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Tuberculosis (TB) remains a worldwide health problem. Treatment, contact tracing and screening of at-risk populations continue to be important issues even in countries with low rates of tuberculosis. In contact tracing, prior BCG vaccination can make interpretation of Mantoux positivity difficult. We had the opportunity to evaluate contacts of a student diagnosed with pulmonary tuberculosis. In the index case's class, 23 of 50 (46%) students screened had TB infection and a further 2 (4%) students had TB disease. Screening was offered to all students in the school (307 students) and 244 students (79%) attended. Students were stratified naturally into classes of ascending age, providing an opportunity to study disease transmission and Mantoux testing in a group who had received BCG at birth. Our findings illustrates that neonatal BCG vaccination has a minimal effect on Mantoux positivity at 12 years and older.

Alpha-1-antitrypsin deficiency is an autosomally inherited disease in which individuals homozygous for the disorder are prone to develop severe emphysema. We report the case of a 43 yr old man with severe deficiency and advanced emphysema and the first experience in Ireland with intravenous alpha-1-antitrypsin replacement. After 1 yr of replacement therapy we report our experience with dosage and frequency of infusion as well as pulmonary function test data before and during treatment.

Serum angiotensin-converting enzyme (ACE) is elevated in many patients with pulmonary sarcoidosis and has been proposed as a measure of disease activity. The present study was designed to evaluate the possible relationship between serum ACE and direct measures of the intensity of the alveolitis of pulmonary sarcoidosis as measured by bronchoalveolar lavage and gallium-67 (67Ga) scans. To accomplish this, 64 measurements of serum ACE, lavage T lymphocytes, and lung uptake of 67Ga were performed in 41 patients with biopsy-proven sarcoidosis. Elevations of serum ACE were found on at least one occasion in 17 patients (41%). However, serum ACE was found to be a poor predictor of the intensity of alveolitis in sarcoidosis as assessed by the quantitation of bronchoalveolar lavage cells that were T lymphocytes and by 67Ga scanning. Elevated serum ACE did not predict which patients would have elevated proportions of lavage T lymphocytes, which patients would demonstrate increased pulmonary uptake of 67Ga, or which patients would have high-intensity alveolitis as defined by a combination of these criteria. These observations suggest that while serum ACE may be useful in diagnosing sarcoidosis, it does not reflect accurately the intensity of the alveolitis of the pulmonary component of this disease.

Evaluation of the gas exchange responses to steady state treadmill exercise of 176 patients with chronic disorders of the lower respiratory tract demonstrated that alveolar disease significantly affects O2 transfer with little effect on CO2 transfer. At exercise levels requiring oxygen delivery 2- to 3-fold above resting levels, patients with interstitial lung disease [idiopathic pulmonary fibrosis (IPF), sarcoidosis, histiocytosis-X (HX)] and "pure" destructive lung disease [alpha l-antitrypsin (alpha IAT) deficiency] demonstrated no ventilation or cardiac limitation, but all exhibited marked reductions in O2 transfer. Strikingly, although resting values of PaO2 were normal or mildly reduced, the average estimated PaO2 at a VO2 of 1 L/min was 47 mmHg in IPF, 65 mmHg in sarcoid, 54 mmHg in HX, and 41 mmHg in alpha IAT deficiency. Comparison of resting and exercise parameters revealed that: (1) exercise studies can uncover alveolar dysfunction in the presence of normal resting parameters, and (2) resting parameters cannot predict the magnitude of O2 related abnormalities induced by exercise. These observations suggest that exercise testing is a useful clinical tool in detecting alveolar disease and gauging the magnitude of abnormalities of O2 transfer.

