- Email: [email protected]
Bronchoalveolar lavage and clearance of 99m-Tc-DTPA in asbestos workers without evidence of asbestosis
Br. J. Dis.
Chest
(1985) 79, 251
BRONCHOALVEOLAR LAVAGE AND CLEARANCE OF 99m-Tc-DTPA IN ASBESTOS WORKERS WITHOUT EVIDENCE OF ASBESTOSIS A. R. GELLERT, The Department
J. A. LANGFORD, S. UTHAYAKUMAR AND R. M. RLJDD of Thoracic Bethnal
Medicine, The London Green, London E2
Chest Hospital,
Summary We performed BAL and measured the clearance of 99m-Tc-DTPA in 20 non-smoking subjects (mean age 50, range 36-68 years) occupationally exposed to asbestos (mean duration 14, range 3-30 years). All had normal lung function and none had clinical or radiological evidence of asbestosis. The mean BAL results were: total cells per ml 737 X lo3 (360-1210), percentage macrophages 79 (49-96)) percentage lymphocytes 13 ( l-42)) percentage -neutrophils 8 (l-40), percentage eosinophils 0 (O-3), asbestos bodies per ml 83 (o-550). Eight subjects showed increased percentage of lymphocytes and four others showed increased percentages of neutrophils when compared with normal ranges in our laboratory. Higher percentages of neutrophils correlated with longer duration of exposure to asbestos (r=0.54, X0.025), and shorter time since last exposure to asbestos (r=-0.54, PCO.025). Four subjects showed faster clearance of 99m-Tc-DTPA than was observed in 31 normal non-smoking control subjects. There was a tendency for faster solute clearance to be associated with greater numbers of BAL macrophages (r=-0.39, P
252
Br. J. Dis. Chest: Vol. 79 No. 3
neutrophils and eosinophils and their association with accelerated clearance of 99m-Tc-DTPA in established asbestosis (Gellert et al. 1984b, 1985b). In investigating the possible early diagnosis of asbestosis, we have also reported accelerated clearance of 99m-Tc-DTPA in non-smoking asbestos workers with no evidence of asbestosis (Gellert et al. 1984a, 1985a). This study was designed to examine BAL profiles and to investigate the possible relationship between BAL variables, physiological variables, the clinical history of asbestos exposure and the clearance of inhaled 99m-Tc-DTPA from the lungs in non-smoking asbestos workers with no evidence of asbestosis.
Methods Patients
We studied 20 non-smoking men (mean age 50 years, range 36-68 years) with a history of heavy occupational asbestos exposure. Eight had never smoked and 12 had ceased smoking at least 5 years beforehand. The mean time since first exposure to asbestos was 30.5 years (range 16-62 years) and the mean duration of exposure to asbestos was 14 years (range 3-30 years). The mean time since last exposure was 13 years (range O-44 years). Of the 20 subjects, 15 had been employed in the lagging industry or in the asbestos removal industry and five had carried out asbestos milling or sawingTen subjects had pleural disease but none showed clubbing of the fingers and none had crackles over the lung fields and none of the standard posteroanterior chest radiographs showed interstitial lung disease by International Labour Office criteria (International Labour Office 1980). The study was approved by the hospital’s ethics committee and informed consent was obtained from each subject. Bronchoalveolar
lauage
Bronchoalveolar lavage (BAL) was carried out in all 20 subjects. The procedure was carried out through a fibreoptic bronchoscope using three sequential aliquots of 50 ml of sterile normal saline at 37°C and the sample prepared for total and differential cell counts as previously described (Studdy et al. 1984). Manual counts of regular-shaped and regular-segmented ferroprotein-coated t’ibres, shown in previous work to almost always represent true asbestos bodies (Churg & Warnock 1979; Churg et al. 1979) were carried out on samples prepared as follows; a 20ml aliquot of BAL fluid was centrifuged at 300g for 10 minutes, the deposit was diluted with 0.5 ml of 0.1 M sodium hydroxide and spun at 300g for 10 minutes in a Shandon Cytospin centrifuge to make slides which were air dried and fixed in methanol. Counts per slide were standardized to 1 ml of fluid. Clearance of 99m- Tc-D TPA The half-time clearance of 99m-Tc-DTPA from lungs to blood (T1/2LB) was measured as has been previously described (Gellert et al. 1985a) in all asbestos workers and in a group of 31 non-smoking normal subjects (mean age 40 years, range 24-62 years) with no known exposure to asbestos. Physiological
assessment
The following physiological measurements were made in all patients: forced expiratory volume in one second, forced vital capacity (Morgan dry spirometer), total lung capacity and residual volume (Morgan constant volume body plethysmograph), transfer factor and its membrane and capillary volume components and transfer coefficient (Morgan Transfer Test Model No. TTC), progressive exercise test on a cycle ergometer with measurement of capillary blood gases and oxygen consumption.
