Document Qgv1m1x0ZyB3209mr7wmkba5v

Medical Methods INCREMENTAL EXERCISE TESTING IN PLEUROPCILMONARY DISEASE DUE TO INHALATION OF INORGANIC DUSTS: PHYSIOLOGIC DEAD SPACE AS THE MOST SENSITIVE INDICATOR ALBERT MILLER, MJX Wajdi Hailoo, M.D. Lee K. Brown, M.U Pulmonary Function Laboratory and Pulmonary Division, Department of Medicine and Division of Occupational Medicine, Department of Community Medicine Mount Sinai School of Medicine, City University of New York, New York, NY, USA INTRODUCTION Evaluation of dyspnea, and of respiratory impairment and disability, is of great social and economic importance, let alone physiologic and clinical interest, in patients thought to have pulmonary and/or pleural fibrosis secondary to in halation of inorganic dusts.1'7 The relationship of abnor malities on exercise to those in standard pulmonary func tion tests (performed at rest) is controversial. Cotes2 has recently concluded that`Toss ofexercise capacity cannot be predicted with acceptable accuracy from die 4 commonly used lung function indices (FVC, FEVj, FEVi/FVC, DlCOsb) alone or in combination." We have correlated FVC and DlCOsb (henceforth further abbreviated as Dl) with a number of exercise variables (both invasive and non-invasive) in 43 patients undergoing maximal incremental exercise to evaluate likely pulmonary and/or pleural fibrosis due to inhalation of inorganic dusts (in 35 patients, the dust was asbestos). Our results indicate that an abnormal DL predicts excessive dead space ventila tion often present at rest, and conversely, that this abnor mality of gas exchange is frequently present even when Dl is normal. METHODS Standard pulmonary function tests were performed accord ing to the recommendations of die American Thoracic Socie ty.8,9 Predicted values for spirometry were modified10 from an earlier publication of Morris11 and for Dl COsb and TLCsb were those separately established by this laboratory12 for current smokers, ex-smokers and nonsmokers. Incremental exercise testing was performed using a model 2000 Medical Graphics, Inc., breath-by-breath system which employs a pneumotachygraph to obtain expiratory flows and volumes, an infra-red CO2 analyzer, and a zirconium fuel cell O2 analyzer. Exercise was performed on a bicycle ergometer which increments 5 to 25 watts per minute. The patient sat quiedy on the bicycle while adjusting to die nose clip, mouthpiece, ear oximeter (Hewlett-Packard model 47201 A), electrocardiographic leads and radial artery catheter. Measurements were then made sitting, during unloaded cycling, during incremental cycling and several times following exercise. Exercise was terminated when the patient was unable to continue (usually limited by dyspnea) or if there were untoward changes in the electrocardiogram, blood pressure or O2 saturation. A microprocessor collected flow, FeCC^, and Fe02 data and computed O2 consumption and CO2 production for each breath. A separate computer (TEKTRONIX 4052 A) stored, analyzed and displayed data. Primary measurements included tidal volume, respiratory frequency, inspired and expired O2 and CO2 concentrations and heart rate (HR). These allow immediate calculation of such parameters as minute ventilation (VE), O2 consumption (\02), CO2 production (VCCy, respiratory equivalent (R; \C02 /VO2), VE/VCO2, VE/\D2, O2 pulse (VO2/HR) etc. Arterial blood was blood sampled every one to two minutes. Samples were stored in ice and analyzed immediately after the test on a Radiometer model ABL30. Entry of these results permits the system to calculate and print values for dead space ventilation (as a percentage of tidal volume, Vj/Vj) and alveolar-arterial differences for P02 (A-aD02) during all phases of the test. yentilatory response was evaluated as the slope of VE vs. VO2 before ventilatory anaerobic threshold is reached; ex cessive values are ^30.13 Limit values for other tests are: FVC < 80% of predicted, FEV]/FVC <0.70 up to age 59 years and <0.65 beyond age 59, Dl <75% of predicted, Vd/Vt ^0.35 at rest and ^0.25 on exercise (V02 LOL)14 and A-a D02 35 Torr during exercise.4 RESULTS Of the 43 patients tested, 35 were studied because of occupa tional exposure to asbestos; several ofthese had normal chest radiographs and one-third had only pleural thickening. Of the remaining 8 patients, 6 were occupationally exposed to hard metal (half had normal chest radiographs) and 2 to beryllium (both had abnormal radiographs). Dl was not available on 4 patients. Dyspnea was equivocal in 9 patients, present in 29 and absent in 5. Because of the small number of patients without dyspnea, correlation with physiologic variables was not possible. It was noted that the 5 patients who did not complain of dyspnea had normal Dl (vs. 14 of the 26 with dyspnea) and 4 of the 5 had normal ventilatory responses (vs. 18 of 27 with dyspnea). 503 Medical Methods Mean values ofthe most important pulmonary function tests (FVC, Dl) and exercise variables (VE at VOj 1.0L, Vd/Vt at VO2I.OL) and of Vd/Vt at rest are shown in Table I. Table I Mean Values of Pulmonary Function and Exercise Tests Variable FVC (% pred) >(_ (% pred) VE 1.0L (L/min) Vd/Vt Rest (x 100) VD/VT 1.0L (x 100) Mean 80.2 80.7 30.2 35.9 28.8 SD 18.2 24.9 9.73 8.6 9.9 Prevalence of Abnormal Test Results (Table II) Ofthe patients studied, 18 (of43) had a reduced FVC (42 %), 13 (of 39) a reduced Dl (38%), 10 (of 41) increased ven tilatory responses (24%) and 8 (of 41) an elevated A-a DOj (20%). The highest prevalence of abnormality was for Vd/Vt at rest and/or exercise (measured at a VO2 of 1.0L): 31 of 43 patients (72%). Of these 31, 19 were abnormal under both conditions, 5 at exercise only and 7 at rest only (4 of these did not have exercise values or did not reach a VO2 of 1.0L). Hence, 24 of 39 patients (62%) showed ab normal Vq/Vj at exercise and 26 of43 (60%) did so at rest. Correlations with DL (Table III) Of the 39 patients with Dl, 15 had abnormal values for this test (as stated above): Dl (percent predicted) showed a moderate correlation with FVC (r=0.315, P 0.05) (Table HI). Comparison of abnor mal results for the two tests is shown in Table IV. 15 pa