A critical evaluation of bronchoalveolar lavage. Criteria for identifying unsatisfactory specimens.

In a multicenter, city-wide study of the use of bronchoalveolar lavage for the evaluation of diffuse interstitial lung diseases, the occurrence of specimens unsuitable for analysis was evaluated. Using a standardized bronchoscopy technique, 26 physicians obtained 1,588 lavage specimens from 787 patients over a 52-month period. After transport to and processing in one laboratory using standardized procedures, all specimens were interpreted by one pathologist. Specimens were considered unsatisfactory if they contained: (1) a paucity of alveolar macrophages (i.e., less than ten alveolar macrophages/high-power field), (2) excessive numbers of airway-derived cells (i.e., more than the alveolar macrophages present), (3) a mucopurulent exudate, (4) cells altered by degeneration or (5) laboratory artifacts. Using these criteria, 30.4% of the specimens were considered unsuitable for analysis. There were no significant differences in the frequency of unsatisfactory specimens among participating physicians and institutions or between smoking and nonsmoking patients. Appraisal of alveolar inflammatory and immune effector cells in bronchoalveolar lavage specimens from patients with interstitial lung disease should include an assessment for contamination from airways proximal to the terminal bronchioles before conclusions are drawn about the activity of alveolar inflammation.

Lung inflammation in scleroderma: clinical, radiographic, physiologic and cytopathological features.

Twenty-five patients with systemic sclerosis were studied by chest radiography, lung function, esophageal motility, gallium-67 (67Ga) lung scanning and bronchoalveolar lavage (BAL). Alveolar inflammation, as defined by an elevation of proportional BAL lymphocyte or neutrophil counts, or increased thoracic uptake of 67Ga was found in 16 patients. An NIH gallium index greater than 65 index units identified a subgroup of patients with a significantly higher proportional BAL lymphocyte count (13.7 +/- 8.5 vs 5.6 +/- 3.1, p less than 0.0005). The presence of an abnormal chest radiograph correlated with physiologic evidence of lung restriction (p less than 0.01), and an elevation of proportional BAL lymphocyte count (15.5 +/- 8.2 vs 6.6 +/- 5.1, p less than 0.01). Eight patients receiving oral penicillamine therapy had significantly lower BAL lymphocyte counts compared to untreated patients (4.7 +/- 3.6 vs 11.3 +/- 7.7, p less than 0.05). We suggest that alveolar inflammation in scleroderma is characterized by lymphocyte accumulation and increased thoracic uptake of gallium.

Assessment of drug disposition in the lung.

Airway disposition of drugs is assessed with either physiological changes in lung mechanics or nuclear scanning of the tagged medication. Several methods have been described for assessment of the pulmonary disposition of drugs delivered by routes other than the airways. These methods include tissue biopsy and sputum analysis of pooled secretions and tracheal washings. More recently, bronchoalveolar lavage fluid has been analysed for a variety of pharmacological agents and comparisons drawn between blood and lavage supernatant levels. Problems in correcting for dilution have been overcome by using a naturally occurring tracer substance, such as creatinine or albumin, which has a similar molecular weight to the test chemicals and which can be assayed readily in blood and lavage fluid. It has become apparent that neither naturally occurring not exogenous chemicals enter the lung in a concentration that is predictable from their levels in the blood. While the alpha 2-macroglobulin level in lavage fluid is approximately 25 times less than that in serum, a 1:1 relationship exists for alpha 1-antitrypsin. Cortisol achieves a concentration in lung fluid equal to that of blood, but lung fluid concentrations of methylprednisolone and prednisone are one-half, or at best one-third, of the blood concentration, respectively. Knowledge regarding the penetration of antibiotics into the lung is useful in determining the potential effectiveness of a given agent and its likely acinar MIC. It appears that the alveolar-capillary unit is not freely permeable to all agents, raising the possibility that a blood-lung barrier exists which is responsible for maintaining the alveolar environment. The knowledge that there is a differential permeability among drugs makes it important for clinicians to assess this characteristic of each agent before conclusions linking dose and response are drawn.

Pulmonary disposition of moxalactam.

