INTRODUCTION — Chronic lung allograft dysfunction (CLAD) remains a major cause of morbidity and mortality following lung transplantation [1]. Two main CLAD phenotypes are recognized: bronchiolitis obliterans syndrome (CLAD-BOS) and restrictive allograft syndrome (CLAD-RAS). 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 CLAD and the infectious complications related to its treatment with intensified immunosuppression are the major causes of late morbidity and mortality after transplantation [2].
The clinical aspects and treatment of CLAD appearing in the form of bronchiolitis obliterans (BO) and bronchiolitis BOS are discussed here. Issues related to acute lung transplant rejection, general transplantation immunobiology, and other causes of bronchiolitis are discussed separately. (See "Chronic lung allograft dysfunction: Restrictive allograft syndrome" and "Evaluation and treatment of acute lung transplant rejection" and "Transplantation immunobiology" and "Overview of bronchiolar disorders in adults".)
DEFINITIONS — CLAD is defined as a substantial and persistent decline (≥20 percent) in forced expiratory volume in one second (FEV1) when compared with the post-transplant baseline [3]. CLAD is an umbrella term that includes different patterns of lung function decline occurring more than three months after lung transplantation. Two predominant phenotypes of CLAD, which may be separate or mixed, are recognized [1]:
●Bronchiolitis obliterans syndrome – Bronchiolitis obliterans syndrome (BOS) is the predominant phenotype of CLAD and presents clinically as obstructive lung disease detected as a decline in FEV1. When histopathology is available to confirm obliterative fibrosis of the small airways, the term bronchiolitis obliterans (BO) is used. While BOS is felt to be largely a manifestation of chronic rejection, several other risk factors have been identified. Less commonly, chronic vascular rejection is also present, but it is rarely a significant clinical feature.
●Restrictive allograft syndrome – Restrictive allograft syndrome (RAS) is another form of CLAD [3,4]. In contrast to the obstructive defect characteristic of BOS, RAS is characterized by upper lobe-predominant fibrotic changes and a restrictive decrement in pulmonary function tests [5]. Evidence indicates that it is useful to consider this as a subtype of allograft dysfunction [4], particularly because it has prognostic implications [6-8] and patients with RAS and lower lobe or diffuse opacities on computed tomography or peripheral blood eosinophilia have a particularly poor survival [9].
Other types of allograft rejection, such as acute cellular rejection and humoral rejection, typically occur earlier after transplantation and are discussed separately. (See "Evaluation and treatment of acute lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection".)
EPIDEMIOLOGY — CLAD is a major source of long-term morbidity after lung and heart-lung transplantation. The exact incidence 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 rates, particularly in their later publications. The largest experience, from the International Society for Heart and Lung Transplant (ISHLT) registry, reports that 50 percent of recipients develop BO or BOS by five years after lung transplant and 74 percent after ten years (figure 2) [10].
ETIOLOGY AND RISK FACTORS — The etiology of BOS 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 CLAD-BOS as the final common pathway of a number of insults, including some that are not purely alloimmune, such as infection and aspiration [1]. Of note, most studies of etiology and risk factors have not differentiated between restrictive allograft syndrome (RAS) and BOS.
Many possible risk factors for the development of BO/BOS following lung transplantation have been proposed [11-16]. A panel of experts organized by the International Society for Heart and Lung Transplantation (ISHLT) and subsequent studies have categorized various risk factors as probable or possible (table 1) [14,15,17]. Medication noncompliance is listed as risk factor, perhaps due to erratic immunosuppressive drug levels [18] and an associated increase in acute rejection. The following factors are considered probable or potential contributors to BOS:
●Chronic rejection – Evidence suggesting that BO is a manifestation of chronic rejection comes from a number of observations [19-22].
Development of donor specific antibodies (DSA) that recognize donor human leukocyte antigens (HLA), most commonly DQ, has been documented in patients with BO [21-23]. The development of DSA may precede the development of BO and de novo development of HLA antibodies, particularly to HLA-DQ antigens, correlates with the loss of pulmonary function [24-27]. An increasing number of HLA mismatches between graft and host, particularly mismatches at the HLA-DQ locus, are associated with an enhanced risk of BO [12,28-31].
