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 (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 (EBV) infections in transplant patients produces varied manifestations ranging from mononucleosis-like syndrome to posttransplant lymphoproliferative disorder (PTLD) (see below).

E. Protozoal

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

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.

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.

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.

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.

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.