tients had abnormal values for FVC; 8 were abnormal for both tests, 17 normal for both, 7 abnormal only for Dl and 7 abnormal only for FVC. Dl (percent predicted) correlated with Vd/Vt at rest (r= --0.274, p <0.1) and more strongly on exercise (r= --0.554, p 0.0005) (Table HI). Comparison of abnormal results for Dl and for Vd/Vx is shown in Table V. 27 pa tients had abnormal values for Vq/Vt; 13 were abnormal for both, 10 normal for both, 14 abnormal for Vd/Vt alone and 2 abnormal for Dl alone. Thus, of foe 15 patients with abnormal Dl, 13 (87%) had abnormal Vd/Vt yet 14 of foe 24 (58%) with normal Dl still had abnormal Vd/Vt. Only 8 patients had abnormal A-a DO2 (Table VI); 6 were abnormal for both tests, 22 normal for both, 2 abnormal for A-a DO2 alone and 8 abnormal for Dl alone. Of foe 8 pa tients with abnormal A-a DO2, only 2 had a normal Dl. Only 9 of foe 39 patients had abnormal A VE/ A VO2 (Table VII); 5 of foe 9 had abnormal Dl- Correlations with FVC (Table 111) FVC (percent predicted) correlated with Vj/VT both at rest (r= --0.359, p 0.02) and on exercise (r= --0.436, p <0.006). Correlations with Exercise \^e (Table III) Exercise VE (at a VO2 of 1.0 L2 showed a weak correlation Table n Frequencies of Abnormal Test Results in 43 Patients with Suspect Pleuropulmonary Disease Due to Inorganic Dusts FVC (FVC dl tf02 peak < 75% pred A VE/ A V02 A-a D02 Reap. Rate > 50/min Resp. Rate > 40/min VD/VT: Rest and/or 1.0L Rest 1.0L 42% 38%) 38% 28% 24% 20% 21% 72% 60% 62% (18/43) (15/39) (15/39) (12/43) (10/41) ( 8/41) 0 ( 9/43) (31/43) (26/43) (24/39) 504 Table in Pearson Correlation Coefficients for Pulmonary Function and Exercise Tests Medical Methods VE FVC dl Vd/Vt VD/Vt Rest 1.0L $E 1.0L 1.00000 FVC -0.22962 Dl vd/vt Rest -0.41311* 0.38629* VD/Vt 1.0L 0.48455* * p < 0.05 -0.22962 1.00000 0.31537* -0.36191* -0.44035* -0.41311* 0.31537* 1.00000 -0.27351 -0.55392* 0.38629* -0.36191* -0.27351 1.00000 0.66262 0.48455* -0.44035* -0.55392* 0.66262* 1.00000 Abnormal D(_ (15) Normal D|_ (24) No Dl (4) Table IV FVC vs. DlCOsb Abnormal FVC (15) 8 7 3 Normal FVC (24) 7 17 1 with FVC (r= --0.230, p 0.15), a strong correlation with Dl (r-- --0.413, p 0.009) and strong correlations with Vj>/VT both at rest (r= 0.386, p 0.0115) and even more so on exercise (r= 0.485, p 0.0021). tf<>2 Max Of the 43 patients, 31 (72%) were able to reach a peak VO2 ^75% of predicted. The 12 who were not able were more likely to manifest other abnormalities, e.g.j 10 had abnor mal V,,/VT (vs. 20 of die 31 with normal VO2 max) and 8 had abnormal FVC (vs. 7 of the 31 with normal VOj max). Of the 10 with decreased VO2 max who performed Dl, 6 had abnormal Dl (vs. 9 of the 29 with normal VO2 max). Nevertheless, 12 of die 18 patients with abnormal VD /VT both at rest and on exercise were able to achieve a VO2 max ^75% of predicted. Respiratory Pattern No patient reached a respiratory rate > 50 min; 9 (21%) reached a rate between 41 and 50. Nine patients achieved a VX/VC ratio ^0.70; 6 of these 9 had normal FVC. The 2 patients whose VT/VC exceeded 0.80 both had reduced FVC. DISCUSSION AND CONCLUSIONS Our goals were to assess (1) "invasive" variables requiring sampling of arterial blood and (2) the responses to incremen tal exercise both non-invasive (VE, A VE/ A VO2, respira- 505 Medical Methods Table V Vd/Vt vs. DlCOsb Abnormal Vp/Vf (31) Normal Vp/Vf . at rest and at VO2 = 1.0L (12) At est and At rest at VO? = only* (7) 1.0L (19) At V02 = 1.0L only (5) Abnormal D|_ (15) 10 12 Normal D|_ (24) 8 33 No Dl (4) 1 30 * Includes inability to reach VO2 = 1.0L or no sample obtained. 2 10 0 Abnormal Dl (14) Normal Dl (24) No Dl (3) Table VI A-a D02 vs. DlCOsb Abnormal A-a D02 (8) 6 2 0 Normal A-a D02 (33) 8 22 3 tory rate and tidal volume) and invasive (Vj>/VT, A-a DO2) compared with standard pulmonary function tests (FVC, Dl). Our patients demonstrated the full spectrum of disease from radiographically inapparent to minimal (1/0 irregular opacities and/or pleural thickening) to advanced diffuse pulmonary fibrosis. Most complained of dyspnea. Vd/V-t was the most sensitive indicator of abnormality, be ing increased in 31 of43 patients (72%), many of whom had normal FVC and/or Dl- The most useful comparison was with Dl; 13 of the IS patients with abnormal Dl had ab normal Vd/Vt. It may, therefore, be said that a decreased Dl predicts abnormal Vo/VT and that measuring die latter is then not required to detect disease. However, more than half the patients (58 % or 14 of 24) with normal Dl still had abnormal Vd/Vt. FVC was as likely to be abnormal as Dl (each was de creased in 15 of 39 patients who had both tests, or 38%). Abnormality of one was not very likely to predict abnormality of the other; roughly half the patients with an abnormal FVC had a normal Dl and vice-versa. A-a D02 and ventilatory response during exercise were least likely to be abnormal (in 20% and 24%, respectively). Widening of the A-a D02 was associated with an abnormal Dl. No patient demonstrated a respiratory rate >50/min. 506 Table VH AVE/ AVOz vs. Dl Medical Methods Abnormal Dj_ (15) Normal D|_ (24) No D|_ (2) Abnormal VE/VO2 (10) 5 4 1 Normal AVE/ A VO2 (31) 10 20 1 About three-quarters of the patients reached a VO2 ^75% of predicted maximum, demonstrating their motivation to perform. Many patients with manifest abnormalities achieved this level of work, e.g., two-thirds (12 of 1$) of those with abnormal Vr/VT both at rest and on exercise. Of die 31 patients with abnormal Vy/Vt at rest or exercise, this was manifest in die majority (26 patients or 84 %) at rest. It may thus be inferred that exercise is not usually necessary to demonstrate this derangement of gas exchange. VE at an exercise level corresponding to a VO2 of l.OL/min has been advocated as a usefiil non-invasive measurement which additionally does not require maximal effort.2 It was strongly correlated with Dl and with Vp/VT both at rest and even more so at (die same level) exercise. An important con sideration is whether anaerobic threshold (AT) has been reached before this level of exercise, which would increase VE non-linearly; almost all our patients had a normal AT, beyond a VO2 of 1.0L. REFERENCES 1. Becklake, M.R., Rodarti, J.R.,Kalica, A.R.: NHLBI Workshop Sum mary. Scientific Issues in the Assessment of Respiratory Impairment. Am. Rev. Respir. Dis. 137:1505-1510 (1988). 