Finally, the histopathology and clinical presentation of BO in lung transplant recipients closely resembles the pulmonary manifestations of graft-versus-host disease after bone marrow transplantation, both histologically and clinically [32]. (See "Clinical manifestations and diagnosis 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 [11,33-35]. 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 [36,37]. Even a single episode of mild rejection has been associated with an increased risk of BOS [38]. (See "Evaluation and treatment of acute lung transplant rejection" and "Evaluation and treatment of antibody-mediated 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 [28,30,39], although this was not found in all studies [40]. At a single center, 231 lung transplant recipients who received CMV-prophylaxis for the first 4 to 14 weeks post-transplant were prospectively followed for development of CMV pneumonitis and BOS [41]. 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). In a separate study, CLAD was associated with CMV infection that led to expression of certain virally encoded UL40 peptide variants [42]. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)
Community respiratory viral infections may contribute to CLAD [43,44]. In a study of 139 lung transplant recipients that prospectively monitored community-acquired respiratory viral (CARV) infections, the risk of CLAD was increased among those with CARV pneumonia (HR 3.94, 95% CI 1.97-7.90) [43]. However, CARV without pneumonia was associated with BOS in a study of 100 lung recipients [44]. (See "Viral infections following lung transplantation", section on 'Community respiratory viruses'.)
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 [45-47].
●Bacterial and fungal infection and colonization – Isolation of pathogens such as Aspergillus fumigatus [48] and Pseudomonas aeruginosa [49-51] 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 airspace 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 [17,52,53]. 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 donor specific HLA antibodies [54-57]. (See "Primary lung graft dysfunction" and "Lung transplantation: Donor lung procurement and preservation", section on 'Steps to optimize lung preservation'.)
●Gastroesophageal reflux (GER) is common in patients prior to and following lung transplantation and may contribute to chronic allograft rejection via acid or alkaline aspiration [58-63]. (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 [58]. 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 [58,62]. In addition, a retrospective cohort study suggests that impedance analysis provides useful predictive value in addition to pH testing [64].
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 [63]. (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 chronic obstructive pulmonary disease [COPD], although progression of COPD in the remaining native lung may be a confounding factor in measurement of airflow limitation) (see 'Pulmonary function testing' below). 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 [65].
●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 [13]. 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 [66].
CLINICAL PRESENTATION — The symptoms associated with the development of BO are nonspecific and include dyspnea on exertion and a nonproductive cough (table 2). 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 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 2).
EVALUATION FOR BO AND BOS — Lung transplant recipients presenting with new onset of shortness of breath or cough or an acute decrease in lung function more than three months after lung transplantation should be evaluated for possible BOS (table 2). In addition, lung transplant recipients should be routinely evaluated for possible BOS as part of ongoing monitoring, which generally includes regular spirometric monitoring and clinical assessment.
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 at least the first year. For patients who do well, the interval may be extended to every two to three 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 BOS, the patient’s ongoing immunosuppression is assessed by checking drug levels as appropriate for the patient’s maintenance immunosuppressive regimen.
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, serum cryptococcal antigen, other viral cultures/immunoassays, urine enzyme immunoassay (EIA) for Histoplasma antigen, serum galactomannan antigen, 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 "Viral infections following lung transplantation" and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Evaluation and treatment of antibody-mediated lung transplant rejection".)
Patients with bronchiectasis due to advanced BOS often grow Pseudomonas in their sputum cultures. 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, but long-term patient compliance with this modality is inconsistent. Additional testing with measurement of lung volumes and diffusing capacity are 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 mean of the two highest values of forced expiratory volume in one second (FEV1) obtained at least three weeks apart and without preceding bronchodilator inhalation [14]. If FEV1 improves with a longer postoperative time, the baseline value is recalculated with the higher value. The ISHLT consensus report advises measuring total lung capacity (TLC) by body plethysmography at three and six months after transplant to obtain a new baseline and annually thereafter [1]. If FEV1 changes by ≥10 percent, the TLC should be reassessed.
The spirometric pattern of BOS is airflow limitation with a decrease in FEV1 from the postsurgical baseline and in the FEV1/forced vital capacity (FVC) ratio. A declining forced expiratory flow 25-75 percent (FEF 25-75) can be a clue to evolving BOS. TLC is typically normal or increased due to air trapping. CLAD staging is based on the degree of decline in FEV1 as described below [1]. (See 'CLAD staging' below.)
As BOS is defined as 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. However, most centers will initiate investigation for CLAD if the FEV1 decreases by ≥10 percent from baseline (CLAD 0) [1]. Once the criteria for BOS have been met, the stage of BOS thereafter is determined by the most recent value of FEV1.