Gellert, Langford, Statistical
Uthayakumar et al.: Bronchoalueolar Lauage
253
analysis
The Mann-Whitney U-test (two-tailed) was used for group comparisons of quantitative data and rank correlation coefficient. Non-parametric correlations were assessed using the Spearman statistics were used because data were not normally distributed.
Results BAL cell counts
The mean fluid recovery was 90 ml (range 40-l 10). The mean total cell count per ml of lavage fluid was 737X103 (360-1210). Th e d i ff erential cell counts showed mean percentages of 79 (49-96) for macrophages, 13 (l-42) for lymphocytes, 8 (l-40) for neutrophils and 0 (O-3) for eosinophils. We classified cell percentages and total cell counts as increased in this study if they exceeded values obtained in our laboratory from a middle-aged population without interstitial lung disease: these results show up to 11% lymphocytes, up to 10% neutrophils, and up to 3% eosinophils and total cell counts up to 945X lo3 per ml BAL fluid (Studdy et al. 1984). Eight patients (40%) showed increased lymphocytes and four others (20%) showed increased neutrophils (see Fig. 1). Greater percentages of neutrophils correlated with longer duration of exposure to asbestos (r=0.54, RO.025) and shorter time since last exposure to asbestos (r=-0.54, X0.025). Greater percentages of macrophages correlated with a longer time since first exposure to asbestos (r=0.53, P
Among all 20 asbestos workers the mean number of bodies per ml of BAL fluid was 83 (range O-550), though asbestos bodies were not detected in six subjects. There were no relationships between numbers of asbestos bodies and clinical, physiological or other BAL variables or rate of solute clearance. Clearance of 99m- Tc-D TPA
The mean T1/2LB in the 20 asbestos workers was 55.5 minutes (range 25-84.5), not significantly different from 59.2 minutes (range 41-101) in the 31 normal subjects. In four asbestos workers, solute clearance was faster than in any of the subjects in the control group (25, 30.5, 33 and 40 minutes): three of these subjects showed normal differential cell counts and one (Tl/ZLB 33 minutes) showed 19% lymphocytes. There was a tendency for more accelerated clearance of 99m-Tc-DTPA to be associated with greater numbers of BAL macrophages, but this did not reach statistical significance (r= -0.39, P
Total cells
Macrophages
1200-
l l
;
llOOlOOO-,
5
900-
2 E g "0 2 ; z E
800700600500400300 200 1 IOOO-
l l
I.
-5 i
:
: l -
: Lymphocytes
100 90 y
80
8
70 l l l
Neutrophils
loo-
Eosinophils
gocn 80-
5
70605040-
l
3020lon.
