Bronchiolitis Obliterans Syndrome in Lung Transplantation: 8 (Respiratory Medicine)

Bronchiolitis Obliterans Syndrome: The Achilles’ Heel of Lung Transplantation

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Although a type 2 immune profile has favored the acquisition of tolerance in some animal models, there is increasing evidence implicating a role for type 2 responses in rejection, especially chronic rejection. Interestingly, recent studies suggest that allograft dysfunction can be associated with immunity against self-antigens e. Interestingly, some but not all studies demonstrate that Tregs are a biomarker of clinical outcomes. Conversely, an analysis on peripheral blood FoxP-3 mRNA expression by qPCR polymerase chain reaction demonstrated that low expression was associated with more chronic renal allograft rejection.

Chemokines and their interaction with specific cell receptors are essential components of inflammatory and immune responses via recruitment of specific leukocyte subpopulations. The immune response to allogeneic tissues is mediated by major histocompatibility complex MHC molecules. These molecules play a critical role in the immune system via the presentation of peptides in a form that can be recognized by T cells. Classically, BOS is considered to be the end-stage consequence of alloimmune-mediated injury to the lung allograft. Observations that support this assertion include the following: Not surprisingly, numerous studies have also implicated acute cellular rejection ACR as the most important risk factor for BOS.

A-grade ACR describes the presence and extent of perivascular inflammatory cell infiltrates.

With increasing severity, these infiltrates extend into the interstitium and alveolar spaces Fig. A-grades range from A0 no rejection to A4 severe rejection. However, B-grade ACR, also known as lympho-cytic bronchiolitis LB , describes the presence and extent of peri-airway lymphocyte infiltration.

Antibody-mediated rejection AMR is a recognized clinical entity in renal and heart transplantation and may be a major cause of late graft loss, especially in renal transplantation. The ability of B cells to recognize alloantigen is not controversial. B cells recognize antigen via their B-cell receptor, internalize and process the antigen to peptide epitopes, and then present it in the context of self-MHC to T cells i.

T cells then stimulate B-cell differentiation and antibody class switching. Stimulated B cells become either plasmablasts i. Activated B cells, with the help of other mononuclear cells, further proliferate, hypermutate, and undergo affinity maturation resulting in their becoming either plasma cells PCs or memory B cells. PCs secrete high-affinity antibodies, whereas memory B cells undergo secondary stimulation, proliferation, and differentiation into PCs when reexposed to alloantigen or other stimuli e. Therefore, the presence of anti-HLA antibodies is undoubtedly a marker of indirect allorecognition.

However, the controversy lies in whether or not a specific pathology in the lung allograft is directly attributable to donor-specific alloantibodies DSA. The strongest evidence for the concept of AMR is hyperacute rejection, clinically manifested as primary graft failure occurring very early after transplantation in the setting of preformed antibodies to donor HLA antigens or endothelial cells. Several early studies demonstrated that an increasing pretransplant panel reactive antibody PRA test is associated with increasing mortality, especially in the first 30 days posttransplant HR 2.

Other studies have investigated the impact of incident humoral responses after LT. Infiltration of B cells in the human lung allograft during ACR was associated with refractoriness to augmented immunosuppression, 91 and several other studies have also correlated the development of anti-HLA antibodies with steroid-refractory ACR.

According to the National Conference to Assess AMR in Solid Organ Transplantation, any degree of humoral reaction greater than a latent humoral response requires the demonstration of C4d deposition in the allograft. But there may be problems extending this proposed criterion to LT because positive C4d staining in a lung allograft may lack the specificity seen in other solid-organ allografts.

For instance, in a cohort of 33 lung transplant recipients, C3d positive in 20 and C4d positive in 11 staining was associated with primary graft dysfunction PGD and airway infection, but not with ACR or chronic rejection, or with presumed morphological features of AMR necrotizing septal capillary injury or the presence of intra-capillary macrophages. In this study, C4d staining was more common in the group with DSA, but it did not reliably separate the two groups.

Possibly, the combination of DSA with a characteristic histopathology and the appropriate clinical scenario will improve our ability to detect AMR in the lung allograft. More work is required to define AMR histopathology in the lung, but capillary inflammation and injury are likely to be key. In the recent study by Yousem and Zeevi, 99 capillaritis was the only histopathologic feature that separated groups with and without anti-HLA antibodies, although it was seen in only a minority of cases.

