Chronic Lung Transplant Rejection

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Chronic lung transplant rejection: Bronchiolitis obliterans

Author: Joseph Pilewski, MD
Section Editor: Elbert P Trulock, MD
Deputy Editor: Helen Hollingsworth, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2020. | This topic last updated: Nov 12, 2018.
INTRODUCTION
Chronic allograft rejection remains a major cause 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 causes 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 "Overview
of bronchiolar disorders 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 anamnestic
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. (See "Evaluation
and treatment of antibody-mediated lung transplant rejection".)
● Chronic lung allograft dysfunction (CLAD) – In recent years, transplant physicians have recognized two
predominant phenotypes of chronic lung rejection:
• Bronchiolitis obliterans syndrome – Bronchiolitis obliterans syndrome (BOS) is the predominant feature of
chronic lung transplant rejection and is manifest clinically as obstructive lung disease detected as a decline
in forced expiratory volume in one second (FEV1), and pathologically as dense fibrous scar tissue affecting
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the small airways (bronchiolitis obliterans). While BOS 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.
• 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 BOS, RAS is
characterized by upper lobe-predominant fibrotic changes and restrictive pulmonary function tests [6].
Evidence indicates that it is useful to consider this as a subtype of allograft dysfunction [1], particularly
because it has prognostic implications [7-9] and patients with RAS and lower lobe or diffuse opacities on
computed tomography or peripheral blood eosinophilia have a particularly poor survival [10].
PATHOLOGY
The predominant 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
[11-13]. The International Society for Heart and Lung Transplantation (ISHLT) has adopted a grading system for the
pathologic findings in pulmonary allograft rejection (table 1) [13].
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) [14].
Other histopathologic findings in BO may include bronchiectasis, organizing pneumonia, and various degrees of
acute cellular rejection [15]. In contrast, the pathology in restrictive allograft syndrome (RAS) includes parenchymal
and pleural changes, with alveolar damage and fibrosis of the alveolar interstitium and interlobular septa and
visceral pleural fibrosis with or without obliterative bronchiolitis lesions [6,16].
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) [2].
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 [17-22]. 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) [17,20,21,23,24]. Medication noncompliance
is listed as risk factor, perhaps due to erratic immunosuppressive drug levels [25] and an associated increase in

acute 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 [26]. 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 [27].
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 [28-30]. The development of anti-HLA class I
antibodies may precede the development of BO, and de novo anti-HLA antibodies correlates with the loss of
pulmonary function [31-33]. 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 [18,34-37].
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 [38]. (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 [12,17,23,39]. 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
[40,41]. Even a single episode of mild rejection has been associated with an increased risk of BOS [42].
Development of donor-specific HLA antibodies after transplantation has also been associated with an
increased risk and greater severity of BOS [32,43]. (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 [34,36,44]. 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 [45]. 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 of 139 lung transplant recipients that prospectively monitored
community-acquired respiratory viral (CARV) infections, the risk of chronic lung allograft dysfunction was
increased among those with CARV pneumonia (HR 3.94, 95% CI 1.97-7.90) [46]. However, this association has
not been confirmed in other studies [47]. (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 [48-50].
● Bacterial and fungal infection and colonization – Isolation of pathogens such as Aspergillus fumigatus [51]
and Pseudomonas aeruginosa [52-54] 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 [24,55,56]. 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 [57-60]. (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 [61-66]. (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 [61]. 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 [61,65]. In addition, a retrospective cohort study suggests that
impedance analysis provides useful predictive value in addition to pH testing [67].
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 [66]. (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 [68].
● 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 [19]. 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 [69].
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 at least 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
appropriate for 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 "Viral infections following lung transplantation" and "Bacterial infections
following lung transplantation" and "Evaluation and treatment of antibody-mediated lung transplant rejection".)
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 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 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 [20]. 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 [20,70-72]. 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 [73], although earlier studies suggested otherwise [74]. (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.
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 [75,76]. 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 with BAL and transbronchial biopsy, BAL neutrophilia was noted in those with biopsies showing
higher grade lymphocytic bronchiolitis, suggestive of BO [77]. However, a neutrophilic BAL fluid (eg, 25 to 50
percent neutrophils) is common in the first three months following transplantation [77]. 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 [78].
● Another study found that transbronchial biopsies confirmed the diagnosis in 82 percent of their patients who
developed clinical BOS [23].
● 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) [79]. 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 [70].
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
[77,80-84]
● Evidence of air trapping on chest CT scan [85-88] (see 'Imaging' above)
● Elevated exhaled nitric oxide levels [89-91]
● Soluble CD30 levels [92]
● An increase in circulating fibrocytes detected by flow cytometry [93]
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 [20].
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 "Viral
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 [20].
(See 'Definitions' above and 'Role of transbronchial biopsy' above and 'Pathology' above.)
Bronchiolitis obliterans syndrome — The International Society for Heart and Lung Transplantation nomenclature
[20,94] 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) [20]. (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 "Viral 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 [1,95-97]. The typical chest high resolution computed
tomography (HRCT) shows increased reticular opacities, predominantly in the upper lung zones, and traction
bronchiectasis [6,98]. 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 [95].
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 [20,95].
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 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 [99]. 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 (immune globulin, rituximab, proteasome inhibitors), and
inhaled cyclosporine (table 6) [100-107]. 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 oral azithromycin (generally 250 mg daily for five days,
followed by 250 mg three times weekly) [66]. 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
[64,99,108-115]. 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 [116].
● 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 [111]. 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 [117]. 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 [66,118],
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 [119,120]. 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 [121]. A second study of 13
patients reported similar results when mycophenolate mofetil was substituted for azathioprine [122]. Other studies
have reported similar results following substitutions in the immunosuppressive regimen [91,123,124]. (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 [125]. 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
[126]. The use of everolimus has been reported in case series of lung transplant recipients, although the effect
on BOS was inconclusive [127,128].
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 [101-103,129-131]. 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 [129]. 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 [104,105]. However, in one study, 10 of 37 patients
were unable to complete the therapy due to progressive BOS or bone marrow suppression [105].
● A single center report demonstrated the possible benefit from aerosolized cyclosporine in this setting [100]. A
separate case report described improvement in BOS with aerosolized tacrolimus [132].
● 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) [133]. 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 [66]. One
randomized study suggested that high-dose inhaled glucocorticoids are not effective in slowing or preventing the
development of BOS [134]. (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 [135]. 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 [136]. (See "Induction immunosuppression following lung transplantation".)
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
https://www.uptodate.com/contents/chronic-lung-transplant-rejection-bronchiolitis-obliterans/print?search=graft versus host desease&topicRef=3548&source… 10/36