2. Cotes, J.E., Zejda, J., King, B.: Lung Function Impairment as a Guide to Exercise Limitation in Work Related Lung Disorders. Am. Rev. Respir. Dis. 137:1089-1093 (1988). 3. Howard, J., Mohsenifar, Z., Brown, H.V., Koerner, S.K.: Role of Exercise Testing in Assessing Functional Respiratory Impairment Due to Asbestos Exposure. /. Occup. Med. 24:685-689 (1982). 4. Oren, A., Sue, D.Y., Hansen, J.E., Torrance, D.J., Wasserman, K.: The Role of Exercise Testing in Impairment Evaluation. Am. Rev. Respir. Dis. 135:230-235 (1987). 5. Agostoni, P., Smith, D.D., Schoene, R.B., Robertson, H.T., Butler, J.: Evaluation of Breathlessness in Asbestos Workers. Results of Ex ercise Testing. Am. Rev. Respir. Dis. 135:812-816 (1987). 6. Wollmer, P., Eriksson, L., Jooson, B., Jakobsson, K., Albin, M., Skerfving, S., Welinder, H.: Relation Between Lung Function, Exercise Capacity and Exposure to Asbestos Cement. Br. J. Iodustr. Med. 44:542-549 (1987). 7. Picado, C., Laporta, D., Grassino, A., Cosio, M., Thibodeau, M., Becklake, M.: Mechanisms Affecting Exercise Performance in Sub jects with Asbestos Related Pleural Fibrosis. Lung. 165:45-57 (1987). 8. Gardner, R.M., Chairman: Standardization of Spirometry--1987 Up date. Am. Rev. Respir. Dis. 136:1285-1298 (1987). 9. Crapo, R.O., Gardner, R.M., Chairmen: Single Breath Carbon Monox ide Diffusing Capacity (Transfer Factor). Recommendations for a Stan dard Technique. Am. Rev. Respir. Dis. 136:1299-1307 (1987). 10. Miller, A., Thornton, J.C., Smith, H. Jr., Morris, J.F.: Spirometric "Abnormality" in a Normal Male Reference Population. Further Analysis of the 1971 Oregon Survey. Am. J. Iodustr. Med. 1:55-68 (1980). 11. Morris, J.F., Koski, A., Johnson, L.C.: Spirometric Standards for Healthy Non-smoking Adults. Am. Rev. Respir. Dis. 103:57-67 (1971). 12. Miller, A., Thornton, J.C., Warshaw, R., Anderson, H., Teirstein, A.S., Selikoff, I.J.: Single Breath Diffusing Capacity in a Represen tative Sample of the Population of Michigan, A Large Industrial State: Predicted Values, Lower Limits of Normal and Frequencies ofAbnor mality by Smoking History. Am. Rev. Respt. Dis. 127:270-277 (1983). 13. Spiro, S.G., Juniper, E., Bowman, P., Edwards, R.H.T.: An Increas ing Work Rate Test for Assessing the Physiologic Strain of Submax ima] Exercise. Clin. Sci. Moiec. Med. 46:191 (1974). 14. Kanarek, D.J.: Exercise Testing in the Evaluation of Pulmonary Func tion, in Pulmonary Function Tests in Clinical and Occupational Lung Disease, pp. 413-424, A. Miller, Ed. Grune and Stratton, Orlando (1986). 507 Medical Methods ROLE OF EXERCISE TESTS IN THE FUNCTIONAL EVALUATION OF SILICOTIC PATIENTS LUIZ EDUARDO NERY, M.D. Ph.D. RosenI Teresinha Florencio Luciano B. Campos Jose Roberto de Brito Jardim Manuel Lopes dos Santos ESCOLA PAUUSTA DE MEDICINA, Sao Paulo, SP, Brasil INTRODUCTION Evaluation of labor capacity is frequently requested for pa tients with pneumoconioses. Spirometry and chest X-rays usually utilized in die diagnosis, have not been regarded as good predictors ofpulmonary disability; and have poor cor relation with die respiratory symptoms.3*8'9 Among the methods utilized in die functional evaluation of pneumoconioses, the exercise tests have emerged as useful, for evaluating the cardiorespiratory abnormalities, not pres ent at rest.1*2 Although the exercise tests have been frequently utilized in die differential diagnosis of dyspnea,4'10'12*13 in occupational medicine, the studies are scattered and utilized diverse methodology, making difficult die comparison of die results.6*7*11 Objectives In this study, our purpose was to establish the role of the cardiorespiratory, metabolic and gas exchange analysis dur ing exercise, in evaluationg ceramic workers with the diagnosis of silicosis; and to correlate these findings with the degree of dyspnea, the radiological alterations and die pulmonary function tests at rest. METHODS Casuistic We have studied forty three ceramic workers with die diagnosis of silicosis based on the occupational history of silica dust exposure and on die radiographic features. They were separated in three groups, based in the ILO Classifica tion, 1980 (Table I).5 The characteristics of die patients, the silica dust and the smoking exposure were not significandy different when com pared to die three groups. However, group HI subjects, were older than the ones of Group I. Protocol The patients were first submitted to a clinical evaluation and thereafter tested for spirometry, flow-volume curves and arterial blood gases at rest. Secondly, they went to an incremental exercise test on a cycloergometer to die maximum tolerance, for car diovascular, ventilatory and metabolic evaluation (n = 40). Finally, after 30 min. of resting, the patients were submit ted to a submaximal test corresponding to 50% of the max imum tolerance, for the analysis ofdie cardiorespiratory and metabolic responses and die arterial blood gases. Table I Classification of the Silicotic Patients, According to the ILO Classification, 1980s GROUP I II III OPACITIES/PROFUSION Small Opac. (up to 3mm) 1/0 to 1/2 Small Opac (up to 3mm) 2/1 to 3/3 Large opac. (A, B or C) n 21 13 9 508 RESULTS AND COMMENTS Dyspnea was the most frequent symptom, being reported by 26 (61%) of the patients, with similar distribution and in tensity in the three groups (Figure 1). Cough, sputum pro duction and bronchospasm, also had similar incidency among the patients. The spirometry was altered in 14 subjects (33%), also with similar distribution in the groups I, n and m. There was no predominant pattern of respiratory impairment (obstruc tive or restrictive) and most patients had slight to moderate abnormalities (Figures 2 and 3). In the analysis of flow-volume curves (n = 41), the Vmax 25 % was die only variable that distinguished Group m from the other groups, being altered in 52% of subjects in Group I, 42% in Group II and 88% in Group CQ (Table HI). Medical Methods In the