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Bronchoalveolar lavage and 99mTc-DTPA clearance as prognostic factors in asbestos workers with and without asbestosis
Respiratory
Medicine
(1993) 87,365-374
Bronchoalveolar lavage and 99mTc-DTPA clearance as prognostic factors in asbestos workers with and without asbestosis N. AL JARAD, A. R. GELLERT AND R. M. RUDD* The London Chest Hospital,
Bower
Road, London E2 9JX, U.K.
The aims of this study are to investigate the change-over time of lung function and chest radiographic findings in patients with asbestosis (AS) and asbestos workers without asbestosis (AW). Secondly, to correlate these changes with broncho-alveolar lavage (BAL) profiles and with lung epithelial permeability, as detected by half-time lungto-blood (ti LB) clearance of an inhaled aerosol of diethylene triamine pentacetate labelled with technetium 99 (99mTc-DTPA) obtained a mean period of 4.2 yr (range 2.3-58) previously. Thirty-three patients with asbestosis and 24 asbestos workers with substantial asbestos exposure were followed-up. Nineteen healthy smokers (HS) with no asbestos exposure who were followed up for a mean period of 3.9 yr were taken as a control group for spirometric changes. Compared with AW, FEV,, FVC and 7tCO were lower in AS (P
2 October
1991 and accepted
correspondence
0954-61 I l/93/050365+
should 10 %08.00/O
in revised
be addressed.
form 4 June 1992.
alveolitis (1,2). Identification of prognostic factors could be useful in planning trials of therapy. Differential cell counts in BAL fluid provide information about the likely rate of progression, and response to treatment, in cryptogenic fibrosing alveolitis (CFA) (3), a disease with many similarities to asbestosis. Several studies have suggested that DTPA clearance may be an index of lung epithelial permeability (4), and that it is accelerated in many interstitial lung diseases (5-8). Abnormal BAL cell counts and accelerated DTPA clearance in asbestos workers with and without asbestosis have been previously demonstrated (9-12). @ 1993 Baillidre Tindall
366
N. Al Jarad et al.
Table I rlLB
AS patients:
No.
Age 64
1 2 3 4 5 6 I 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 21 28 29 30
36 46 49 49 50 52 54 56 56 56 57 57 58 59 59 61 62 62 64 65 64 66 68 68 12 13 16 77 78 58
Mean*
60 9.6
SD
demographic
Sex
Smoking
M M M M M M M M M M M M M M F M
Current Ex Ex Ex Current
M M M M M M M M M M M M M M
data,
baseline
Duration of exposure (yr)
Current Current Ex Ex Never Current Current Current Ex Current Current Ex Current Ex Ex Ex Ex Ex Ex Current Ex Never Ex
Baseline lung functions expressed as % BAL profiles expressed as total cells ( x L, lymphocytes; N + E, neutrophils plus *For percentages of BAL profiles these
lung function,
Time since first exposure W
in lung function,
baseline
dFEV, FEV,
FVC
7X0
KC0
yrr
BAL
profiles
dFVC (1)
70 100 59 16 55 61 66 105 101 85 107 81 89 66 81 69 48 71 134 58 62 81 64 102 12 80 51 53 103 64
71 100 16 82 50 63 84 96 103 99 93 82 100 67 71 90 84 81 91 47 66 88 83 93 69 74 71 13 91 80
60 88 69 75 36 52 49 83 88 47 86 83 83 51 71 68 79 66 38 46 55 81 64 67 64 75 47 89 62 54
89 105 114 119 16 81 12 106 123 64 140 114 103 96 103 85 109 127 53 124 138 200 81 109 96 122 56 113 51 61
0.06 0.25 0.00 0.10 0.04 0.08 0.20 0.10 0.23 0.04 0.08 0.10 0.15 0.08 0.13 0.09 0.13 0.00 0.08 0.07 0.08 0.08 0.15 0.15 0.08 0.08 0.08 0.1 0.15 0.33
0.02 0.24 0.23 0.18 0.11 0.10 0.30 0.30 0.30 0.08 0.07 0.15 0.08 0.15 0.15 0.22 0.15 0.07 0.02 0.02 0.02 0.23 0.10 0.23 0.15 0.08 0.16 0.25 0.10 0.50
17.7 11.8
31.6 7.1
II 20.3
81 14.3
66 15.6
101 31.2
0.11 0.07
0.16 0.1
of predicted. 10’ ml-‘) and % of total BAL eosinophils; M, macrophages; figures are median.
ASSESSMENT
A total of 73 patients (37 AS and 36 AW) had previously been assessed. They were 17 current smokers,
cells. ASB = no. of asbestosis
bodies
per ml of BAL
and
yr- ’
(1)
22 31 24 38 35 38 35 40 29 38 40 41 34 33 40 37 43 24 51 50 44 40 32 51 30 36 34 51 39 38
Patients and Methods PATIENT
declines
5 17 16 4 25 26 12 36 9 25 30 30 1 13 19 17 2 1 41 27 40 6 3 29 13 13 13 31 18 8
In this study clinical examination, plain chest radiograph and lung function tests, were carried out in asbestos workers with no evidence of asbestosis (AW), and patients with asbestosis (AS), on whom BAL and DTPA clearance had been performed previously, to determine the prognostic value of these indicators.
THE INITIAL
annual
fluid.