treatment of antibody-mediated lung transplant rejection", section on 'Treatment'.)
Retransplantation — 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 [137];
however, several single center reports have demonstrated comparable outcomes with retransplantation in carefully
selected candidates.
● Among 29 patients who underwent retransplantation for chronic lung allograft dysfunction (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
[138]. However, the rates of cardiopulmonary bypass, re-exploration for bleeding, and post-retransplant 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 [139].
● 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 [9]. 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 [140,141]. (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 [142,143]. 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 [23,79,144]. Among grades of BOS (table 5),
the risk of death increases approximately three-fold with each step higher in grade [144]. 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 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 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 BOS is graded as outlined in the table (table 5). Some patients will have restrictive physiology, defined as
restrictive allograft syndrome (RAS). (See 'Diagnosis' above.)
● The differential diagnosis of BOS includes airway complications of lung transplantation (eg, bronchial stenosis,
tracheobronchomalacia), infection, and progression or recurrence of the underlying lung disease (eg, COPD,
diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangiomyomatosis). (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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94. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for
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95. Sato M, Hwang DM, Waddell TK, et al. Progression pattern of restrictive allograft syndrome after lung
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96. Verleden SE, Ruttens D, Vandermeulen E, et al. Bronchiolitis obliterans syndrome and restrictive allograft
syndrome: do risk factors differ? Transplantation 2013; 95:1167.
97. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft
dysfunction in lung transplantation. J Heart Lung Transplant 2005; 24:1260.
98. Verleden SE, de Jong PA, Ruttens D, et al. Functional and computed tomographic evolution and survival of
restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant 2014; 33:270.
99. Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic
rejection after lung transplantation. Eur Respir J 2011; 37:164.
100. Iacono AT, Corcoran TE, Griffith BP, et al. Aerosol cyclosporin therapy in lung transplant recipients with
bronchiolitis obliterans. Eur Respir J 2004; 23:384.

