultures, assays for cytomegalovirus, bronchoalveolar lavage, high resolution chest tomography) to exclude infection, malignancy, or recurrence of the underlying disease are indicated. (See 'Bronchoscopy and bronchoalveolar lavage' above and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Bacterial infections following lung transplantation" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

Bronchiolitis obliterans — The diagnosis of BO in a lung transplant recipient requires histopathologic examination of a biopsy specimen. The term bronchiolitis obliterans should only be used when histology demonstrates dense fibrous scar tissue affecting the small airways. The presence of a lymphocytic submucosal infiltrate or intraluminal granulation tissue (without fibrous scarring) is not sufficient for a diagnosis of BO [16]. (See 'Definitions' above and 'Role of transbronchial biopsy' above and 'Pathology' above.)

Bronchiolitis obliterans syndrome — The International Society for Heart and Lung Transplantation nomenclature [16,84] makes a distinction between histologically proven BO and suspected BO, which is called bronchiolitis obliterans syndrome (BOS). In the absence of histologic evidence of BO, the diagnosis of BOS is made in the presence of "graft deterioration secondary to progressive airways disease for which there is no other cause". The severity of airflow limitation as determined by the decrease in forced expiratory volume in one second (FEV1), determines the severity of BOS (table 5) [16]. (See 'Definitions' above and 'Pulmonary function testing' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BOS/BO includes airway complications of lung transplantation (eg, bronchial stenosis, tracheobronchomalacia), progression or recurrence of the underlying lung disease (eg, COPD, diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangiomyomatosis, sarcoidosis), and infection. These can usually be distinguished by the work up described above. Acute cellular rejection is also in the differential, as it is associated with a decrease in the forced expiratory volume in one second (FEV1), although the likelihood of acute cellular rejection decreases beyond the first 6 to 12 months. These are distinguished pathologically; acute airway-centered cellular rejection is associated with a lymphocytic bronchiolitis on biopsy rather than the dense fibrous scarring of BO. (See "Airway complications after lung transplantation" and "Noninfectious complications following lung transplantation" and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Evaluation and treatment of acute lung transplant rejection".)

Restrictive allograft syndrome (RAS) develops over approximately the same time frame as BOS and is characterized by restrictive physiology and peripheral lung fibrosis [1,85-87]. The typical chest high resolution computed tomography (HRCT) shows increased reticular opacities, predominantly in the upper lung zones, and traction bronchiectasis [6,88]. Pathologic examination shows fibrosis in the alveolar septa, visceral pleura, and scattered obliterative bronchiolitis lesions [6]. Patients frequently experience episodes of acute exacerbation with patchy or diffuse ground glass opacities on the chest CT and diffuse alveolar damage on lung biopsy [85].

For patients with a decreased FEV1, but normal FEV1/FVC, the differential diagnosis focuses on diseases that cause a restrictive ventilatory defect, such as an increase in body mass index, muscular weakness, pleural effusion, infection, acute cellular rejection, disease recurrence, certain anastomotic complications, and RAS [16,85]. Evaluation includes physical examination for muscle weakness and weight gain, chest radiograph looking for pleural effusion, evidence of new interstitial lung disease, or airway occlusion, and also bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy. (See "Evaluation and treatment of acute lung transplant rejection".)

PREVENTION — The best strategy to deal with chronic rejection is primary prevention, as there is no reliable therapy once patients develop symptomatic airflow obstruction. Potential interventions for prevention of BO/BOS include aggressive initial immunosuppression to eliminate early episodes of acute cellular rejection, prophylaxis against cytomegalovirus (CMV) with oral valganciclovir in recipients who are at risk for CMV infection, vaccination against influenza and pneumococcus, reduction in cold ischemia time and other methods to reduce primary graft dysfunction, treatment of gastroesophageal reflux to reduce acid aspiration, and long-term azithromycin.

Macrolide antibiotics are used in a variety of bronchiolar disorders (eg, panbronchiolitis, constrictive bronchiolitis) and are thought to act more through anti-inflammatory than antimicrobial mechanisms. The effect of azithromycin in preventing BO was assessed in a randomized trial of 83 lung transplant recipients who received azithromycin 250 mg three times a week for two years. BOS developed in 12 percent of patients on azithromycin compared with 44 percent of those on placebo [89]. The overall survival between the groups was not different. Side effects related to chronic azithromycin therapy included nausea and diarrhea; one case of pseudomembranous colitis occurred in the each of the active treatment and placebo groups.