incremental exercise tests (n = 40), the patients of Group m had lower VC^max compared to Group I and II (p <0.05--Gr. I vs. Gr. HI) (Table IV). The symptoms reported at the interruption of exercise were mostly dyspnea and leg pain, with similar distribution and intensity in the three groups. A value of VC^max <70% Pred., indicating some degree of functional limitation was found in 14 patients, however with different distribution in the three groups: 3 of them were from Group I (16%), 4 from Group II (31%) and 7 (88%) were from Group III (p <0.05--Group I + m vs. Group HI) (Figure 4). This indicates an association between the more severe X-ray alterations and the lower working tolerance. However there were subjects of Group I, with reduced exercise capacity and conversely, subjects of Group HI with normal exercise capacity (Figure 4). No correlations were found between the exercise capacity Table II Characteristics of the Silicotic Patients X AGE GR. n (yrs) ft Ht (cm) Silica Dust Exposition (vrs) % Smoking Pack/vears I 21 39.3 72.8 169 18.2 53 16.0 II 13 42.4 73.9 170 21.1 61 18.5 III 9 51.1* 65.4 165 22.6 33 29.0 * p < 0. 05 - Gr. Ill > Gr I. Kruskal-Wallis analysis of variance. and Dunn contrast test. %: percent <of smokers in each group. Table m Flow-Volume Curve Variables in Silicotic Patients of die Three Groups X V max V max 50% GR. n 1/sea % Pred __ 1/sea % I 21 7.26 88 3.79 67 II 12 8.09 95 4.29 75 III 8 5.51 71 2.47 46 V max: 25% 1/sea* % Pred* 1.81 65 1.83 64 0.99 33 * p < 0 .05 -1 > III, II :> III (1/seg); ]C > III (% Prev.) Kruskal-Wallis analysis of variance, and Dunn contrast test. 509 Medical Methods Table IV Maximal Exercise Test Variables, Obtained in the Patients of the Three Groups GROUP I II III n WORK LOAD* (watts) 19 191 13 189 8 103 V02max % Pred FCmax (1/min) bpm 2.32 86.5 150 2.35 89.2 149 1.24 55.1 128 % Pred 83 82 75 p < 0. 05 - *Gr. I and II > III; Gr. I > III. Kruskal-Wallis analysis of variance and Dunn contrast test. of fee patients and die clinical symptoms or the pulmonary taction tests at rest. THe arterial Mood gases at rest and during exercise were imilar to the three groups; and the percentual frequency of hypoxemia and of decrease in Pa02 <5 mmHg (restexercise) was not significantly different when compared to fee groups I, II and HI. As the pulmonary function tests, fee analysis of blood gases at rest and during exercise did not correlate with fee exercise tolerance and fee radiological changes of fee patients (Figure S). Summarizing, the evaluation of the silicotic patients during an exercise test, revealed a certain number of incorrect prediction of working capacity, based on fee resting data. We concluded that fee functional analysis during exercise cm complete or modify fee clinical, radiological and pulmonary function test analysis, in evaluating fee impair ment of patients wife pneumoconioses. REFERENCES 1. American Medical Association: Guides to the evaluation ofpermanent impotnnent. 2nd Ed. p 245 AMA, Chicago (1984). 2. American Thoracic Society: Evaluation ofimpairment/ disability secon dary to respiratory disease. Awer. Rev. Resp. Dis. 126:945-51 (1982). 3. Bagarin, E.: AvaliaQ Clinica, Radidogica e da Fungao Pulmonarem Trabalhadores Expostos a Poeira de Silica. Faculdade de Ciencias M&icas da UNICAMP, Campinas, SP, 1988 (PhD. Thesis). 4. Brown, H.V., Wassennan, K.V.: Exercise Performance in Chronic Obstructive Pulmonary Disease. Med. Clin. N. Amer. 65:52547 (1981). 5. Classification of Radiographs of the Pneumoconioses. Med. Radiogr. Pbotogr. 57:2-17 (1981). 6. Decortis, A., Toussaint, C., Venneire, P., Petit, J.M.:. Interet des cpreuves d'exercises musculaires et des mesures de pressioo des gaz du ang arteriel dans revaluation de la capacite'de travail des silicotiques. Acta tub. pneumol. belg. 64:272-86 (1973). 7. Dierckx, I.P., Gillard, C., Lavalle, R., Ostan, B.: Reflexions sur 1'UtUite' de la Mesure de la PO2 au Repos et a 1`Exercice dans l'Expertise de la Silicose. Acta tub. pneumol. belg. 61:382:7 (1970). 8. Meades, R., Puelma, H.D., Alice, S.H.: Doencas profisskmais causadas por poeiras I. Silicose. In: Meades, R. Medicina do Trabalho Doenqas Profissionais. pp 129-96. Sao Paulo, Sarvier, (1980). 9. Motley, H.L., Fordon, B., Lang, L.P., Tbeodos, P.A.:. Impairment ofpulmonary function in anthracosilicosis. Aich. Industr. Hyg. 1:133-59 (1950). 10. Nery, L.E., Wassennan, K., French, W., Oren, A., Davis, J.A.: Con trasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary disease. Chest 83:446-53 (1983). 11. Roelsen, E., Esldldsen, P.: Investigations of the lung function in silicotics. Acta wed. Scand. 109:377-96 (1941). 12. Spiro, S.G.: Exercise testing in clinical medicine. Br. J. Dis. Cbest 71:145-72 (1977). 13. StanA, V., Widimsky, J., Kasalicky, J., Navratil, M., Daum, S., Levin- sky, L.: The pulmonary gas exchange during exercise in patients with pulmonary fibrosis. Scand. J. Resp. Dis. 48:11-22 (1967). 3H) Medical Methods TIME DOMAIN SPIROGRAM INDICES OF SILICA EXPOSED WORKERS K. S. CHIA T. R Mg J. Jeyaratnam Community, Occupational and Family Medicine Department National University of Singapore ABSTRACT Time domain spirogram indices had been shown to be sensitive indicators of small airway function. The aim of this study is to assess the small airway function of 110 silica-exposed workers using these indices. The workers were subdivided into high, moderate and low exposure groups, based on their occupational history. Their spirograms were digitized electronically and conventional indices as well as time domain indices (MTT--mean transit time, COVTT--coefficient of variation of transit time and IOSTT--index of skewness of transit time) were derived. With adjustment for age, height and smoking status the FEVi and FVC did not differ significantly among the groups whereas all the time domain indices showed significant differences. FEF75% and FEF75.g5* were also significantly lower in the high exposure group although the difference in FEF75% in the moderate and high exposure groups was not statistically significant. Separate analysis were performed for smokers and non-smokers, while excluding all