101. O'Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis
obliterans complicating lung transplantation. Chest 1999; 115:1459.
102. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome
103. Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation: a 10-year
single-center experience. Transplantation 2008; 86:1625.
104. Verleden GM, Lievens Y, Dupont LJ, et al. Efficacy of total lymphoid irradiation in azithromycin nonresponsive
chronic allograft rejection after lung transplantation. Transplant Proc 2009; 41:1816.
105. Fisher AJ, Rutherford RM, Bozzino J, et al. The safety and efficacy of total lymphoid irradiation in progressive
bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant 2005; 5:537.
106. Corcoran TE, Smaldone GC, Dauber JH, et al. Preservation of post-transplant lung function with aerosol
cyclosporin. Eur Respir J 2004; 23:378.
107. Benden C, Haughton M, Leonard S, Huber LC. Therapy options for chronic lung allograft dysfunction-
bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: A systematic review. J
108. Yates B, Murphy DM, Forrest IA, et al. Azithromycin reverses airflow obstruction in established bronchiolitis
109. Gerhardt SG, McDyer JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans
syndrome: results of a pilot study. Am J Respir Crit Care Med 2003; 168:121.
110. Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung
transplantation. Transplantation 2004; 77:1465.
111. Gottlieb J, Szangolies J, Koehnlein T, et al. Long-term azithromycin for bronchiolitis obliterans syndrome after
lung transplantation. Transplantation 2008; 85:36.
112. Jain R, Hachem RR, Morrell MR, et al. Azithromycin is associated with increased survival in lung transplant
recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010; 29:531.
113. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of
azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;
94:101.
114. Shitrit D, Bendayan D, Gidon S, et al. Long-term azithromycin use for treatment of bronchiolitis obliterans
syndrome in lung transplant recipients. J Heart Lung Transplant 2005; 24:1440.
115. Corris PA, Ryan VA, Small T, et al. A randomised controlled trial of azithromycin therapy in bronchiolitis
obliterans syndrome (BOS) post lung transplantation. Thorax 2015; 70:442.
116. Vos R, Vanaudenaerde BM, Ottevaere A, et al. Long-term azithromycin therapy for bronchiolitis obliterans
syndrome: divide and conquer? J Heart Lung Transplant 2010; 29:1358.
117. Federica M, Nadia S, Monica M, et al. Clinical and immunological evaluation of 12-month azithromycin therapy
in chronic lung allograft rejection. Clin Transplant 2011; 25:E381.
118. Kesten S, Chaparro C, Scavuzzo M, Gutierrez C. Tacrolimus as rescue therapy for bronchiolitis obliterans
syndrome. J Heart Lung Transplant 1997; 16:905.

119. Belperio JA, Weigt SS, Fishbein MC, Lynch JP 3rd. Chronic lung allograft rejection: mechanisms and therapy.
Proc Am Thorac Soc 2009; 6:108.
120. Hayes D Jr. A review of bronchiolitis obliterans syndrome and therapeutic strategies. J Cardiothorac Surg 2011;
6:92.
121. Cairn J, Yek T, Banner NR, et al. Time-related changes in pulmonary function after conversion to tacrolimus in
bronchiolitis obliterans syndrome. J Heart Lung Transplant 2003; 22:50.
122. Whyte RI, Rossi SJ, Mulligan MS, et al. Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung
transplantation. Ann Thorac Surg 1997; 64:945.
123. Revell MP, Lewis ME, Llewellyn-Jones CG, et al. Conservation of small-airway function by
tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung
transplantation. J Heart Lung Transplant 2000; 19:1219.
124. Roman A, Bravo C, Monforte V, et al. Preliminary results of rescue therapy with tacrolimus and mycophenolate
mofetil in lung transplanted patients with bronchiolitis obliterans. Transplant Proc 2002; 34:146.
125. Verleden GM, Verleden SE, Vos R, et al. Montelukast for bronchiolitis obliterans syndrome after lung
transplantation: a pilot study. Transpl Int 2011; 24:651.
126. Hachem RR, Yusen RD, Chakinala MM, et al. A randomized controlled trial of tacrolimus versus cyclosporine
127. Roman A, Ussetti P, Zurbano F, et al. A retrospective 12-month study of conversion to everolimus in lung
transplant recipients. Transplant Proc 2011; 43:2693.
128. Parada MT, Alba A, Sepúlveda C. Everolimus in lung transplantation in Chile. Transplant Proc 2010; 42:328.
129. Jaksch P, Scheed A, Keplinger M, et al. A prospective interventional study on the use of extracorporeal
photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung
Transplant 2012; 31:950.
130. Baskaran G, Tiriveedhi V, Ramachandran S, et al. Efficacy of extracorporeal photopheresis in clearance of