+
Normal range
Asbestos workers
Normal range
Asbestos workers
Fig. 1. BAL profiles in 20 non-smoking asbestos workers with normal ranges in our laboratory. Closed circles indicate results of individual patients. Dotted lines indicate the normal range in our laboratorv. Horizontal bars refer to median values
Gellert, Langford,
Uthayakumar et al.: Bronchoalueolar Lauage
255
Lung function
In all subjects the observed values for all variables were within 2 SD of the predicted values for age and height (Cotes 1979). Within the ranges observed there were weak associations between Kco and higher total BAL cell counts (r=-0.5, P
Discussion
This study has demonstrated that BAL cell profiles in asbestos workers with no clinical or radiological evidence of asbestosis may show increased percentages of neutrophils and lymphocytes and increased total cell counts when compared with normal values in our laboratory. The normal range of total cell counts encountered in our laboratory (mean 249X 10” per ml of BAL fluid, range 48-954, Studdy et al. 1984) is considerably lower than the values from the subjects in the present study and because the majority of cells are macrophages it is evident that an important feature of the BAL profiles of these subjects is an increase in the absolute numbers of macrophages. The finding of increased numbers of macrophages and the association of greater percentages of macrophages with longer time since first exposure to asbestos are compatible with experimental evidence showing that acute exposure to asbestos causes accumulation of macrophages and subsequent attraction of neutrophils into the alveolar structures. Begin et al, (1983) demonstrated macrophage accumulation in the sheep model of the disease and Kagan et al. (1983) reported the enhanced release of an alveolar macroph,age chemoattractant directed against other macrophages after asbestos exposure in rats and suggested that this may explain the peribronchiolar accumulations of macrophages described in early asbestotic lesions (Spencer 1977; Jaurand et al. 1980; Miller et al. 1980; Brody et al. 1981; Craighead et al. 1982). Schoenberger et al. (1982) showed that acute exposure to chrysotile asbestos fibres led to an intense neutrophil alveolitis within 3 days and suggested that neutrophils may be attracted by the release of neutrophil chemotactic factor by alveolar macrophages. Our observations that greater percentages of neutrophils correlated with longer duration of asbestos exposure and with shorter time since last exposure are consistent with these findings. Our findings of increases in percentage neutrophils or percentage lymphocytes in some subjects conflict with those of Bignon et al. (1978) who reported that BAL cell profiles in asbestos-exposed workers with no evidence of asbestosis were normal. However, Bignon and colleagues only studied nine subjects and details regarding the nature and extent of exposure to asbestos were not available. It is likely that the degree of exposure is relevant: McDonald et al. (1980) showed that there is a linear relationship between the development of asbestosis and increasing dust exposure in Canadian chrysotile workers. We have previously
256
Br. J. Dis. Chest:Vol. 79No. 3
found that some patients with established asbestosis had increased lymphocytes while others had increased neutrophils and eosinophils and that the latter group had more advanced disease (Gellert et al. 198413, 1985b). We have previously reported faster clearance of 99m-Tc-DTPA in another group of non-smoking asbestos workers compared with non-smoking normal subjects (Gellert et al. 1984a, 1985a). In the present study the difference in rates of clearance of 99m-Tc-DTPA between asbestos-exposed and control groups did not reach statistical significance. In this study we were unable to include all six subjects from the earlier group in whom solute clearance was accelerated because four declined bronchoalveolar lavage. Because few subjects in this study had accelerated clearance comment on its relationship to BAL profiles must be speculative. We found a tendency for faster solute clearance to be associated with greater numbers of BAL macrophages which may support the key role of the alveolar macrophage in the early stages of the pathogenesis of asbestosis. The early detection of asbestosis remains an important clinical problem because of the suggestion that corticosteroids may be useful in the earliest stages of alveolitis that precede fibrosis Crystal et al. 1981). The suggestion of Begin et al. (1983) that abnormalities in 6c gallium scanning may provide early indicators of asbestos-induced fibrosis must await long-term follow-up for confirmation. Murphy et al. (1984) suggested that auscultation for crackles is a useful method for screening for asbestosis: the absence of crackles in any of our subjects, including those with definite abnormalities in BAL cell profiles does not support this view. Begin et al. (1984) reported that only 80% of 99 patients with asbestosis and only 12% of a group of 67 asbestos workers with increased (j7Ga lung uptake and/or rigid lung pressure-volume curves were found to have crackles and suggested that early peribronchiolar alveolitis was probably better detected by investigative techniques rather than by auscultation for crackles. We conclude that BAL profiles may be abnormal in subjects previously exposed to asbestos but without clinical or radiological evidence of asbestosis. Long-term follow-up of these subjects will show whether or not abnormalities in BAL profiles represent the early stages of development of asbestosis. Acknowledgements Dr Gellert is supported by a grant from the Clinical National Heart and Chest Hospitals.