Moxalactam is a new synthetic oxa-beta-lactam antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It has proven clinical efficacy in pneumonia caused by a variety of infecting organisms. Therapeutic concentrations of moxalactam are achieved in most body tissues and fluids, including pleural fluid and sputum. However, assessment of the adequacy of lung tissue levels in pneumonia requires the sampling of material at an alveolar level. We performed bronchoalveolar lavage (BAL) in 13 patients one hour after they had been given moxalactam intravenously in doses ranging from 250 mg to 2 g. Absolute alveolar drug levels ranged from less than 1 to 6 micrograms/ml, and serum levels from 8 to 50 micrograms/ml. When expressed per micromole of creatinine, there was a significant relationship (r = 0.85; p less than 0.01) between serum and alveolar moxalactam levels in those patients in whom the drug concentration could be quantified accurately in BAL fluid.

An in vitro gallium-67 lung index for the evaluation of sarcoidosis.

In the evaluation of the active alveolitis of pulmonary sarcoidosis, both the proportional lymphocyte count obtained by bronchoalveolar lavage and state of activation of the alveolar macrophage by gallium scanning are required. We injected 6 mCi (200 MBq) of 67Ga intravenously on 24 occasions in 13 patients with biopsy-proved sarcoidosis. Forty-eight hours later, patients were scanned with a rectilinear scanner and the generated scintigrams were evaluated using the NIH index. Seventy-two hours after injection, bronchoalveolar lavage was performed, and venous blood was sampled. The harvested lavage fluid was analyzed for absolute and proportional cell counts, and radioactivity was measured in blood and BAL fluid. An in vitro 67Ga index was generated and expressed as counts/100,000 alveolar macrophages/ml blood (mean, 0.0146 +/- 0.0087 SD). There was a significant relationship between the in vitro index and proportional lymphocyte BAL counts (r = 0.79; p less than 0.002) that was comparable to that obtained using the NIH index (r = 0.74; p less than 0.005). These data suggest that the in vitro index might offer a more objective assessment of 67Ga uptake by the lung, but this would require validation against clinical parameters in a prospective study.

Prednisone and methylprednisolone disposition in the lung.

To compare the penetrability of methylprednisolone into lung tissue with that of prednisone, blood and bronchoalveolar lavage (BAL) fluid levels of methylprednisolone and prednisone were measured in 17 patients with a variety of lung diseases. To correct for variations in the quantity of lung fluid obtained by BAL, steroid levels were expressed in relation to creatinine concentrations. The level of methylprednisolone penetration in the pulmonary parenchyma, expressed by the slope of the relation between blood and BAL fluid, was 0.5 (r = 0.8; p less than 0.03). By contrast, despite serum levels of between 59 and 219 ng/ml, prednisone could not be detected in the BAL fluid in 3 patients; the overall correlation between blood and BAL fluid for all patients was r = 0.5 (slope = 0.3; p less than 0.1). Thus methylprednisolone is better able than prednisone to penetrate lung acini.

Bronchoalveolar lavage in asbestosis.

The interstitial lung disease associated with asbestosis is unique in that the etiological agent and its effects on the pulmonary parenchyma can be studied on a serial basis using bronchoalveolar lavage. In this way both disease activity and structural derangements can be assessed and used in the treatment of the affected individual. In this review, attention has been drawn to the cascade of inflammatory changes induced by asbestos fibers. The activated inflammatory cells are responsible for the alveolitis characteristic of this condition. Like the other forms of diffuse interstitial lung disease, it is the alveolitis that precedes and predicts eventual fibrosis.

Pulmonary disposition of tobramycin.

Each antibiotic has a characteristic penetration into respiratory secretions, influenced by serum concentration, protein binding, transport systems, and the presence of infection. Whereas previous studies have used only bronchial secretions and blood, in the present study, blood, bronchial secretions, and bronchoalveolar lavage (BAL) fluid were analyzed for tobramycin levels. In 10 studies in 9 patients, serum levels were significantly related to BAL fluid levels (r = 0.8, p less than 0.01) when both were expressed as a function of creatinine (mean BAL level +/- SD = 144 +/- 124 micrograms/mg creatinine; serum level, 293 +/- 216 micrograms/mg creatinine). The level of drug penetration in BAL fluid, expressed by the slope of the relationship between blood and fluid, was 0.5. The penetration of tobramycin into bronchial secretions ranged from 0 to 1.4 micrograms/ml, the ratio of secretions to serum being 0.2 (r = 0.68; p less than 0.05). It is concluded that the disposition of tobramycin in bronchial secretions and BAL fluid differ. Thus, sampling both fluids offers a more suitable method to study antibiotic pharmacokinetics in bronchi and alveoli.

