Infections in the Lung Transplant
Recipient
IV. Types of Infections in the Lung Transplant
Recipient
A. Major Transplant Centers
Stanford (1993) Frist |
Pneumonia(bacterial, CMV, fungal)
Lung Abscess
Anastomosis(candida, pseudomonas, aspergillus)
Empyema
|
29/37 4/37 3/37 1/37 |
Vanderbilt (1994) Kramer |
Bacterial Pseudomonas
Serratia
Enterobacter
Staphylococcus
Enterococcus
Fungal
Aspergillus
Candida
Viral
CMV, HSV, H. zoster
Protozoal
Nocardia
|
48%
14%
31% 5% 2%
|
Vanderbilt (1993) Horvath |
Bacterial Pneumonia
CMV Pneumonia
Anastomosis |
10/18 5/18 3/18 |
Toronto (1992) Maurer |
Bacterial Pneumonia
Bacterial Bronchitis
Viral Pneumonia
C. albicans empyema
A. fumigatis pneumonia
PCP
|
18/35 8/35 6/35 1/35 1/35 1/35 |
Washington University (1992) Haydock |
CMV disease
Bacterial
Fungal |
18/32 11/32 3/32 |
Pittsburgh (1986) Dummer |
Bacterial
Viral
Protozoal
Fungal
|
50% 19% 19% 12% |
B. Bacterial Infections
The common types of bacteria include Pseudomonas, Coagulase
Positive Staphylococcus, Enterobacter, Enterococcus, Streptococcus pneumoniae
Acinetobacter, Hemophilus, and Klebsiella. Pneumonias occur most commonly
early
(within first the 2 months) and late in the transplant course (especially after the
development of bronchiolitis obliterans).
The most efficacious methods to diagnose bacterial and fungal
pneumonias are listed below (in each of these culture and cytologic/histologic
examination may be performed):
Bronchoalveolar Lavage |
The combination of culture and cytologic examination is efficacious
in detecting bacterial, fungal, and viral pathogens. |
Bronchial Brush |
This procedure is safe and rapid. Cytologic examination and
bacterial cultures provide results with short turnaround time. |
Fine Needle Aspiration |
Useful in identifying localized infections such as Nocardia
abscesses. |
Transbronchial Biopsy |
Low sensitivity for bacterial infections, but an important tool for
assessing rejection |
Wedge Lung Biopsy |
Considered the gold standard when less invasive procedures have not
provided an adequate diagnosis. The currently popular thoracoscopic procedure
provides sufficient tissue with low morbidity and mortality. |
When considering infectious processes, an important issue is
the determination of the significance of identified microorganism. This depends on
multiple factors including type of species isolated, colony count, and clinical
manifestations. The diagnosis of bacterial pneumonia depends on the documentation
of new fevers, infiltrates on chest radiograph, and isolation of significant
numbers of the organism (generally greater than 100,000).
C. Fungal infections
Candida and Aspergillus are the most common fungi
affecting the
lung allograft. They are most common in the early period posttransplant but may
occur any time afterwards. The anastomotic site is often a site of infection and
this area becomes highly susceptible if dehiscence has occurred. Consequently, the
infection may spread into the mediastinum to produce an abscess. While Candida
mainly infests the upper tracheobronchial tree with only an occasional chance of
dissemination, Aspergillus has the potential to involve the deeper parenchyma. As
in the nontransplant situation, the finding of Aspergillus in specimens must be
taken in the appropriate context of whether it represents colonization, allergic
fungal response, or invasive disease.
Other potential fungal pathogens include Cryptococcus,
Pseudallerscheria and Coccidioides.
D. Viral infections
Cytomegalovirus (CMV) is the most common viral infection
in the
lung transplant population and a major cause of morbidity. Due to the high
prevalence of this virus and protean manifestations, the identification of CMV must
be taken in the appropriate context. CMV illness may be subdivided into CMV
infection recognizing only the presence of the virus with or without associated
clinical/pathological manifestations and CMV disease with recognizable clinical
manifestations thought to due to the virus.
To assess the appropriate risk, both the recipient and donor
are tested for circulating CMV antibodies. Recipients who are serologically
negative and acquire serologically negative donor lungs (R-/D-) are at the lowest
risk for the development of any significant CMV disease and require only the use of
CMV negative blood products when transfusion is required. On the other hand, those
recipients who are serologically negative who receive serologically positive lungs
(R-/D+) are at the highest risk for CMV disease and require the most aggressive
anti-CMV prophylactic regimen. R+/D- and R+/D+ combinations are at intermediate
risk and receive a less aggressive prophylactic regimen.