Alveolitis is thought to precede permanent lung derangement in a variety of interstitial lung diseases (ILD). Bronchoalveolar lavage (BAL) cell differentials can be used to evaluate the intensity of alveolitis, whereas clinical, roentgenographic, and functional studies are insensitive monitors of lung inflammation. As ILD is generally diffuse, unilobar lavage is widely used and presumed to gauge overall lung inflammation. Consistency of lobe to lobe cell differential findings has not been systematically addressed. We analyzed 53 bilateral lobar lavages (right middle lobe and lingula) in 34 patients with sarcoidosis, idiopathic pulmonary fibrosis-collagen vascular disease (IPF-CV) and a group of mixed interstitial diseases. Cellular differentials from each lobe were independently assessed and compared. The sarcoid group, with predominantly T-lymphocytes in BAL, showed excellent interlobar correlation (r = 0.92, p less than 0.001), with only 17% showing a discrepancy of greater than 10% in percentage of T-lymphocytes. In contrast, the IPF-CV group, with predominantly neutrophils in BAL, showed good interlobar correlation (r = 0.79; p less than 0.01), but 35% had a greater than 10% discrepancy in percentage of neutrophils. Finally, the mixed group, with lymphocytes as the predominant cell in BAL, showed poor interlobar correlation (r = 0.58; p greater than 0.10), with 42% showing a greater than 10% discrepancy in percentage of lymphocytes. These results were not explicable on the basis of differences in volume of lavage fluid or total cells recovered, these parameters being remarkably consistent between lobes in the 3 patient groups and in a control group of 8 subjects without ILD. The chest roentgenogram was markedly insensitive to lavage interlobar variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder in which chronic accumulation of neutrophils within the alveolar structures occurs. These cells with their large stores of preformed mediators likely play a major role in subsequent lung derangement. To evaluate the adjunctive use of intermittent high dose "pulse" corticosteroid therapy as a means of inhibiting neutrophil accumulation in the IPF lung, 5 patients were treated in a single blind random fashion with "high dose" corticosteroids (2 g methylprednisolone given intravenously once a week plus 0.25 mg/kg prednisone given orally daily) and 8 patients were treated with "low dose" corticosteroids only (0.25 mg/kg prednisone given orally daily). All patients had biopsy-proved disease in midcourse, and the 2 groups were matched for clinical and physiologic criteria. To evaluate the effect of these therapies on the quantity of neutrophils in the lungs of these patients, both groups underwent bronchoalveolar lavage and 67Ga scanning at the beginning and end of the 6-month study period; both methods gave an estimate of the intensity of the neutrophil alveolitis in these patients. Low dose corticosteroids had little effect on neutrophil accumulation (% neutrophils in lavage, - 5 +/- 8% change from baseline; 67Ga uptake, + 27 +/- 14% change from baseline), whereas high dose corticosteroids significantly reduced neutrophil accumulation (% neutrophils in lavage, - 46 +/- 8% change from baseline, p less than 0.02 compared with that in the low dose group; 67 Ga uptake, - 23 +/- 11% change from baseline, p less than 0.05 compared with that in the low dose group). In addition, 2 patients in the high dose group were reevaluated 6 months after cessation of the intermittent high dose pulse corticosteroids. Both had marked increases in lavage neutrophils compared with when they were receiving the high dose therapy (10 to 22% and 18 to 52%, respectively). These findings suggest that massive doses of intermittent intravenously administered corticosteroids may help to suppress the neutrophil component of the alveolitis of IPF.

Although the etiology of rheumatoid interstitial lung disease (RILD) remains unknown, bronchoalveolar lavage (BAL) has been useful in studying potentially pathogenic mechanisms in this disorder. Previous investigations in patients with rheumatoid arthritis (RA) and RILD revealed abnormal BAL T-lymphocyte subpopulations and a significant elevation in BAL neutrophils. Because neutrophils have been implicated as important effector cells in inflammatory disorders such as ARDS and idiopathic pulmonary fibrosis, we evaluated BAL fluid in patients with RA for neutrophil chemotactic and activating properties and for evidence of neutrophil activation. The BAL fluid from patients with RILD contained significant neutrophil chemotactic activity derived from both lipid and nonlipid components. Evidence for neutrophil stimulation in the lower respiratory tract of patients with RILD was suggested by elevations in both myeloperoxidase activity and immunologically determined levels of human neutrophil elastase in BAL fluid. Free uninhibited elastolytic activity, however, was not demonstrated, suggesting that adequate protease inhibitor levels were present to inhibit active elastase activity. In addition to elevated myeloperoxidase activity, a potential role for neutrophil-derived oxidant injury was indirectly suggested by the enhanced release of superoxide anion (O2-) from resting normal human blood neutrophils challenged with concentrated BAL fluid from patients with RA and interstitial lung disease. Significant correlations were found between physiologic parameters and the percentage of BAL neutrophils, as well as levels of neutrophil-derived mediators. For example, levels of human neutrophil elastase were strongly correlated with diminished diffusion capacity (r = -0.73, p less than 0.001) and reduced forced vital capacity (r = -0.63, p less than 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated 17 clinically unaffected members of three families with an autosomal dominant form of idiopathic pulmonary fibrosis for evidence of alveolar inflammation. Each person in the study was examined by gallium-67 scanning for a general estimate of pulmonary inflammation, and by bronchoalveolar lavage for characterization of the types of recovered cells and their state of activation. Eight of the 17 subjects had evidence of alveolar inflammation on the lavage studies. Supporting data included increased numbers of neutrophils and activated macrophages that released one or more neutrophil chemoattractants, and growth factors for lung fibroblasts--findings similar to those observed in patients with overt idiopathic pulmonary fibrosis. Four of these eight also had a positive gallium scan; in all the other clinically unaffected subjects the scan was normal. During a follow-up of two to four years in seven of the eight subjects who had evidence of inflammation, no clinical evidence of pulmonary fibrosis has appeared. These results indicate that alveolar inflammation occurs in approximately half the clinically unaffected family members at risk of inheriting autosomal dominant idiopathic pulmonary fibrosis. Whether these persons with evidence of pulmonary inflammation but no fibrosis will proceed to have clinically evident pulmonary fibrosis is not yet known.