those with FEVj/FVC ratio of less than 0.75. Similar trend of greater small airways obstruction in the higher exposure groups was also seen. The most significant differences were seen with time domain indices, FEF75_g5% and FEF75%. This preliminary study supports the presence of small airway dysfunction among silica exposed workers. Furthermore, time domain spirogram indices appear to be more sensitive to small airway dysfunction. INTRODUCTION Airway resistance of the lungs can be partitioned into cen tral and peripheral components. The peripheral component is composed of the resistance from airways of less than 2mm in internal diameter down to the gas exchange areas. This region is commonly termed as die small airways. Since small airways resistance contribute only 10-15% of total airway resistance, it is possible for a subject to have significant dif fuse obstruction in the small airways while the total airway resistance are essentially normal.1'2 In normal individuals, maximum expiratory flow at large lung volumes like die peak flow and the forced expiratory volume in one second (FEVj), depend mainly on flow in the larger airways whereas maximum flow at small lung volumes reflect predominandy the function of small airways.3'4,5 Several spirometric indices especially flow rates at low lung volumes may reflect die status of small airways. These would include forced expiratory flow at 50% and 75% of forced vital capacity (FEF$o% and FEF75$), forced expiratory flow between 25 and 75%, 75 and 85% of forced vital capacity (FEF25_75%, FEF75_85%).w Time domain indices by using moments analysis of the volume time spirogram have also been shown to be sensitive indicators of small airways obstruction.4'9'15 The mean transit time (MTT) is an index ofthe average rate of emptying of the vital capacity. It is influenced by all parts of the spirogram. Mathematically, this is the first moment about the origin (see appendix 1). The coefficient of varia tion of transit times (CoVTT), represents die amount of varia tion between the initial and the terminal slower portion of the VC. It is derived from the second moment about die mean. The index of skewness of transit times (IoSTT), is a measure of the `slow finish' at the terminal end of the ex piration. This is derived from die third moment about the mean. Some workers analyzed moments about the origin rather than moments about the mean.9"11,16 As an index of dispersion, these authors used the moment ratio (MR). There had been few studies utilizing time domain indices to assess the small airways function of dust exposed workers. In this study we have applied the various spirometric indices as well as time domain indices on a group of granite quarry workers to evaluate their small airways function in relation to their dust exposure. METHODS Subjects The volume-time spirograms of 132 currently employed granite quarry workers were selected. Each spirogram had 511 Medics/ Methods at least 3 satisfactory tracings. The tracing with the highest FVC was digitized using an electronic digitizer. The digitized data is stored into a micro-computer and volume-time as well as flow-volume curves are plotted on the computer screen for visual checking. Flow was calculated by least square regression using pairs of volume-time data in an interval of 0.05 seconds on either side ofa given time point. This method of digitizing volume-time tracings had been shown to be an accurate and useful way of deriving volume-time and flowvolume indices from volume-time tracings.17'18 Early ter mination increases die error in indices at low lung volumes.6 Early truncation increases the variability of time domain indices.16'19 Hence only spirograms that had a flow rate of less than 0.05 1/s in the last 0.5 s were selected for further analysis.20 Of the 132 spirograms, only 110 satisfy the above criteria. The FEVj, FVC, FEF50*, FEF75%, FEF2$.t5%, FEF75^j5, Mi l , CoVTT, IoSTT and MR were calculated. Detailed information including age, height measurement, smoking habits and a lifetime history of occupational ex posure to dust were recorded for each worker. The 110 workers were divided into three dust exposure groups based on occupational history and environmental assessment ofper sonal dust exposure by job categories. The average quartz content in die respirable dust was 28%. The low exposure group comprised those who were in die administrative sec tion all of their working life. The moderate exposure group consists of transport and maintenance workers. The high ex posure group were those who were past or current drillers and crusher workers for most years of their working life. Recent full-sized chest radiographs taken ofeach worker had been read independently by three experienced readers ac cording to die International Labour Organization Standard Classification of Radiographs of Pneumoconiosis. None of the 110 workers had radiological films with profusion of small opacities greater than 1/0. Statistics The data was processed on an IBM 3033 mainframe com puter using statistical procedures from Statistical Analysis System (SAS). Adjustment for group differences in age, height and smoking was done using analysis of co-variance and separate analysis for smokers and non-smokers. RESULTS Description of Study Population There were 50 non-smokers and 60 smokers in die study population. Non-smokers were younger (41.0 compared with 47.6 years for smokers). The mean height were similar (1.66 m for non-smokers and 1.64 m for smokers). 