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, chronic obstructive pulmonary disease [COPD], panbronchiolitis) [67]. 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 [68], although earlier studies suggested otherwise [69]. (See "Bronchoprovocation testing".)
Imaging — Chest imaging studies have a low sensitivity for identification of BO/BOS 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 or a decline in FEV1 of 10 percent or greater should have a chest radiograph. 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 can demonstrate areas of hyperinflation and possibly bronchiectasis [70,71].
ISHLT consensus report on CLAD advises obtaining a high resolution computed tomography (HRCT) scan (inspiratory views with a maximum width of 3-mm sections, and expiratory sections as well) six months post-transplant as a new baseline for future comparisons [1]. The role of HRCT in identification of early BOS is unclear, but many transplant pulmonologists obtain HRCT as part of the initial evaluation of obstructive lung disease after transplant. The presence of parenchymal opacities and/or increasing pleural thickening is suggestive of RAS rather than BOS. Bronchiectasis can be present in later phases of BOS, but also can be due to traction effects in patients with RAS [1]. Thus, bronchiectasis can be present in patients with isolated BOS or RAS or with combined BOS and RAS.
Flexible bronchoscopy — 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 anastomotic site stenosis or endobronchial tumor.
●Bronchoalveolar lavage (BAL) – BAL is typically performed to exclude infection (eg, bacterial, viral, fungal) 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, and samples are sent for cell counts and differential, microbiologic stains and cultures, viral testing (eg, immunoassay or polymerase chain reaction), and cytology (eg, malignancy, Pneumocystis, fungus). (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 with BAL and transbronchial biopsy, BAL neutrophilia was noted in those with biopsies showing higher grade lymphocytic bronchiolitis, suggestive of BO [72]. However, a neutrophilic BAL fluid (eg, 25 to 50 percent neutrophils) is common in the first three months following transplantation [72]. 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.
●Transbronchial biopsy – In general, our practice is to perform transbronchial biopsy when a diagnosis of CLAD is suspected on the basis of symptoms, a decline in FEV1 (eg, 10 percent or greater) on spirometry, and/or chest imaging. The biopsy is used to identify evidence of RAS or acute cellular rejection and exclude other causes of dyspnea and airflow limitation (eg, airway stenosis or bronchomalacia, infection, or recurrence of an original lung disease such as sarcoid), but is not useful for the diagnosis of BO due to sampling issues and a variable yield [1,34,73-75]. 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 "Chronic lung allograft dysfunction: Restrictive allograft syndrome" and "Evaluation and treatment of acute lung transplant rejection", section on 'Flexible bronchoscopy'.)
Histopathology — While biopsy is not necessary to make a diagnosis of BOS, lung biopsy may be obtained for other reasons. The predominant histopathologic manifestation of CLAD-BO in the airways is fibrotic obliteration of bronchi (also called obliterative bronchiolitis or OB) [1,76]. The pathologic findings associated with BO are assessed in the C grade (C0: BO absent or C1: BO present) of the biopsy grading report described in the table (table 3) [76].
The early lesions of BO are submucosal lymphocytic inflammation and disruption of the epithelium of small airways (picture 1) [1,63,77]. These are followed by an in-growth 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) [78].
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 [14].
In contrast, the characteristic histopathology of RAS includes parenchymal and pleural changes, with alveolar damage and fibrosis of the alveolar interstitium and interlobular septa and visceral pleural fibroelastosis with or without obliterative bronchiolitis lesions [3,5,79]. (See "Chronic lung allograft dysfunction: Restrictive allograft syndrome", section on 'Pathology'.)
DIAGNOSIS — The diagnosis of CLAD due to BOS is based on a ≥20 percent decline in forced expiratory volume in one second (FEV1) that is persistent for three months after the first value is obtained, a normal or increased total lung capacity, and absence of new pulmonary opacities [1]. The decrease in FEV1 should be without other explanation (eg, acute cellular/antibody-mediated rejection, infection, airway stenosis, or tracheomalacia).
At the time of the first abnormal value, CLAD is considered “probable”; after three months without improvement, CLAD is considered “confirmed” [1]. If the FEV1 returns to the baseline value after therapy, the diagnosis of CLAD is not sustained.
For the majority of lung transplant recipients, the underlying presence of BO is assumed, but usually is not confirmed by biopsy. (See 'Definitions' above and 'Histopathology' above.)
