Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long-term management of lung recipients.
Acute cellular rejection (T-Lymphocyte rejection)
Acute cellular rejection (ACR) is the predominant type of rejection in lung transplant that affects the vasculature and small airways, thus potentially resulting in acute graft dysfunction and failure over time. The key distinction between acute and chronic rejection is the presence of irreversible airway fibrosis. ACR is an important risk factor for the development of bronchiolitis obliterans syndrome (BOS), and its severity, particularly the pathologic evidence of lymphocytic bronchiolitis, is associated with the greatest risk of BOS .
The lung is more susceptible to rejection than other transplanted organs because of its higher susceptibility to injury and infection and constant exposure to the environment, which result in innate immune activation, directly contributing to higher rates of rejection. In a recently published report by the Registry of the International Society for Heart and Lung Transplantation (ISHLT), 28% of adult lung transplant surviving recipients have at least one episode of treated acute rejection between discharge and 1-year follow-up .
The alloimmune response in ACR is primarily driven by T-cell recognition of foreign major histocompatibility complexes, which is also referred to as human leukocyte antigens (HLAs) . The activation of the innate immune system starts the cascade of ACR resulting in a proinflammatory effect, which shapes the adaptive immune response. Innate immune activation against donor antigens, which are recognized by recipient lymphocytes as nonself, through infection or injury, as well as autoimmune response at the time of transplant, results in the process of allorecognition and is the driving force for ACR in lung transplantation.
Lung recipients with ACR can present as asymptomatic or with a wide range of clinical manifestations including dyspnea, fever, leukocytosis, cough, phlegm, and hypoxemia. The nonspecific presentation of ACR makes the diagnosis challenging, which can potentially result in delayed treatment.
In 2007, the ISHLT Pathology Council Working Group revised the lung transplant pathology nomenclature for the diagnosis of lung rejection. Detailed ISHLT ACR grading schema is summarized in Table 1 . Briefly, ACR is based on perivascular and interstitial mononuclear infiltrates. The presence of coexisting airway inflammation should be mentioned on the pathology report, along with the amount of perivascular and interstitial infiltrates. Chronic rejection is divided into airway and vascular rejections, which are defined as the presence of bronchiolitis obliterans or vascular atherosclerosis, respectively .
| Category of rejection | ISHLT grade | Severity | Histologic appearance |
|---|---|---|---|
| Grade A: Acute rejection | A0 | None | Normal pulmonary parenchyma without evidence of mononuclear cell infiltration, hemorrhage, or necrosis |
| A1 | Minimal | Scattered and infrequent perivascular mononuclear infiltrates, venules cuffed by small and round plasmacytoid cells, and transformed lymphocytes forming rings of 2–3 cell thickness within perivascular adventitia | |
| A2 | Mild | More frequent perivascular mononuclear infiltrates seen, endothelialitis. Perivascular interstitium can be expanded by mononuclear cells, but no infiltration into adjacent alveolar septa or airspaces | |
| A3 | Moderate | Cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates extending into perivascular and peribronchial alveolar septa and airspace. Eosinophils and neutrophils are common. Can involve endothelialitis. | |
| A4 | Severe | Diffuse perivascular, interstitial, and airspace infiltrates of mononuclear cells with prominent alveolar pneumocyte damage and endothelialitis. | |
| Grade B: Lymphocytic bronchiolitis (small airways) | B0 | None | No evidence of bronchiolar inflammation |
| B1R b | Low grade | Mononuclear cells in bronchiolar submucosa; no evidence of epithelial damage or intraepithelial lymphocytic infiltration | |
| B2R | High grade | Greater number of eosinophils and plasmacytoid cells. Evidence of epithelial damage (necrosis and metaplasia), marked intraepithelial lymphocytic infiltration | |
| BX | Upgradeable | No small airways identified on tissue biopsy or overt evidence of infection |
a Based on the 2007 Revision of the 1996 ISHLT Working Formulation for the Standardization of Nomenclature in the Diagnosis of Lung Rejection.
b This grade combines and replaces previous B1 and B2 grades.
Clinical indications for performing transbronchial biopsies (TBBx) include new infiltrates, decline in lung function, new cough, and unexplained dyspnea. TBBx can help distinguish between ACR and alternative clinical explanations including viral infections and organizing pneumonia, bacterial/fungal bronchopneumonia, and chronic lung allograft dysfunction (CLAD), which can present similarly .
There is considerable inter-observer variability in the diagnosis and interpretation of pathologic specimens for ACR, particularly in lower grade rejection . The ISHLT recommends obtaining five “adequate” samples of alveolated parenchyma; however, this is not always possible because of the technical limitations of TBBx and many centers attempt to obtain 6–12 samples to achieve 5 “good specimens” . Although the sensitivity of TBBx to ACR has been reported to range between 50% and 90% , it is difficult to definitely rule out ACR when the clinical suspicion is high even with adequate samples of alveolated parenchyma . Because of inconsistent biopsy readings and technical limitations of TBBx, patients are likely unnecessarily exposed to excessive immunosuppression and morbidity due to opportunistic infections, or in cases where biopsies are under-read, potential development of high-grade rejection increases the risk of development of CLAD.
