Pulmonary alveolar hemorrhage is an important cause of respiratory symptoms and respiratory distress syndrome in immunocompromised patients (14
) (see Chapter 31
), and it accounts for 11% to 64% of pneumonic infiltrates in this group. However, alveolar hemorrhage is rarely the sole cause of pulmonary infiltrates, with fewer than 5% of patients exhibiting pulmonary hemorrhage as the only respiratory manifestation. Even when it is clinically considered an isolated phenomenon in immunocompromised patients, it is important to exclude occult invasive aspergillosis infection; close to 50% of patients with severe pulmonary hemorrhage may have documented aspergillosis. The association between thrombocytopenia and Aspergillus
infection and pulmonary hemorrhage is significant. Alveolar hemorrhage is also associated with other complications, such as mucormycosis, pulmonary veno-occlusive disease, graft versus host disease, mitomycin therapy, and other processes. Alveolar hemorrhage is seen frequently in recipients of heart transplants. In one study, 75% of BAL samples deemed positive for alveolar hemorrhage were in recipients of heart transplants. In another study, alveolar hemorrhage was detected in 21% of 141 consecutive recipients of autologous bone marrow transplants. Alveolar hemorrhage is significantly associated with thrombocytopenia (platelet count <50,000/mm3
), other coagulopathies, renal failure (serum creatinine = 2.5 mg/dL), a history of heavy smoking (>10 pack-years), leukopenia, thoracic radiation, and chemotherapy.
The difficulty of establishing the diagnosis of alveolar hemorrhage can be ascribed to the following factors: highly nonspecific clinical and roentgenographic features, absence of hemoptysis in most patients, and lack of specificity of the imaging procedures, including chest roentgenography, HRCT, and radionuclide scans. The diffusing capacity of the lung for carbon monoxide, when measured serially, has been reported to increase during alveolar bleeding as a result of an increased uptake of carbon monoxide by red blood cells in the alveoli. The need to perform this test serially renders it impractical in sick patients. Furthermore, its reliability in the diagnosis of alveolar hemorrhage has not been established.
Although thoracoscopy and open lung biopsy can document the diagnosis, these are high-risk procedures in immunocompromised patients. BAL has been used to diagnose alveolar hemorrhage in immunocompromised patients. The mere presence of hemosiderin-laden macrophages in the BAL effluent without quantification is not diagnostic. Therefore, estimation of the number of hemosiderin-laden macrophages is used to diagnose this complication. In a study of 240 BAL fluid samples in 194 immunocompromised hosts, a proportion of siderophages of at least 20% was considered to be diagnostic of alveolar hemorrhage (14
). By this definition, alveolar hemorrhage was present in 87 (36%) of the samples; a proportion of siderophages of 20% to 65% was correlated with moderate hemorrhage (Golde score between 20 and 100), and a proportion higher than 67% was correlated with severe hemorrhage (Golde score >100). Even when a diagnosis of alveolar hemorrhage is established, it is essential to exclude the coexistence of the basic disease process and infections in the lungs.
Obstructive Airways Disease
Progressive airways disease leading to life-threatening respiratory distress is one of the most serious pulmonary complications encountered in immunocompromised patients. Obstructive airways disease can take the form of bronchospastic disease, lymphocytic bronchitis, or bronchiolitis obliterans.
A lymphocyte-mediated pathologic process is most likely responsible for these complications.
Obstructive airways disease secondary to immunocompromise is almost exclusively limited to recipients of organ transplants (Fig. 55.3
). Patients with graft versus host disease are at risk for the development of this complication. Bronchiolitis obliterans secondary to rheumatoid arthritis and other collagen diseases is not considered here. However, it is important to recognize that in a patient with rheumatoid arthritis or another collagen disorder who is being treated with specific nonsteroidal antiinflammatory agents (e.g., penicillamine, gold preparations), the development of features of obstructive airways disease may be caused by the drugs themselves.
FIGURE 55.3. Bronchiolitis obliterans–associated progressive obstruction of airflow following bone marrow transplantation. Note fibrous thickening of the submucosa and distortion of the muscularis, with resultant compromise of the bronchiolar lumen.
Nonspecific Interstitial Pneumonitis
The histopathologic findings in the lung tissue of immunocompromised patients with a diffuse pulmonary process may not fit any specific pattern and are therefore described as nonspecific
. The nonspecificity of a biopsy-based diagnosis is helpful in excluding other causes of an interstitial process (Fig. 55.4
). For example, in a study of 70 immunosuppressed patients with diffuse lung disease who underwent open lung biopsy, even though the procedure was diagnostically accurate in 97%, 45% of the diagnoses were nonspecific (fibrosis); no significant difference in mortality was found between the patients with a specific diagnosis and those without, or between the patients whose biopsy diagnosis resulted in an alteration of therapy and those whose biopsy diagnosis did not. In contrast, another study noted a recovery rate of only 25% in patients without a specific diagnosis following lung biopsy, whereas in patients in whom a treatable problem had been diagnosed, the overall recovery rate was 70%.
FIGURE 55.4. Nonspecific interstitial pneumonitis in an immunocompromised patient in whom dyspnea and cough developed after thoracic radiation and multiple courses of chemotherapy for Hodgkin lymphoma. Open lung biopsy revealed nonspecific inflammation and fibrosis.
High-dose whole-body irradiation is commonly included in the conditioning regimens that precede bone marrow transplantation in patients with hematologic malignancies. Interstitial pneumonitis is a major complication after bone marrow transplantation, and nearly one fourth of all patients with bone marrow transplants die of this complication. In approximately half of these patients, an infectious agent, particularly cytomegalovirus, is involved. Additional factors, such as remission-induction chemotherapy, cyclophosphamide, methotrexate, cyclosporine, and graft versus host disease, combine to cause interstitial lung disease in these patients.
Lymphocytic Interstitial Pneumonitis
The differential diagnosis of lymphocytic interstitial pneumonitis is discussed in Chapter 24
. In immunocompromised patients, the causes of lymphocytic interstitial pneumonitis include HIV infection (see Chapter 18
), other viral infections, graft versus host disease, and agammaglobulinemia. Because many of the diseases associated with lymphocytic interstitial pneumonitis are forms of lymphoma, immunocompromised patients with lymphocytic interstitial pneumonitis should be closely observed to detect possible lymphoproliferative disease.