CLAD staging — CLAD staging is based on the degree of decline in FEV1 and applies to both BOS and RAS [1]:
●CLAD 0: Current FEV1 >80 percent of FEV1 baseline
●CLAD 1: Current FEV1 >65 to 80 percent of FEV1 baseline
●CLAD 2: Current FEV1 >50 to 65 percent of FEV1 baseline
●CLAD 3: Current FEV1 >35 to 50 percent of FEV1 baseline
●CLAD 4: Current FEV1 ≤35 percent of FEV1 baseline
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BOS/BO includes airway complications of lung transplantation, progression or recurrence of the underlying lung disease, other types of allograft rejection, and infection. These can usually be distinguished by the evaluation described above. (See 'Evaluation for BO and BOS' above and "Noninfectious complications following lung transplantation" and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Viral infections following lung transplantation".)
●Airway complications – Lung transplant recipients are at risk of airway complications, such as bronchial stenosis, granulation tissue, and tracheobronchomalacia, at the site of the bronchial anastomoses. Generally, the diagnosis is made via airway inspection during flexible bronchoscopy. (See "Airway complications after lung transplantation".)
●Progression or recurrence of the underlying lung disease – Several lung diseases that can lead to lung transplantation have been reported to progress in the native lung in single lung transplant recipients (eg, chronic obstructive pulmonary disease [COPD]) and others may recur in the allograft (eg, diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, sarcoidosis). (See "Noninfectious complications following lung transplantation", section on 'Recurrent primary disease'.)
●Acute cellular rejection – Acute cellular rejection may be associated with a decrease in the forced expiratory volume in one second (FEV1), similar to BOS. However, the likelihood of acute cellular rejection decreases beyond the first 6 to 12 months, while the likelihood of BOS increases over time. The pathologic appearance is also different; acute airway-centered cellular rejection is associated with a lymphocytic bronchiolitis on biopsy rather than the dense fibrous scarring of BO. (See "Evaluation and treatment of acute lung transplant rejection", section on 'Evaluation of symptomatic patients'.)
●Restrictive allograft syndrome (RAS) – RAS develops over approximately the same time frame as BOS and is characterized by restrictive physiology and peripheral lung fibrosis [3,4,80-82]. The typical chest high resolution computed tomography (HRCT) shows increased reticular opacities, predominantly in the upper lung zones, and traction bronchiectasis [5,83]. Pathologic examination shows fibrosis in the alveolar septa, visceral pleura, and scattered obliterative bronchiolitis lesions [5]. 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 [80]. (See "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)
●Other restrictive processes – For patients with a decreased FEV1, but normal FEV1/forced vital capacity (FVC), the differential diagnosis focuses on diseases that cause a restrictive ventilatory defect, such as an increase in body mass index, muscular weakness (eg, diaphragmatic paralysis), pleural effusion, aging, or infection [1,80]. 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".)
TREATMENT — A variety of therapies have been tried for BO/BOS, but there are no clinical trials or well-established protocols to guide therapy. 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 (immune globulin, rituximab, proteasome inhibitors), and inhaled cyclosporine (table 4) [84-91]. 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 — In the absence of clinical trial data to guide therapy for patients with new onset BOS, we typically add azithromycin (if not already in place), review the maintenance immunosuppressive regimen for possible adjustment, and ensure that serum levels of the various immunosuppressive agents are appropriate (table 5). Response to therapy is assessed with ongoing measurement of spirometry.
Azithromycin — 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 oral azithromycin (generally 250 mg daily for five days, followed by 250 mg three times weekly) [63,92]. 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 [61,93-101]. While awaiting further data to guide decision-making, we generally continue azithromycin long-term, even in patients who do not have improvement in lung function. BOS tends to be progressive so it is difficult to determine whether azithromycin is slowing progression in an individual patient. An alternative would be to discontinue azithromycin if BOS continues to progress after a minimum three month trial period.
●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 [102].
●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 [97]. The majority of responders were identified by three months of treatment.
●Among 62 patients with potential BOS or stage 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 [103]. Those with potential BOS were more likely to respond to azithromycin than those with more advanced disease.
The macrolide clarithromycin would theoretically be an alternative to azithromycin [104]; however, due to drug-drug interactions, azithromycin is generally preferred.
Adjusting maintenance immunosuppression — 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 [63,105], 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 [106,107]. 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 [108]. A second study of 13 patients reported similar results when mycophenolate mofetil was substituted for azathioprine [109]. Other studies have reported similar results following substitutions in the immunosuppressive regimen [110-112]. (See "Maintenance immunosuppression following lung transplantation", section on 'Monitoring and adjusting maintenance therapy'.)