Surveillance bronchoscopies are often performed on lung recipients at specific time points; however, the time and usage tend to differ from center to center. “Silent” or asymptomatic rejection has been reported as frequently as 30% in the first year after lung transplantation . Unfortunately, TBBx are not without risk (pneumothorax, bleeding, respiratory failure, and pneumonia), and therefore, it is unclear whether usage of surveillance bronchoscopy and treatment of early asymptomatic rejection can help to improve long-term outcomes after lung transplantation . The approach to surveillance bronchoscopy after lung transplantation remains controversial in the field, and protocols vary among centers.
Management of ACR
There are also variations in the management of ACR between transplant centers and debate on whether to treat grade A1 minimal rejection. Grade A1 rejection has been shown to progress, and along with lymphocytic bronchiolitis, it is also an important risk factor for the development of BOS ; however, it remains unclear whether treatment alters this risk. Gordon and colleagues’ survey of 41 lung transplant pulmonologists from 41 different transplant centers in the United States found that 35% would treat asymptomatic grade A1 rejection and 80% would treat symptomatic grade A1 rejection. Additionally, 12% would not consider lymphocytic bronchiolitis as rejection and would not treat .
Treatment of ACR consists of augmentation of immunotherapy and pulse steroids and is considered the first-line therapy. As there are no data to clearly guide the dosage of steroids and specify the duration of treatment, treatment protocols vary among different centers. Intravenous (IV) methylprednisolone 10–15 mg/kg daily for 3–5 days is recommended for the initial treatment of minimal (grade A1) or mild (grade A2) rejection. In cases of moderate (grade A3) or severe (grade A4) rejection or steroid-resistant/steroid-refractory ACR, IV antithymocyte globulin 1.5 mg/kg is administered daily for 3–5 days .
Antibody-mediated rejection (humoral rejection)
Hyperacute rejection is a form of rejection that occurs rapidly after transplantation and is caused by preformed anti-HLA antibodies, and it is associated with an extremely high mortality. Fortunately, given the advances in HLA screening, the incidence of hyperacute rejection after lung transplantation is now extremely rare. The other form of humoral rejection, antibody-mediated rejection (AMR), is associated with four specific factors: (1) donor-specific anti-HLA antibodies (DSAs), (2) evidence of complement deposition on TBBx, (3) histologic tissue injury, and (4) clinical evidence of lung dysfunction . The presence of all four is uncommon, thus making the diagnosis of AMR challenging.
There is increased recognition of DSAs after lung transplantation because of advancements in detection methods. DSAs may have been present at low levels prior to transplantation or may have developed “de-novo” after transplantation . Increased survival and the decreased incidence of BOS have been associated with the clearance of DSAs , suggesting the role of the presence of DSAs in the development of a chronic inflammatory state that leads to CLAD. Lung recipients may have pre-existing HLA antibodies from prior transfusion, pregnancy, or organ transplantation or can develop de novo HLA antibodies after lung transplantation .
Development of AMR is well recognized in heart and renal transplantation; however, in lung transplantation, it remains challenging because there is no general consensus, which leads to a universally accepted diagnosis criteria.
Although pathologic evidence from C4d immunohistochemistry, by either immunofluorescence or immunoperoxidase assays, demonstrates that complement activation is both classic and generally pathognomonic for AMR in heart and renal transplantation, that in lung transplantation is different . C4d staining is rarely seen on routine TBBx, while C4d immunostaining can be seen with infection and primary graft dysfunction (PGD), and both processes can also activate the complement cascade . In 2016, the ISHLT released a consensus report on AMR diagnosis recommending that AMR diagnosis be characterized as clinical or subclinical. Furthermore, clinical AMR can be subcategorized as definite, probable, or possible, depending on the presence or absence of lung histology, C4d staining on biopsy, DSAs, allograft dysfunction, and alternative explanations . Unfortunately, despite advances in diagnosis of circulating DSAs, the diagnosis of AMR remains difficult and confusing, and therefore, more evidence is needed.
Management of AMR
The treatment of AMR is focused on depleting circulating antibodies and suppressing B cells, thus mitigating further antibody-mediated injury to lung allografts. There are only limited published data on the management of AMR, and there have been no randomized controlled trials or head-to-head comparisons in the use of different treatment regimens.