41 ex-smokers, and 15 non-smokers. Forty-eight patients had worked in the lagging industry and the rest had carried out asbestos cutting, milling and spinning. The diagnosis of asbestosis had been made on the basis of previous asbestos exposure, persistent late inspiratory crackles over the lung bases and predominantly middle and lower lung-zone radiographic shadowing, consisting usually of small, irregular opacities and often associated with pleural thickening or calcification. Duration of asbestos exposure and time since first exposure had been assessed. A posterior-anterior chest radiograph was performed in all patients. Spirometry was performed using a dry
Prognostic
dIIC0 W)
yr-’
dKC0 yr-’ W)
Total Cells
0.08 0.00
0.06 0.03
1460 383
131 126
9 33
73 27
0.23 0.43 0.48
0.01 0.15 0.11
600 380 386 510 810 370 480 639
156 8 8 5 32 170 106 300
26 2 2 1 4 46 22 47
66 236 54 61 81 4 34 26
660 636 636
13 6 32
2 1 5
33 159 159
264
37
14
180
480 435 463
34 109 9 9 71 31
7 25 2 2 13 6
438 -
35
8
48
548 244
68 76
8
89 75
0.05 0.11
0.34 0 0.31 0.09 0.29
0.03 0.09
0.18 0.15
436 548 510
bellows spirometer (Vitalograph) or a dry cylinder spirometer (PK Morgan) and single-breath carbon monoxide transfer factor and coefficient using TCC transfer factor machines (PK Morgan). Bronchoalveolar lavage Bronchoalveolar lavage was carried out through a fibre optic bronchoscope with three sequential aliquots of 50 ml of sterile normal saline at 37°C and the sample was analysed for total differential cell counts as previously described (13). Manual counts of regular shaped and regular segmented ferroprotein-coated fibres were carried out on samples prepared as follows: a 20 ml aliquot of BAL fluid was centrifuged at 300g for 10 min, the deposit was diluted with 0.5 ml of 0.1 M sodium hydroxide and spun at 300g for 10min in a
245 13 60 35 82 199
factorsfor
asbestos
367
N+E (%I
M
M
r;LB
ASB
(n)
(%)
(min)
(fibres ml- ‘)
5 7
1256 230
86 60
120
378 137 324 444 697 196 341 313
63 36 84 87 86 53 71 49
614 471 445
93 74 70
48
18
15 62 18 32 13 20 12 22 29 29 21 18 16 14 27 57 66 10
202 313 394
42 72 85
392 395 281
90 72 55
355
81
391 247
53
11 62 14 12 10 1 7 4 5 25 25 68 51 3 13 8 15 39 11 7
130 280 380 38 60 33
642 30 18 -
21 41 19 27 14 33 60 25 49 55
23 57 462
49 23
160 184
129 54 108
Chandon Cytospin centrifuge to make slides that were air-dried and fixed in methanol. Counts-per-slide were standardized to 1 ml of fluid. Clearance of wrnTc D TPA The half time clearance in min of 99mTc DTPA from lung to blood (t+LB) was measured a few days before or after the BAL. An aerosol was generated from an Acorn jet nebulizer containing 20 mCi 99mTc DTPA in 4ml saline. The output was modified by passage through an array of stainless steel ball bearings to remove large particles. A cascade impactor showed that 77% of particles were less than 0.9pm and only 4% were greater than 2 pm in diameter. Subjects inhaled for 5 min from the nebulizer and retained about 5% of the radioactivity. Data were
368 Table 2 r;LB
N. Al Jarad et al. AW
No.
2 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean* SD
patients:
demographic
Age W
Sex
Smoking
42 44 45 41 46 47 47 47 49 50 54 55 59 61 65 66 70 70 72 57
M M M M M M M M M M M F M M M M F M M M
Never Never Ex Never Never Ex Ex Ex Ex Never Never Never Ex Ex Ex Never Ex Ex Ex
54 10.1
Baseline lung functions expressed *For percentages of BAL profiles
data, baseline
Duration of exposure W
lung function,
Time since first exposure 64
declines
in lung function,
baseline
dFEV, FEV,
FVC
7tCO
KC0
yrr’
BAL
profiles
dFVC
and
yr-’
(1)
0)
21 20 20 9 15 20 11 5 29 30 3 13 18 11 4 6 10 48 28 19
4 24 30 28 30 31 21 27 31 34 20 33 32 47 51 66 31 54 40 39
121 109 113 113 121 114 57 114 87 133 91 94 103 120 84 115 143 100 111 77
114 108 117 109 110 114 103 109 91 138 101 102 100 111 74 107 166 93 105 76
95 95 115 92 81 80 105 93 104 98 93 83 104 92 104 94 97 87 91
115 101 112 110 84 91 125 52 118 122 119 117 121 136 125 81 140 102 158
0.15 0.13 0.01 0.10 0.20 0.00 0.19 0.20 0.00 0.23 0.02 0.05 0.2 0.13 0.02 0.1 0 0.25 0.23 0.15
0.10 0.02 0.16 0.02 0.3 0.00 0.20 0.14 0.00 0.18 0 0.08 0.25 0.16 0 0.06 0.02 0.25 0.25 0.13
17.6 11.5
32.6 14.8
106 20.1
107 19.7
95 8.85
112 23.7
0.12 0.09
0.12 0.09
as % of predicted. these figures are median.
collected for 15 min with Siemens 37 ZLC y scintillation camera, linked with an MDS A2 computer. Correction for background tissue activity was achieved by giving an i.v. injection of 0.5 mCi 99mTc DTPA and by continuous scanning of the area between the kidneys. THE FOLLOW
annual
UP ASSESSMENT
Patients andmethods A total of 57 patients were followed up. They were 33 AS and 24 AW. A total of six patients (three AW and three AS) died during the 4-yr interval (two AS and three AW due to lung cancer and one AS due to gastric cancer) and one AW had pneumonectomy for lung cancer and was therefore excluded. The AS remaining group comprised 12 current smokers, 16 ex-smokers and two non-smokers, and the AW group comprised 12 ex-smokers and eight non-smokers. Smoking status did not change during the study period. Auscultation by two examiners was carried out on the AW group for detection of fine persistent endinspiratory crackles characteristic of interstitial lung disease. Posterior-anterior chest radiograph and res-
piratory function tests, including spirometry, were performed using similar equipment to those used in the previous assessment. Gas transfer measurements were not obtained in all subjects because of logistic problems. Nineteen healthy smokers with no asbestos exposure who have been followed up for a mean period of 3.9 yr (range 2-5 yr) were used as a control group for spirometric changes. Annual declines in lung function measurements were calculated in all study groups by subtracting the last measurement from the measurement at the time of BAL and dividing the resulting value by the precise period of time separating the two measurements. Predicted annual declines in lung functions were calculated from standard regression equations (14). Three readers were asked to assess a pair of chest radiographs from each patient taken at the time of BAL and the latest follow up. Readers were blinded to the date of radiographs and asked to state whether either of the films showed a greater profusion of intrapulmonary small opacities or whether they were similar. The majority opinion was taken.
Prognostic factors for asbestos 369
d7ICO yrr’ @I)
dKC0 yrr’ @I)
0.00 0.15 0.50 090 0.50 0.13 0.00 0.16
0.00 0.04 0.06 0.00 0.13 0.01 0.00 0.16
0.34
0.05
0.14 0.04 0.12
0.10 0.16 0.00
Total cells 840 780 810 635 405 900 700 665 635 1210 600 660 -
235 -117 154
28 15 19
17 86 49
44 20 216
7 5 24
89 162 27
91 140
13 21
42 27
19 508
3 42
83 109
42 152
7 23
6 20
N+E (%)
M (n)
M %
t;LB (min)
2
588
70
11 6 14 40 3 6 4
577 608
74 75
502 223 657
79 55 73
567 499
81 75
13 9 1 3
533 593
84 49
552 488
92 74
48 30 82 33 14 70 29 48 102 84 78 54 54 64 31 66 28 14 14 45
532 109
70
-
-
0.17 0.18
0.06 0.07
144 135
736 198
Table 3 Base line lung function, non-smokers
BAL
n
profiles
and DTPA
Smokers
FEV, (%) FVC (%) 7x0 (%) KC0 (%)
13 13 8 8
69.8 74.0 62.0 96
Total cells Lymphocytes (n) Lymphocytes (%) Neutrophils and eosinophils Neutrophils and eosinophils Macrophages (n) Macrophages (%) Asbestos bodies t;LB
10 10 10 10 10 10 10 7 11
665 (327) 29(39) S(l-9) 117(72) 26(5-68) 518 (321) 68 (18-87) 217 (3-2) 29(21)
(n) (%)
12
(15.9) (15.8) (16.2) (20.9)
60 47
5
clearance
in smokers
n
Ex- and non-smokers
37 37 18 18
95.5 93 82 108
23 23 23 23 23 23 23 21 37
599 (206) 120(113) 20 (362) 64 (59) lO(l-51) 414 (157) 70 (43-92) 94 (O-462) 37 (23)
(23.5) (19.5) (18) (30.6)
34 21
ASB (fibres ml-‘) 0 70 1 333 0 1 130 140 35 150 85 1
78 97
and ex- and
P < 0.0007 < 0.0005
r+LB and lung function expressed as Mean (SD). BAL profiles % expressed as median (range). STATISTICAL
ANALYSIS
Annual declines in lung function measurements and percentages of BAL cells were compared between the study groups using the Mann-Whitney U-test.