Significant CMV disease occurs most commonly in the first 2 to
3 months post-transplant, although presentation may occur at anytime thereafter.
Histologically, the manifestation of CMV pneumonitis ranges from a subtle patchy
interstitial mononuclear cell infiltrate with rare inclusions to diffuse
interstitial and perivascular neutrophilic and mononuclear cell infiltrates with
alveolar damage and numerous CMV inclusions. On rare occasions, isolated CMV
inclusions are found without any associated inflammation. The interpretation would
depend on the clinical context; it may represent the earliest manifestation of a
developing pneumonitis or the detection of a latent virus. Close followup is
warranted in these circumstances. The detection of CMV by culture or Shell-vial
assay alone without clinical disease or histologic confirmation indicates CMV
infection without disease. On such occasions the decision for treatment would
depend on the clinical situation. With the availability of current antiviral
regimens, mortality from CMV pneumonitis has been relatively uncommon. CMV
infection has also been associated with an increased risk for the development of
chronic airway rejection (bronchiolitis obliterans). The upregulation of HLA Class
II antigens following CMV infection has been postulated as a mechanism for its
development. Such associations cloud the distinction between rejection and
infection.
Herpes Simplex Virus
Due to prophylactic acyclovir, the incidence and morbidity
from
Herpes simplex pneumonia has diminished. Nevertheless, those susceptible present
commonly in the first posttransplant month and the lung may be the only site of
infection. Although mucocutaneous lesions may not be identified, an association
between Herpes tracheitis and prolonged intubation has been noted. The histologic
findings of HSV pneumonia are similar to those occurring in other immunocompromised
patients. The pneumonia tends to be florid with extensive necrosis and the
presence
of infected cells with intranuclear ground glass inclusions and occasional Cowdry
type A inclusions. Multinucleated giant cells with similar nuclear changes are
also
common features. Rapid treatment following its detection is critical as the
disease may be fatal if left unchecked.
Adenovirus
Adenovirus (ADV) infections have reported sporadically in the
lung transplant literature. The manifestation ranges from an acute
bronchitis/bronchiolitis to diffuse alveolar damage. Even in cases of DAD, a
bronchocentric distribution of severe necrosis is often noted. In our series, the
patients were typically young, acquired the infection within the first one and a
half months post-transplant and had a rapidly fatal course. Smudgy basophilic
nuclear inclusions are characteristic of ADV infections and in cases which are
equivocal, the use of an immunohistochemical stain or in situ hybridization probe
for ADV may be helpful. A note of importance is that an indeterminate number of
patients may carry ADV subclinically without ever developing disease. The relative
high incidence in the pediatric population in contrast to the adult population
suggests that ADV pneumonia is a primary infection and not reactivation. Those who
develop antibodies may acquire lasting immunity.
Epstein Barr Virus
Epstein Barr virus (EBV) infections in transplant patients produces varied
manifestations ranging from mononucleosis-like syndrome to posttransplant
lymphoproliferative disorder (PTLD) (see below).
E. Protozoal
Pneumocystis carinii
The depressed cellular immunity provides an opportune setting
for pneumocystis infection and early in the history of lung transplantation,
Pneumocystis carinii pneumonia (PCP) was a common problem. However, with the
institution of PCP prophylaxis (sulfonamides), the incidence of PCP has markedly
diminished. Nevertheless, some patients are allergic to sulfonamides and in rare
instances prophylaxis may not prevent the infection. For these reasons, diagnostic
procedures (BAL culture and cytology, transbronchial and open biopsies) must include
screening for pneumocystis. Immunohistochemical methods and polymerase chain
reaction (PCR) may provide added sensitivity and specificity to the established
methods. However, the indications for their optimal use have not been as yet
determined and for the moment, morphologic and culture identification remains a
sensitive, specific, and rapid modality for diagnosis.
The pattern of PCP in the lung transplant recipient is similar
to that in other settings. The gross appearance of the lung appears as
bronchopneumonia or diffuse consolidation. Histologically, there is a range of
tissue response from minimal alterations to granulomatous response and florid
diffuse alveolar damage. Foamy alveolar exudates are characteristic findings
on H&E
sections although this appearance may be mimicked by alveolar fibrin, macrophages
and other cellular debris. Therefore, the Grocott stain is indispensable in
assessing the possibility of PCP and should be a component of every BAL cytology
and
lung biopsy workup. The typical Grocott morphology shows cup shaped cysts with
central intracystic bodies. The differential diagnoses include Candida,
Torulopsis, Coccidioides, Histoplasma, and Cryptosporidia.