Along these lines, we have also shown that capillary inflammation, defined as capillary neutrophilic infiltration with at least two back-to-back intracapillary neutrophils Fig. This response is due to a combination of cellular and antibody-mediated injuries and has been described in cardiac transplantation e. Moreover, oral tolerance to col V in a non—fully mismatched rat transplant model was protective of lung allograft rejection.

Both allo- and autoimmunity occur together and may have the potential to drive one another in the immunopathogenesis of BOS. A growing body of literature supports an association between BOS and ostensibly nonalloimmune responses to local injury and foreign antigens unrelated to donor-specific MHC. This supports the hypothesis that innate immunity appears to be an important cofactor linking alloimmune-independent mechanisms of lung injury to accelerated alloimmune responses and BOS. Primary graft dysfunction PGD is a form of acute lung injury that arises within the first 72 hours of transplantation, resulting from multiple pathological mechanisms inherent to the process of transplantation, including physiological changes in the donor following brain death, ex-plantation, cold ischemia, and reperfusion within the recipient.

Multiple infectious processes have been linked to the development of BOS. The best evidence for this is in patients who develop cytomegalovirus CMV pneumonitis. Our group recently found that CXCR3 chemokines are upregulated during CARV infection, and elevated expression of these chemokines among infected patients is associated with chronic allograft dysfunction, suggesting a potential mechanistic link between nonalloimmune responses to these acute infections and the subsequent development of alloreactivity. Low-grade chronic infections may also be important risk factors for BOS. In two retrospective studies, pseudomonal colonization was associated with increased risk and higher stage of BOS, — and levels of antipseudomonal antibodies in BAL among colonized transplant recipients have been associated with local innate immune responses.

Treatment options for BOS generally remain disappointing. Historically, uncontrolled studies have cited treatment responses with diverse strategies, but interpretation is often clouded by small sample sizes and lack of suitable controls. Uncontrolled studies have cited slower rates of FEV 1 decline after conversion to mycophenolate mofetil MMF from azathioprine AZA , , or to tacrolimus from cyclosporine. Antilymphocyte and antithymocyte preparations deplete T cells and can have prolonged effects on T-cell function through nondepletive mechanisms e.

No controlled data exist for alemtuzumab or other cytolytics for the treatment of BOS at this time. Gerhardt et al first reported the results of a small pilot study using add-on azithromycin mg three times a week for BOS in This sparked intense interest in azithromycin as an immune-modulating agent with relatively few side effects. Most, but not all, subsequent studies have also suggested that a subset of patients with BOS do respond to treatment with azithromycin.

Recently, the results of a small, single-center, randomized trial of azithromycin for the treatment of BOS were published in abstract form. At the press time for this review, the final peer-reviewed publication is not yet available. However, as the drug is relatively inexpensive, has few side effects, and there is little else to offer, a trial of therapy seems indicated for any patient who develops BOS.

This forms covalent bonds to DNA pyrimidine bases, cell-surface molecules, and cytoplasmic components in exposed cells. ECP is a safe and effective treatment of cutaneous T-cell lymphoma.

However, studies suggest that ECP results in leukocyte apoptosis and induction of regulatory T cells. There are no controlled studies of ECP in lung transplant recipients. Several observational studies have shown that the rate of decline in FEV 1 is reduced after initiation of ECP for the majority of patients, whereas a minority experience improved lung function.

However, appropriately controlled studies examining this question are welcomed. Retransplantation has been performed for lung transplant recipients with BOS, with lower survival rates than with initial transplants. By the time BOS is diagnosed, it may be too late for treatments to reverse the airways pathology for the majority of patients. Therefore, strategies aimed at the prevention of BOS are most likely to favorably impact long-term morbidity and mortality outcomes after LT. In this same report, any induction therapy was associated with a significantly better overall survival.

Furthermore, the large sample size in this comparison permits statistical significance for a small difference that may not be clinically meaningful. There is a limited clinical trial experience examining the effectiveness of different induction therapies. The most important message may be that prospective, multicenter studies are needed to determine if and which induction therapy is beneficial in LT.

Studies have demonstrated that 2-hour postdrug concentrations C 2 are a more accurate measure of drug exposure than C 0 levels. Sirolimus rapamycin and related compounds e. In a multicenter, randomized, double-blind trial, lung transplant recipients who were free of BOS received maintenance immunosuppression consisting of cyclosporine and corticosteroids together with either everolimus or AZA. However, by 24 months, freedom from BOS was similar between groups. Interestingly, the incidence of treated ACR was significantly reduced at both 12 and 24 months in the everolimus cohort.