15 (25%) of die smokers have a FEVj/FVC ratio of less than 0.75 whereas all die non-smokers have a ratio ofgreater than 0.75. The mean age, height, duration of exposure as well as die proportion of smokers in die three exposure groups are significantly different (Table I). The high exposure group had the longest duration of employment while the low ex posure group had the shortest. The high exposure group can therefore be expected to have the greatest dose of dust and the low exposure group, the lowest dose. Age and duration of employment was highly correlated (r=0.78 for non smokers, r=0.67 for smokers). Lung Function With adjustment for age, height and smoking status the FEVi and FVC did not differ significantly among die groups whereas all die time domain indices showed signifi cant differences (Table IQ. FEF75* and FEF75_g5* were also significantly lower in the high exposure group although die difference in FEF75% between the moderate and high ex posure groups was not statistically significant. Table I General Characteristics of Study Population Exposure Low Moderate High p value Number Age (years) Height (m) Duration of exposure (years) Smokers (%) 26 36.4 1.67 7.9 27 39 44.1 1.64 13.2 62 45 48.7 1.63 15.9 64 0.0001 0.0232 0.0215 < 0.05 512 Table H Age, Height and Smoking Status Adjusted Lung Function Parameters of die Three Exposure Groups* Medical Methods PARAMETER FEV1 (1/S) FVC (1) FEF25-75X (1/s) FEF75-85X (1/s) FEF50X (1/s) FEF75X (1/S) MTT (s) CoVTT IoSTT MR EXPOSURE GROUPS LMH 2.77 (0.08) 2.69 (0.06) 2.65 (0.06) 3.16 (0.09) 3.23 (0.07) 3.26 (0.07) 3.40 (0.17) 3.09 (0.13) 2.86 (0.13) 1.35 (0.08) 0.93 (0.06) 0.75 (0.06) 3.98 (0.21) 3.86 (0.16) 3.61 (0.15) 1.88 (0.10) 1.35 (0.08) 1.14 (0.07) 0.51 (0.03) 0.63 (0.02) 0.71 (0.02) 1.00 (0.04) 1.22 (0.03) 1.45 (0.03) 0.88 (0.26) 1.58 (0.20) 3.21 (0.19) 1.42 (0.03) 1.59 (0.02) 1.77 (0.02) p VALUES L vs M L VS H M vs H 0.3868 0.2607 0.7078 0.5359 0.4301 0.8042 0.1582 0.0188 0.1995 0.0001 0.0001 0.0283 0.6475 0.1722 0.2423 0.0001 0.0001 0.0572 0.0019 0.0001 0.0202 0.0001 0.0001 0.0001 0.0367 0.0001 0.0001 0.0001 0.0001 0.0001 * Adjusted for age, height and smoking status 'using analysis of covariance ( ) - standard error of adjusted means Exposure groups : L - Low exposure H - Moderate expsoure H * High exposure 513 Medical Methods Separate analysis were performed for smokers and non smokers, while excluding all those with FEVj/FVC ratio of less than 0.75. Except for FEVj and FVC in the low ex posure group, all die other parameters showed that the smokers have greater degree of airway obstruction than the non-smokers (Tables m and IV). Similar trend of greater small airways obstruction in the higher exposure groups was also seen. The most significant differences were seen with time domain indices, FEF75_g3* and FEF75%. Table III Age and Height Adjusted Lung Function Parameters of the Three Exposure Groups in Non-Smokers PARAMETER FEV1 (1/S) FVC (1) FEF25-75X (1/s) FEF75-85X (1/s) FEF50X (1/s) FEF75X (1/s) MTT (S) CoVTT IoSTT MR EXPOSURE GROUPS LM H - 2.81 (0.10) 2.93 (0.10) 2.79 (0.10) 3.15 (0.12) 3.38 (0.12) 3.32 (0.13) 3.72 (0.20) 3.57 (0.22) 3.25 (0.22) 1.49 (0.11) 1.19 (0.12) 0.87 (0.12) 4.25 (0.25) 4.34 (0.26) 4.10 (0.27) 2.11 (0.13) 1.65 (0.14) 1.28 (0.14) 0.46 (0.03) 0.56 (0.04) 0.63 (0.03) 0.99 (0.04) 1.16 (0.05) 1.46 (0.05) 0.51 (0.26) 1.15 (0.27) 2.44 (0.27) 1.42 (0.03) 1.54 (0.02) 1.78 (0.02) p VALUES L VS M L vs H M vs H 0.4182 0.8522 0.3224 0.1818 0.3347 0.7421 0.6301 0.1500 0.3062 0.0753 0.0007 0.0547 0.8192 0.7026 0.5356 0.0225 0.0002 0.0733 0.0519 0.0022 0.1720 0.0135 0.0001 0.0001 0.1009 0.0001 0.0014 0.0164 0.0001 0.0001 * Adjusted for age, height and smoking status using analysis of covariance ( ) - standard error of adjusted means Exposure groups : L - Low exposure M - Moderate expsoure H - High exposure 514 Medical Methods Table IV Age and Height Adjusted Lung Function Parameters of the Three Exposure Groups in Smokers PARAMETER FEV1 (1/s) FVC (1) FEF25-75X (1/s) FEF75-85X (1/s) FEF50X (1/s) FEF75X (1/s) MTT (s) CoVTT IoSTT MR EXPOSURE GROUPS LMH 3.00 (0.12) 2.61 (0.07) 2.74 (0.08) 3.38 (0.13) 3.15 (0.08) 3.33 (0.08) 3.47 (0.29) 3.04 (0.17) 2.96 (0.19) 1.32 (0.13) 0.82 (0.08) 0.74 (0.08) 4.22 (0.34) 3.91 (0.20) 3.64 (0.21) 1.75 (0.18) 1.23 (0.10) 1.18 (0.11) 0.48 (0.05) 0.64 (0.03) 0.67 (0.03) 1.04 (0.06) 1.29 (0.04) 1.51 (0.04) 0.68 (0.46) 1.82 (0.27) 3.04 (0.29) 1.45 (0.05) 1.64 (0.03) 1.81 (0.03) p VALUES L vs M L vs H M vs H 0.0076 0.0794 0.2213 0.1318 0.7207 0.1311 0.2146 0.1563 0.7500 0.0017 0.0006 0.4923 0.4321 0.1658 0.3766 0.0161 0.0109 0.7266 0.0074 0.0018 0.3912 0.0015 0.0001 0.0003 0.0381 0.0001 0.0041 0.0024 0.0001 0.0002 * Adjusted for age, height and smoking status using analysis of covariance ( ) - standard error of adjusted means Exposure groups : L - Low exposure M - Moderate expsoure H - High exposure DISCUSSION A few studies have reported evidence suggestive of small airways obstruction in occupationally exposed groups. In coal worker's pneumoconiosis without evidence of large airway obstruction, frequency dependence of compliance was demonstrated suggestive of small airways obstruction.21 Evidence of small airways abnormalities were also seen among asbestos exposed workers22*23 as well as mineral dust exposure24 and hard rock miners.25 Among gold miners, those with silicosis had lower FEF^s* suggestive of small airways obstruction attributable to silica exposure.26 Our present study suggests that small airway obstruction is present among silica exposed workers in the absence of radiological evidence of silicosis. There was also evidence of a trend of increasing small airways obstruction in higher dust exposure group. Wiles and Faure27 demonstrated an 515 Medical Methods exposure-effect relationship between dust exposure and FEF25.75*. Smoking is known to affect both the larger and smaller air ways.28 As expected, smokers showed greater evidence of small airways obstruction even after excluding those with evidence of significant airway obstruction (FEVj/FVC <0.75). The amount ofcigarettes smoked (number of sticks per day x number of years smoked) was not significantly different in the three groups. Hence the trend of small air ways obstruction in smokers is suggestive of die effect of silica exposure. Our study also suggests that time domain indices are more sensitive to small airways obstruction. These indices give greater emphasis to the end of die forced expiratory manouvre and are hence more sensitive to events in the small airways. The clinical and prognostic significance of early airways obstruction is still far from clear. Further studies would be required to evaluate its predictive value in identifying workers who will progress on to clinical airflow obstruction. REFERENCES 1. Macklem FT, Mead J: Resistance of central and peripheral airways measured by a retrograde catheter. JAppI Physio 22:395-401 (1967). 