Alveolar macrophages obtained by bronchoalveolar lavage (BAL) were evaluated by electron dispersive microanalysis (EDX) for the presence of elemental gold. EDX revealed gold in 90% (9/10) of patients with RA who were currently receiving chrysotherapy or who had discontinued chrysotherapy less than 24 months before BAL. All patients who had discontinued chrysotherapy more than 24 months before BAL (range: 3-14 years) were EDX negative (4/4), as were patients with RA who had never received gold therapy (5/5). Seven patients with RA (7/19) had clinical evidence of interstitial lung disease and 12 patients (12/19) had no interstitial lung disease. There was no correlation between chrysotherapy and the development of interstitial lung disease. These results demonstrate that gold is retained for prolonged periods in pulmonary tissue macrophages but do not identify any relationship between gold and chronic rheumatoid lung disease.

Current concepts of the pathogenesis of sarcoidosis suggest that the alveolitis of this disorder is related to increased numbers of mononuclear phagocytes and activated T-lymphocytes within the lung. To determine if 67Ga scanning, a procedure commonly used in the evaluation of inflammation, would be useful in staging the alveolitis of sarcoidosis, we studied 41 patients with this disorder and correlated estimates of pulmonary 67Ga accumulation with clinical, roentgenographic, physiologic, and bronchoalveolar lavage studies in these patients. Although 65% of patients with sarcoidosis showed increased amounts of 67Ga accumulation in the lung compared with control subjects, only weak correlations (r less than +/- 0.42, all comparisons) were found between the degree of gallium uptake and the clinical, roentgenographic, or physiologic data. In contrast, there was a strong correlation of 67Ga uptake and the number of lymphocytes and T-lymphocytes recovered from the lungs of these patients by bronchoalveolar lavage (p less than 0.0001, r greater than or equal to 0.67, both comparisons). This data suggested that gallium uptake reflects the intensity of the T-lymphocytes mediated component of the alveolitis in sarcoidosis. Because 67Ga scans are noninvasive, simple to perform, and widely available, they should prove useful to stage the activity of sarcoidosis and to make decisions regarding therapy directed against the alveolitis of the disease.

Over a three-year period, 281 fiberoptic bronchoalveolar lavage procedures were performed on 119 individuals with interstitial lung disease and 22 normal volunteers. There were no major complications. Less than 5 percent of the procedures were associated with minor complications including (2.5 percent), pneumonitis (0.4 percent), bleeding (0.7 percent) and bronchospasm (0.7 percent); none of these complications required therapy. Those individuals developing complications had a wide range of physiologic findings; functional tests could not predict which subjects were more likely to develop minor complications associated with lavage. These findings suggest that bronchoalveolar lavage for interstitial disease is a safe procedure associated with minor risks.