Although everolimus is a promising therapy, a potential serious concern raised in this study was the increased rate of adverse reactions in the everolimus-treated patients, including bacterial infections, fungal infections, and elevated serum creatinine. Given the relationship between the severity and recurrence of ACR with the development of BOS, a surveillance protocol aimed at the early diagnosis and treatment of ACR has been advocated by some as a strategy for the prevention of BOS. TBBx is the principal diagnostic modality for the assessment of ACR in the lung allograft, but the sensitivity of this procedure is dependent upon the number of samples taken.

Irrespective of these concerns, studies have demonstrated that surveillance bronchoscopy protocols can detect asymptomatic acute rejection. In one study of 1, TBBx in lung transplant recipients, Therefore, the utility of surveillance TBBx beyond 4 to 6 months is a matter of debate. Still others advocate for no routine surveillance after LT. In this study, there were no differences in freedom from BOS or survival between groups receiving either clinically indicated or surveillance bronchoscopy, but the small size of the study was vastly underpowered to answer this question conclusively.

There remains no consensus on the best practice, but most programs report some version of a surveillance bronchoscopy protocol after LT. Full or mixed-chimerism has long been recognized for the potential to facilitate allograft tolerance. Patients who have undergone myeloablative conditioning and human lymphocyte antigen HLA -matched bone marrow transplantation for a hematologic-oncology disorder, who later receive a renal transplant from the same donor, have not required immuno-suppression, confirming that chimerism can lead to tolerance. Unfortunately, even if effective, the sporadic and unpredictable timing of cadaveric donors for LT make the implementation of pretransplant conditioning logistically impossible at this time.

Furthermore, the risks of infections with conditioning regimens required to induce chimerism may outweigh the benefits for LT. Lung transplant recipients are uniquely susceptible to posttransplant infections for a variety of reasons, including chronic pretransplant immunosuppression, pretransplant colonization, PGD, prolonged mechanical ventilation, and disrupted cough reflex. Protocols for the simple infusion of donor bone marrow BM , without conditioning, simultaneous or prior to transplant, would be preferable in LT.

In a human study, 26 lung transplant recipients receiving infusion of donor BM without conditioning in combination with LT were compared with 13 patients receiving LT alone. Patient survival and freedom from ACR were similar between groups. This technique has promise, but additional studies are required to determine the efficacy, safety, and role of this procedure in humans.

BOS is the dominant factor as to why long-term outcomes after LT remain disappointing. Although alloimmune pathways have a clear role in the pathogenesis of chronic rejection, nonspecific causes of airway injury also appear to promote the development of BOS. Although nonspecific immunosuppression seems to allow lung allograft accommodation for some, most lung transplant recipients eventually experience late allograft dysfunction in the form of BOS. Unfortunately, there is currently no proven therapy for the prevention or treatment of BOS. National Center for Biotechnology Information , U.

Semin Respir Crit Care Med. Author manuscript; available in PMC Feb Belperio , MD 1.

Author information Copyright and License information Disclaimer. Address for correspondence S. See other articles in PMC that cite the published article. Abstract Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Open in a separate window. Mechanisms of BOS Pathogenesis The pathogenesis of BOS is complex and is driven by both alloimmune and nonalloimmune mechanisms that may act alone or in combination. Alloimmune Reactivity The immune response to allogeneic tissues is mediated by major histocompatibility complex MHC molecules.

Humoral Immunity Antibody-mediated rejection AMR is a recognized clinical entity in renal and heart transplantation and may be a major cause of late graft loss, especially in renal transplantation. Innate Immunity A growing body of literature supports an association between BOS and ostensibly nonalloimmune responses to local injury and foreign antigens unrelated to donor-specific MHC. Changes in Maintenance Immunosuppression Uncontrolled studies have cited slower rates of FEV 1 decline after conversion to mycophenolate mofetil MMF from azathioprine AZA , , or to tacrolimus from cyclosporine.

Cytolytic Therapy Antilymphocyte and antithymocyte preparations deplete T cells and can have prolonged effects on T-cell function through nondepletive mechanisms e. Azithromycin Gerhardt et al first reported the results of a small pilot study using add-on azithromycin mg three times a week for BOS in Retransplantation Retransplantation has been performed for lung transplant recipients with BOS, with lower survival rates than with initial transplants.