Numbers of BAL cells were compared in study groups using two unpaired t-tests. The relation between basic lung function measurements and annual declines of lung function measurements were calculated using
370 Table
N. Al Jarad
et
al.
4 Annual declines (Mean and
FEV, (1) FVC (1) 7tCO (mmol mini kPam’) KC0 (mmol min-’ kPa-I 1-r)
SD)
in lung function measurements in study groups*
n
AS
n
AW
n
HS
30 30 14 14
0.11 (0.07) 0.16(0.11) 0.18 (0.15) 0~08(0~05)
20 20 12 12
0.12 (0.09) 0.12 (0.09) 0.17(0~18) 0.06(0.06)
19
0.05 (0.06) 0.04 (0.05)
‘9 -
Predicted reduction 0.02 0.03 0.07 0.01
*Differences in annual declines in AS and AW compared with HS and with predicted reduction were significant, PiO.002 in each case. Differences between AS and AW were ns. in each case. Table 5 Annual declines (Mean and asbestos-exposed subjects (AS + AW)
SD)
in lung function in smoker and ex- and non-smoker
Smokers AS+AW dFEV, (1) dFVC (1) dDCO* (mmol min’ kPaml) dKCO** (mmol min’ kPa-’ 1-l) *p40.05,
n = 13 ?I=13 n=8 n=8
Ex- and non-smokers AS+AW
0.09 (0.05) 0.14(0.09) 0.26(0.16) 0.11 (0.03)
n=37
0~12(0~08) 0.14(0.12) n=l8 0.14(0.12) n = 18 0.06 (0.05)
n=37
**p
Table 6 Numbers ( x 10’ ml-‘) and percentages of BAL profiles in patients in whom dTLC0 was less than and more than 0.3 mmol mini kPam’
Total BAL cells Lymphocytes (cells)
Mean SD
Mean SD
(%I
Neutrophils and eosinophils (cells)
Median Range Mean SD
(%I
Macrophages (cells)
Median Range Mean SD
(%I
Median Range
dTtC0 less than 0.3 mmol min-’ kPa-’ n= 15
dZX0 more than 0.3 mmol min-’ kPa-’
691 249
451 151
n.s.
19 11 19 247
5 5 4 2-15
< 0.008
9 9 6 1-39
37 24 32 868
509 243 74 3843
385 185 63 18-84
simple regression analysis. The relations between lung function declines and t+LB, asbestos body counts, duration of exposure and time since first exposure were calculated using Speam-ran’s rank correlation tests.
n=6
P
10.02 <0.02 < 0.03 n.s. n.s.
Results Baseline lung function, BAL profiles and t+LB, and also the annual declines in lung function in AS and AW
Prognosticfactorsfor
40 -
asbestos
371
0
60 t j30-
0
$
-
m20ae
t
g
40
--*--
0
8,8 0 ? <0.3 Annual
Fig
I
2ok
:
ot -@f
--QoQ-00 I >0.3
0
co.3
>0.3
in TLCO (mmol min-’ kPa-‘) and (b) BAL neutrophils and eosinophils (PcO.03) in patients in whom
reduction
Percentage of: (a) BAL lymphocytes (Pt0.02)
dltC0 Lower
------
t
0
lo-
0
t
8
yrr’wasless than0.3 mmol-‘min-I kPa-‘versuspatientsinwhomdZKOyrr’wasmorethan0~3 BAL lvmphocvtes and higher BAL neutrophils and eosinophils were associated
with
greater
mmol~‘min~‘kPa~‘. reduction in TACO.
Horizontal lines iepreient the median values. are illustrated in Tables l-3. Patients with AS had significantly lower baseline values for FEV,, FVC and RCO than AW. Baseline FEV,, FVC and 7tCO in smoker, AS and AW combined were significantly lower than those in ex- and non-smokers (P
SIGNS
On auscultation of AW, persistent late endinspiratory crackles, characteristic of interstitial lung disease, could not be heard in any subject. Crackles were heard in all AS. LUNG
FUNCTION
Annual declines in FEV, and FVC in AS and AW were significantly greater than in HS and predicted annual declines (PxO.002 in each case). Annual declines in 7KO and KC0 in AS and AW were significantly greater than predicted annual declines
(P~O.002 in each case). Declines in lung function in AS and AW did not differ significantly. These results are shown in Table 4. Annual declines in 7ICO and KC0 were greater in current smokers than in ex- and non-smokers (P < 0~05, P < 0.04, respectively). Annual declines in FEV, and FVC in smokers and in ex- and non-smokers did not differ signficantly (Table 5). Annual declines in lung function did not relate to asbestos body counts, duration of asbestos exposure and time since first exposure. CHEST
X-RAY
The chest X-ray deteriorated in 19 subjects (six AW and 13AS) (39%) and remained unchanged in 31 (14AWand 17AS)(61%). BRONCHO-ALVEOLAR
LAVAGE
PROFILES
Subjects, AS and AW combined, were divided into two groups according to whether their annual decline in 7tCO was less or more than 0.3 mmol min-’ kPa-‘, a value which was twice the mean d7tCOyr-’ in the whole group. Numbers and percentages of BAL lymphocytes were significantly lower (PC 0.008 and P
372
N. Al Jaradet al.
50 (a) I
*’ @I 0
0
40
0
2 &y 30 2
: 8
20
-&3-
;
1
60
0
8
40 f
8
0
0
CD
0
111 ; &I X-ray unchanged
20-J& OO
0
X-ray deteriorated
?? X-ray
X-ray unchanged
deteriorated
120(c)]
T
01
Fig 2 Percentage of: (a) BAL lymphocytes (P~O401) according to radiographic changes. Radiographic Horizontal lines refer to median values.
