Role of bronchoalveolar lavage in diagnosis of interstitial lung disease
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INTRODUCTION — Bronchoalveolar lavage (BAL) is a minimally invasive procedure performed during flexible fiberoptic bronchoscopy to obtain a sample of alveolar cells. Analysis of BAL cell counts, cytology, and culture provides insights into immunologic, inflammatory, neoplastic, and infectious processes occurring at the alveolar level.
This topic will review the role of BAL in the setting of interstitial lung disease (ILD) and the cell profiles found in common interstitial lung diseases [1]. The technique of BAL and the analysis of lavage fluid are discussed separately, as is the overall approach to the patient with ILD.
CONSTITUENTS OF BAL IN ILD — In the evaluation of interstitial lung disease, BAL findings are typically nonspecific, being consistent with or suggestive of a given condition, rather than pathognomonic. In patients with an acute presentation of dyspnea and interstitial opacities, BAL is sometimes helpful to identify alveolar hemorrhage, malignancy, or opportunistic infection [1].
When BAL fluid is obtained from healthy adults, only small numbers of lymphocytes, neutrophils, and eosinophils accompany the predominant population of alveolar macrophages. In patients with ILD, a variety of changes in the relative and absolute numbers of individual cell constituents have been described. Usually, these changes are nonspecific, but occasionally, the pattern is sufficiently characteristic to guide the differential diagnosis (table 3), or rarely, to confirm the diagnosis of a particular ILD [1-4].
As examples:
- Lymphocytosis (usually greater than 30 percent of the total white cells) .
- The ratio of CD4 positive to CD8 positive lymphocytes (CD4/CD8) may permit further narrowing of the possible diagnoses [2,5].
- Eosinophilic (usually greater than 5 percent of the white cells).
- Malignant cells (eg, metastatic carcinoma, Reed-Sternberg cells, monoclonal B lymphocytes) .
LYMPHOCYTIC BAL
Hypersensitivity pneumonitis — BAL, especially when combined with transbronchial biopsy, is a sensitive tool for detecting an alveolitis in patients suspected of hypersensitivity pneumonitis (HP) [6]. A marked lymphocytosis (often exceeding 50 percent of the cells recovered) is a nonspecific but helpful finding, since this level of lymphocytosis is uncommon in diseases often considered in the differential diagnosis. The CD4/CD8 ratio is usually decreased (<1.0) [2].
An increased number of mast cells (>1 percent) may be noted, although this is not generally used clinically. The presence of mast cells may also be helpful in monitoring for ongoing exposure to the responsible antigen, as mast cells are usually increased following acute exposure and decline toward normal within one to three months after removal of exposure [7].
Sarcoidosis — The diagnosis of sarcoidosis cannot be established on the basis of BAL findings alone. However, certain patterns on BAL can help to narrow the differential diagnosis. Criteria for the diagnosis of sarcoidosis are discussed separatelyIn the majority of patients with sarcoidosis, the BAL lymphocyte count and percentage are increased, while the neutrophil and eosinophil percentages are normal [5,8]. In addition, a predominance of T-lymphocytes with an elevated CD4/CD8 ratio is a frequent finding [2,8,9]. The duration of disease and the clinical variables (eg, the presence of extrapulmonary disease) appear to affect the cellular patterns in the recovered fluid, as follows [10]:
- "Early" or active sarcoidosis is characterized by increases in the total numbers of cells recovered, the number of lymphocytes ("high intensity alveolitis"), and the CD4/CD8 T-lymphocyte ratio (>2:1) [9].
- "Late" or advanced sarcoidosis is characterized by a relative increase in CD8 T-lymphocytes and neutrophils (to greater than 3 percent of the total). Significant numbers of mast cells in BAL fluid (>1 percent), particularly in combination with BAL lymphocytosis or neutrophilia, are associated with advanced or progressive sarcoidosis [10,11].
- A single BAL that shows a normal CD4/CD8 T-lymphocyte ratio may predict a good prognosis [11,12].
- Serial lavage analysis may be more helpful in defining the disease course than a single BAL analysis early in the course of the disease, although it does not add substantially to the information obtained from serial pulmonary function tests. In the subset of patients with persistent BAL lymphocytosis and/or a persistently elevated CD4/CD8 T-lymphocyte ratio, declines in lung function are more likely, particularly in untreated patients [11-16].
MIXED CELLULARITY BAL — In a number of interstitial lung diseases, more than one type of cell may be increased in the BAL, or the proportions may vary over the course of the disease (table 3 and table 4 and table 7). For these ILDs, even when a particular pattern is more common, the BAL results are not diagnostic.
Idiopathic pulmonary fibrosis — Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP). BAL has a limited role in the diagnosis and management of IPF, as the diagnosis usually depends on the results of a high resolution computed tomography (HRCT) scan and lung biopsy. In patients with IPF, BAL cell counts usually show a several-fold increase in the total number of inflammatory cells [17-23]. However, the percentages of various cell types found in the lavage fluid do not correlate with clinical parameters, or pulmonary function studies. The main value of BAL in these patients is to exclude other processes. Nevertheless, some cell count patterns have been noted and may be helpful. As examples:
- Among patients with suspected IPF, a BAL lymphocyte count less than 30 percent is consistent with IPF, whereas a higher percentage may suggest an alternate diagnosis. As an example, among 74 patients with IPF suggested by the clinical presentation and HRCT scanning, the only patients who were determined to have a non-IPF diagnosis (eg, hypersensitivity pneumonitis, nonspecific interstitial pneumonia) had a BAL lymphocytosis of 30 percent or greater [5].
