Infections in the Lung Transplant Recipient
V. Post Transplant Lymphoproliferative Disorder
(PTLD)
Although PTLD is not typically thought of as an infectious
process, it is discussed here because of the strong association with Epstein Barr
virus (EBV). In short PTLD is a lymphoproliferation of EBV infected lymphocytes
(usually of B-cell origin) arising in the background of overimmunosuppression. The
incidence ranges from 3.5% to 7.8% in long term lung transplant recipients. In
lung
transplant recipients, there is a relatively high incidence (60%) of PTLD occurring
in the allograft. The reason for this may be multifactorial and postulations
include 1) the lung being the primary site of inoculation (since PTLD is recognized
as evolving from a primary EBV infection, not reactivation), 2) relatively high
doses of immunosuppression when compared to other organ transplants, and 3)
bronchial associated lymphoid tissue acting as "homing" sites for EBV infected host
B-cells.
Morphologically, PTLD typically grows as a mass lesion with
some showing angioinvasion. Histologically they may divided into monomorphous and
polymorphous subtypes. The majority of the former are monoclonal proliferations
whereas the latter are polyclonal. As the mass expands, foci of necrosis may
appear, leaving viable lymphoid cells at the periphery. When these areas are
biopsied transbronchially, distinction from acute cellular rejection may be
difficult. In these instances, demonstrating the presence of Epstein Barr virus
latent protein (EBV-LMP) by immunohistochemistry or Epstein Barr virus encoded RNA
(EBER) by in-situ hybridization have been shown to be a very specific for PTLD.
Caution should be exercised because extremely sensitive techniques such as
Polymerase Chain Reaction may detect very small quantities of EBV genomes in
patients without evidence of PTLD.
VI. Histologic Tissue Reactions and their Differential
Diagnosis
Miliary pattern of acute inflammation
CMV and HSV infections and tuberculosis may produce a miliary
pattern of neutrophilic infiltrates particularly in the interstitium. The process
is suspected at low power magnification and diagnostic cytopathic changes are
identified at higher magnification. When the cytopathic changes of these viral
infections are not well developed, immunohistochemical stains aid in their
recognition.
Perivascular Inflammation
While perivascular mononuclear lymphoplasmacytic infiltrate is
considered the hallmark of acute cellular rejection, it may be seen in infection
due
to CMV or pneumocystis. Therefore, the interpretation of a perivascular mononuclear
cell infiltrate must be undertaken with caution. Search for CMV inclusions should
be performed on every biopsy and Grocott stains are recommended as routine stains.
As a rule, if the perivascular infiltrate is due to either of these two infections,
clues are often present which would guide one to the correct diagnosis.
Acute Bronchitis/ Bronchiolitis
An acute inflammation of the airways would suggest an
infectious process. However, in the context of transplantation, the finding of
acute bronchitis/ bronchiolitis (ABB) suggests other differential diagnostic
possibilities. In addition to acute infection, other graft syndromes producing ABB
include harvest injury, acute cellular rejection, and bronchiolitis obliterans.
Distinction between these entities requires careful clinicopathologic correlation
and the recognition of histologic clues favoring one process over another. For
example, ABB secondary to harvest injury presents with a background of diffuse
alveolar damage. In acute cellular rejection, the predominant inflammatory cell
population is lymphoplasmacytic and the neutrophilic component is relatively
minor.
Nevertheless, secondary infections must be considered and BAL culture should be
obtained at the time of biopsy. Within the grades of acute rejection, moderate and
severe ACR would potentially give problems in interpretation. One of the hallmarks
of chronic rejection is bronchiolitis obliterans (OB). The current Working
Formulation divides OB into active and inactive lesions. Active lesions are
characterized by an "activated" mononuclear cell infiltrate permeating through the
scarred airway. With increased intensity of the infiltrate, bronchiolar epithelial
cell necrosis is followed by a neutrophilic infiltrate, producing the lesion of
ABB.
On the other hand, scarring of the airways results in cylindrical bronchiectasis
with alternating areas of dilatation and constriction. With such altered anatomy,
airways distal to constricted foci would develop obstruction and become susceptible
to microbial growth. Therefore, ABB in the syndrome of bronchiolitis obliterans
may be secondary to rejection, post obstructive infection or both.