X-ray unchanged
,
X-ray deteriorated
and (b) neutrophils deterioration was
and eosinophils associated with
(P, n.s.) and (c) f+LB (P=O.O6), lower lymphocyte percentages.
unchanged had higher numbers (PcO.002) and percentages (P
have faster t+LB although this difference statistically significant P=O.O6 (Fig. 2).
t;LB DTPA
Discussion
CLEARANCE
t+LB inversely correlated with dfiCOyr-’ in AS and AW combined r= -0.51 (P
was not
Declines in lung functions in AS and AW were significantly greater than in healthy smokers without asbestos exposure, and than predicted values. Those who continued to smoke deteriorated to a greater extent than ex- and non-smokers. Previous studies have suggested that smoker asbestos workers tend to develop signs of advanced asbestosis more frequently than non-smokers (15-l 7). There were no significant differences between AS and AW in rate of lung function deterioration, suggesting that, even in the absence of clinical and radiological signs of asbestosis,
Prognostic
2
ok ,,,,,,,,,,,,,,,,,,,,, 0
0.1
J 0.2
Annual decline in TLCO
0.3
0.4
0.5
(mmol min-’ kPa-‘)
Fig 3 Annual decline in TX0 in AS and AW combined versus r+LB. Accelerated clearance of DTPA was associated with greater decline in 7X0. (0) Smokers; (0) ex- and non-smokers. r= -0.51, PcO.008. pathological processes leading to functional deterioration may be occurring. Duration of asbestos exposure and asbestos body counts were not related to functional and radiological deterioration. This is consistent with the evidence suggesting that individual susceptibility, rather than the dose of asbestos, may be the most important factor determining the rate of deterioration. Although the risk of development and severity of asbestosis are dose related, it was demonstrated in a radiographic study that the dose of asbestos accounted for only about one third of the variability in individual response (18). We have previously shown that, in patients with asbestosis, higher percentage counts of BAL neutrophils plus eosinophils were associated with longer duration of asbestos exposure, and greater impairment of lung function (9). Furthermore an increase in total BAL cells, in asbestos workers with no evidence of asbestosis, and a correlation between percentage of BAL neutrophils and duration of asbestos exposure, have been demonstrated (10). In this study, higher BAL lymphocytes were associated with less deterioration in lung function and in radiographic appearance, while higher neutrophils plus eosinophils were associated with greater deterioration. The findings are generally consistent with previous work in patients with cryptogenic fibrosing alveolitis, showing that patients with high BAL lymphocyte percentages had a better prognosis than those with increased BAL neutrophils plus eosinophils without increased BAL lymphocytes, who responded poorly to steroids, deteriorated faster and had shorter survival (3).
factors for asbestos
373
DTPA clearance was first suggested as a noninvasive method for assessment of epithelial integrity. Subsequently it has been shown that clearance of DTPA is accelerated in numerous conditions including interstitial lung disease (55lo), asthma (19), obliterative bronchiolitis (20) and in otherwise healthy smokers. The technique is, therefore, a fairly nonspecific indicator of lung damage. Little work has been done to assess its prognostic significance in interstitial lung disease. Previous studies have demonstrated accelerated DTPA clearance in patients with asbestosis and in some workers without asbestosis (IO, 1 l), and smoker groups had faster clearance than non-smokers. In the current study, accelerated clearance was associated with greater deterioration in gas transfer, but the association could be mainly due to the effect of smoking, which increases clearance and accelerates lung function decline. The mean time of follow up (4.2 yr) is relatively short for a slowly progressive condition like asbestosis, and further follow up 5-10 yr later may provide further information. References 1.
Crystal RG, Gedak JE, Ferrans VJ, Fulmer JD, Line BR, Hunninghake GW. Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am JA4ed 1981; 70: 542-568.
Keogh BA, Crystal RG. Alveolitis: The key to the interstitial lung disorders. Thorax 1982; 37: l-lb. 3. Rudd RM. Haslam PL, Turner-Warwick M. Crvutogenie fibrosing alveolitis: relationship of pulmonary physiology and bronchoalveolar lavage to response to treatment and pathogenesis. Am Rev Respir Dis 1981;
2.
124: 1-8.
O’Brodovich H, Coates G. Pulmonary clearance of ““Tc-DTPA: a non-invasive assessment of eoithelial integrity. Thorax 1985; 40: 508-514. 5. Rinderknicht J, Shapiro L, Krauthammer M. Accelerated clearance of small solutes from lungs in interstitial lung disease. Am Rev Respir Dis 1980; 121: 105-l 17. 6. Jacobs MP, Baugnan RP, Hughes J, Fernandez-Uloa M. 4.
Radioaerosol
lung clearance
in patients
with
active
pul-
monary fibrosis. Am Rev Respir Dis 1985; 31: 687689. 7. Jones DK, Higenbottom TW, Bailess J, Barber R, Wright
P, Flower
CDR.
Clearance
of WmTc-DTPA
sarcoidosis with and without pulmonary Thorax 8.
in
involvement.
1985; 40: 722.
Pantin CFA, Britten A, Lawrence R, Sweetman MCM,
Turner-Warwick M. Lung permeability in patients with interstitial lung disease. Thorax 1984; 39: 709. 9. Gellert RJ, Winter RJD, Uthayakumar S, Sinha G, Rudd RM. Asbestosis: assessment by bronchoalveolar lavage and measurement of epithelial permeability. Thorax 1985; 40: 508-514. 10. Gellert AR, Langford JA, Uthayakumar S, Rudd RM. Bronchoalveolar lavage and clearance of 99mTc-DTPA in asbestos workers without evidence of asbestosis. Br J Dis Chest 1985; 7% 251-257.
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11. Gellert RJ, Langford JA, Winter RJD, Lewis CA, Tolfree CEJ, Rudd RM. Clearance of 99m-Technetiumlabelled DTPA in asbestos-exposed workers without clinical or radiological evidence of interstitial lung disease. Br J Dis Chest 1985; 79: 3741. 12. Gellert AR, Langford JA, Winter RJD, Lewis CA, Tolfree SEJ, Rudd RM. Regional distribution of pulmonary epithelial permeability in normal subjects and patients with asbestosis. Thorax 1985; 40: 734740. 13. Studdy PR, Rudd RM, Gellert AR, Uthayakumar S, Sinha G, Geddes DM. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary shadowing. Br J Dis Chest 1984; 78: 46-54. 14. Cotes JE. Lung Function Assessment and Application in Medicine. Fourth edn. Oxford: Blackwell, 1979. 15. Weiss W. Cigarette smoking, asbestos, and pulmonary fibrosis. Am Rev Respir Dir 1971; 104: 223-227.
16. Weiss W, Theodas PA. Pleuropulmonary disease among asbestos workers in relation to smoking and type of exposure. J Occup Med 1978; 20: 341-346. 17. Lilis R, Selikoff IJ, Lerman Y, Seidman H, Gelb SK. Asbestosis: Interstitial pulmonary fibrosis and pleural fibrosis in a cohort of asbestos insulation workers: Influence of cigarette smoking. Am J Ind Med 1986; 10: 459470. 18. Finkelstein MM. A study of dose-response relationships for asbestos associated disease. Br J Ind Med 1985; 42: 319-325. S, Belzberg A, Hogg JC, Pare PD. 19. Elwood RK, Kennedy Respiratory mucosal permeability is asthma. Am Rev ResDir Dis 1983: 128: 523-527. 20. Sweatman MC&l, Pantin CFA, Lawrence R, TurnerWarwick M. Lung permeability in adult obliterative bronchiolitis. Respir Med 1989; 83: 323-327.