F. Some uncommon infections of interest
Pseudallerscheria boydii
P. boydii is ubiquitous in the environment and produces an
opportunistic infection which mimics aspergillosis both clinically and
pathologically. Like aspergillus infections, the isolation of P. boydii needs
to be
assessed in the context of the finding. Colonization commonly occurs in the
remodeled pulmonary parenchyma and cavities. On the other hand, invasive
necrotizing pneumonia with abscess formation or pleural involvement with empyema
may
be associated with hematogenous dissemination to the brain, kidney, heart, and
thyroid. A manifestation of allergic bronchopulmonary fungal disease has been also
recently reported.
Morphologically, P. boydii and Aspergillus are similar with
both showing narrow (2 to 5 micron) septate hyphae with acute angle branching. The
hyphae of P.boydii may show thin-walled vesicles with terminal conidia, features
which are helpful in distinguishing it from Aspergillus. This distinction has
clinical significance because amphotericin which is usually used for Aspergillosis
is not an effective agent for Pseudallerscheriasis in which a miconazole or
ketoconazole may be effective.
Mycobacteria
Because of the relative low prevalence of M. tuberculosis in
the United States, the tuberculosis in the lung transplant population is uncommon.
The diagnostic evaluation utilizes the same methodologies as in the
nonimmunocompromised population. The clinical and pathologic manifestations are
also protean and a certain index of suspicion is required for establishing the
diagnosis. Transbronchial biopsies may only reveal nonspecific chronic
inflammation and granulomas may not be present.
Nocardia
These gram positive aerobic, filamentous rods infect the
immunocompromised or those with underlying medical conditions. The manifestations
include bronchopneumonia, abscess formation, cavitation, and empyema. Furthermore,
the infection may involve sites such as brain, bone, skin, and subcutaneous tissue.
Eighty-five percent of nocardiosis is due to N. asteroides. The irregularly
branching thin, beaded, filamentous rods are characteristic of Nocardia although
from a purely morphologic point of view, Actinomyces and Streptomyces should also
be
considered in the differential diagnosis. While some of these cases are positive
on
Gram, Grocott, and Fites stain (modified Ziehl-Neehlsen) others may stain with only
one or two of these stains.
Legionella
Legionellosis may be community acquired or nosocomial and
occurs in the settings related to contaminated heating or water supplies. While
immunocompetent hosts recover from the infection, the immunocompromised patients
are
at a risk for high mortality. Laboratory diagnosis depends on the demonstration of
organisms in tissues, secretions, or culture. Direct fluorescent antibody stain
(DFA) is useful for quick diagnosis although the sensitivity may be low. Cultures
provide definitive identification, although up to one week may be necessary for
adequate growth. Serum antibody titers of greater than 1:256 provide presumptive
evidence of Legionella pneumonia in the appropriate clinical setting. However, it
should be noted that recovering individuals may still retain high antibody titers
and low titers would not rule out an infection in the setting of an
immunocompromised host.
Histomorphologic features of Legionella pneumonia are
characterized as focal lobular to confluent lobular pneumonia. Although frank
necrosis and cavitation are not common, microscopic abscesses are seen frequently.
The population of the inflammatory cell infiltrate ranges from predominantly
neutrophilic to predominantly histiocytic with some cases showing a mixture of cell
populations. Silver stains such as Dieterle, Steiner, and Warthin-Starry stains
aid
in the detection of the organisms on tissue sections. Immunohistochemical stains,
including monoclonal preparations, may cross react with other bacterial species and
therefore lack specificity. In the chronic phase, Legionella pneumonia may
manifest as an organizing pneumonia or interstitial fibrosis.
Toxoplasmosis
Toxoplasma gondii infects humans as the intermediate host
during its life cycle. Sporogeny and sexual reproduction occurs in the intestines
of cats. Humans become infected by consuming the soil contaminated by feline
excrement. Infection may also occur by ingestion of undercooked meats (pork,
mutton, and beef). Ingested sporozoites (from oocyte) or bradyzoites (from meats)
circulate in the blood and upon multiplying asexually, transform into tachyzoites.
The acute phase of the infection is characterized by infected cells filled with
tachyzoites ("pseudocyst") whereas the chronic phase is characterized by "tissue
cysts" filled with bradyzoites. Morphologically, the infected lungs show
bronchopneumonia, alveolar fibrin deposits and coagulative necrosis. Pseudocysts
containing tachyzoites are seen in the alveoli with necrotic debris. For serologic
diagnosis, serial tests identifying IgG and IgM against tachyzoites are required.
Acute toxoplasmosis is characterized by rising antibody titers. Antitoxoplasmosis
prophylaxis for recipients with negative serology acquiring organs from donors with
positive serology has also contributed to the low incidence of this infection.
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