antibodies to donor-specific and lung-specific antigens in lung transplant recipients. J Heart Lung Transplant
2014; 33:950.
131. Del Fante C, Scudeller L, Oggionni T, et al. Long-Term Off-Line Extracorporeal Photochemotherapy in Patients
with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre
Analysis. Respiration 2015; 90:118.
132. Hayes D Jr, Zwischenberger JB, Mansour HM. Aerosolized tacrolimus: a case report in a lung transplant
recipient. Transplant Proc 2010; 42:3876.
133. Date H, Lynch JP, Sundaresan S, et al. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J
134. Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression
after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002; 73:1793.
135. Reams BD, Musselwhite LW, Zaas DW, et al. Alemtuzumab in the treatment of refractory acute rejection and
bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant 2007; 7:2802.
136. Moniodis A, Townsend K, Rabin A, et al. Comparison of extracorporeal photopheresis and alemtuzumab for
the treatment of chronic lung allograft dysfunction. J Heart Lung Transplant 2018; 37:340.
137. Benden C, Goldfarb SB, Edwards LB, et al. The registry of the International Society for Heart and Lung
Transplantation: seventeenth official pediatric lung and heart-lung transplantation report--2014; focus theme:
retransplantation. J Heart Lung Transplant 2014; 33:1025.
138. Biswas Roy S, Panchanathan R, Walia R, et al. Lung Retransplantation for Chronic Rejection: A Single-Center
Experience. Ann Thorac Surg 2018; 105:221.
139. Sommer W, Ius F, Kühn C, et al. Technique and Outcomes of Less Invasive Lung Retransplantation.
Transplantation 2018; 102:530.
140. Brugière O, Thabut G, Castier Y, et al. Lung retransplantation for bronchiolitis obliterans syndrome: long-term
follow-up in a series of 15 recipients. Chest 2003; 123:1832.
141. Kawut SM, Lederer DJ, Keshavjee S, et al. Outcomes after lung retransplantation in the modern era. Am J
Respir Crit Care Med 2008; 177:114.
142. Levine SM, Bryan CL. Bronchiolitis obliterans in lung transplant recipients. The "thorn in the side" of lung
transplantation. Chest 1995; 107:894.
143. Finlen Copeland CA, Snyder LD, Zaas DW, et al. Survival after bronchiolitis obliterans syndrome among
bilateral lung transplant recipients. Am J Respir Crit Care Med 2010; 182:784.
144. Burton CM, Carlsen J, Mortensen J, et al. Long-term survival after lung transplantation depends on
development and severity of bronchiolitis obliterans syndrome. J Heart Lung Transplant 2007; 26:681.
Topic 4654 Version 27.0

GRAPHICS
Improved survival after lung transplantation
Survival following lung transplantation was calculated using the Kaplan-Meier method, which incorporates information from all
transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to
follow-up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients.
The median survival is the estimated time point at which 50% of all of the recipients have died.
The conditional median survival is the estimated time point at which 50% of the recipients who survive to at least one year have
died. Because the decline in survival is greatest during the first year following transplantation, the conditional survival provides a
more realistic expectation of survival time for recipients who survive the early post-transplant period.
Survival rates were compared using the log-rank test statistic. Adjustments for multiple comparisons were done using Scheffe's
method.
Reproduced with permission from: Adult Lung Transplantation Statistics: Kaplan-Meier Survival by Era. International Society for Heart and Lung
Transplantation. JHLT 2019 Oct; 38(10):1015-1066. Copyright © 2019 ISHLT. All rights reserved. For additional and updated information, please see
the International Society for Heart and Lung Transplantation slide sets at: https://ishltregistries.org/registries/slides.asp.
Graphic 64657 Version 7.0

Classification and grading of pulmonary allograft rejection
A: Acute rejection*: characterized by perivascular and interstitial mononuclear cell infiltrates
Grade 0: none
Grade 1: minimal
Grade 2: mild
Grade 3: moderate
Grade 4: severe
B: Airway inflammation (lymphocytic bronchiolitis)*: characterized by mononuclear cell infiltrates in the submucosa of bronchioles
Grade 0: none
Grade 1R ¶: low grade
Grade 2R ¶: high grade
Grade X: ungradeable
C: Chronic airway rejection (bronchiolitis obliterans): manifest by fibrous scarring that is often dense and eosinophilic
0: absent
1: present
D: Chronic vascular rejection - accelerated graft vascular sclerosis: characterized by fibrointimal thickening of the pulmonary arteries and veins.
These lesions are not seen on TBB as they affect larger blood vessels than those accessed with TBB.
TBB: transbronchial biopsy.

* Acute vascular rejection (A1 to A4) and acute airway inflammation (B1 to B2R) can be seen independently or may both be present.
¶ "R" denotes revised grade to avoid confusion with 1996 scheme.
Reproduced from: Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J
Heart Lung Transplant 2007; 26:1229. Table used with the permission of Elsevier Inc. All rights reserved.

Bronchiolitis obliterans
Bronchiolitis obliterans in chronic lung transplant rejection. Photomicrograph of early

lesion of chronic lung transplant rejection, demonstrating inflammation and disruption
of the epithelium of small airways.
Courtesy of L Kobzik, MD.

Bronchiolitis obliterans
Bronchiolitis obliterans in chronic lung transplant rejection. Photomicrograph of

chronic lung transplant rejection showing granulation tissue within the lumen of a
small airway.

