NON-REJECTION RELATED PATHOLOGY OF THE
ALLOGRAFT LUNG
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.
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TPIS administration at the UPMC.
