Transplantation-Related Lung Pathology

Complications of Lung Transplantation

Lung transplantation, whether single, bilateral, or, less often, heart–lung, has been an accepted mode of therapy for a variety of end-stage lung diseases for about 25 years. The most common indications for transplantation in adults are emphysema, cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, and primary pulmonary hypertension (PPH), whereas for children most common indications are CF and PPH. Advances in donor management, surgical techniques, and immunosuppressive drugs increased the early survival to 90% in the first 3 months and 85% in the first year. Infections and acute rejection continue to be the most common causes of death in the first year posttransplantation. However, in contrast to other solid organ transplantation, over half of the lung transplant recipients continue to suffer and die of chronic lung allograft dysfunction (CLAD), generally occurring 3 to 10 years posttransplantation. Methods evaluating allograft dysfunction are variable and depend on the clinical differential diagnosis, posttransplant time, and complications suspected ( Table 24.1 ).

Vascular Complications

Postsurgical complications of the arterial or venous anastomoses, although rare, are associated with high morbidity and mortality rates. Several types of complications have been described, from kinking of anastomosis, thrombosis, stricture, and extramural mass pressure (with use of omental pedicle) to problems with vessel orientation (inversion of the donor vessel). Venous anastomoses are more prone to complications due to their extensive length. Management of a vascular complication depends on the underlying cause and includes medical, catheter-based, and surgical interventions.

Airway Anastomotic Complications

Multiple factors are involved in the development of airway anastomotic complications. These include (1) donor and recipient procedural problems involving ischemia and length of donor bronchus, size mismatch, type of immunosuppressive therapy, and postoperative tracheostomy; (2) type of surgical procedure performed, including end-to-end or telescoping technique; and (3) the presence of infection in preoperative and postoperative periods. Bronchial stenosis usually develops 2 to 9 months after transplantation and is the most common complication, occurring in 1.6% to 32% of transplanted patients. Necrosis at the anastomotic site is very common 1 to 5 weeks posttransplantation and is part of the normal healing process. In rare instances, extensive necrosis and ischemia lead to dehiscence of the anastomosis. Patients with dehiscence may clinically present with evidence of pneumothorax or pneumomediastinum, or may develop tracheobronchomalacia. Ischemia is also an important factor in the development of fistula (bronchopleural, bronchomediastinal, and bronchovascular). In 7% to 24% of patients, excessive granulation tissue is formed at the site of anastomosis causing airway obstruction. Management depends on the type of airway complication and on its severity ( Fig. 24.1 ).

Primary Graft Dysfunction

Primary graft dysfunction (PGD), which occurs in 10% to 25% of posttransplanted patients, is the result of a combination of ischemia, reperfusion, donor brain death, and cold organ preservation. PGD is the leading cause of morbidity and mortality in the early posttransplantation period and is a risk factor for development of bronchiolitis obliterans syndrome (BOS). Mechanisms leading to acute lung injury with diffuse alveolar damage (DAD) ( Fig. 24.2 ) include ischemia-induced endothelial and epithelial injury, abnormalities in coagulation and fibrinolysis, alterations in cell adhesion, and chemotaxis. The absence of perivascular and airway mononuclear cell infiltrates helps distinguish PGD from acute rejection.

Rejection

Transbronchial biopsies (TBBs) from pulmonary allograft are evaluated for the presence or absence of vascular and airway rejection and are graded according to a grading system developed by the International Society for Heart and Lung Transplant (ISHLT) in 1990 and revised in 1996 and in 2007 ( Table 24.2 ). The biopsies are obtained either as a part of surveillance protocol or from symptomatic patients. Because rejection is a patchy process, it is recommended to obtain at least five fragments of alveolar lung tissue. Three different levels are stained with hematoxylin and eosin. Connective tissue stains and silver stain can be performed to assess submucosal fibrosis and fungal infection, respectively.

Acute Antibody-Mediated Rejection

Acute antibody-mediated rejection (AMR) presents a diagnostic challenge due to the lack of widely accepted diagnostic criteria. AMR is caused by binding of preformed or de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) to the antigens on the capillary endothelial cells. Interaction between antibody and antigen leads to allograft injury through activation of complement and complement cascade and leukocyte recruitment. Currently, the diagnosis of AMR is based on clinical evidence of allograft dysfunction, presence of circulating DSA, and pathologic findings of acute lung injury. The incidence of AMR is not known.

Acute Rejection

Acute rejection is a cell-mediated process with progressive infiltration of the graft by host mononuclear cells. Immune cell activation causes release of inflammatory chemokines and up-regulation of adhesion molecules. Major cellular targets include endothelial and epithelial cells.

Radiologic Features

Chest imaging studies in the setting of ACR can show perihilar or lower zone alveolar or interstitial infiltrates, septal lines, subpleural edema, peribronchial cuffing, and pleural effusion. Computed tomography (CT) scans show ground-glass opacities, septal thickening, and pleural effusions. These findings are suggestive of acute rejection; however, sensitivity is only 35%.

Pathologic Features

Microscopic Findings

Acute rejection is characterized by mononuclear cell infiltrates. The intensity and distribution of the infiltrate form the base of the ISHLT grading system. In minimal acute rejection (grade A1) perivascular infiltrates are infrequent. Blood vessels, particularly venules, are cuffed by small, round, plasmacytoid and transformed lymphocytes forming a layer two to three cells thick ( Fig. 24.3 ). In mild acute rejection (grade A2) perivascular infiltrates are more frequent and consist of more than three layers of lymphocytes, with eosinophils around venules and arterioles ( Figs. 24.4 and 24.5 ). Grade A2 or higher-grade acute rejection is often accompanied by lymphocytic airway inflammation ( Fig. 24.6 ). Moderate acute rejection (A3) is characterized by an extension of the inflammation into alveolar septa ( Fig. 24.7 ) in contrast to grades A1 and A2, in which infiltrate is limited to the perivascular adventitia. In severe acute rejection (grade A4), diffuse perivascular, interstitial, and airspace infiltrates associated with pneumocyte damage, macrophages, hyaline membranes, hemorrhage, and neutrophils or epithelial ulceration with fibrinopurulent exudates are seen.

In the 2007 revision, airway rejection (lymphocytic bronchiolitis) is graded from low to high grade (B1R–B2R). In low-grade lymphocytic bronchiolitis, mononuclear cells, with occasional eosinophils, are present in submucosa of the bronchioli either as scattered cells or as a circumferential band, without infiltration or necrosis of the epithelium. High-grade lymphocytic bronchiolitis ( Fig. 24.8 ) is characterized by dense bronchiolar inflammatory cell infiltrates with epithelial cell dropout, lymphocytic infiltration of the epithelium, and sometimes ulceration. The inflammatory infiltrate is the same as seen in perivascular rejection with the lymphocyte as the predominant cell and smaller numbers of eosinophils and neutrophils.

Ancillary Studies

Bronchoalveolar Lavage

Although the inflammatory cells, as well as mediators of inflammation, during acute rejection have been extensively studied in bronchoalveolar lavage (BAL) fluid, neither has been shown to accurately distinguish rejection from infection.

Differential Diagnosis

The main differential diagnosis for acute rejection is infection caused by bacteria, viruses, or fungi. The clinical and radiologic features are very similar to those of rejection. Microbiologic cultures and TBB are most useful. Special stains, including IHC for cytomegalovirus (CMV), Gomori methenamine silver (GMS) stain for fungus and Pneumocystis jirovecii, and Ziehl-Neelsen stain for acid-fast bacteria (AFB), should be performed as indicated.

Chronic Rejection