In addition to our focus on lung rejection, there are several histologic abnormalities which affect the pulmonary parenchyma which may cause confusion with rejection reactions. This brief discussion will focus on these changes.

Harvest injuries/reimplantation response:

As part of the harvesting of the allograft lung, the pulmonary parenchyma experiences some degree of ischemic damage. This is dependent to a variable extent on the quality of the donor lung, the type of preservation solution, and the length of time between harvest and re- anastomosis. As a result the lung demonstrates hypoperfusion injury, which may range from patchy foci of acute lung injury to diffuse ischemic alterations which manifest clinically as pulmonary edema, almost as soon as the patient leaves the operating room. Morphologically these alterations conform to what one would expect to see in diffuse alveolar damage and clinically as the Adult Respiratory Distress Syndrome (ARDS). Because the lesion is patchy in many instances, patients may not develop the full fledged adult respiratory distress syndrome. They do however show the same morphologic alterations - endothelial cell vacuolation and focal necrosis, accompanied by interstitial and airspace edema. Fibrin microthrombi may be seen, and sloughing of alveolar pneumocytes is also common. The result of this injury is the formation of airspace hyaline membranes within days, which over the next week progressively organize and are incorporated into the pulmonary interstitium. This graft injury predisposes to infection, and may closely mimic acute rejection reactions, in that it is a diffuse process radiographically and is accompanied by hypoxemia. From a morphologic perspective, diffuse alveolar damage is accompanied by scattered collections of neutrophils within the airspaces, and acute bronchitis/bronchiolitis. This contrasts with acute rejection which displays perivascular mononuclear infiltrates of small round, small cleaved, and large lymphoid cells. Diagnostic confusion does occur in some instances when processes are superimposed. In fact it is believed by some pulmonologists that diffuse alveolar damage predisposes to acute lung rejection (by virtue of increased class II HLA antigen expression by endothelial and epithelial cells) and bronchiolitis obliterans.

Early in the description of lung allograft pathology, a phenomenon labeled the "reimplantation response" was described. This response manifested as diffuse pulmonary parenchymal opacification on chest radiographs, within a day or two of transplantation. Histologically, interstitial and airspace edema is noted with neutrophil margination. The etiology for this reaction is probably multiple. First, the interruption of the pulmonary lymphatics as part of the transplantation procedure impairs lymphatic drainage of the lung and predisposes to pulmonary edema. Similarly the severing of nervous connections may play a role in airspace edema (neurogenic edema). Finally mild cases of diffuse alveolar damage may manifest as pulmonary edema, and probably have been lumped into this category of lung injury.

The presence of severe diffuse alveolar damage in the postoperative course is important to recognize in that the healing reaction of this process can persist for several weeks after transplantation. In fact scarring of the pulmonary parenchyma as a consequence of persistent ARDS can be accompanied airway fibrosis. Identifying airway fibrosis early in the patients clinical course allows one to recognize "bronchiolitis obliterans" due to ischemic lung damage, rather than immunologic, rejection related reactions. Late cases of diffuse alveolar damage have also been described and probably are related to infection, or uncontrolled lung rejection (usually due to patient noncompliance).

Anastomotic complications:

Two major anastomotic complications occur in the lung allograft. First, the anastomosis of the donor and recipient bronchi is a site where inflammatory and fibrotic damage occur. It has become rather routine that at the time of surgery the donor bronchus is telescoped within the recipient bronchus and sutures applied. This has led to an increased number of cases of bronchial stenosis, with patients having a marked compromise of their tracheobronchial tree at the site of surgical anastomosis. Frequently this requires repeated laser therapy or even the insertion of endobronchial stents. From the pathologist's perspective, this site of stenosis demonstrates extensive scarring with necrosis and calcification of bronchial cartilage. What is important to note however, is that these sites of anastomosis are common areas of microbial superinfection. In particular aspergillus and candida infections of the anastomosis may lead to dehiscence and mediastinitis. Their development is often tied to the presence of airway infection at the time of surgery, particularly in patients with cystic fibrosis.

A second complication occurs at the site of the anastomosis of the aorta or pulmonary vasculature. In combination heart/lung transplants, there have been well documented cases of aortic anastomotic breakdown usually due to candida infection. In these cases, candida has been frequently cultured from the tracheobronchial tree prior to the development of acute exsanguinating hemorrhage from the vascular breakdown.

Long term pulmonary parenchymal alterations of the lung allograft:

The lung allograft is bombarded with a variety immunologic and infectious complications. If one excludes the pathology associated with these reactions, a variety of "chronic" changes occur. First, as expected, the pleural surfaces are irregularly scarred as a result of adhesions and pleuritis associated with the surgical insertion of the lung allograft. The remainder of the pulmonary parenchyma shows changes primarily associated with the loss of the bronchial artery circulation and nervous connections. Some have documented that the allograft lung shows very mild bronchiectasis even in cases unassociated with bronchiolitis obliterans. From a morphologic perspective, almost all allograft lungs show a mild increase in submucosal fibrosis in the major bronchi, accompanied by a diffuse scattering of mononuclear inflammatory cells. The bronchial cartilage is frequently calcified or ossified, and lacks the normal plate-like configuration of the airway cartilage. Bronchial arteries are frequently calcified or thrombosed. The remainder of the pulmonary parenchyma is morphologically unremarkable, although functionally investigators have noted abnormal smooth muscle reactions in the tracheobronchial and vascular tree, as well as impaired muco-ciliary clearance and ciliary motion.

Recurrent native disease:

Lung transplantation is being offered for more and more patients with end stage obstructive and restrictive lung disease. In only rare instances have there been cases of recurrent native disease in the lung allograft. This is particularly true of patients who have been transplanted for sarcoidosis, where approximately 80% of sarcoid recipients will develop non-necrotizing granulomas within their allograft lung. These recurrences are unaccompanied by pulmonary function abnormalities and frequently spontaneously remit, with the persistence of the patients immunosuppressive therapy. They appear to have no association with the development of acute or chronic lung rejection. Other diseases which have been shown to recur in the allograft lung include giant cell interstitial pneumonia and lymphangioleiomyomatosis. No examples of pulmonary fibrosis, histiocytosis X, emphysema, or pulmonary hypertension have been described.

Donor lung pathology:

Several studies have investigated the pathology of unused donor lungs. Presumably alterations in the unused lung are also present in lungs utilized for transplantation. These alterations include the presence of thromboembli, acute pneumonia, aspiration bronchitis/ bronchopneumonia, and pulmonary hemorrhage. Perhaps the most significant of these alterations is the presence of pulmonary emboli, in that they explain aberrations of lobar functions in the allograft lung. We have also had experience with two patients who have developed donor cerebral emboli, and have expired as a result of a diffuse coagulopathy, - this complication occurs in donors who have received gunshot wounds to the head or vehicular trauma.