Chronic lung transplant rejection
Peribronchiolar fibrosis in chronic lung transplant rejection. Photomicrograph

demonstrating fibrosis around the lumen of a small airway.

Freedom from bronchiolitis obliterans syndrome in adult lung recipients
Adult lung transplant recipient freedom from bronchiolitis obliterans syndrome (BOS), conditional on survival to 14 days (transplant follow-up
assessments: January 1995-June 2017).
Reproduced with permission from: Adult Lung Transplantation Statistics: Freedom from Bronchiolitis Obliterans Syndrome. International Society for Heart and Lung
Transplantation. JHLT 2019; 38(10):1015-1066. Copyright © 2019 ISHLT. All rights reserved.

Risk factors for bronchiolitis obliterans syndrome
Probable
Acute rejection
Lymphocytic bronchitis/bronchiolitis
CMV pneumonitis
Medication noncompliance
Primary graft dysfunction
Potential
CMV infection (without pneumonitis)
Organizing pneumonia
Recurrent infection other than CMV
Older donor age
Prolonged allograft ischemia
Donor antigen-specific reactivity
Gastroesophageal reflux with aspiration
HLA-mismatching
Underlying cause of lung disease
HLA: human leukocyte antigen; CMV: cytomegalovirus.
Adapted from: Estenne M, Maurer JR, Bohler A, et al. Bronchiolitis obliterans syndrome 2001: An update of the diagnostic criteria. J Heart Lung Transplant 2002; 21:297.

Clinical presentation of chronic allograft dysfunction (CLAD) after lung transplantation
Early Late
Symptoms Nonproductive cough; dyspnea on exertion; fever in RAS (sometimes) Productive cough; dyspnea at rest
Physical examination Clear chest "Pops and squeaks"
Chest radiograph Clear Bronchiectasis, hyperinflation
Pulmonary function tests ≥20% decline in FEV 1 Severe obstruction

BOS: obstructive pattern
RAS: restrictive pattern
Sputum culture Negative Pseudomonas
RAS: restrictive allograft syndrome; FEV 1 : forced expiratory volume in one second; BOS: bronchiolitis obliterans syndrome.

Agents for maintenance of immunosuppression following lung transplantation
Metabolism/transporter
Mechanism Suggested Drug Common major
Drug* effects with selected Comments
of action dose* monitoring adverse effects
drug interactions ¶
Glucocorticoids
Methylprednisolone, Inhibits At time of N/A Cytochrome P450 3A4 Diabetes Do not stop
prednisone humoral and transplant: 500 to substrate GERD, PUD abruptly; may be
cell-mediated 1000 mg Numerous clinically relevant taken with food to
Osteoporosis
immunity methylprednisolone interactions in transplant reduce dyspepsia
intravenously Skeletal muscle
Binds with patients ◊
wasting
DNA Maintenance oral
sequences (+/– prednisone dose: Hypertension
nuclear factor- 0.5 to 1 mg/kg per Hypercholesterolemia
kB) to inhibit day initially after
Change in appetite
production of transplant with
inflammatory taper to a goal of 5 Weight gain
cytokines to 10 mg per day
over several
months to one year
Protocols may vary
by institution
Calcineurin inhibitors
Cyclosporine Δ Prevents T cell 2 to 3 mg/kg per Monitor BUN, Metabolized by cytochrome Renal dysfunction High inter- and intra-
activation and day intravenously Cr, P450 enzyme system including acute individual
proliferation at time of magnesium, Cytochrome P450 3A4 nephrotoxicity absorption
by inhibiting transplantation potassium substrate/inhibitor, p- Hypertension variability
the production given in a 24 hour Trough levels glycoprotein Blood concentration
Hypercholesterolemia
of interleukins infusion or 1 to 1.5 typically used substrate/inhibitor monitoring is
and other mg/kg in two or Gingival hyperplasia
but levels Marked increase in levels of necessary for any
cytokines more four hour drawn two Neurotoxicity (tremor, change in
statin drugs when co-
infusions and until hours post headache, formulation
administered
patient can tolerate dose (C2) are encephalopathy, focal (including switch
oral intake. Adjust Numerous clinically relevant deficits)
most accurate between generics or
dose to target interactions in transplant
Hirsutism brands) to
trough patients ◊
determine need for
concentration of dose alteration. The
250 to 350 ng/mL microemulsion form,
and two hour post which is also known
dose (C2) as "modified"
concentration of (Neoral) is generally
900 to 1200 ng/mL better absorbed
Maintenance oral than the non-
dose: 3 to 5 mg/kg modified form
twice per day 12 (Sandimmune)
hours apart at a
consistent time
each day in relation
to meals and
adjusted according
to trough or C2
concentration as
above
Tacrolimus Δ Prevents T cell Initial dose Monitor Metabolized by cytochrome Renal dysfunction High inter- and intra-
activation and sublingually: 0.04 to glucose, LFTs, P450 enzyme system Diabetes individual
proliferation 0.05 mg/kg per day BUN, Cr, Cytochrome P450 3A4 absorption
Hypertension (less
by inhibiting in two divided calcium, substrate variability
than cyclosporine)
the production doses (eg, 1 to 2 mg magnesium, Blood concentration
Numerous clinically relevant Hypercholesterolemia
of interleukins sublingually every potassium
§ interactions in transplant monitoring is
and other 12 hours) [1,2] ; OR Monitor Altered mental status necessary for
patients ◊
cytokines Initial dose trough levels change in
Headache
intravenously: 0.03 formulation
Focal neurological
to 0.05 mg/kg per (including switch
deficits
day by continuous between generics or
infusion over 24 brands) and
hours; risk of between methods of
infusion reactions administration (eg,
and other toxicities sublingual, oral, and
(refer to IV administration) to
accompanying text) determine need for
Maintenance oral dose alteration
dose: 0.05 mg/kg
twice daily taken 12
hours apart at a