Lymphocytic Bronchitis/ Bronchiolitis
The finding of a mononuclear cell infiltrate involving the
airways as well as the vasculature is characteristic of acute cellular rejection,
as
long as the corresponding BAL cultures are sterile. When airway mononuclear cell
infiltrates are seen alone, the term lymphocytic bronchitis/bronchiolitis is
applied. While this lesion has been documented as the "cellular phase" of airway
rejection, it should be noted that an identical lesion may be produced by
infection.
In that instance, correlation with culture results becomes critical.
Interstitial, Airway and Airspace Granulation Tissue
Fibromyxoid plugs of granulation tissue within airways,
airspaces, and interstitium are seen in three clinicopathologic settings: acute
cellular rejection, harvest injury, and infection. At least a moderate grade of
acute cellular rejection is generally necessary to produce significant airway
injury
and the ingrowth of loose myxoid granulation tissue. This reaction should be
distinguished from bronchiolitis obliterans which demonstrates scarred airways with
dense eosinophilic collagen. The myxoid material is generally reversible and does
not necessarily progress to bronchiolitis obliterans. Similar changes are seen in
organizing pneumonia secondary to infection. Search for active bronchopneumonic
foci and/or the identification of the microorganism would assist in its distinction
from rejection or harvest injury. The airway injury secondary to an infectious
pneumonia manifests as young myxoid granulation tissue which is to be distinguished
from the dense fibrosis seen in obliterative bronchiolitis. Nonspecific airspace
granulation tissue is often seen adjacent to a nidus of infection which may not be
sampled by transbronchial biopsy. Localized processes such as Nocardia abscesses
and PTLD are better sampled by fine needle aspiration and biopsy (FNAB).
Granulomas and Giant Cells
While mycobacterial and fungal infections need to considered in
the differential diagnosis of granulomas and giant cells, one should be aware of
noninfectious etiologies for this type of tissue reaction. Aspiration with
secondary giant cell reaction is not uncommon and in such cases, the identification
of the foreign material leads one to the correct diagnosis. Some recurrences of
primary diseases manifest with granulomas or giant cells. Recurrent cases of
sarcoidosis have been documented by transbronchial biopsy and at autopsy with the
documentation of nonnecrotizing granulomas. This diagnosis is one of exclusion as
there is no specific marker for sarcoidosis. When one encounters nonnecrotizing
granulomas on transbronchial biopsy in a patient with a primary diagnosis of
sarcoidosis, grocott and acid fast bacilli stains should be ordered on the
sections.
If they are negative, the findings would be consistent with recurrent
sarcoidosis.
Giant cells have also been documented to reappear in single lung transplant
recipients with the diagnosis of Giant Cell Interstitial Pneumonia which is
currently thought to be an occupational pneumoconiosis secondary to inhalation of
hard metal dust particles. In the cases reported, the recipients had not returned
to work and it is postulated that the remaining native lung may "seed" the
allograft with hard metal particles and subsequently evoke a giant cell reaction.
Bronchial Cartilage Alterations
Anastomosis of the major airways currently utilizes the
telescoping procedure and in the past omentopexy. While the bronchi and pulmonary
arteries and veins are reanastomosed, the bronchial circulation is interrupted.
Since the bronchial artery supplies the large airways, some degree of airway
ischemia is expected in all transplants. Changes in the bronchial cartilage with
interruption of the cartilaginous contours, perichondrial fibrosis, and
ossification
have been demonstrated. While ischemia may produce these changes, rejection and
infection may be superimposed on the ischemic process, adding further injury to the
airways. Therefore, the airway wall demonstrating inflammation, necrosis, and
scarring should be evaluated for an infectious process and rejection as well. If an
infectious agent is identified, the distinction between airway colonization,
bronchitis, and invasive disease should be made.
Graft Eosinophilia
While eosinophils are known to be a cellular component of
acute
cellular rejection, parenchymal eosinophilia is associated with a variety of
nonrejection related conditions including asthma, drug reactions, and infections.
The infectious organisms identified include Aspergillus, coxsackie virus, and
Pseudomonas maltophilia. The histopathologic tissue reaction demonstrates acute
eosinophilic pneumonia which is not a form of acute cellular rejection. Although
rare, parasitic infections producing eosinophilia should also be added to the
differential diagnosis. The finding of marked eosinophilia on BAL or a pattern of
eosinophilic pneumonia on transbronchial biopsy should alert one to search for an
infectious etiology.
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