Plasmapheresis is usually reserved for AMR with significant allograft dysfunction, allowing the removal of antibodies from circulation, potentially resulting in clinical improvement in lung recipients. It is important to understand that plasmapheresis, while having the ability to remove circulating antibodies, does not suppress the formation of new antibodies and may result in rebound antibody production, thus requiring suppressive agents. Other treatments include IV immunoglobulin 1–2 g/kg for 3–6 days, IV rituximab 375 mg/m 2 weekly × 4 doses or 1000 mg every 2 weeks × 2 doses, and IV bortezomib 1–1.3 mg/m 2 every 72 h × 4 doses.
Antibody-mediated rejection (humoral rejection)
Hyperacute rejection is a form of rejection that occurs rapidly after transplantation and is caused by preformed anti-HLA antibodies, and it is associated with an extremely high mortality. Fortunately, given the advances in HLA screening, the incidence of hyperacute rejection after lung transplantation is now extremely rare. The other form of humoral rejection, antibody-mediated rejection (AMR), is associated with four specific factors: (1) donor-specific anti-HLA antibodies (DSAs), (2) evidence of complement deposition on TBBx, (3) histologic tissue injury, and (4) clinical evidence of lung dysfunction . The presence of all four is uncommon, thus making the diagnosis of AMR challenging.
There is increased recognition of DSAs after lung transplantation because of advancements in detection methods. DSAs may have been present at low levels prior to transplantation or may have developed “de-novo” after transplantation . Increased survival and the decreased incidence of BOS have been associated with the clearance of DSAs , suggesting the role of the presence of DSAs in the development of a chronic inflammatory state that leads to CLAD. Lung recipients may have pre-existing HLA antibodies from prior transfusion, pregnancy, or organ transplantation or can develop de novo HLA antibodies after lung transplantation .
Development of AMR is well recognized in heart and renal transplantation; however, in lung transplantation, it remains challenging because there is no general consensus, which leads to a universally accepted diagnosis criteria.
Although pathologic evidence from C4d immunohistochemistry, by either immunofluorescence or immunoperoxidase assays, demonstrates that complement activation is both classic and generally pathognomonic for AMR in heart and renal transplantation, that in lung transplantation is different . C4d staining is rarely seen on routine TBBx, while C4d immunostaining can be seen with infection and primary graft dysfunction (PGD), and both processes can also activate the complement cascade . In 2016, the ISHLT released a consensus report on AMR diagnosis recommending that AMR diagnosis be characterized as clinical or subclinical. Furthermore, clinical AMR can be subcategorized as definite, probable, or possible, depending on the presence or absence of lung histology, C4d staining on biopsy, DSAs, allograft dysfunction, and alternative explanations . Unfortunately, despite advances in diagnosis of circulating DSAs, the diagnosis of AMR remains difficult and confusing, and therefore, more evidence is needed.
Management of AMR
The treatment of AMR is focused on depleting circulating antibodies and suppressing B cells, thus mitigating further antibody-mediated injury to lung allografts. There are only limited published data on the management of AMR, and there have been no randomized controlled trials or head-to-head comparisons in the use of different treatment regimens.
Plasmapheresis is usually reserved for AMR with significant allograft dysfunction, allowing the removal of antibodies from circulation, potentially resulting in clinical improvement in lung recipients. It is important to understand that plasmapheresis, while having the ability to remove circulating antibodies, does not suppress the formation of new antibodies and may result in rebound antibody production, thus requiring suppressive agents. Other treatments include IV immunoglobulin 1–2 g/kg for 3–6 days, IV rituximab 375 mg/m 2 weekly × 4 doses or 1000 mg every 2 weeks × 2 doses, and IV bortezomib 1–1.3 mg/m 2 every 72 h × 4 doses.
Chronic rejection
Lung transplantation remains the only viable treatment option for patients with end-stage lung disease; however, long-term survival of these patients remains limited because of chronic lung allograft dysfunction, with BOS as the leading cause of late mortality and morbidity. Bronchiolitis obliterans is a small airway disease, mofetil triggered by an insult to small airway epithelial and subepithelial cells with the subsequent formation of excessive fibrosis and airway constriction. Ultimately, injury to the respiratory epithelium and subepithelium causes dysregulation in the ability of the epithelium to repair itself , which leads to an irreversible decline in lung function, as a result of airway obstruction and air trapping. Approximately 50% of lung recipients will experience BOS within 5 years following transplantation, with a median survival after diagnosis between 3 and 5 years .