consistent time
to meals.
Initial and
maintenance:
Adjust dose to
target whole blood
concentration of 8
to 15 ng/mL
Antimetabolites
Mycophenolate Nucleotide IV equivalent to oral Monitor WBC Levels decreased by: ¥ Nausea, vomiting, Serum concentration
mofetil (CellCept) blocking agent Starting dose: 250 Dose adjusted Antacids diarrhea, abdominal monitoring is not
Inhibits T cell mg twice daily for leukopenia Aluminum hydroxide pain routinely
proliferation within 72 hours Diarrhea may occur performed ¥
Serum Magnesium (oral)
by blocking after concentration Bile acid sequestrants after months of
nucleotide transplantation monitoring (eg, cholestyramine) treatment
synthesis Gradually increase not routinely GI tolerability may
Cyclosporine (but not
dose by 250 mg performed ¥ tacrolimus) improve with more
twice daily to a goal Magnesium (oral) frequent dosing
dose of 1000 mg Proton pump inhibitors (same total daily
twice daily (with dose) or by changing
Rifamycins (eg, rifampin)
tacrolimus) or 1500 to enteric-coated
Levels increased by: ¥
mg twice daily (with mycophenolate
cyclosporine) Acyclovir sodium (below)
Probenecid
Alternatively, Myelosuppression,
patients may be May inactivate protein bound anemia
initiated at goal drugs, especially hormonal
Increased risk of CMV
dose contraceptives (use
disease
nonhormonal method of
Oral doses should
contraception)
be taken on an
empty stomach or
at a consistent time
to meals if taken
with food to
improve tolerability
Giving total daily
dose in three or
four equally divided
doses might
improve GI
tolerability
Mycophenolate Nucleotide 360 to 720 mg Monitor WBC Levels decreased by: ¥ Nausea, vomiting Serum concentration
sodium, enteric blocking agent orally twice per day Dose adjusted Antacids Diarrhea monitoring is not
coated (Myfortic) Inhibits T cell on an empty for leukopenia Aluminum hydroxide routinely
performed ¥
Myelosuppression,
proliferation stomach
Serum Bile acid sequestrants anemia
by blocking To convert from concentration (eg, cholestyramine)
Increased risk of CMV
nucleotide mycophenolate monitoring Cyclosporine (but not
disease
synthesis mofetil 1000 mg not routinely tacrolimus)
every 12 hours, performed ¥ Magnesium (oral)
switch to
Rifamycins (eg, rifampin)
mycophenolate
Levels increased by: ¥
sodium enteric
coated 720 mg Acyclovir
every 12 hours Probenecid
May inactivate protein bound
drugs, especially hormonal
contraceptives (use
nonhormonal method of
contraception)
Azathioprine Nucleotide IV equivalent to oral Monitor WBC Levels increased by: Nausea, vomiting Requires TPMT
blocking agent Starting dose: 1 to 2 Dose adjusted Allopurinol (Preferably Diarrhea enzyme for
Inhibits T and mg/kg daily and for leukopenia avoid co-administration. metabolism.
Bone marrow
B cell adjusted to prevent If co-administration Individuals with
Monitor LFTs suppression
proliferation development of required, reduce profound initial side
azathioprine by up to 70 Liver abnormality effects may be
by blocking leukopenia
nucleotide percent.) deficient in this
synthesis Use with febuxostat is enzyme
contraindicated
May diminish anticoagulant
effects of warfarin
mTOR inhibitors
Sirolimus Inhibits T cell Sirolimus is Monitor CBC, Metabolized by cytochrome Delayed wound Associated with
proliferation initiated at least LFTs P450 3A enzyme system healing increased incidence