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, slowed decline in FEV1 compared with control in an open-label study [113]. However, a small randomized trial did not support a survival benefit [114].
●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 [115]. The use of everolimus has been reported in case series of lung transplant recipients, although the effect on BOS was inconclusive [116,117].
Development of BOS may be reduced or delayed among lung recipients taking everolimus for maintenance immunosuppression, although data are limited [118,119]. 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'.)
●Extracorporeal psoralen photopheresis (ECP) reduced the rate of decline in lung function in the setting of BOS in single center experiences [85-87,120-122]. 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 [120]. Those who responded to ECP had better survival and a lower rate of retransplantation than nonresponders. Clinical trials are in progress (clinicaltrials.gov NCT03500575 and NCT02181257).
●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 [88,89]. However, in one study, 10 of 37 patients were unable to complete the therapy due to progressive BOS or bone marrow suppression [89].
●Aerosolized cyclosporine demonstrated preliminary evidence of benefit in two single center reports [84,123] Multi-center, multi-national studies of liposomal cyclosporine for early stage CLAD in single and double lung transplant recipients are in progress (NCT03657342 and NCT03656926). A separate case report described improvement in BOS with aerosolized tacrolimus [124].
●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) [125]. 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
●Glucocorticoids – While systemic glucocorticoids are the cornerstone of management of acute lung transplant rejection, they appear to have limited utility in the management of BOS [1]. High-dose inhaled glucocorticoids are included in regimens to treat bronchiolitis obliterans following hematopoietic cell transplantation (see "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'). It is hoped that local delivery of the glucocorticoids will control the lymphocytic bronchiolitis seen on biopsies. However, a randomized trial did not find evidence that inhaled glucocorticoids slowed or prevented BOS, possibly due to insufficient power [126]. (See "Evaluation and treatment of acute lung transplant rejection", section on 'High-dose glucocorticoids'.)
●Alemtuzumab – 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 [127]. In addition, a small retrospective study comparing alemtuzumab with extracorporeal photopheresis demonstrated a comparable improvement in the slope of FEV1 decline with either therapy compared with an untreated population, but no appreciable difference in infections or survival compared with an untreated population [128]. (See "Induction immunosuppression following lung transplantation", section on 'Alemtuzumab'.)
Retransplantation for refractory BOS — The role of retransplantation after the development of chronic lung rejection is controversial. Registry data suggest that the retransplant outcome is not as good as with the first transplant [129]; however, several single center reports have demonstrated comparable outcomes with retransplantation in carefully selected candidates [8,130-132].
●Among 29 patients who underwent retransplantation for CLAD between March 2010 and May 2016, one and five year survival rates were 89 and 64 percent, which compares with survival rates of 89 and 58 percent among 391 primary lung transplants performed at the same institution [130]. However, the rates of cardiopulmonary bypass, re-exploration for bleeding, and post-retransplant extracorporeal membrane oxygenation (ECMO) were higher in retransplant recipients, and the small sample size limits generalizability. Chronic lung rejection was the most common cause of death in both groups.
Similarly, at a different center, for carefully selected retransplants from 2010 to 2016 using a protocol for less invasive surgery, early and mid-term survival was comparable to first time transplants [131].
●In a separate study of 143 patients who underwent retransplantation at one of four large volume centers (2003 to 2013), the five-year survival was 51 percent among those retransplanted for BOS, compared with 28 percent for those retransplanted for restrictive CLAD [8]. BOS recurred in 30 percent of retransplant recipients.
Outcomes of retransplantation are 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. Notably, 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 [133,134]. (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 [135,136]. Some patients experience a rapid, relentless progression, some have stabilization after an initial rapid deterioration, and others experience a subtle onset and slow progression.
The mortality rate associated with BOS ranges from 25 to 55 percent [137,138]. Among stages of CLAD, the risk of death increases approximately three-fold with each step higher [137]. Unfortunately, in many patients, BOS results in progressive respiratory failure, similar to the initial lung disease for which the transplant was originally performed.