Medicine
(1993) 87,365-374
Bronchoalveolar lavage and 99mTc-DTPA clearance as prognostic factors in asbestos workers with and without asbestosis N. AL JARAD, A. R. GELLERT AND R. M. RUDD* The London Chest Hospital,
Bower
Road, London E2 9JX, U.K.
The aims of this study are to investigate the change-over time of lung function and chest radiographic findings in patients with asbestosis (AS) and asbestos workers without asbestosis (AW). Secondly, to correlate these changes with broncho-alveolar lavage (BAL) profiles and with lung epithelial permeability, as detected by half-time lungto-blood (ti LB) clearance of an inhaled aerosol of diethylene triamine pentacetate labelled with technetium 99 (99mTc-DTPA) obtained a mean period of 4.2 yr (range 2.3-58) previously. Thirty-three patients with asbestosis and 24 asbestos workers with substantial asbestos exposure were followed-up. Nineteen healthy smokers (HS) with no asbestos exposure who were followed up for a mean period of 3.9 yr were taken as a control group for spirometric changes. Compared with AW, FEV,, FVC and 7tCO were lower in AS (P
2 October
1991 and accepted
correspondence
0954-61 I l/93/050365+
should 10 %08.00/O
in revised
be addressed.
form 4 June 1992.
alveolitis (1,2). Identification of prognostic factors could be useful in planning trials of therapy. Differential cell counts in BAL fluid provide information about the likely rate of progression, and response to treatment, in cryptogenic fibrosing alveolitis (CFA) (3), a disease with many similarities to asbestosis. Several studies have suggested that DTPA clearance may be an index of lung epithelial permeability (4), and that it is accelerated in many interstitial lung diseases (5-8). Abnormal BAL cell counts and accelerated DTPA clearance in asbestos workers with and without asbestosis have been previously demonstrated (9-12). @ 1993 Baillidre Tindall
366
N. Al Jarad et al.
Table I rlLB
AS patients:
No.
Age 64
1 2 3 4 5 6 I 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 21 28 29 30
36 46 49 49 50 52 54 56 56 56 57 57 58 59 59 61 62 62 64 65 64 66 68 68 12 13 16 77 78 58
Mean*
60 9.6
SD
demographic
Sex
Smoking
M M M M M M M M M M M M M M F M
Current Ex Ex Ex Current
M M M M M M M M M M M M M M
data,
baseline
Duration of exposure (yr)
Current Current Ex Ex Never Current Current Current Ex Current Current Ex Current Ex Ex Ex Ex Ex Ex Current Ex Never Ex
Baseline lung functions expressed as % BAL profiles expressed as total cells ( x L, lymphocytes; N + E, neutrophils plus *For percentages of BAL profiles these
lung function,
Time since first exposure W
in lung function,
baseline
dFEV, FEV,
FVC
7X0
KC0
yrr
BAL
profiles
dFVC (1)
70 100 59 16 55 61 66 105 101 85 107 81 89 66 81 69 48 71 134 58 62 81 64 102 12 80 51 53 103 64
71 100 16 82 50 63 84 96 103 99 93 82 100 67 71 90 84 81 91 47 66 88 83 93 69 74 71 13 91 80
60 88 69 75 36 52 49 83 88 47 86 83 83 51 71 68 79 66 38 46 55 81 64 67 64 75 47 89 62 54
89 105 114 119 16 81 12 106 123 64 140 114 103 96 103 85 109 127 53 124 138 200 81 109 96 122 56 113 51 61
0.06 0.25 0.00 0.10 0.04 0.08 0.20 0.10 0.23 0.04 0.08 0.10 0.15 0.08 0.13 0.09 0.13 0.00 0.08 0.07 0.08 0.08 0.15 0.15 0.08 0.08 0.08 0.1 0.15 0.33
0.02 0.24 0.23 0.18 0.11 0.10 0.30 0.30 0.30 0.08 0.07 0.15 0.08 0.15 0.15 0.22 0.15 0.07 0.02 0.02 0.02 0.23 0.10 0.23 0.15 0.08 0.16 0.25 0.10 0.50
17.7 11.8
31.6 7.1
II 20.3
81 14.3
66 15.6
101 31.2
0.11 0.07
0.16 0.1
of predicted. 10’ ml-‘) and % of total BAL eosinophils; M, macrophages; figures are median.
ASSESSMENT
A total of 73 patients (37 AS and 36 AW) had previously been assessed. They were 17 current smokers,
cells. ASB = no. of asbestosis
bodies
per ml of BAL
and
yr- ’
(1)
22 31 24 38 35 38 35 40 29 38 40 41 34 33 40 37 43 24 51 50 44 40 32 51 30 36 34 51 39 38
Patients and Methods PATIENT
declines
5 17 16 4 25 26 12 36 9 25 30 30 1 13 19 17 2 1 41 27 40 6 3 29 13 13 13 31 18 8
In this study clinical examination, plain chest radiograph and lung function tests, were carried out in asbestos workers with no evidence of asbestosis (AW), and patients with asbestosis (AS), on whom BAL and DTPA clearance had been performed previously, to determine the prognostic value of these indicators.
THE INITIAL
annual
fluid.
41 ex-smokers, and 15 non-smokers. Forty-eight patients had worked in the lagging industry and the rest had carried out asbestos cutting, milling and spinning. The diagnosis of asbestosis had been made on the basis of previous asbestos exposure, persistent late inspiratory crackles over the lung bases and predominantly middle and lower lung-zone radiographic shadowing, consisting usually of small, irregular opacities and often associated with pleural thickening or calcification. Duration of asbestos exposure and time since first exposure had been assessed. A posterior-anterior chest radiograph was performed in all patients. Spirometry was performed using a dry
Prognostic
dIIC0 W)
yr-’
dKC0 yr-’ W)
Total Cells
0.08 0.00
0.06 0.03
1460 383
131 126
9 33
73 27
0.23 0.43 0.48
0.01 0.15 0.11
600 380 386 510 810 370 480 639
156 8 8 5 32 170 106 300
26 2 2 1 4 46 22 47
66 236 54 61 81 4 34 26
660 636 636
13 6 32
2 1 5
33 159 159
264
37
14
180
480 435 463
34 109 9 9 71 31
7 25 2 2 13 6
438 -
35
8
48
548 244
68 76
8
89 75
0.05 0.11
0.34 0 0.31 0.09 0.29
0.03 0.09
0.18 0.15
436 548 510
bellows spirometer (Vitalograph) or a dry cylinder spirometer (PK Morgan) and single-breath carbon monoxide transfer factor and coefficient using TCC transfer factor machines (PK Morgan). Bronchoalveolar lavage Bronchoalveolar lavage was carried out through a fibre optic bronchoscope with three sequential aliquots of 50 ml of sterile normal saline at 37°C and the sample was analysed for total differential cell counts as previously described (13). Manual counts of regular shaped and regular segmented ferroprotein-coated fibres were carried out on samples prepared as follows: a 20 ml aliquot of BAL fluid was centrifuged at 300g for 10 min, the deposit was diluted with 0.5 ml of 0.1 M sodium hydroxide and spun at 300g for 10min in a
245 13 60 35 82 199
factorsfor
asbestos
367
N+E (%I
M
M
r;LB
ASB
(n)
(%)
(min)
(fibres ml- ‘)
5 7
1256 230
86 60
120
378 137 324 444 697 196 341 313
63 36 84 87 86 53 71 49
614 471 445
93 74 70
48
18
15 62 18 32 13 20 12 22 29 29 21 18 16 14 27 57 66 10
202 313 394
42 72 85
392 395 281
90 72 55
355
81
391 247
53
11 62 14 12 10 1 7 4 5 25 25 68 51 3 13 8 15 39 11 7
130 280 380 38 60 33
642 30 18 -
21 41 19 27 14 33 60 25 49 55
23 57 462
49 23
160 184
129 54 108
Chandon Cytospin centrifuge to make slides that were air-dried and fixed in methanol. Counts-per-slide were standardized to 1 ml of fluid. Clearance of wrnTc D TPA The half time clearance in min of 99mTc DTPA from lung to blood (t+LB) was measured a few days before or after the BAL. An aerosol was generated from an Acorn jet nebulizer containing 20 mCi 99mTc DTPA in 4ml saline. The output was modified by passage through an array of stainless steel ball bearings to remove large particles. A cascade impactor showed that 77% of particles were less than 0.9pm and only 4% were greater than 2 pm in diameter. Subjects inhaled for 5 min from the nebulizer and retained about 5% of the radioactivity. Data were
368 Table 2 r;LB
N. Al Jarad et al. AW
No.