by cell cycle three months post- Obtain trough Cytochrome P450 3A4 Fatal airway of deep venous
arrest in G1 transplantation, level three to substrate, p-glycoprotein anastomotic thrombosis [3]
phase due to effects on four days after substrate dehiscence if
wound healing initiation and Cyclosporine dose should be administered early
Administer seven days decreased by one-half to two- after lung
sirolimus four after any thirds when co-administered transplantation
hours after change in with sirolimus Myelosuppression
cyclosporine, when dose
Numerous clinically relevant Hypercholesterolemia
both medications interactions in transplant Pulmonary toxicity
are being used patients ◊
LFT abnormalities
Liquid and tablet
form Diarrhea
Starting dose: 2 mg Nausea

orally per day.
Adjusted to
maintain a trough
target between 8
and 12 ng/mL when
used without
calcineurin
inhibitor. Adjust to
maintain trough
level between 4 and
8 ng/mL when used
with calcineurin
inhibitor.
Everolimus Inhibits T cell Everolimus is Monitor CBC, Metabolized by cytochrome Delayed wound
proliferation initiated at least LFTs, BUN, Cr, P450 3A enzyme system healing
by cell cycle three months post- glucose Cytochrome P450 3A4 Bone marrow
arrest in G1 transplantation, Monitor substrate, p-glycoprotein suppression
phase due to effects on trough levels; substrate/inhibitor Hypercholesterolemia
wound healing steady state Cyclosporine dose should be Pulmonary toxicity
Starting dose: 1.5 levels are decreased by one-half to two-
mg orally every 12 reached four Diarrhea
thirds when co-administered
hours and adjusted to five days with everolimus Nausea
to maintain a after a dose
Numerous clinically relevant
trough target change
interactions in transplant
between 3 and 12
patients ◊
ng/mL in
combination with
cyclosporine and a
glucocorticoid
In combination with
tacrolimus, higher
doses of everolimus
may be needed to
maintain trough
levels within target
range compared to
doses when used
with cyclosporine
GERD: gastroesophageal reflux disease; PUD: peptic ulcer disease; Cr: creatinine; LFT: liver function tests; BUN: blood urea nitrogen; ECG: electrocardiogram; WBC:
white blood cell count; CMV: cytomegalovirus; MPA: mycophenolic acid (active metabolite of mycophenolate); TPMT: thiopurine methyltransferase; mTOR:
mechanistic target of rapamycin; CBC: complete blood count.
* Initial immunosuppressant doses shown should be adjusted based upon patient-specific factors including organ function and potential drug interactions. Drug
therapy should be managed by transplant specialists with expertise in therapeutic drug monitoring and doses should be adjusted based upon measurement of
immunosuppressant concentrations. The US Food and Drug Administration has not approved any medications specifically for lung transplantation, so the doses are
suggested based on the experience of large lung transplantation centers. Dosing protocols vary by institution.
¶ Immunosuppressants are subject to numerous drug interactions, particularly with drugs or foods that inhibit or induce cytochrome CYP 450 3A4 and/or P-
glycoprotein transporters (P-gp). Drug therapy should be managed by transplant specialists with expertise in therapeutic drug monitoring and doses adjusted based
upon measurement of immunosuppressant concentrations, particularly whenever drug therapy is altered. The table is NOT a complete list of all possible interactions.
To determine specific drug interactions and suggestions for management, the Lexi-Interact program included within UpToDate may be used.
Δ For additional information, refer to UpToDate topic on pharmacology and side effects of cyclosporine and tacrolimus.
◊ For additional information, refer to UpToDate table on major drug interactions with immunosuppressants: cyclosporine, tacrolimus, sirolimus, or everolimus.
§ Sublingual administration of tacrolimus may be an alternative for lung transplant recipients who are unable to swallow capsules [1,2].
¥ Serum levels of mycophenolate active metabolite (MPA) can be altered by some drug interactions. However, adjustment of mycophenolate dose may not be
necessary depending upon the expected effect of the interaction and patient factors (eg, rejection risk); single MPA serum levels are not reliable for determining
mycophenolate exposure or predicting efficacy and are not routinely performed (refer to accompanying text).
References:
1. Tsapepas D, Saal S, Benkert S, et al. Sublingual tacrolimus: a pharmacokinetic evaluation pilot study. Pharmacotherapy 2013; 33:31.
2. Watkins KD, Boettger RF, Hanger KM, et al. Use of sublingual tacrolimus in lung transplant recipients. J Heart Lung Transplant 2012; 31:127.
3. Ahya VN, McShane PJ, Baz MA, et al. Increased risk of venous thromboembolism with a sirolimus based immunosuppression regimen in lung transplantation. J Heart
Lung Transplant 2011; 30:175.
Prepared with data from:
1. Bhorade SM, Stern E. Immunosuppression for lung transplantation. Proc Am Thorac Soc 2009; 6:47.
2. Korom S, Boehler A, Weder W. Immunosuppressive therapy in lung transplantation: state of the art. Eur J Cardiothorac Surg 2009; 35:1045.
3. Floreth T, Bhorade SM. Current trends in immunosuppression for lung transplantation. Semin Respir Crit Care Med 2010; 31:172.