Arterial PCO2 as an index of activity in fibrosing alveolitis.

Alveolar hyperventilation is a characteristic feature of the interstitial lung diseases, yet its pathogenesis remains unknown. We examined the relationship between inflammatory alveolar acinar cell counts and the steady state, resting arterial PCO2 in patients with fibrosing alveolitis. To eliminate the influence of overwhelming mechanical lung restriction or resting hypoxemia, we studied 20 patients who, despite having clinicopathologically confirmed fibrosing alveolitis, had vital capacities exceeding 50 percent of predicted, and arterial O2 saturations above 90 percent. There was a significant inverse relationship between the proportion of polymorphonuclear leukocytes (PMNs) in the recovered BAL fluid and the arterial PCO2 (r = -0.67; p less than 0.01). When PCO2 was above 35 mm Hg, the BAL PMN count was 8 percent or less (mean = 3.4; SD = 2.5), while the mean BAL PMN count among those patients whose PCO2 was less than 35 mm Hg was significantly higher (mean = 11.7; SD = 3.7; p less than 0.01). PCO2 levels were unrelated to arterial O2 saturation or PaO2. No relationship was found between the PCO2 and BAL lymphocyte counts. The findings suggest that in fibrosing alveolitis, the arterial PCO2 may be used as an indicator of the state of the inflammatory component of the alveolitis.

Pulmonary disposition of gallium-67 in humans: concise communication.

Pulmonary gallium-67 imaging for inflammatory and neoplastic diseases has become an important diagnostic tool in respiratory medicine. However, the extent to which Ga-67 is delivered to normal lungs has not been fully evaluated. Accordingly, we measured the disposition of Ga-67 using scintiscanning, bronchoalveolar lavage (BAL), and blood analysis in healthy subjects. Following an intravenous dose of 6 mCi Ga-67 citrate, the gallium scan showed no pulmonary uptake at 48 hr. In all subjects, radioactivity was detected in both blood and recovered BAL fluid at 72 hr, being predominantly in the cellular component of the BAL washings. We conclude that despite negative pulmonary imaging, Ga-67 accumulates in the cells that line the alveolar acini of normal nonsmoking individuals.

Pulmonary disposition of cortisol.

High-dose corticosteroid therapy is used in various lung diseases, yet it is not known if the drug enters the alveolar acinus. Cortisol levels, expressed as a function of albumin concentration, were measured in serum and bronchoalveolar lavage fluid in 12 patients with lung disease. There was a linear relation of cortisol concentration between blood level and bronchoalveolar lavage fluid level when expressed in relation to the albumin concentration (r = 0.93, p less than 0.001). Incremental doses of intravenous hydrocortisone reach alveolar structures in a concentration directly related to the circulating blood levels.

Proportional analysis of respiratory cells obtained by bronchoalveolar lavage.

Bronchoalveolar lavage was performed during fibreoptic bronchoscopy in 17 patients with biopsy-proven interstitial lung disease and in 12 control subjects who had focal lesions in the lung. The volume of fluid recovered was unrelated to disease activity or diagnosis. In the control subjects alveolar macrophages represented over 95% of the lavaged cells. The proportion of lymphocytes in the lavaged cells enabled a natural division of the diffuse interstitial lung diseases into two categories: active sarcoidosis, indicated by a large proportion of lymphocytes but a normal proportion of polymorphonuclear leukocytes; and idiopathic pulmonary fibrosis and asbestosis, indicated by a normal proportion of lymphocytes but a variable proportion of polymorphonuclear leukocytes. Bronchoalveolar lavage is a safe and well tolerated method for evaluating the role of alveolitis in diffuse interstitial lung disease through the sampling of respiratory alveolar cells.