An inherited deficiency of alpha 1-antitrypsin with blood concentrations less than 80 mg/dl is associated with the accelerated development of emphysema. Current concepts of the pathogenesis of emphysema suggest that an imbalance between neutrophil elastase and alpha 1-antitrypsin in the lung allows neutrophil elastase to work unimpeded to destroy the alveolar structures. Because the common form of the inherited deficiency (homozygous Z) results from impaired hepatic release of alpha 1-antitrypsin, one therapeutic approach to increase plasma and hence lung alpha 1-antitrypsin concentrations is to enhance hepatic release or production of alpha 1-antitrypsin. In a preliminary trial with 6 alpha 1-antitrypsin-deficient subjects, we have previously shown that in 1 month, the impeded androgen danazol can augment serum alpha 1-antitrypsin concentrations by 37%. To evaluate the use of impeded androgens in alpha 1-antitrypsin deficiency on a broader scale, we have treated: 43 homozygous Z patients with danazol 200 mg given orally 3 times a day for 30 days; 6 homozygous Z patients with a similar danazol dose but given for 6 to 18 months; and 7 homozygous Z patients with stanazolol, another synthetic androgen, 2 mg given orally 3 times a day for 30 days. Of the 43 patients treated with danazol for 1 month, 23 (53%) responded with a serum alpha 1-antitrypsin concentration greater than or equal to 20% higher than baseline, an average increase of 52% over the pretreatment concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Rheumatoid arthritis (RA), a systemic disorder of unknown cause, is associated with a variety of well-recognized pulmonary abnormalities including interstitial lung disease. To investigate possible pathogenic events in this disorder, we performed bronchoalveolar lavage (BAL) in 24 patients with classic or definite RA. Using radiographic and physiologic parameters as well as BAL cell differentials, 3 distinct groups emerged. Group I consisted of 9 patients with evidence of clinical interstitial lung involvement. Group II consisted of 5 patients without evidence of clinical interstitial lung disease (normal chest roentgenogram and functional testing) but who had abnormal BAL cellular differentials. The 10 remaining patients (Group III) had no evidence of clinical interstitial lung disease and had normal BAL cell differentials. Bronchoalveolar lavage in Group I had a significantly increased percentage of neutrophils (12.4 +/- 4.2; p less than 0.05) compared with Group II (2.4 +/- 0.8) and Group III (2.9 +/- 0.6). All patients in Group II had elevated BAL lymphocytes (24.4 +/- 6.4) compared with Group I (10.1 +/- 3.8; p greater than 0.05) and Group III (5.4 +/- 0.7; p less than 0.01). Both Groups I and II had detectable IgM in BAL (0.02 +/- 0.01 and 0.04 +/- 0.02 mg/mg of albumin, respectively), whereas Group III patients and normal control subjects did not (p less than 0.01). There was a marked reduction in BAL T-lymphocyte Leu 3/Leu 2A (helper/suppressor) cell ratios in Group I (0.92 +/- 0.02; p less than 0.05) compared with Group II (2.6 +/- 0.6) and Group III (1.6 +/- 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Current concepts of the pathogenesis of pulmonary sarcoidosis suggest that a mononuclear cell alveolitis, comprised of activated T-lymphocytes and activated alveolar macrophages, precedes and modulates the formation of granuloma and fibrosis that characterize the disease. To evaluate the natural history of this alveolitis and determine the relationship it has to subsequent changes in lung function, 19 untreated patients with pulmonary sarcoidosis without extrapulmonary manifestations were studied at 6-month intervals over 10.1 +/- 1.6 months with bronchoalveolar lavage, 67Ga scanning, and pulmonary function tests to evaluate lung T-cells, lung alveolar macrophages, and lung function, respectively. In this group of patients with sarcoidosis, low intensity alveolitis (lung T-cells less than or equal to 28% of all lung effector cells and/or 67Ga scan negative) was much more common (80% of all observations) than high intensity alveolitis (lung T-cells greater than 28% and 67Ga scan positive, 20% of all observations). However, the alveolitis can be unstable; 75% of all episodes of high intensity alveolitis spontaneously reverted to low intensity, whereas 12% of all episodes of low intensity alveolitis spontaneously reverted to high intensity. Furthermore, conventional clinical, roentgenographic, or physiologic studies could not predict the alveolitis status; the low intensity and high intensity groups were indistinguishable by usual criteria (p greater than 0.3, all comparisons). Interestingly, of the 51 alveolitis evaluations in the 19 patients, there were 24 occurrences (47%) where the alveolitis was "split," i.e., 67Ga scans positive and T-cells low (39%) or 67Ga negative and T-cells high (8%). In fact, 79% of all patients had either a positive 67Ga scan and/or high lung T-cells at least once during the study period, suggesting that most untreated patients with sarcoidosis without extrapulmonary symptoms often have some inflammatory processes ongoing in their alveolar structures. Overall, whenever a high intensity alveolitis episode occurred, it was followed by deterioration over the next 6 months in at least one lung function parameter 87% of the time. In contrast, a low intensity alveolitis episode was followed by functional deterioration only 8% of the time. Strikingly, while the alveolitis parameters (lavage and 67Ga scanning) clearly predicted prognosis, clinical, roentgenographic, and physiologic tests could not distinguish those patients who would subsequently deteriorate functionally. These observations should prove useful in understanding the natural history of pulmonary sarcoidosis, in staging patients with this disease, and in making rational therapy decisions.