2 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean* SD
patients:
demographic
Age W
Sex
Smoking
42 44 45 41 46 47 47 47 49 50 54 55 59 61 65 66 70 70 72 57
M M M M M M M M M M M F M M M M F M M M
Never Never Ex Never Never Ex Ex Ex Ex Never Never Never Ex Ex Ex Never Ex Ex Ex
54 10.1
Baseline lung functions expressed *For percentages of BAL profiles
data, baseline
Duration of exposure W
lung function,
Time since first exposure 64
declines
in lung function,
baseline
dFEV, FEV,
FVC
7tCO
KC0
yrr’
BAL
profiles
dFVC
and
yr-’
(1)
0)
21 20 20 9 15 20 11 5 29 30 3 13 18 11 4 6 10 48 28 19
4 24 30 28 30 31 21 27 31 34 20 33 32 47 51 66 31 54 40 39
121 109 113 113 121 114 57 114 87 133 91 94 103 120 84 115 143 100 111 77
114 108 117 109 110 114 103 109 91 138 101 102 100 111 74 107 166 93 105 76
95 95 115 92 81 80 105 93 104 98 93 83 104 92 104 94 97 87 91
115 101 112 110 84 91 125 52 118 122 119 117 121 136 125 81 140 102 158
0.15 0.13 0.01 0.10 0.20 0.00 0.19 0.20 0.00 0.23 0.02 0.05 0.2 0.13 0.02 0.1 0 0.25 0.23 0.15
0.10 0.02 0.16 0.02 0.3 0.00 0.20 0.14 0.00 0.18 0 0.08 0.25 0.16 0 0.06 0.02 0.25 0.25 0.13
17.6 11.5
32.6 14.8
106 20.1
107 19.7
95 8.85
112 23.7
0.12 0.09
0.12 0.09
as % of predicted. these figures are median.
collected for 15 min with Siemens 37 ZLC y scintillation camera, linked with an MDS A2 computer. Correction for background tissue activity was achieved by giving an i.v. injection of 0.5 mCi 99mTc DTPA and by continuous scanning of the area between the kidneys. THE FOLLOW
annual
UP ASSESSMENT
Patients andmethods A total of 57 patients were followed up. They were 33 AS and 24 AW. A total of six patients (three AW and three AS) died during the 4-yr interval (two AS and three AW due to lung cancer and one AS due to gastric cancer) and one AW had pneumonectomy for lung cancer and was therefore excluded. The AS remaining group comprised 12 current smokers, 16 ex-smokers and two non-smokers, and the AW group comprised 12 ex-smokers and eight non-smokers. Smoking status did not change during the study period. Auscultation by two examiners was carried out on the AW group for detection of fine persistent endinspiratory crackles characteristic of interstitial lung disease. Posterior-anterior chest radiograph and res-
piratory function tests, including spirometry, were performed using similar equipment to those used in the previous assessment. Gas transfer measurements were not obtained in all subjects because of logistic problems. Nineteen healthy smokers with no asbestos exposure who have been followed up for a mean period of 3.9 yr (range 2-5 yr) were used as a control group for spirometric changes. Annual declines in lung function measurements were calculated in all study groups by subtracting the last measurement from the measurement at the time of BAL and dividing the resulting value by the precise period of time separating the two measurements. Predicted annual declines in lung functions were calculated from standard regression equations (14). Three readers were asked to assess a pair of chest radiographs from each patient taken at the time of BAL and the latest follow up. Readers were blinded to the date of radiographs and asked to state whether either of the films showed a greater profusion of intrapulmonary small opacities or whether they were similar. The majority opinion was taken.
Prognostic factors for asbestos 369
d7ICO yrr’ @I)
dKC0 yrr’ @I)
0.00 0.15 0.50 090 0.50 0.13 0.00 0.16
0.00 0.04 0.06 0.00 0.13 0.01 0.00 0.16
0.34
0.05
0.14 0.04 0.12
0.10 0.16 0.00
Total cells 840 780 810 635 405 900 700 665 635 1210 600 660 -
235 -117 154
28 15 19
17 86 49
44 20 216
7 5 24
89 162 27
91 140
13 21
42 27
19 508
3 42
83 109
42 152
7 23
6 20
N+E (%)
M (n)
M %
t;LB (min)
2
588
70
11 6 14 40 3 6 4
577 608
74 75
502 223 657
79 55 73
567 499
81 75
13 9 1 3
533 593
84 49
552 488
92 74
48 30 82 33 14 70 29 48 102 84 78 54 54 64 31 66 28 14 14 45
532 109
70
-
-
0.17 0.18
0.06 0.07
144 135
736 198
Table 3 Base line lung function, non-smokers
BAL
n
profiles
and DTPA
Smokers
FEV, (%) FVC (%) 7x0 (%) KC0 (%)
13 13 8 8
69.8 74.0 62.0 96
Total cells Lymphocytes (n) Lymphocytes (%) Neutrophils and eosinophils Neutrophils and eosinophils Macrophages (n) Macrophages (%) Asbestos bodies t;LB
10 10 10 10 10 10 10 7 11
665 (327) 29(39) S(l-9) 117(72) 26(5-68) 518 (321) 68 (18-87) 217 (3-2) 29(21)
(n) (%)
12
(15.9) (15.8) (16.2) (20.9)
60 47
5
clearance
in smokers
n
Ex- and non-smokers
37 37 18 18
95.5 93 82 108
23 23 23 23 23 23 23 21 37
599 (206) 120(113) 20 (362) 64 (59) lO(l-51) 414 (157) 70 (43-92) 94 (O-462) 37 (23)
(23.5) (19.5) (18) (30.6)
34 21
ASB (fibres ml-‘) 0 70 1 333 0 1 130 140 35 150 85 1
78 97
and ex- and
P < 0.0007 < 0.0005
r+LB and lung function expressed as Mean (SD). BAL profiles % expressed as median (range). STATISTICAL
ANALYSIS
Annual declines in lung function measurements and percentages of BAL cells were compared between the study groups using the Mann-Whitney U-test.