Research Committee
of the
References Begin, R., Cantin, A., Berthiaume, Y. et al. (1984) Rales in asbestos workers: an auscultation based profusion analysis in relation to early detection and assessment of severity of asbestosis. Am. Rev. resp. Dis 129, Al69 (Abstract). Begin, R., Cantin, A., Drapeau, G. et al. (1983) Pulmonary uptake of gallium-67 in asbestosexposed humans and sheep. Am. Rev. resp. Dis. 127. 623-630. Bignon, J., Atassi, K., Jaurand, M. C. et al. (1978) Cellular and protein content analysis of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and asbestosis. Rev. Fr. Mal. Resp. 6, 353-358.
Gellert, Langford,
Uthayakumar et al.: Bronchoalveolar Lavage
257
Brody, A. R., Hill, L. H., Adkins, B. Jr. & O’Connor, R. W. (1981) Chrysotile asbestos inhalation in rats: deposition pattern and reaction of alveolar epithelium and pulmonary macrophages. Am.
Rev.
resp. Dis.
123: 670-679.
Churg,
A. & Warnock, M. L. (1979) Analysis of the cores of asbestos bodies from members of the general population: patients with probable low-degree exposure to asbestos. Am. Rev. resp. Dis. 120, 781-786. Churg, A., Warnock, M. L. & Green, N. (1979) Analysis of the cores of ferruginous (asbestos) bodies from the general population. II. True asbestos bodies and pseudoasbestos bodies. Lab. Invest. 40, 31-38. Cotes, J. E. (1979) Lung Function Assessment and A,bplication in Medicine, 4th edn. Oxford: Blackwell Scientific, Craighead, J. E., Abraham, J. L., Churg, A. et al. (1982) The pathology of asbestos-associated diseases of the lung and pleural cavities. Archs Path. lab. Med. 106, 544-596. Crystal, R. G., Gadek, J. E., Ferrans, V. J., Fulmer, J. D., Lune B. R. & Hunninghake, G. W. (1981) Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am. J. Med.
Gellert,
70. 542-568.
A. R., Langford, J. A., Winter, R. J. D., Lewis, C., Tolfree, S. E. J. & Rudd, R. M. (1985a) Clearance of 99m-technetium-labelled DTPA in asbestos exposed subjects without clinical or radiological evidence of interstitial lung disease. Br. J. Dis. Chest 79, 37-42. Gellert, A. R., Langford, J. A., Winter, R. J. D. & Rudd, R. M. (1984a) Clearance of 99m-Tc-labelled DTPA in asbestos exposed subjects. Thorax 39, 709 (Abstract). Gellert, A. R., Langford, J. A., Winter, R. J. D., Uthayakumar, S., Sinha, G. & Rudd, R. M. (1985b) Asbestosis: assessment by bronchoalveolar lavage and measurement of pulmonary epithelial permeability. Thorax (in press). Gellert, A. R., Winter, R. J. D., Uthayakumar, S., Langford, J. A. & Rudd R. M. (1984b) Bronchoalveolar lavage and clearance of 99m-Tc-DTPA in asbestosis. Thorax 39, 709 (Abstract). International Labour OfIice (1980) Guidelines for the use of IL0 International Classification of Radiographs of Pneumoconioses. Occup. Saf. Hlth Series No. 22 (Rev. 80). Geneva: ILO. Jaurand, M. C., Gaudichet, A., Atassi, K. et al. (1980) Relationship between the number of asbestos fibers and the cellular and enzymatic content of bronchoalveolar fluid in asbestos exposed subjects. Bull. Eur. Physiopath. Resp. 16, 595-606. Kagan, E., Oghiso, Y. & Hartmann, D. (1983) Enhanced release of a chemoattractant for alveolar macrophages after asbestos