2. Brown R, Woolcock AJ, Vincent NJ, Macklem PT: Physiological ef fects of experimental airway obstruction with beads. / Appl Physio. 3. Mead J, Tamer JH, Macklem PT, Little IB: Significance of the rela tionship between lung recoil and the maximumexpiratory flow. JAppl Physio 22:95-108 (1967). 4. Pride NB: Editorials--Analysis offorced expiration: a return to the re cording spirometer? Thorax 34:144-9 (1979). 5. Dosman I, Macklem PT: Disease of small airways. Adv Intern Med 22:355-76 (1977). 6. Morris JF, Koski A, Breese JD: Normal values and evaluation offorced expiratory flow. Am Rev Respir Dis 111:755-62 (1975). 7. McFadden ER Jr, Linden DA: A reduction in maximum arid-expiratory flow rate: a spirographic manifestation of small airway disease. Am JMcd 52:725-37 (1972). 8. Miller A: Spirometry and maximum expiratory flow-volume curves. In- Pulmonary fimrtinn texts in clinical and omiparinnal hmg diseases, ed A. Miller, chapter 2, Grune & Stratton, Orlando (1986). 9. Tockman M, Menkes H, Cohen B, Permutt S, Benjamin J, Ball WC Ir, Tonascia I: A comparison of pulmonary function in male smokers and nonsmokers. Am Rev Respir Dis 114:711-22 (1976). 10. Permutt S, Menkes HA: Spirometry--analysis ofthe forced expiration within the time domain. In: ed Macklem P, Permutt S. The lung in transition between health and disease, volume 12, New York, Marcel and Dekker (1979). 11. Webster PM, Zamel N, Bryan AC, Kruger K: Volume dependence of instantaneous time constants derived from the maximal expiratory flowvolume curve. A new approach to the analysis of forced expiration. Am Rev Respir Dis 115:805-10 (1977). 12. Neuburger N, Levison H, Kruger K.: Transit time analysis ofthe forced expiratory vital capacity in cystic fibrosis. Am Rev Resp. 13. Liang A, Macfie AE, Harris EA, Whitlock RML: Transit time analysis ofthe forced expiratory spirogram Airing clinical remission in juvenile asthma. Thorax 34:194-9 (1979). 14. Chia KS, Phoon WO, Ong CN, Koh D: Transit time analysis of the forced expiratory spirogram of fire-fighters. Ann Ac Med 16:324-7 (1987). 15. Chia KS, Phoon WO, Ong CN, Koh D: Assessment of small airway function of fire-fighters using the forced expiratory spirogram. AsiaPac J Pub Hlth fin press). 16. Miller MR, Pincock AC: Repeatability ofthe moments ofthe truncated forced expiratory spirogram. Thorax 37:205-11 (1982). 17. O'Docmel CR, Sneddon SL, Scheoker M, Garshick E, SpeizerFE, Mead J: Accuracy ofspirometric and flow-volume indices obtained by digitiz ing volume-time tracings. Am Rev Respir Dis 136:100-12 (1987). 18. Qua KS, I-"> TK, Jeyaratnam J: Digitizing ofvolume-time spirograms: its accuracy and repeatability. In Proceedings ofthe 5th International Conference on Biomedical Engineering (in press). 19. Miller MR, DM Grove, AC Pincock: Time domain spirogram indices-- their variability and reference values in non-smokers. Am Rev Respir Dis 132:1041-8 (1985). 20. Ferris BG: Epidemiology standardization project M--Recommended standardization procedures for pulmonary function testing. Am Rev Respir Dis (Suppl) 118:55-88 (1978). 21. Seaton A, Lapp NL and Morgan WKC: Lung mechanics and frequen cy dependence ofcompliance in coal miners. / Clin Invest 51:1203-11 (1972). 22. Wright JL, Churg A: Severe diffuse small airways abnormalities in long term chrysotile asbestos miners. Br J Ind Med 42:556-9 (1985). 23. Wright JL, Churg A: Morphology of small-airway lesions in patients with asbestos exposure. Ham Pathol 15:68-74 (1984). 24. Churg A, Wright JL, Wiggs B, Pare PD, Lazar N: Small airways disease and mineral dust exposure. Am Rev Respir Dis 131:139-43 (1985). 25. Manfreda J, Sidwall G, Maini K, West P, Cherniak RM:. Respiratory abnormalities in employees of the hardrock mining industry. Am Rev Respir Dis 126:629-34 (1982). 26. Irwing LM, Rocks P: Lung function and respiratory symptoms in silicotic and nonsilicotic gold miners. Am Rev RespirDis 117:429-35 (1978). 27. Wiles FJ, Faure MH: Chronic obstructive lung disease In gold miners. In: Walton WH, McGovern B eds. Inhaled Particles IV. New York: Pergamon Press 727-35 (1977). 28. Da Silva AMT, Hamosh P: Effect of smoking a single cigarette on the `small airways*. I Appl Physio 34:361-5 (1973). 516 Volume (litres) APPENDIX I Medical Methods M. (MTT) - dV x tt 2 --------------- FVC (dV x tt)2 " 2---------------- FVC MR Mi/M2 SDH - 1/2 (tt - H|)2 x dV FVC SKEWTT (tt - Mi)3 x dV 2-------- i--------- FVC 1/3 CoVTT - SDTT/MTT IoSTT - SKEWTT/(SDTT)3/2 Mn : Nth moment about the origin SDTT : Standard deviation of transit times SKEtfTT : Skewness of transit times 517 Medical Methods LUNG FUNCTION IN SILICA EXPOSED WORKERS R. BEGIN, M.Dl G. Ostiguy, M.IX A. Cantin, M.D. D. Bergeron, M.D. Universite de Sherbrooke, Sherbrooke (QC) Hopital Maisonneuve-Rosemont, Montreal (QC) INTRODUCTION In long term silica-exposed workers, the attribution of changes in lung function to a direct effect of dust exposure or to the development of silicosis has been the subject ofcon siderable debate in the literature and occupational lung con ferences. The topic remains to this date a controversial issue, particularly in view of a recent pathological study which documented the presence at autopsy of fibrotic lesions and silicotic nodules in men who had normal pre-mortem chest radiographs.7 Also, clinical studies4-6 in silica exposed workers documented on lung lavage that a subclinical quartzinduced alveolitis may be present in silica-exposed workers with normal chest radiograph. In that regard, we have documented that CT scan does not identify more patients with minimal parenchymal disease, although it images die disease more clearly in several cases with significantly higher CT scan score of disease. Also we have clearly demonstrated that CT scan identifies significant ly more coalescence and/or large opacities in 33% of pa tients who were thought to have simple silicosis on the plain chest radiograph. To further investigate die clinical significance of these CT scan observations, we expanded our studied population to 