Original and proposed classifications of BOS
Original classification Current proposition
BOS 0 FEV 1 80 percent or more of baseline BOS 0 FEV 1 >90 percent of baseline and
FEF 25-75 >75 percent of baseline
BOS 0-p FEV 1 81 to 90 percent of baseline and/or

FEF 25-75 ≤75 percent of baseline
BOS 1 FEV 1 66 to 80 percent of baseline BOS 1 FEV 1 66 to 80 percent of baseline
BOS 2 FEV 1 51 to 65 percent of baseline BOS 2 FEV 1 51 to 65 percent of baseline
BOS 3 FEV 1 50 percent or less of baseline BOS 3 FEV 1 50 percent or less of baseline
After lung transplantation, "baseline values" for FEV 1 and FEF 25-75 are ascertained by taking the average of the two highest values obtained at least three
weeks apart and without preceding bronchodilator inhalation. The baseline values may be adjusted upward if lung function improves in the months after
transplantation.
BOS: bronchiolitis obliterans syndrome; FEF 25-75 : mid-expiratory flow rate; FEV 1 : forced expiratory volume in one second.
Reproduced with permission from: Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant
2002; 21:297. Copyright © 2006 The International Society for Heart and Lung Transplantation.

Evaluation of possible chronic lung transplant rejection
BAL: bronchoalveolar lavage.

Potential therapies for bronchiolitis obliterans following lung transplantation
First line therapy

Azithromycin
Substitution of tacrolimus for cyclosporine
Substitution of mycophenolate for azathioprine
Second line therapy

Substitution of sirolimus for azathioprine
Everolimus
Montelukast
Therapy for refractory BOS

Photopheresis
Total lymphoid irradiation
Plasmapheresis
Cytolytic therapy: ATG
Retransplantation
The anti-CD3 antibody (OKT3) is no longer available.
BOS: bronchiolitis obliterans syndrome; ATG: antithymocyte globulin.

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Chronic lung transplant rejection: Bronchiolitis obliterans

Transplanted lungs are susceptible to several different types of rejection.

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ETIOLOGY AND RISK FACTORS

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● Autoimmunity and pre-transplant alloimmunity – An emerging theory concerning the pathobiology of

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EVALUATION FOR BO AND BOS

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● Evidence of air trapping on chest CT scan [85-88] (see 'Imaging' above)

● Elevated exhaled nitric oxide levels [89-91]

● Soluble CD30 levels [92]

● An increase in circulating fibrocytes detected by flow cytometry [93]

Bronchiolitis obliterans — The diagnosis of BO in a lung transplant recipient requires histopathologic

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immunosuppressive medications, extracorporeal photopheresis, total lymphoid irradiation, plasmapheresis and

Response to therapy is assessed with ongoing measurement of spirometry.

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

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treatment of antibody-mediated lung transplant rejection", section on 'Treatment'.)

Retransplantation — The role of retransplantation after the development of chronic lung rejection is

SUMMARY AND RECOMMENDATIONS

Clinical manifestations and diagnosis

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Prevention and treatment

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3. Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 2003; 22:1007.

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130. Baskaran G, Tiriveedhi V, Ramachandran S, et al. Efficacy of extracorporeal photopheresis in clearance of

Topic 4654 Version 27.0

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Improved survival after lung transplantation

Graphic 64657 Version 7.0

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Classification and grading of pulmonary allograft rejection

A: Acute rejection*: characterized by perivascular and interstitial mononuclear cell infiltrates

Grade 1R ¶: low grade

Grade 2R ¶: high grade

TBB: transbronchial biopsy.

Graphic 61800 Version 5.0

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Bronchiolitis obliterans in chronic lung transplant rejection. Photomicrograph of early

Courtesy of L Kobzik, MD.

Graphic 67871 Version 1.0

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Bronchiolitis obliterans in chronic lung transplant rejection. Photomicrograph of

Courtesy of L Kobzik, MD.

Graphic 76542 Version 1.0

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Peribronchiolar fibrosis in chronic lung transplant rejection. Photomicrograph

Courtesy of L Kobzik, MD.

Graphic 51639 Version 1.0

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