inhalation. Am. Rev. resj. Dis. 126, 680-687, McDonald, J. C., Lidell, F. D. K., Gibbs, G. W.: Eyssen, G. E. & McDonald, A. D. (1980) Dust exposure and mortality in chrysotile mining, 1910-1975. Br. J. ind. Med. 37, 1 l-24. Miller, K., Calverley, A. & Kagan, E. (1980) Evidence of a quartz-induced chemotactic factor for guinea pig alveolar macrophages. Environ. Res. 22, 31-39. Murphy R. L. H., Gaensler, E. A., Holford, S. K., Del Bono, E. ‘4. & Epler, G. (1984) Crackles in the early detection of asbestosis. Am. Rev. resp. Dis. 129, 375-379. Schoenberger, C. I., Hunninghake, G. W., Kawanami, O., Ferrans, V. J. & Crystal, R. G. (1982) Role of alveolar macrophages in asbestosis: modulation of neutrophil migration to the lung after acute asbestos exposure. Thorax 37, 803-809. Spencer, H. (1977) Pathology of the Lung (excluding pulmonary tuberculosis): Vol. 1, pp. 423-431. Oxford: Pergamon Press. Studdy, P. R., Rudd, R. M., Gellert, A. R., Uthayakumar, S., Sinha, G. & Geddes, D. M. (1984) Bronchoalveolar lavage in the diagnosis of diffuse pulmonary shadowing. Br. J. Dis. Chest 78, 4&54.
Chest
(1985) 79, 251
BRONCHOALVEOLAR LAVAGE AND CLEARANCE OF 99m-Tc-DTPA IN ASBESTOS WORKERS WITHOUT EVIDENCE OF ASBESTOSIS A. R. GELLERT, The Department
J. A. LANGFORD, S. UTHAYAKUMAR AND R. M. RLJDD of Thoracic Bethnal
Medicine, The London Green, London E2
Chest Hospital,
Summary We performed BAL and measured the clearance of 99m-Tc-DTPA in 20 non-smoking subjects (mean age 50, range 36-68 years) occupationally exposed to asbestos (mean duration 14, range 3-30 years). All had normal lung function and none had clinical or radiological evidence of asbestosis. The mean BAL results were: total cells per ml 737 X lo3 (360-1210), percentage macrophages 79 (49-96)) percentage lymphocytes 13 ( l-42)) percentage -neutrophils 8 (l-40), percentage eosinophils 0 (O-3), asbestos bodies per ml 83 (o-550). Eight subjects showed increased percentage of lymphocytes and four others showed increased percentages of neutrophils when compared with normal ranges in our laboratory. Higher percentages of neutrophils correlated with longer duration of exposure to asbestos (r=0.54, X0.025), and shorter time since last exposure to asbestos (r=-0.54, PCO.025). Four subjects showed faster clearance of 99m-Tc-DTPA than was observed in 31 normal non-smoking control subjects. There was a tendency for faster solute clearance to be associated with greater numbers of BAL macrophages (r=-0.39, P
252
Br. J. Dis. Chest: Vol. 79 No. 3
neutrophils and eosinophils and their association with accelerated clearance of 99m-Tc-DTPA in established asbestosis (Gellert et al. 1984b, 1985b). In investigating the possible early diagnosis of asbestosis, we have also reported accelerated clearance of 99m-Tc-DTPA in non-smoking asbestos workers with no evidence of asbestosis (Gellert et al. 1984a, 1985a). This study was designed to examine BAL profiles and to investigate the possible relationship between BAL variables, physiological variables, the clinical history of asbestos exposure and the clearance of inhaled 99m-Tc-DTPA from the lungs in non-smoking asbestos workers with no evidence of asbestosis.