Numbers of BAL cells were compared in study groups using two unpaired t-tests. The relation between basic lung function measurements and annual declines of lung function measurements were calculated using
370 Table
N. Al Jarad
et
al.
4 Annual declines (Mean and
FEV, (1) FVC (1) 7tCO (mmol mini kPam’) KC0 (mmol min-’ kPa-I 1-r)
SD)
in lung function measurements in study groups*
n
AS
n
AW
n
HS
30 30 14 14
0.11 (0.07) 0.16(0.11) 0.18 (0.15) 0~08(0~05)
20 20 12 12
0.12 (0.09) 0.12 (0.09) 0.17(0~18) 0.06(0.06)
19
0.05 (0.06) 0.04 (0.05)
‘9 -
Predicted reduction 0.02 0.03 0.07 0.01
*Differences in annual declines in AS and AW compared with HS and with predicted reduction were significant, PiO.002 in each case. Differences between AS and AW were ns. in each case. Table 5 Annual declines (Mean and asbestos-exposed subjects (AS + AW)
SD)
in lung function in smoker and ex- and non-smoker
Smokers AS+AW dFEV, (1) dFVC (1) dDCO* (mmol min’ kPaml) dKCO** (mmol min’ kPa-’ 1-l) *p40.05,
n = 13 ?I=13 n=8 n=8
Ex- and non-smokers AS+AW
0.09 (0.05) 0.14(0.09) 0.26(0.16) 0.11 (0.03)
n=37
0~12(0~08) 0.14(0.12) n=l8 0.14(0.12) n = 18 0.06 (0.05)
n=37
**p
Table 6 Numbers ( x 10’ ml-‘) and percentages of BAL profiles in patients in whom dTLC0 was less than and more than 0.3 mmol mini kPam’
Total BAL cells Lymphocytes (cells)
Mean SD
Mean SD
(%I
Neutrophils and eosinophils (cells)
Median Range Mean SD
(%I
Macrophages (cells)
Median Range Mean SD
(%I
Median Range
dTtC0 less than 0.3 mmol min-’ kPa-’ n= 15
dZX0 more than 0.3 mmol min-’ kPa-’
691 249
451 151
n.s.
19 11 19 247
5 5 4 2-15
< 0.008
9 9 6 1-39
37 24 32 868
509 243 74 3843
385 185 63 18-84
simple regression analysis. The relations between lung function declines and t+LB, asbestos body counts, duration of exposure and time since first exposure were calculated using Speam-ran’s rank correlation tests.
n=6
P
10.02 <0.02 < 0.03 n.s. n.s.
Results Baseline lung function, BAL profiles and t+LB, and also the annual declines in lung function in AS and AW
Prognosticfactorsfor
40 -
asbestos
371
0
60 t j30-
0
$
-
m20ae
t
g
40
--*--
0
8,8 0 ? <0.3 Annual
Fig
I
2ok
:
ot -@f
--QoQ-00 I >0.3
0
co.3
>0.3
in TLCO (mmol min-’ kPa-‘) and (b) BAL neutrophils and eosinophils (PcO.03) in patients in whom
reduction
Percentage of: (a) BAL lymphocytes (Pt0.02)
dltC0 Lower
------
t
0
lo-
0
t
8
yrr’wasless than0.3 mmol-‘min-I kPa-‘versuspatientsinwhomdZKOyrr’wasmorethan0~3 BAL lvmphocvtes and higher BAL neutrophils and eosinophils were associated
with
greater
mmol~‘min~‘kPa~‘. reduction in TACO.
Horizontal lines iepreient the median values. are illustrated in Tables l-3. Patients with AS had significantly lower baseline values for FEV,, FVC and RCO than AW. Baseline FEV,, FVC and 7tCO in smoker, AS and AW combined were significantly lower than those in ex- and non-smokers (P
SIGNS
On auscultation of AW, persistent late endinspiratory crackles, characteristic of interstitial lung disease, could not be heard in any subject. Crackles were heard in all AS. LUNG
FUNCTION
Annual declines in FEV, and FVC in AS and AW were significantly greater than in HS and predicted annual declines (PxO.002 in each case). Annual declines in 7KO and KC0 in AS and AW were significantly greater than predicted annual declines
(P~O.002 in each case). Declines in lung function in AS and AW did not differ significantly. These results are shown in Table 4. Annual declines in 7ICO and KC0 were greater in current smokers than in ex- and non-smokers (P < 0~05, P < 0.04, respectively). Annual declines in FEV, and FVC in smokers and in ex- and non-smokers did not differ signficantly (Table 5). Annual declines in lung function did not relate to asbestos body counts, duration of asbestos exposure and time since first exposure. CHEST
X-RAY
The chest X-ray deteriorated in 19 subjects (six AW and 13AS) (39%) and remained unchanged in 31 (14AWand 17AS)(61%). BRONCHO-ALVEOLAR
LAVAGE
PROFILES
Subjects, AS and AW combined, were divided into two groups according to whether their annual decline in 7tCO was less or more than 0.3 mmol min-’ kPa-‘, a value which was twice the mean d7tCOyr-’ in the whole group. Numbers and percentages of BAL lymphocytes were significantly lower (PC 0.008 and P
372
N. Al Jaradet al.
50 (a) I
*’ @I 0
0
40
0
2 &y 30 2
: 8
20
-&3-
;
1
60
0
8
40 f
8
0
0
CD
0
111 ; &I X-ray unchanged
20-J& OO
0
X-ray deteriorated
?? X-ray
X-ray unchanged
deteriorated
120(c)]
T
01
Fig 2 Percentage of: (a) BAL lymphocytes (P~O401) according to radiographic changes. Radiographic Horizontal lines refer to median values.
