GRADING OF LUNG REJECTION - GENERAL COMMENTS
The grading of lung rejection derived initially
from animal
studies begun in the early 1970s and culminated in a series of elegant
works by Prop
et al. In these models, it was noted that the insertion of an allograft lung
precipitated an inflammatory reaction which was initially localized to the
perivascular zones. If uncontrolled, the inflammatory infiltrate progressed to
involve all portions of the pulmonary interstitium, including blood vessels and
airways, ultimately resulting in a hemorrhagic infarcted lung and extensive
vasculitis. With the administration of cyclosporin and/or steroids this
inflammatory reaction became muted. When lung transplantation was offered for the
treatment of patients with chronic pulmonary disorders, a more regimented
classification scheme became necessary for therapeutic decisions. At this point an
international group of pathologists convened in Palo Alto, CA to devise a
classification scheme which would incorporate the beneficial components of the many
schemes in use. This required much cajoling and negotiation, as part of the effort
to create a relatively simple classification scheme which could be easily taught,
easily reproduced by competent pathologists and could be used for
inter-institutional collaborations and comparisons. Ultimately in 1990, this led to
the Working Formulation for the Standardization of Nomenclature In The Grading of
Lung Rejection, a project sponsored by the International Society for Heart and Lung
Transplantation. After five years of use, a second expanded group of pathologists
convened in Pittsburgh in 1995 to revise the Working Formulation. The result is the
enclosed revised Working Formulation for the Classification of Lung Allograft
Rejection. This revision is to be published in the Journal of Heart and Lung
Transplantation. It is a simplified system which highlights the degree of airway
inflammation as a significant variable in acute lung rejection.
In both the original and revised grading schemes,
there are
overriding themes. First the alloreactive infiltrate which permeates the
transplanted lung affects two major sites - the perivascular zones and the airways,
both large and small. It was recognized by all participants that the initial
mononuclear infiltrates occur in the perivascular zones, particularly in the
perivenular areas, and as their intensity increases, more blood vessels (including
arteries) are affected and the infiltrate surrounding these blood vessels becomes
more pronounced. At some point the infiltrate expands the adjacent alveolar septae
where it is accompanied by reactive change of the alveolar epithelium, and in some
instances, cell necrosis with sloughing of these cells and associated proteins into
the airspaces. This results in a prominent alveolar macrophage response and
hyperreactive pneumocytes. At the same time as the pulmonary vasculature is
affected, the airways of the lung become actively infiltrated and inflamed. This
affects both large and small airways, and results in epithelial cell necrosis and
metaplasia of adjacent preserved epithelium. The dual injury to the vessels and
airways provided the impetus for a classification of pulmonary rejection based on
injury to these two sites. While these two zones of the lung represent the two
major areas of focus, it should be recognized that with persistent high grade
rejection, the alveolar septae may also be injured, resulting in areas of
interstitial scarring.
Rather than recapitulate the description of the grading
scheme indicated in the attached preprint, several key points are presented here.
First, as acute rejection progresses in intensity, several alterations occur: (1)
increased cellular permeation of the alveolar septae (2) increased numbers of
eosinophils (3) increased numbers of neutrophils and alveolar macrophages (4)
increased degrees of subendothelial permeation by mononuclear cells and (6)
increased degrees of small and large airway inflammation. In general, the vascular
and airway alterations occur hand-in-hand and any dissociation of inflammatory
infiltrates should raise the possibility of a non-rejection related process,
particularly infection. Pulmonary rejection frequently occurs without cardiac
rejection in heart-lung recipients (66%) and endomyocardial biopsy is inadequate to
evaluate the lung allograft.
In 1995, the pathologists with expertise in lung allograft
rejection felt that more emphasis on the airway inflammatory component of acute
rejection was necessary. In the past, the subscripts of large and small airway
inflammation in acute rejection were largely ignored by clinicians. In the 1995
proposal, it is necessary to comment on the degree of airway inflammation and assign
an intensity score to it. This feeling derived from two studies by Yousem et al.
First, one study on acute rejection noted that those cases with airway inflammation
and intraluminal fibromyxoid tissue were predisposed to develop bronchiolitis
obliterans. A second study on lymphocytic bronchitis/bronchiolitis of
noninfectious origin suggested an increased risk of obliterative airway disease. In
addition to these studies, it is an informal observation that children have much
more pronounced airway damage in acute rejection. This may be a consequence of the
relatively large amount of bronchial associated lymphoid tissue in the pediatric
transplant population and the resulting exuberant mixed lymphocyte reaction that
occurs in the wall of these airways.
For those who utilized the old working formulation,
lymphocytic bronchitis and bronchiolitis would be diagnosed as "no acute cellular
rejection with airway inflammation".
In addition to the prototype rejection reactions described
in the Working Formulation, two other forms of acute rejection should be recognized.
First, some rejection reactions are rich in eosinophils, to the point where the
mononuclear inflammatory infiltrate is obscure. These eosinophilic rejection
reactions must be distinguished from infectious causes of parenchymal eosinophilia,
primarily fungal infestations. Aspergillus, cocciodiodomycosis, and mycobacteriosis
have been described as inducing an eosinophilic pulmonary reaction which can mimic
acute rejection. Second, partially treated acute rejection reactions may be
characterized by plugs of fibromyxoid connective tissue within the airways and
airspaces, resembling an organizing pneumonia. This granulation tissue reaction
occurs as a result of alveolar septal and airway epithelial damage. It usually
reflects partial resolution of a rejection reaction treated with immunosuppressives.
Other cases represent acute rejection superimposed on the proliferative phase of
diffuse alveolar damage, resulting from graft ischemic injury. Finally, instances
of recurrent native disease occurring in the allograft have been reported, and this
can cause diagnostic confusion. Examples of recurrent disease described in the
literature include sarcoidosis, giant cell interstitial pneumonia, and
lymphangioleiomyomatosis.
The histopathology of bronchiolitis obliterans is described
in the subsequent lecture. It is however important to emphasize that acute
rejection reactions may be superimposed on underlying bronchiolitis obliterans. It
is also worthwhile noting that in patients with bronchiolitis obliterans, airway
colonization by bacteria and fungi is common in the late clinical course. This
causes much difficulty and consternation to the pathologist who is trying to
distinguish chronic inflammation of the airways due to immunologic injury from that
induced by persistent pseudomonas or aspergillus colonization of the
tracheobronchial tree.
Hyperacute lung rejection, in its classical sense, has not
been convincingly reported in the literature e.g. necrotizing vasculitis and
hemorrhage soon after insertion of the allograft. If one utilizes a different
clinical or pathological definition however, there are reports of cases in which
graft failure within days or weeks, has been accompanied by the development of or
pre-operative presence of anti-HLA antibodies, anti-endothelial cell antibodies, or
high panel reactive antibody measurements. Certainly antibody and complement
deposition may play a role in acute rejection in addition to cellular mechanisms -
we have just not seen convincing cases where the presumed immune complex deposits
have elicited vascular necrosis. Subtle, early cases of hyperacute rejection may
also be confused with diffuse alveolar damage from ischemic injury in which
neutrophil margination and migration through vessel walls can resemble vasculitis.
In summary, the Working Formulation is not a diagnostic
scheme without problems. However it is clinically revelant and does offer a
general
diagnostic construct for all institutions to report their clinicopathologic data.
This discussion has served to clarify certain areas described broadly in the 1990
publication and its 1995 revision.
|