FUTURE DIRECTIONS
Surrogate markers — A major area of unmet need in lung transplantation is the identification of surrogate markers for early CLAD. A number of potential markers of early BOS have been suggested, but none is used clinically. These include:
●Neutrophil-predominant bronchoalveolar lavage fluid with increased levels of interleukin (IL)-12 and/or IL-17 [72,139-143]
●Evidence of air trapping on chest computed tomography (CT) scan [144-147]
●Elevated exhaled nitric oxide levels [110,148,149]
●Soluble CD30 levels [150]
●An increase in circulating fibrocytes detected by flow cytometry [151]
●Donor-derived cell free DNA in plasma in the first three months after transplant [152,153]
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 [14].
Investigational therapies
●Belatacept – Belatacept is an immunosuppressant that blocks a T-cell costimulation pathway and is approved by the US Food and Drug Administration for use in kidney transplant recipients. It is has shown preliminary benefit in lung transplant recipients who are intolerant of calcineurin inhibitors due to kidney toxicity [154-156].
●Plasmapheresis – Plasmapheresis has been used to treat humoral lung transplant rejection but has not been formally studied in BOS. (See "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection", section on 'Treatment'.)
●Pirfenidone – Based on the use of pirfenidone as an anti-fibrotic agent for idiopathic and other forms of pulmonary fibrosis, a randomized trial for CLAD is in progress (NCT03473340).
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 and alkaline 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 [93]. The overall survival between the groups was not different. Side effects related to chronic azithromycin therapy included nausea and diarrhea; one case of Clostridioides difficile 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 [93,157].
For patients who have Pseudomonas aeruginosa in their post-lung transplant respiratory secretions, preliminary evidence suggests that successful eradication with targeted antibiotic treatment may improve CLAD-free survival [158].
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".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)
SUMMARY AND RECOMMENDATIONS
●Chronic lung allograft dysfunction (CLAD) is defined as a substantial and persistent decline (≥20 percent) in forced expiratory volume in one second (FEV1) when compared with the post-transplant baseline. CLAD typically develops more than three months after transplant and can predominantly affect the airways (bronchiolitis obliterans/bronchiolitis obliterans syndrome [BO/BOS]) or the lung parenchyma (restrictive allograft syndrome [RAS]). (See 'Definitions' above.)
●BO/BOS, which is more common than RAS, is characterized by airflow limitation in the absence of other etiologies, while BO is identified histologically by the presence of BO (picture 1 and picture 2). (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. Other potentially contributory factors include recurrent and severe episodes of acute lung transplant rejection, cytomegalovirus and other viral infections, primary graft dysfunction, gastroesophageal reflux, and possibly autoimmunity. (See 'Etiology and risk factors' above.)
●The clinical presentation of BOS/BO is nonspecific with dyspnea on exertion and nonproductive cough, often similar to an upper respiratory tract infection. Or, patients may simply present with subtle increases in exertional dyspnea and/or a decline in spirometry. Early on, the physical examination is typically normal, but in more advanced stages, the chest examination usually reveals end-inspiratory pops and squeaks. (See 'Clinical presentation' above.)
●In early BO/BOS, the chest radiograph and high resolution computed tomography (HRCT) scan, if obtained, are clear, but in advanced disease can demonstrate bronchiectasis and hyperinflation. (See 'Clinical presentation' above and 'Pulmonary function testing' above and 'Imaging' above.)
●The usual approach to a lung transplant recipient presenting with dyspnea, nonproductive cough, and/or declining spirometry includes laboratory assessment of maintenance immunosuppression and infection, chest imaging, and flexible bronchoscopy. (See 'Evaluation for BO and BOS' above.)
●The diagnosis of CLAD-BOS can be made conditionally on the basis of increasing airflow limitation on spirometry and exclusion of alternate explanations; histopathologic confirmation is generally not needed. The severity of BOS is determined based on the degree of airflow limitation. (See 'Diagnosis' above and 'CLAD staging' above.)
●The differential diagnosis of BOS includes airway complications of lung transplantation (eg, bronchial stenosis, tracheobronchomalacia), infection, CLAD due to RAS, and progression or recurrence of the underlying lung disease (eg, COPD, diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangiomyomatosis). (See 'Differential diagnosis' above.)
●Clinical trial data are not available to guide therapy for BOS. Observational data indicate that high-dose glucocorticoids are not likely to be of benefit and have substantial adverse effects. (See 'Treatment' above.)
●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 5). (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). We ensure that serum levels of the various immunosuppressive agents are appropriate (table 5). (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 4). 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 for refractory BOS' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge John Reilly, Jr, MD, who contributed to an earlier version of this topic review.