X-ray unchanged
,
X-ray deteriorated
and (b) neutrophils deterioration was
and eosinophils associated with
(P, n.s.) and (c) f+LB (P=O.O6), lower lymphocyte percentages.
unchanged had higher numbers (PcO.002) and percentages (P
have faster t+LB although this difference statistically significant P=O.O6 (Fig. 2).
t;LB DTPA
Discussion
CLEARANCE
t+LB inversely correlated with dfiCOyr-’ in AS and AW combined r= -0.51 (P
was not
Declines in lung functions in AS and AW were significantly greater than in healthy smokers without asbestos exposure, and than predicted values. Those who continued to smoke deteriorated to a greater extent than ex- and non-smokers. Previous studies have suggested that smoker asbestos workers tend to develop signs of advanced asbestosis more frequently than non-smokers (15-l 7). There were no significant differences between AS and AW in rate of lung function deterioration, suggesting that, even in the absence of clinical and radiological signs of asbestosis,
Prognostic
2
ok ,,,,,,,,,,,,,,,,,,,,, 0
0.1
J 0.2
Annual decline in TLCO
0.3
0.4
0.5
(mmol min-’ kPa-‘)
Fig 3 Annual decline in TX0 in AS and AW combined versus r+LB. Accelerated clearance of DTPA was associated with greater decline in 7X0. (0) Smokers; (0) ex- and non-smokers. r= -0.51, PcO.008. pathological processes leading to functional deterioration may be occurring. Duration of asbestos exposure and asbestos body counts were not related to functional and radiological deterioration. This is consistent with the evidence suggesting that individual susceptibility, rather than the dose of asbestos, may be the most important factor determining the rate of deterioration. Although the risk of development and severity of asbestosis are dose related, it was demonstrated in a radiographic study that the dose of asbestos accounted for only about one third of the variability in individual response (18). We have previously shown that, in patients with asbestosis, higher percentage counts of BAL neutrophils plus eosinophils were associated with longer duration of asbestos exposure, and greater impairment of lung function (9). Furthermore an increase in total BAL cells, in asbestos workers with no evidence of asbestosis, and a correlation between percentage of BAL neutrophils and duration of asbestos exposure, have been demonstrated (10). In this study, higher BAL lymphocytes were associated with less deterioration in lung function and in radiographic appearance, while higher neutrophils plus eosinophils were associated with greater deterioration. The findings are generally consistent with previous work in patients with cryptogenic fibrosing alveolitis, showing that patients with high BAL lymphocyte percentages had a better prognosis than those with increased BAL neutrophils plus eosinophils without increased BAL lymphocytes, who responded poorly to steroids, deteriorated faster and had shorter survival (3).
factors for asbestos
373
DTPA clearance was first suggested as a noninvasive method for assessment of epithelial integrity. Subsequently it has been shown that clearance of DTPA is accelerated in numerous conditions including interstitial lung disease (55lo), asthma (19), obliterative bronchiolitis (20) and in otherwise healthy smokers. The technique is, therefore, a fairly nonspecific indicator of lung damage. Little work has been done to assess its prognostic significance in interstitial lung disease. Previous studies have demonstrated accelerated DTPA clearance in patients with asbestosis and in some workers without asbestosis (IO, 1 l), and smoker groups had faster clearance than non-smokers. In the current study, accelerated clearance was associated with greater deterioration in gas transfer, but the association could be mainly due to the effect of smoking, which increases clearance and accelerates lung function decline. The mean time of follow up (4.2 yr) is relatively short for a slowly progressive condition like asbestosis, and further follow up 5-10 yr later may provide further information. References 1.
Crystal RG, Gedak JE, Ferrans VJ, Fulmer JD, Line BR, Hunninghake GW. Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am JA4ed 1981; 70: 542-568.
Keogh BA, Crystal RG. Alveolitis: The key to the interstitial lung disorders. Thorax 1982; 37: l-lb. 3. Rudd RM. Haslam PL, Turner-Warwick M. Crvutogenie fibrosing alveolitis: relationship of pulmonary physiology and bronchoalveolar lavage to response to treatment and pathogenesis. Am Rev Respir Dis 1981;
2.
124: 1-8.
O’Brodovich H, Coates G. Pulmonary clearance of ““Tc-DTPA: a non-invasive assessment of eoithelial integrity. Thorax 1985; 40: 508-514. 5. Rinderknicht J, Shapiro L, Krauthammer M. Accelerated clearance of small solutes from lungs in interstitial lung disease. Am Rev Respir Dis 1980; 121: 105-l 17. 6. Jacobs MP, Baugnan RP, Hughes J, Fernandez-Uloa M. 4.
Radioaerosol
lung clearance
in patients
with
active
pul-
monary fibrosis. Am Rev Respir Dis 1985; 31: 687689. 7. Jones DK, Higenbottom TW, Bailess J, Barber R, Wright
P, Flower
CDR.
Clearance
of WmTc-DTPA
sarcoidosis with and without pulmonary Thorax 8.
in
involvement.
1985; 40: 722.
Pantin CFA, Britten A, Lawrence R, Sweetman MCM,
Turner-Warwick M. Lung permeability in patients with interstitial lung disease. Thorax 1984; 39: 709. 9. Gellert RJ, Winter RJD, Uthayakumar S, Sinha G, Rudd RM. Asbestosis: assessment by bronchoalveolar lavage and measurement of epithelial permeability. Thorax 1985; 40: 508-514. 10. Gellert AR, Langford JA, Uthayakumar S, Rudd RM. Bronchoalveolar lavage and clearance of 99mTc-DTPA in asbestos workers without evidence of asbestosis. Br J Dis Chest 1985; 7% 251-257.
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11. Gellert RJ, Langford JA, Winter RJD, Lewis CA, Tolfree CEJ, Rudd RM. Clearance of 99m-Technetiumlabelled DTPA in asbestos-exposed workers without clinical or radiological evidence of interstitial lung disease. Br J Dis Chest 1985; 79: 3741. 12. Gellert AR, Langford JA, Winter RJD, Lewis CA, Tolfree SEJ, Rudd RM. Regional distribution of pulmonary epithelial permeability in normal subjects and patients with asbestosis. Thorax 1985; 40: 734740. 13. Studdy PR, Rudd RM, Gellert AR, Uthayakumar S, Sinha G, Geddes DM. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary shadowing. Br J Dis Chest 1984; 78: 46-54. 14. Cotes JE. Lung Function Assessment and Application in Medicine. Fourth edn. Oxford: Blackwell, 1979. 15. Weiss W. Cigarette smoking, asbestos, and pulmonary fibrosis. Am Rev Respir Dir 1971; 104: 223-227.
16. Weiss W, Theodas PA. Pleuropulmonary disease among asbestos workers in relation to smoking and type of exposure. J Occup Med 1978; 20: 341-346. 17. Lilis R, Selikoff IJ, Lerman Y, Seidman H, Gelb SK. Asbestosis: Interstitial pulmonary fibrosis and pleural fibrosis in a cohort of asbestos insulation workers: Influence of cigarette smoking. Am J Ind Med 1986; 10: 459470. 18. Finkelstein MM. A study of dose-response relationships for asbestos associated disease. Br J Ind Med 1985; 42: 319-325. S, Belzberg A, Hogg JC, Pare PD. 19. Elwood RK, Kennedy Respiratory mucosal permeability is asthma. Am Rev ResDir Dis 1983: 128: 523-527. 20. Sweatman MC&l, Pantin CFA, Lawrence R, TurnerWarwick M. Lung permeability in adult obliterative bronchiolitis. Respir Med 1989; 83: 323-327.