Strategies for the Prevention of BOS By the time BOS is diagnosed, it may be too late for treatments to reverse the airways pathology for the majority of patients. Sirolimus and Everolimus Sirolimus rapamycin and related compounds e. Surveillance Bronchoscopy with Transbronchial Biopsy Given the relationship between the severity and recurrence of ACR with the development of BOS, a surveillance protocol aimed at the early diagnosis and treatment of ACR has been advocated by some as a strategy for the prevention of BOS. Hematopoietic Cell Transplant Full or mixed-chimerism has long been recognized for the potential to facilitate allograft tolerance.

Diagnosis of BOS

J Heart Lung Transplant. Knoop C, Estenne M. Acute and chronic rejection after lung transplantation. The effect of bronchiolitis obliterans syndrome on health related quality of life. Bronchiolitis obliterans syndrome and additional costs of lung transplantation. Bronchiolitis obliterans syndrome The predictive value of bronchiolitis obliterans syndrome stage 0-p. Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients. Revision of the working formulation for the standardization of nomenclature in the diagnosis of lung rejection.

Revision of the working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft. Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Acute and chroniconsetof bronchiolitis obliterans syndrome BOS: Course of FEV 1 after onset of bronchiolitis obliterans syndrome in lung transplant recipients.

Introduction

Verleden G, Dupont L. Lung and Heart—Transplantation Lung Obliterative bronchiolitis. Lung Biology in Health and Disease.

Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Epithelial to mesenchymal transition EMT and airway remodelling after human lung transplantation. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Interleukin 6 and interferon-gamma gene expression in lung transplant recipients with refractory acute cellular rejection: Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation.

Bronchoalveolar lavage cytokine profile in a cohort of lung transplant recipients: Expression of gamma-IFN mRNA in bronchoalveolar lavage fluid correlates with early acute allograft rejection in lung transplant recipients. Enhanced T cell cytokine gene expression in mouse airway obliterative bronchiolitis. Leukocyte-suppressing influences of interleukin IL in cardiac allografts: IL is pivotal in the fibroobliterative process of bronchiolitis obliterans syndrome.

Obligatory role for interleu-kin in obstructivelesion development in airway allografts. Th1 and Th2 cytokines in organ transplantation: The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr Opin Organ Transplant. Control of heterotypic fibril formation by collagen V is determined by chain stoichiometry.

Lung transplant ischemia reperfusion injury: Evidence for immune responses to a self-antigen in lung transplantation: Antibodies toMHC class I induce autoimmunity: ILdependent cellular immunity to collagen type V predisposes to obliter-ative bronchiolitis in human lung transplants. Local IL production and a decrease in peripheral blood regulatory T cells in an animal model of bronchiolitis obliterans.

Neutralizing IL prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Ismonitoring of FOXP3 Treg cells in renal transplants during acute cellular rejection episodes useful? Clinical significance of regulatory T-cell-related gene expression in peripheral blood after renal transplantation. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants.

Increased chime-rism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury. Obliterative bronchiolitis after lung transplantation: Role of platelet-derived growth factor in obliterative bronchiolitis chronic rejection in the rat. Role of platelet-derived growth factor and vascular endothelial growth factor in obliterative airway disease. Prediction of lung-transplant rejection by hepatocyte growth factor. Insulinlike growth factor-1 in lung transplants with obliterative bronchiolitis. Transforming growth factor beta TGF-beta and obliterative bronchiolitis following pulmonary transplantation.

Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration. Airway colonization and gastric aspiration after lung transplantation: Munich Lung Transplant Group Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients.

Multiple pathways to allograft rejection. Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. The definitive treatment for BOS and resulting bronchiectasis is retransplantation. However, lung retransplantation remains very controversial due to limited organ availability and lower survival rates as compared to initial transplants. In , Novick et al [ 86 ] reviewed the records of 72 patients who underwent retransplantation for BOS at 26 North American and European centers.

Further study in larger cohorts of retransplant recipients in and retransplant recipients in demonstrated very similar survival statistics [ 87 , 88 ]. Although survival rates for lung retransplantation were lower than survival rates for initial transplants, lung retransplantation continued to be performed in recipients who developed BOS. More recently, survival rates after lung retransplantation have improved [ 89 - 94 ]. These authors did not assess the outcomes of patients undergoing retransplantation specifically for BOS, but there was definite improvement in outcomes for all patients after lung retransplantation in the modern era.

For lung transplant recipients, BOS remains to be the primary cause of mortality after the first year. In the current lung allocation score era of lung transplantation, recipients have significantly fewer BOS-free days after 3-year follow-up [ 95 ]. Further research is needed to better define the pathophysiologic mechanisms in BOS in order to either prevent or delay onset of the disorder. The therapies available for BOS currently are very limited and serve only to slow the decline in pulmonary function.