Methods Patients
We studied 20 non-smoking men (mean age 50 years, range 36-68 years) with a history of heavy occupational asbestos exposure. Eight had never smoked and 12 had ceased smoking at least 5 years beforehand. The mean time since first exposure to asbestos was 30.5 years (range 16-62 years) and the mean duration of exposure to asbestos was 14 years (range 3-30 years). The mean time since last exposure was 13 years (range O-44 years). Of the 20 subjects, 15 had been employed in the lagging industry or in the asbestos removal industry and five had carried out asbestos milling or sawingTen subjects had pleural disease but none showed clubbing of the fingers and none had crackles over the lung fields and none of the standard posteroanterior chest radiographs showed interstitial lung disease by International Labour Office criteria (International Labour Office 1980). The study was approved by the hospital’s ethics committee and informed consent was obtained from each subject. Bronchoalveolar
lauage
Bronchoalveolar lavage (BAL) was carried out in all 20 subjects. The procedure was carried out through a fibreoptic bronchoscope using three sequential aliquots of 50 ml of sterile normal saline at 37°C and the sample prepared for total and differential cell counts as previously described (Studdy et al. 1984). Manual counts of regular-shaped and regular-segmented ferroprotein-coated t’ibres, shown in previous work to almost always represent true asbestos bodies (Churg & Warnock 1979; Churg et al. 1979) were carried out on samples prepared as follows; a 20ml aliquot of BAL fluid was centrifuged at 300g for 10 minutes, the deposit was diluted with 0.5 ml of 0.1 M sodium hydroxide and spun at 300g for 10 minutes in a Shandon Cytospin centrifuge to make slides which were air dried and fixed in methanol. Counts per slide were standardized to 1 ml of fluid. Clearance of 99m- Tc-D TPA The half-time clearance of 99m-Tc-DTPA from lungs to blood (T1/2LB) was measured as has been previously described (Gellert et al. 1985a) in all asbestos workers and in a group of 31 non-smoking normal subjects (mean age 40 years, range 24-62 years) with no known exposure to asbestos. Physiological
assessment
The following physiological measurements were made in all patients: forced expiratory volume in one second, forced vital capacity (Morgan dry spirometer), total lung capacity and residual volume (Morgan constant volume body plethysmograph), transfer factor and its membrane and capillary volume components and transfer coefficient (Morgan Transfer Test Model No. TTC), progressive exercise test on a cycle ergometer with measurement of capillary blood gases and oxygen consumption.
Gellert, Langford, Statistical
Uthayakumar et al.: Bronchoalueolar Lauage
253
analysis
The Mann-Whitney U-test (two-tailed) was used for group comparisons of quantitative data and rank correlation coefficient. Non-parametric correlations were assessed using the Spearman statistics were used because data were not normally distributed.
Results BAL cell counts
The mean fluid recovery was 90 ml (range 40-l 10). The mean total cell count per ml of lavage fluid was 737X103 (360-1210). Th e d i ff erential cell counts showed mean percentages of 79 (49-96) for macrophages, 13 (l-42) for lymphocytes, 8 (l-40) for neutrophils and 0 (O-3) for eosinophils. We classified cell percentages and total cell counts as increased in this study if they exceeded values obtained in our laboratory from a middle-aged population without interstitial lung disease: these results show up to 11% lymphocytes, up to 10% neutrophils, and up to 3% eosinophils and total cell counts up to 945X lo3 per ml BAL fluid (Studdy et al. 1984). Eight patients (40%) showed increased lymphocytes and four others (20%) showed increased neutrophils (see Fig. 1). Greater percentages of neutrophils correlated with longer duration of exposure to asbestos (r=0.54, RO.025) and shorter time since last exposure to asbestos (r=-0.54, X0.025). Greater percentages of macrophages correlated with a longer time since first exposure to asbestos (r=0.53, P
Among all 20 asbestos workers the mean number of bodies per ml of BAL fluid was 83 (range O-550), though asbestos bodies were not detected in six subjects. There were no relationships between numbers of asbestos bodies and clinical, physiological or other BAL variables or rate of solute clearance. Clearance of 99m- Tc-D TPA
The mean T1/2LB in the 20 asbestos workers was 55.5 minutes (range 25-84.5), not significantly different from 59.2 minutes (range 41-101) in the 31 normal subjects. In four asbestos workers, solute clearance was faster than in any of the subjects in the control group (25, 30.5, 33 and 40 minutes): three of these subjects showed normal differential cell counts and one (Tl/ZLB 33 minutes) showed 19% lymphocytes. There was a tendency for more accelerated clearance of 99m-Tc-DTPA to be associated with greater numbers of BAL macrophages, but this did not reach statistical significance (r= -0.39, P
Total cells
Macrophages
1200-
l l
;
llOOlOOO-,
5
900-
2 E g "0 2 ; z E
800700600500400300 200 1 IOOO-
l l
I.