- Conflicting results have been reported regarding the significance of BAL neutrophilia [24-26]. In the largest series of 156 patients with biopsy proven IPF, each doubling of baseline BAL fluid neutrophil percentage was associated with a 30 percent increase in risk of mortality [26]. In a separate study of 81 IPF patients, BAL fluid neutrophil and lymphocyte counts predicted mortality in current smokers, but not among never smokers or former smokers in an adjusted analysis [25].
- Increased BAL fluid lymphocyte and eosinophil percentages have been variably associated with increased mortality [25,26].
- The value of serial BAL is unclear, due to the absence of large, well-characterized study populations [20].
Nonspecific interstitial pneumonia — Several case series have noted a lymphocytic BAL in patients with nonspecific interstitial pneumonia (NSIP), although others have not found this. It is possible that this reflects varying proportions of patients with cellular versus fibrotic NSIP. In a study that compared BAL cell counts from 35 patients with IPF and 19 with fibrotic NSIP, no significant difference was noted in the numbers or relative proportions of cells [24]. Cryptogenic organizing pneumonia — The consistent, though nonspecific, BAL findings in cryptogenic organizing pneumonitis (COP) include an increased total numbers of cells and often a "mixed pattern" characterized by increases in the total number of macrophages, lymphocytes, neutrophils, and eosinophils. The CD4/CD8 ratio is usually decreased. These findings are discussed further separately.
Connective tissue diseases — BAL appears to have a limited value in the diagnosis, assessment, and monitoring of connective tissue diseases affecting the lung [2,27]. However, BAL may be valuable in clarifying other pulmonary problems which may develop in this setting, including drug-induced pulmonary disease, infection, pulmonary hemorrhage, alveolar proteinosis, and malignancy.
The typical BAL cell counts reported in various connective tissue diseases with and without concomitant ILD are shown in the table . These findings are discussed further under the individual topic reviews.
Drug-induced pulmonary disease — Many drugs have been associated with interstitial lung disease. Examples include amiodarone, methotrexate, nitrofurantoin, chemotherapeutic agents, and cocaine (see appropriate topic reviews). Often the diagnosis is not suspected or is difficult to confirm. BAL may be of value in suggesting the presence of drug-related lung injury, or in ruling out other problems (eg, infection or recurrent malignancy) that are common when chemotherapeutic agents are used [28]. The patterns of BAL findings suggestive of drug-related lung disease .
EOSINOPHILIC BAL — A marked increase in the BAL eosinophil count (≥ 30 percent) is typically a manifestation of idiopathic acute eosinophilic pneumonia, chronic eosinophilic pneumonia (CEP), or tropical pulmonary eosinophilia. More modest increases in BAL eosinophils (<30 percent) may be seen in IPF, sarcoidosis, pulmonary Langerhans cell histiocytosis, drug-induced pneumonitis, coccidioidal infection, and connective tissue diseases affecting the lungs .
Acute eosinophilic pneumonia — Idiopathic acute eosinophilic pneumonia is an acute febrile pneumonitis of less than one week duration with marked eosinophil accumulation in the lungs. At the onset, the chest radiograph may show only subtle reticular or hazy opacities, often with Kerley B lines. However, most patients present with or develop diffuse, mixed alveolar and reticular opacities. BAL eosinophil counts are typically over 25 percent. The differential diagnosis includes drug-induced pneumonitis, tropical pulmonary eosinophilia, fungal infection, and Churg-Strauss syndrome. Chronic eosinophilic pneumonia — Chronic eosinophilic pneumonia (CEP) is a disorder characterized by an indolent onset of dyspnea and a chest radiograph with bilateral peripheral opacities described as the "photographic negative" of pulmonary edema. In a patient with a compatible clinical presentation, a BAL eosinophil count greater than 40 percent is strongly suggestive of CEP.
Eosinophilia and infection — BAL eosinophilia may also be seen in patients with Coccidioidomycosis infection and tropical filarial pulmonary eosinophilia [29,30]. The presentation and diagnosis of these diseases are discussed separately
HEMORRHAGIC BAL — Diffuse pulmonary hemorrhage occurs in a variety of conditions and is frequently a life-threatening event. Patients usually report dyspnea, but hemoptysis is variable. The chest radiograph usually shows new patchy or diffuse alveolar opacities, although recurrent episodes may result in interstitial opacities. Frankly bloody or blood-tinged BAL fluid suggests this diagnosis, particularly when the amount of blood in the effluent increases over three successive lavages.