Lung retransplantation continues to be controversial, but survival rates have improved in patients with BOS over the past decade and thus should be considered as a treatment option in this patient population. A list of abbreviations used in this manuscript in alphabetical order are: The author of this manuscript completed the literature review and developed the manuscript without assistance.

There were no contributors in the preparation and development of this manuscript. No funding was required to complete this work. National Center for Biotechnology Information , U. Journal List J Cardiothorac Surg v. Published online Jul Don Hayes, Jr 1. Author information Article notes Copyright and License information Disclaimer. Received Feb 24; Accepted Jul This article has been cited by other articles in PMC.

Abstract Lung transplantation is an important treatment option for patients with advanced lung disease. Introduction Lung transplantation is a treatment option for patients with advanced lung disease or irreversible pulmonary failure. Table 1 Bronchiolitis obliterans syndrome BOS classification. Open in a separate window. Diagnosis The diagnosis of BOS is typically made by clinical, physiological, and radiographic parameters. Table 2 Risks factors for bronchiolitis obliterans syndrome after lung transplantation.

Acute rejection Acute rejection is well defined as a primary risk factor in the development of BOS [ 9 , 20 - 25 ]. Type of transplant The type of transplant, whether single or bilateral, may be a risk factor for the development of BOS. Viral infection Lower respiratory tract infections due to community acquired respiratory viruses have been reported to increase the risk for BOS, including rhinovirus, coronavirus, respiratory syncytial virus, influenza A, parainfluenza, human metapneumovirus, and human herpes virus-6 [ 32 - 35 ].

Primary graft dysfunction Ischemia-reperfusion injury after lung transplantation or primary graft dysfunction was associated with the later development of BOS [ 41 - 43 ]. Gastroesophageal reflux Gastroesophageal GE reflux is very common post-lung transplant and may contribute to chronic allograft rejection. Human leukocyte antigen mismatches The effect of human leukocyte antigen HLA mismatches upon the development of BOS has been reported but remains controversial. Autoimmunity An emerging concept regarding BOS is the possibility of autoimmunity rather than alloimmunity to hidden epitopes of collagen type V.

Therapies for BOS Immunosuppressant therapy A small number of studies have assessed the different therapeutic modalities that are reportedly beneficial in these patients. Novel or emerging therapies The use of other immunosuppressant therapies in novel ways may improve outcomes for BOS. Azithromycin therapy Azithromycin displays immunomodulatory effects that seem to be beneficial in several pulmonary disorders, including BOS.

Statin therapy Statins 3-Hydroxymethylglutaryl coenzyme A reductase inhibitors are widely used lipid lowering agents that have demonstrated immunomodulatory effects. Extracorporeal photopheresis There is evidence that extracorporeal photopheresis is an effective method of treatment of any inflammatory disorder that is T-cell dependent, including BOS. Management Strategies in BOS An important therapeutic strategy in treating BOS is initial prevention and aggressive treatment of known associated factors, as well as early identification of BOS in order to immediately begin available therapies.

Table 3 Lung retransplantation for bronchiolitis obliterans syndrome. Conclusions For lung transplant recipients, BOS remains to be the primary cause of mortality after the first year. List of Abbreviations A list of abbreviations used in this manuscript in alphabetical order are: Competing interests The author declares that they have no competing interests. Authors' contributions The author of this manuscript completed the literature review and developed the manuscript without assistance. Prospective analysis of 1, transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant.

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Is it bronchiolitis obliterans syndrome or is it chronic rejection: Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. Interstitial and airspace granulation tissue reactions in lung transplant recipients. Am J Surg Pathol.

A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. Acute and chronic onset of bronchiolitis obliterans syndrome BOS: Acute and chronic rejection after lung transplantation. Semin Respir Crit Care Med. Course of FEV 1 after onset of bronchiolitis obliterans syndrome in lung transplant recipients. Bronchiolitis obliterans following lung transplantation: Bronchiolitis obliterans syndrome in heart-lung transplant recipients: Bronchiolitis obliterans after lung transplantation: Risk factors for the development of obliterative bronchiolitis after lung transplantation.

Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg.

A review of bronchiolitis obliterans syndrome and therapeutic strategies

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Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome. Treated cytomegalovirus pneumonia is not associated with bronchiolitis obliterans syndrome. Detection of Epstein-Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation.

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Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction.

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