-5 i
:
: l -
: Lymphocytes
100 90 y
80
8
70 l l l
Neutrophils
loo-
Eosinophils
gocn 80-
5
70605040-
l
3020lon.
+
Normal range
Asbestos workers
Normal range
Asbestos workers
Fig. 1. BAL profiles in 20 non-smoking asbestos workers with normal ranges in our laboratory. Closed circles indicate results of individual patients. Dotted lines indicate the normal range in our laboratorv. Horizontal bars refer to median values
Gellert, Langford,
Uthayakumar et al.: Bronchoalueolar Lauage
255
Lung function
In all subjects the observed values for all variables were within 2 SD of the predicted values for age and height (Cotes 1979). Within the ranges observed there were weak associations between Kco and higher total BAL cell counts (r=-0.5, P
Discussion
This study has demonstrated that BAL cell profiles in asbestos workers with no clinical or radiological evidence of asbestosis may show increased percentages of neutrophils and lymphocytes and increased total cell counts when compared with normal values in our laboratory. The normal range of total cell counts encountered in our laboratory (mean 249X 10” per ml of BAL fluid, range 48-954, Studdy et al. 1984) is considerably lower than the values from the subjects in the present study and because the majority of cells are macrophages it is evident that an important feature of the BAL profiles of these subjects is an increase in the absolute numbers of macrophages. The finding of increased numbers of macrophages and the association of greater percentages of macrophages with longer time since first exposure to asbestos are compatible with experimental evidence showing that acute exposure to asbestos causes accumulation of macrophages and subsequent attraction of neutrophils into the alveolar structures. Begin et al, (1983) demonstrated macrophage accumulation in the sheep model of the disease and Kagan et al. (1983) reported the enhanced release of an alveolar macroph,age chemoattractant directed against other macrophages after asbestos exposure in rats and suggested that this may explain the peribronchiolar accumulations of macrophages described in early asbestotic lesions (Spencer 1977; Jaurand et al. 1980; Miller et al. 1980; Brody et al. 1981; Craighead et al. 1982). Schoenberger et al. (1982) showed that acute exposure to chrysotile asbestos fibres led to an intense neutrophil alveolitis within 3 days and suggested that neutrophils may be attracted by the release of neutrophil chemotactic factor by alveolar macrophages. Our observations that greater percentages of neutrophils correlated with longer duration of asbestos exposure and with shorter time since last exposure are consistent with these findings. Our findings of increases in percentage neutrophils or percentage lymphocytes in some subjects conflict with those of Bignon et al. (1978) who reported that BAL cell profiles in asbestos-exposed workers with no evidence of asbestosis were normal. However, Bignon and colleagues only studied nine subjects and details regarding the nature and extent of exposure to asbestos were not available. It is likely that the degree of exposure is relevant: McDonald et al. (1980) showed that there is a linear relationship between the development of asbestosis and increasing dust exposure in Canadian chrysotile workers. We have previously
256
Br. J. Dis. Chest:Vol. 79No. 3