Pathogenesis of BOS remains poorly understood, and several divergent inflammatory mechanisms have been hypothesized in an attempt to explain its occurrence in lung recipients. Mechanisms implicated or suggested to play a role in BOS include airway injury due to PGD, infection, airway ischemia, and gastroesophageal reflux, which in turn increase the likelihood of tissue damage and inflammation resulting in initiating and intensifying the alloimmune recipient response [ Table 2 ].
| Nonalloimmune |
| Primary graft dysfunction |
| Gastroesophageal reflux and microaspiration |
| Infection |
| Viral (Cytomegalovirus) |
| Bacterial ( Pseudomonas aeruginosa ) |
| Fungal ( Aspergillus ) |
| Alloimmune |
| Grade A Rejection (Acute vascular) |
| Grade B Rejection (Lymphocytic bronchiolitis) |
| Antibody-mediated rejection (Humoral rejection) |
| Autoimmunity (collagen V sensitization) |
| Other |
| Single vs. double lung transplant |
| Immunosuppression medication noncompliance |
Cytomegalovirus (CMV) engages innate and adaptive components of immunity, causing the upregulation of HLA class I and class II antigens and stimulating and augmenting allogenic immune responses and proinflammatory cytokines . Other published studies have demonstrated that transient bacterial airway colonization results in increases in bronchoalveolar lavage (BAL) neutrophils , Pseudomonas aeruginosa colonization , and fungal pneumonia and Aspergillus colonization as significant risk factors for the development of BOS . The diagnosis of BOS is defined by a persistent decrease in forced expiratory volume in 1 s (FEV 1 ) compared with the mean of the two best postoperative values in the absence of any other identifiable cause [ Table 3 ] . It should be noted that not all lung recipients with a decline in FEV 1 and/or airflow obstruction have BOS. Patients may have evidence of occult BOS and not display any significant decline in FEV 1 , which indicates that a decline in FEV 1 may occur for other reasons, potentially leading to variability and delay in the diagnosis of BOS.
| BOS Grade | Baseline spirometry |
|---|---|
| 0 | FEV 1 > 90% and FEF 25–75% >75% |
| 0-p | FEV 1 81–90% and FEF 25–75% ≤75% |
| 1 | FEV 1 66–80% |
| 2 | FEV 1 51–65% |
| 3 | FEV 1 ≤ 50% |
Unlike ACR, the diagnostic yield of BOS by TBBx is extremely low. Multiple studies have focused on various modalities of diagnostic testing for BOS in the attempts to identify surrogate markers by use of BAL. Past studies have indicated that evidence of neutrophilia in the BAL predicts progression toward BOS, while other studies have implicated that proinflammatory cytokines, such as interleukin-8 (IL-8), act as a driver of neutrophil chemotaxis. Myeloperoxidase and glutathione, the markers of oxidative stress, have also been implicated in the development of BOS . Such studies with small sample sizes and variations in collection methodologies and clinical follow-up have made reported results difficult to generalize.
The development of BOS is a multifaceted process of inflammation and fibrotic transition. Precipitating factors such as injury-related environmental factors and ischemia-reperfusion injury likely contribute to the formation of BOS; however, despite the evidence of ample physiological links, further studies are needed to identify key biomarkers from BAL, to enhance our ability to identify and characterize patients at risk for BOS. We hope that they will lead to targeted therapy for the prevention of CLAD.
Management of chronic rejection
There has been no universally accepted treatment protocol adopted for BOS, and there is considerable variability among transplant centers. Given that BOS is a complex process that involves both alloimmune and nonalloimmune mechanisms, altering and increasing immunosuppressive therapy is a potential option ; however, it is not without increased risk, because of the potential for increased infection and risk of malignancies.
A sustained use of high-dose steroids is not recommended and has not been shown to improve BOS. Lung recipients, who develop BOS while receiving cyclosporine, should be switched over to tacrolimus by discontinuing cyclosporine and transiently increasing maintenance corticosteroid dosage until tacrolimus blood levels have reached the target range of 5–15 ng/ml .
About 35–40% of lung recipients with BOS respond to azithromycin with an increase in FEV 1 ≥ 10% . A few studies have reported that early treatment of BOS with azithromycin is associated with a reduction in mortality . Azithromycin is generally administered orally at 250 mg daily for 5 days, followed by 250 mg three times per week for a minimum of 3 months .
Extracorporeal photopheresis (ECP) is a newer potential treatment where isolated white blood cells are exposed to photoactivatable 8-methoxypsoralen and ultraviolet radiation. ECP is considered to induce lymphocyte apoptosis and the production of regulatory T cells . It has been used in heart transplantation and, more recently, it has been shown to reduce the rate of decline in lung function in lung transplant recipients with BOS; however, its efficacy remains unclear as these studies were single-center observational studies .
Gastroesophageal reflux is prevalent in lung transplant recipients and has been commonly identified as a risk factor for BOS . Antireflux surgery with fundoplication can be performed safely in lung transplant recipients to reduce reflux, and multiple studies have shown improved FEV 1 following antireflux surgery and even improved survival . The decision to pursue antireflux surgery must be weighed carefully against the risk of perioperative complication and mortality . The ISHLT currently recommends considering fundoplication in patients with a steady decline in FEV 1 , consistent with BOS and confirmed gastroesophageal reflux disease .
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