Based on the accumulated data and clinical experience, it is reasonable to use azithromycin as prophylaxis against chronic rejection, although an impact on survival has not been demonstrated.

The role of induction and maintenance immunosuppression in prevention of BOS is discussed separately. (See "Induction immunosuppression following lung transplantation" and "Maintenance immunosuppression following lung transplantation".)

TREATMENT — A variety of therapies have been tried for BO/BOS, but there is no well-established protocol. Potential treatments include adding long-term azithromycin (if not already used for prevention), changing the maintenance immunosuppressive medications, extracorporeal photopheresis, total lymphoid irradiation, plasmapheresis, and other therapies to target antibodies to the allograft (immunoglobulin, rituximab, proteasome inhibitors), and inhaled cyclosporine (table 6) [90-96]. The decision among these choices depends on the severity of BOS, underlying immunosuppressive regimen, preferences of individual transplant centers, and response to treatment.

New onset BOS — For patients with a new diagnosis of BOS and no evidence of infection who are not already on azithromycin for prevention of BOS, we typically initiate azithromycin (generally 250 mg orally three times weekly). Preliminary reports suggest that prolonged oral azithromycin therapy may stop or reverse the decline in pulmonary function associated with BOS in some (but not all) patients [56,89,97-103].

In a retrospective study of 107 patients with BOS, azithromycin treatment for three to six months (250 mg daily for five days, followed by 250 mg three times weekly) resulted in a 10 percent or greater increase in forced expiratory volume in one second (FEV1) in 40 percent of patients [104].

Among 81 lung transplant recipients with at least BOS stage 0p treated with azithromycin 250 mg three times a week, 24 showed an improvement in FEV1, whereas 35 showed disease progression [100]. The majority of responders were identified by three months of treatment.

Among 62 patients with potential BOS or grade 1 to 3 BOS who were treated with azithromycin (250 mg daily for five days, then 250 mg three times per week) for one year, 13 had a 10 percent or greater improvement in FEV1, 35 had stabilization, and 14 further deteriorated [105]. Those with potential BOS were more likely to respond to azithromycin than those with more advanced disease.

In addition, we review the maintenance immunosuppressive regimen for adequacy and ensure that serum levels of the various immunosuppressive agents are appropriate (table 4).

Some patients with early BOS have responded to changes in their maintenance immunosuppression regimen in favor of tacrolimus and mycophenolate. Thus, for patients on cyclosporine, we often substitute tacrolimus [106], and for patients on azathioprine, we substitute mycophenolate. These choices are based on case series that reported success with these substitutions, and are not universally accepted [107,108]. As an example, a study of 32 patients with BO found that conversion from cyclosporine to tacrolimus was associated with slower rates of decline in spirometry over 12 months of follow-up and slightly better one-year survival statistics [109]. A second study of 13 patients reported similar results when mycophenolate mofetil was substituted for azathioprine [110]. Other studies have reported similar results following substitutions in the immunosuppressive regimen [81,111,112]. (See "Maintenance immunosuppression following lung transplantation", section on 'Monitoring and adjusting maintenance therapy'.)

Response to therapy is assessed with ongoing measurement of spirometry.  

Progressive BOS — For patients with a progressive decline in FEV1 despite azithromycin and optimization of the maintenance immunosuppressive regimen, we choose among the following options based on a case-by-case evaluation. As an example, extracorporeal photopheresis requires frequent visits to the transplant center and may not be possible for patients who live at a distance. Sirolimus and everolimus are associated with bone marrow suppression and are often avoided in patients with significant cytopenias; they should be used with caution in patients with significant renal impairment.

The evidence in favor of various salvage therapies includes the following:

Montelukast, a leukotriene receptor antagonist, was compared with control in an open-label study [113]. The rate of decline in FEV1 decreased in the montelukast group from 112 +/-26 to 13 +/-13 mL/month, but did not decrease in the control group. Of note, both groups had received or were concurrently receiving azithromycin.

Sirolimus and everolimus are mTOR inhibitors that suppress T-lymphocyte activation and proliferation; they have a similar structure to the calcineurin inhibitors (tacrolimus, cyclosporine), but exert their immunosuppressive effects through calcineurin-independent mechanisms. In an open label study, BOS was less likely to progress when sirolimus was substituted for azathioprine in 37 subjects receiving either cyclosporine or tacrolimus; however, side effects led to sirolimus discontinuation in 59 percent of patients [114]. The use of everolimus has been reported in case series of lung transplant recipients, although the effect on BOS was inconclusive [115,116].