Additional cytologic findings include the demonstration of hemophagocytosis by alveolar macrophages or the presence of hemosiderin-laden macrophages [2,31-33]. The latter appear approximately 48 hours following the onset of pulmonary hemorrhage [34]. A hemosiderin scoring system has been developed based upon the colorimetric intensity of Prussian blue-stained alveolar macrophages. The score by this system correlates with the degree of pulmonary hemorrhage on histologic sections [35-37]. Scores greater than 100 connote significant hemorrhage, while normal subjects have scores that range from 4 to 25 [38].
Once the diagnosis of pulmonary hemorrhage is confirmed, then the specific cause of the process must be sought [32,38].
OTHER USEFUL BAL FINDINGS — In addition to changes in the number and proportion of cells, other findings in the BAL may be helpful. Some of these are described below and include the presence of lipid-laden macrophages, malignant cells, mineral dust, and an increase in the number of CD1 positive Langerhans cells. The presence of alveolar macrophages with large, lamellated inclusion bodies is consistent with amiodarone use, but not necessarily indicative of amiodarone toxicity.
Chronic microaspiration — Gastroesophageal reflux with aspiration is frequently considered in the differential diagnosis of recurrent pneumonia or atypical, diffuse interstitial opacities. When chronic aspiration is suspected, BAL should be performed in the area of greatest radiographic abnormality (usually the dependent lung zones).
BAL cellularity is increased and the differential reveals increases in lymphocytes, eosinophils, and macrophages. The most important diagnostic finding is the presence of large numbers of lipid-laden macrophages, which is suggestive of chronic aspiration or lipoid pneumonia [39]. Marked vacuolization of the alveolar macrophages is appreciated on routine modified Wright's staining; fat staining with oil-red-O or Sudan black demonstrates the lipid nature of the vacuoles [39]. Multinucleated giant cells may be recovered by BAL and frequently contain lipid droplets within their cytoplasm [40-43].
Malignant cells — Malignancies such as lymphangitic carcinomatosis and pulmonary lymphoma can sometimes present with diffuse interstitial opacities and be diagnosed by BAL [44]. As examples:
- In a series of patients with lymphangitic breast cancer, the BAL cytology revealed metastatic tumor in 10 of the 14 [45].
- Reed-Sternberg cells were identified in the BAL from 6 of 50 patients [44].
- In patients with primary pulmonary lymphoma, lymphocytic alveolitis (> 20 percent lymphocytes) is suggestive. Flow cytometry of BAL fluid can then be used to identify a clonal B-cell population with Ig gene clonal rearrangements [46].
- Pneumoconioses — The diagnosis of occupational lung disease rarely requires tissue biopsy or BAL. However, BAL can sometimes demonstrate respiratory tract deposition and retention of mineral dusts. The amount of mineral dust recovered appears to bear some relationship to the severity of the exposure, but considerable overlap occurs among asymptomatic, exposed workers and those with clinical disease. (See "Asbestosis".) Thus, BAL findings in individual patients must be considered with caution.
The potential usefulness of antigen-specific lymphocyte transformation tests (eg, beryllium) in the diagnosis of specific occupational lung diseases is under investigation. The beryllium lymphocyte proliferation test performed on peripheral blood or BAL fluid has become the standard industry surveillance tool for identifying beryllium-exposed workers who are beryllium-sensitized or in the early stages of chronic beryllium disease. Pulmonary Langerhans cell histiocytosis — The characteristic finding in BAL from patients with pulmonary Langerhans cell histiocytosis is an increase in CD1 positive Langerhans cells to greater than 5 percent of total cells [33]. However, this finding has a low sensitivity and is only found in half of patients.
SUMMARY AND RECOMMENDATIONS
- Bronchoalveolar lavage (BAL) is a minimally invasive procedure performed during flexible fiberoptic bronchoscopy to obtain a sample of alveolar cells.
- Changes in the relative and absolute numbers of cells in BAL fluid have been described in a variety of interstitial lung diseases (ILD). Usually, these changes are nonspecific, but occasionally they are sufficiently characteristic to narrow the differential diagnosis
- In sarcoidosis lung disease, the BAL lymphocyte count and percentage are increased, while the neutrophil and eosinophil percentages are normal . The CD4/CD8 T-lymphocyte ratio (>2) is typically increased in early, active disease, but may be lower in more advanced disease.
- In hypersensitivity pneumonitis, BAL typically shows a marked lymphocytosis (often exceeding 50 percent of the cells recovered), which is uncommon in diseases often considered in the differential diagnosis. The CD4/CD8 ratio is usually decreased (<1).
- A number of ILDs have nonspecific and variable increases in the BAL cell constituents, including idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, connective tissue disease-related ILD, and drug-induced ILD. In these diseases, the role of BAL is largely to exclude other processes
- The main causes of BAL eosinophilia (>25 percent eosinophils) are idiopathic acute eosinophilic pneumonia, chronic eosinophilic pneumonia, and infection (eg, fungal and parasitic).
- In patients with ILD and a compatible clinical presentation, BAL fluid should be examined for the presence of hemosiderin or lipid-laden macrophages, Langerhans cells, and malignant cells that would indicate alveolar hemorrhage, lipoid pneumonia, pulmonary Langerhans histiocytosis, or neoplastic disease, respectively.