found that some patients with established asbestosis had increased lymphocytes while others had increased neutrophils and eosinophils and that the latter group had more advanced disease (Gellert et al. 198413, 1985b). We have previously reported faster clearance of 99m-Tc-DTPA in another group of non-smoking asbestos workers compared with non-smoking normal subjects (Gellert et al. 1984a, 1985a). In the present study the difference in rates of clearance of 99m-Tc-DTPA between asbestos-exposed and control groups did not reach statistical significance. In this study we were unable to include all six subjects from the earlier group in whom solute clearance was accelerated because four declined bronchoalveolar lavage. Because few subjects in this study had accelerated clearance comment on its relationship to BAL profiles must be speculative. We found a tendency for faster solute clearance to be associated with greater numbers of BAL macrophages which may support the key role of the alveolar macrophage in the early stages of the pathogenesis of asbestosis. The early detection of asbestosis remains an important clinical problem because of the suggestion that corticosteroids may be useful in the earliest stages of alveolitis that precede fibrosis Crystal et al. 1981). The suggestion of Begin et al. (1983) that abnormalities in 6c gallium scanning may provide early indicators of asbestos-induced fibrosis must await long-term follow-up for confirmation. Murphy et al. (1984) suggested that auscultation for crackles is a useful method for screening for asbestosis: the absence of crackles in any of our subjects, including those with definite abnormalities in BAL cell profiles does not support this view. Begin et al. (1984) reported that only 80% of 99 patients with asbestosis and only 12% of a group of 67 asbestos workers with increased (j7Ga lung uptake and/or rigid lung pressure-volume curves were found to have crackles and suggested that early peribronchiolar alveolitis was probably better detected by investigative techniques rather than by auscultation for crackles. We conclude that BAL profiles may be abnormal in subjects previously exposed to asbestos but without clinical or radiological evidence of asbestosis. Long-term follow-up of these subjects will show whether or not abnormalities in BAL profiles represent the early stages of development of asbestosis. Acknowledgements Dr Gellert is supported by a grant from the Clinical National Heart and Chest Hospitals.
Research Committee
of the
References Begin, R., Cantin, A., Berthiaume, Y. et al. (1984) Rales in asbestos workers: an auscultation based profusion analysis in relation to early detection and assessment of severity of asbestosis. Am. Rev. resp. Dis 129, Al69 (Abstract). Begin, R., Cantin, A., Drapeau, G. et al. (1983) Pulmonary uptake of gallium-67 in asbestosexposed humans and sheep. Am. Rev. resp. Dis. 127. 623-630. Bignon, J., Atassi, K., Jaurand, M. C. et al. (1978) Cellular and protein content analysis of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and asbestosis. Rev. Fr. Mal. Resp. 6, 353-358.
Gellert, Langford,
Uthayakumar et al.: Bronchoalveolar Lavage
257
Brody, A. R., Hill, L. H., Adkins, B. Jr. & O’Connor, R. W. (1981) Chrysotile asbestos inhalation in rats: deposition pattern and reaction of alveolar epithelium and pulmonary macrophages. Am.
Rev.
resp. Dis.
123: 670-679.
Churg,
A. & Warnock, M. L. (1979) Analysis of the cores of asbestos bodies from members of the general population: patients with probable low-degree exposure to asbestos. Am. Rev. resp. Dis. 120, 781-786. Churg, A., Warnock, M. L. & Green, N. (1979) Analysis of the cores of ferruginous (asbestos) bodies from the general population. II. True asbestos bodies and pseudoasbestos bodies. Lab. Invest. 40, 31-38. Cotes, J. E. (1979) Lung Function Assessment and A,bplication in Medicine, 4th edn. Oxford: Blackwell Scientific, Craighead, J. E., Abraham, J. L., Churg, A. et al. (1982) The pathology of asbestos-associated diseases of the lung and pleural cavities. Archs Path. lab. Med. 106, 544-596. Crystal, R. G., Gadek, J. E., Ferrans, V. J., Fulmer, J. D., Lune B. R. & Hunninghake, G. W. (1981) Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am. J. Med.
Gellert,
70. 542-568.
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