Development of BOS may be reduced or delayed among lung recipients taking everolimus for maintenance immunosuppression. Sirolimus and everolimus are contraindicated within the first 90 days after lung transplant due to problems with dehiscence of the bronchial anastomosis. The use of mTOR inhibitors for maintenance immunosuppression and the dosing and adverse effects of these agents in lung recipients are discussed separately. (See "Maintenance immunosuppression following lung transplantation", section on 'mTOR inhibitors'.)

Several reports of single center experiences with extracorporeal psoralen photopheresis (ECP) in the setting of BOS suggest that it reduces the rate of decline in lung function [91-93,117]. In extracorporeal photopheresis, peripheral blood lymphocytes are collected via apheresis, treated with 8-methoxypsoralen followed by exposure to a source of ultraviolet A light, and reinfused. This process is thought to act by inducing lymphocyte apoptosis and induction of T regulatory (Treg) cells. Among 51 patients with BOS treated with ECP (two successive days every two weeks for three months and then every four weeks), the FEV1 improved or stabilized in 61 percent [117]. Those who responded to ECP had better survival and a lower rate of retransplantation than nonresponders. (See "Treatment of chronic graft-versus-host disease", section on 'Psoralen ultraviolet irradiation'.)

Total lymphoid irradiation has been assessed in small observational studies in which the rate of decline in lung function was generally slower after irradiation than before [94,95]. However, in one study, 10 of 37 patients were unable to complete the therapy due to progressive BOS or bone marrow suppression [95].

A single center report demonstrated the possible benefit from aerosolized cyclosporine in this setting [90]. A separate case report described improvement in BOS with aerosolized tacrolimus [118].

Antilymphocyte and antithymocyte therapies were evaluated in a series of 48 lung transplant recipients with BOS who received 64 courses of treatment with a cytolytic agent (antilymphocyte globulin, antithymocyte globulin, or muromononab-CD3 (OKT3) monoclonal antibody) [119]. The rate of decline in FEV1 slowed in the three months after treatment, but BOS eventually progressed in all patients.

Less established or ineffective therapies — While systemic glucocorticoids are the cornerstone of management of acute lung transplant rejection, they appear to have limited utility in the management of BOS. One randomized study suggested that high-dose inhaled glucocorticoids are not effective in slowing or preventing the development of BOS [120]. (See "Evaluation and treatment of acute lung transplant rejection", section on 'High-dose glucocorticoids'.)

An open label study evaluating the anti-CD52 antibody alemtuzumab for BOS showed stabilization or improvement in the BOS grade in 7 of 10 patients [121]. (See "Induction immunosuppression following lung transplantation", section on 'Alemtuzumab'.)

Plasmapheresis has been used to treat humoral lung transplant rejection, but has not been formally studied in BOS.

Retransplantation — The role of retransplantation after the development of chronic lung rejection is controversial. Early experience suggested that the outcome was not as good as with the first transplant, and conflicting data has been reported on the risk of BOS recurrence following retransplantation. Among patients who underwent retransplantation between 2001 and 2006, retransplant patients had a higher risk of BOS than initial transplant recipients (HR 2.0, 95% CI 1.4–3.0) [122]. However, other series have not found an increased risk of BOS following retransplant. This is discussed in greater detail separately. (See "Lung transplantation: Procedure and postoperative management", section on 'Retransplantation'.)

Candidates for retransplantation need to be carefully selected and meet most if not all general guidelines for a first lung transplant. However, dependence on mechanical ventilation at the time of retransplantation does not by itself appear to have a significant adverse effect on survival in patients being retransplanted for BOS [122,123]. (See "Lung transplantation: General guidelines for recipient selection".)

Opinions concerning the appropriateness of retransplantation vary widely, given the limited availability of donor lungs. Most centers have more potential first-time recipients than donors, and mortality on the waiting list is a significant problem. As a result of these considerations, transplant programs vary in policy concerning the availability of retransplantation as a therapeutic option. (See "Lung transplantation: Procedure and postoperative management", section on 'Retransplantation'.)

PROGNOSIS — BOS is usually progressive, although the rate of progression varies from one patient to another [124,125]. Some patients experience a rapid, relentless progression, some have stabilization after an initial rapid deterioration, and others experience a subtle onset, but relentless progression.

