Revision of the 1996 Working Formulation for the Standardization
of Nomenclature in the Diagnosis of Lung Rejection
D. CHRONIC VASCULAR REJECTION
In chronic vascular rejection/accelerated graft vascular
sclerosis there is fibrointimal thickening of arteries and
veins, which is similar to coronary artery disease in
transplanted hearts (Figure 25). In the veins, the histologic
appearance is usually of poorly cellular hyaline
sclerosis and it is recognized that the use of older
donors is associated with a higher incidence of this
phlebosclerosis in biopsy material. Chronic vascular
rejection is not applicable to transbronchial biopsies
but may be noted on open biopsy material.
Figure 25. Graft atherosclerosis. In this example of accelerated
vascular atherosclerosis due to alloreactive injury the pulmonary
arteries adjacent to airways show fibro-intimal thickening of the
subendothelial zones with atrophy of the media. H&E.
Acute Antibody-mediated (Humoral) Rejection
Acute humoral rejection is now recognized as a clinical
entity in heart and renal transplants, although it remains
controversial with a highly varied incidence between
different centers.15-17 There is no consensus on its
recognition and diagnosis either histopathologically or
immunologically, nor on its significance and treatment.
The 2004 ISHLT cardiac rejection meeting reviewed
evidence from histopathology, immunopathology and
clinical task forces and was able to suggest diagnostic
criteria in specific clinical circumstances so that further
assessment of this entity could be encouraged.5 Pathologists
can follow the guidance in that consensus report
if they intend to investigate the possibility of antibodymediated
rejection as a cause of cardiac dysfunction.
Recommendations were published to allow incorporation,
as required, into the revised working formulation
for heart rejection. It was noted that acute antibodymediated
rejection is associated with worse graft survival
and is observed in allosensitized patients, including
those with previous transplantation, transfusion or
pregnancy, and those with prior use of a ventricular
assist device.15
The diagnosis and recognition of antibody-mediated
rejection of the lung is more controversial and less well
developed than for other solid-organ grafts.16-18 However,
the presence of serum anti-HLA antibodies and the
deposition of complement in alveolar tissue after transplantation
suggest a role for humoral immune responses
in lung transplantation.19 A significant portion
of the lung consensus meeting was devoted to reviewing
evidence for antibody-mediated acute lung rejection.
Pulmonary transplant recipients with evidence of
sensitization, as demonstrated by elevated titers of
panel-reactive antibodies, have significantly more ventilator
days post-operatively compared with non-sensitized
patients.20 Humoral immune responses are also
implicated in the pathogenesis of obliterative bronchiolitis,
possibly due to anti-HLA antibodies contributing
to the development of scarring fibrosis via stimulation
of epithelial cells within the airway.21
Historically, acute antibody-mediated rejection of the
lung has been associated with "hyperacute rejection,"
which is clinically manifested by primary graft failure
occurring very early after transplantation in the setting
or pre-formed antibodies to donor HLA antigens or
endothelial cells.16 Morphologically, this is associated
with fibrin thrombi in alveolar septa, fibrinoid necrosis
of alveolar septal walls and hemorrhage. In 2006, no
histologic features for antibody-mediated rejection in
the lung were agreed upon. However, there was a
consensus that, although pulmonary capillaritis has
been described as possibly related to acute lung rejection,
it is not recognized in transbronchial biopsies in
the majority of institutions performing pulmonary transplants
and this term should not be used to indicate the
histologic hallmark of antibody-mediated rejection.22
Pulmonary capillaritis should also be distinguished from
neutrophil margination and congestion. It was agreed
that the term capillary injury is more useful as it can
indicate a morphologic spectrum of capillary damage,
although it can be a non-specific finding occurring in
infection, diffuse alveolar damage and severe cellular
rejection.23
Extrapolating from other solid-organ descriptions of
antibody-mediated rejection, it was agreed that small
vessel intimitis could raise the suspicion of humoral
rejection. It was also agreed, on an empirical basis, that,
should antibody-mediated rejection be suspected clinically,
immunopathologically or with histologic evidence
of capillary injury, immunohistochemistry could
be performed on the transbronchial biopsies for C3d,
C4d, CD31 and CD68. This extrapolates from experience
in heart and kidney grafts. The use of broad
immunofluorescence panels and electron microscopy
was not recommended. It was emphasized that antibody-
mediated rejection in the lung is not as well
developed as an entity as in the heart and kidney and
more work is required for its evaluation.
The use of agreed-upon immunohistochemical markers
may prove helpful in understanding the diagnosis.
The use of C4d staining in particular may allow the
humoral response to a lung graft to be interpreted along
the lines of the NIH recommendations from the 2003
national conference (Table 2). However, recent studies
of C4d staining of pulmonary allograft biopsies have
shown conflicting results with immunohistochemistry
by indicating positive staining in a variable, focal,
non-specific pattern without a consistent staining pattern
within different diagnostic groups.24 Specifically,
C4d deposition has been variably demonstrated as present or absent in the microvasculature of lung
biopsies in patients with acute and chronic rejection.
25,26 Specific immunohistochemical sub-endothelial
C4d deposition has been suggested as a marker for
the involvement of HLA antibodies in lung allograft
rejection.19 However, the patchy nature and low sensitivity
and specificity of the C4d staining suggested
limited clinical use in protocol biopsies, but raised the
possibility of specific C4d deposition serving as a
marker of co-existent antibody-mediated rejection in
patients with refractory acute cellular rejection.
No recommendations could be made on the diagnosis
of concomitant acute cellular rejection and antibodymediated
rejection at this time, although it is likely to
occur by extrapolation from other solid-organ grafts.
The true specificity and sensitivity of a diagnosis of
antibody-mediated rejection (with and without concomitant
acute cellular rejection, infection or even
primary graft dysfunction) requires further careful
study. Caution is urged in the diagnosis of acute antibody-
mediated rejection in the lung until this evidence
is forthcoming and a multidisciplinary approach is again
recommended in view of the wide differential diagnosis
and the potential toxicity of treatments.
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TPIS administration at the UPMC.