The mortality rate associated with BOS ranges from 25 to 55 percent [19,69,126]. Among grades of BOS (table 5), the risk of death increases approximately three-fold with each step higher in grade [126]. Unfortunately, in many patients, BOS results in progressive respiratory failure, similar to the initial lung disease for which the transplant was originally performed.

SUMMARY AND RECOMMENDATIONS

Clinical manifestations and diagnosis

Chronic lung transplant rejection can affect the airways or the pulmonary vasculature or both. Chronic airway rejection, the more common and morbid of the two types of rejection, is identified histologically by the presence of bronchiolitis obliterans (BO) (picture 1 and picture 2). When a patient has airflow limitation in the absence of other etiologies, but histopathology documenting BO is not available, a diagnosis of bronchiolitis obliterans syndrome (BOS) is made. (See 'Definitions' above.)

The exact etiology of BOS/BO is unclear, but it is believed to be primarily a manifestation of chronic rejection of the allograft. However, several other factors appear to participate, including recurrent and severe episodes of acute lung transplant rejection, cytomegalovirus infection, primary graft dysfunction, gastroesophageal reflux, and possibly autoimmunity. (See 'Etiology and risk factors' above.)

The clinical presentation of BOS/BO is often similar to an upper respiratory tract infection. It is not known whether such a presentation reflects an etiologic role of viral infection or the nonspecific nature of the symptoms. Alternatively, patients may simply present with subtle increases in exertional dyspnea and a decline in spirometry. (See 'Clinical presentation' above.)

In the early stages of BOS/BO, the physical examination is typically normal and the chest radiograph is clear. In more advanced stages, the chest examination usually reveals end-inspiratory pops and squeaks. Airflow obstruction is the usual pattern on pulmonary function testing. The chest radiograph and high resolution computed tomography scan may demonstrate signs of bronchiectasis and hyperinflation, but are often normal in early disease. (See 'Clinical presentation' above and 'Pulmonary function testing' above and 'Imaging' above.)

The usual approach to a lung transplant recipient presenting with dyspnea and declining spirometry or with an asymptomatic decline in spirometry is summarized in the figure (algorithm 1). The first step is to exclude anastomotic stenosis or infection, so virtually all patients undergo bronchoscopy with bronchoalveolar lavage to obtain samples for bacterial and viral cultures. When possible, a transbronchial biopsy is performed to look for histopathologic evidence of infection or BO. (See 'Evaluation for BO and BOS' above.)

The diagnosis of chronic lung transplant rejection can be made conditionally on the basis of increasing airflow limitation on spirometry without histopathology (ie, BOS) or definitively with histopathology (BO). The severity of BO is graded as outlined in the table (table 5). (See 'Diagnosis' above.)

The differential diagnosis of BOS includes airway complications of lung transplantation (eg, bronchial stenosis, tracheobronchomalacia), progression or recurrence of the underlying lung disease (eg, COPD, diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangiomyomatosis), and infection. (See 'Differential diagnosis' above.)

Prevention and treatment

For patients with new onset BOS, we suggest addition of long-term azithromycin therapy rather than other therapies. The usual dose is 250 mg daily for five days, followed by 250 mg three times weekly (Grade 2C). In addition, the maintenance immunosuppression regimen is assessed and optimized (table 4). (See 'New onset BOS' above.)

For patients who develop BOS while on a maintenance immunosuppression regimen that includes cyclosporine, we suggest changing cyclosporine to tacrolimus (Grade 2C). For patients on azathioprine, we suggest substituting mycophenolate for azathioprine (Grade 2C). (See 'New onset BOS' above.)

For patients with a progressive decline in FEV1 despite azithromycin and optimization of the immunosuppressive regimen, the choice among the less well-established options is based on a case-by-case evaluation and the preferences of the local transplant team (table 6). Potential choices include montelukast, everolimus or sirolimus, extracorporeal photophoresis, total lymphoid irradiation, and antilymphocyte or antithymocyte therapy. (See 'Progressive BOS' above.)

BOS is often progressive despite these interventions, although the rate of progression varies from one patient to another. The mortality rate is 25 to 55 percent. Among patients who develop respiratory failure due to BOS, retransplantation is an option. Candidates for retransplantation need to be carefully selected and meet most if not all general guidelines for a first lung transplant. (See 'Prognosis' above and 'Retransplantation' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John Reilly, Jr, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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