94 long-term silica-exposed workers who were examined concomitantly by standard clinical, radiographic and pulmonary function tests. SUBJECTS AND METHODS Silica Exposed Workers The 94 workers of this study had worked in either the granite or foundry industries or gold mines ofQuebec for an average of 29 3 years (range 14-42 years). Ninety percent were either current or former cigarette smokers and they had smoked on die average 21 5 pack-years. Eighty of the 94 were granite workers, 10 were foundry workers and 4 were gold miners. Pulmonary Function Tests The lung volumes, pressure-volume curves, flow-volume curves and diffusing capacities were measured according to standard methods1 as previously applied in our laboratory.2 Chest Radiograph Standard high-kilovoltage posteroanterior, lateral, and o blique films were obtained at maximal inspiration. The radio graph was graded by three observers according to the Inter national Labour Organization (ILO) 1980 classification.8 518 CT Scan of the Thorax Eighty CT examinations were performed on a General Elec tric Model 8800 scanner in Sherbrooke (Canadian General Electric, Co., Montreal, Quebec) and 14 were done on a Picker 600 scanner (Picker, New York, N.Y.). For each pa tient, at least 10 slices of 1-cm thickness were obtained with wide windows, and 10 with narrow windows, for adequate assessment of pulmonary, chest wall, and pleural changes. CT scans were obtained within 48-72 hr of the plain chest film. Subsets of Workers Based on Diagnostic Criteria and CT Scan The 94 silica exposed workers were divided into 4 categories on the bases of evidence of silicosis and the findings of CT scan of the thorax. Group 1 consisted of 21 workers who did not meet the diagnostic criteria for silicosis. Group 2 consisted of 28 workers with simple silicosis on chest radiograph and CT scan of the thorax. Group 3 consisted of 18 workers with simple silicosis on chest radiograph but with coalescence and/or conglomera tion on CT scan of the thorax. Group 4 consisted of 27 workers with complicated silicosis on chest radiograph and CT scan of die thorax. Statistical Analysis All results are expressed as the mean standard error of measurement. The data were tested by die Student t-test or Mann-Whitney U test for differences between groups, by die Wilcoxon matched-pairs signed-rank test for differences be tween radiologic methods, and by Spearman's correlation procedure when appropriate.9*10 RESULTS The lung volumes, compliance and change in vital capacity were within normal prediction in group 1. Subjects ofgroup 2 had no significant change in lung volumes but lung com pliance was significandy lower than that of group 1. In group 3, die silicotics with coalescence and/or large opacity on CT scan, we found significant reduction in vital capacity, lung compliance and an increased loss of vital capacity/year. The subjects of group 4 had lower total lung capacity, vital capaci ty, lung compliance and a significandy increased loss ofvital capacity per year. Diffusing capacity was normal in group 1 and decreased gradually with increased disease severity. This was signifi cant in groups 3 and 4. Exercise gas exchange parameters were also significantly reduced in groups 3 and 4. Group 2, patients with simple silicosis had gas exchange parameters between those without obvious disease, group 1, and patients with conglomerate disease, groups 3 and 4. These changes reached significance level for VE/C>2 ratio and exercise A(A-a)P02. In workers with radiographic silicosis, group 2, expiratory flow rates were lower than in group 1 and this reduction was more severe in groups 3 and 4, the workers with radiographic and/or CT scan coalescence/conglomeration. The lowest values were in group 4. DISCUSSION This study of lung function in long term silica exposed workers documents that the disease severity which is better defined radiographically by CT scan, is also reflected on lung function as restrictive changes. The disease severity also ap pears to be associated with excessive airflow limitation. These data document that early coalescence/conglomeration in silicosis as seen often only on CT scan, is associated with worsened lung functions, a finding which strengthens our prior recommendation for the CT scan exam in radiographic simple silicosis.3 These data also support the Medical Methods concept of a relationship of disease severity, loss of lung function and airflow limitation in silicosis. REFERENCES 1. Bates, D.V., Macklem, P.T., Christie, R.V.: The normal lung: Physiology and methods of study. In: Respiratory Function in Disease, pp. 11-94, 276-280. W.B. Saunders Co., Philadelphia (1971). 2. Begin, R., Bureau, M.A., Lupien, L., Bernier, J.P., Lemieux, B.: Pathogenesis of Respiratory Insufficiency in Myotonic Dystrophy: The Mechanical Factors. Am. Rev. Respir. Dis. 125:312-318 (1982). 3. Begin, R., Bergeron, D., Samson, L., Boctor, M., Cantin, A.: CT Assessment of Silicosis in Exposed Workers. Am. J. Roent. 148:509-514 (1987). 4. Begin, R., Cantin, A., Boileau, R., Bisson, G.: Spectrum of Alveolitis in Quartz-Exposed Human Subjects. Chest 92:1061-1067 (1987). 5. Calhoun, W.J., Christman, J.W., Ershler, W.B., Graham,. W.G.B., Davis, G.S.: Raised Immunoglobulin Concentrations in Bronchoalveolar Lavage Fluid of Healthy Granite Workers. Thorax 41:266-273 (1986). 6. Christman, J.W., Emerson, R.J., Graham, W.G.B., Davis, G.S.: Mineral Dust and Cell Recovery from the Bronchoalveolar Lavage of Healthy Vermont Granite Workers. Am. Rev. Respir. Dis. 132:393-399 (1985). 7. Craighead, J.E., Vallyathan, N.V.: Cryptic Pulmonary Lesions in Workers Occupational Exposed to Dust Containing Silica. JAMA 244:1939-1941 (1980). 8. International Classification ofRadiographs ofPneumoconiosis 1980. No. 22 revised. International Labour Office/University of Cincinnati, Occupational Safety and Health series. Geneva (1980). 9. Siegel, S.: Non-parametric Statistics, pp. 195-240. McGraw-Hill, NewYork (1956). 10. Snedecor, GW., Cochran, W.C.: Statistical Methods. Iowa State Univ. Press, Ames, IO (1967). 519 Medical Methods-Nr. 313 THE VALIDITY OF RADIOLOGICAL AND HISTOLOGICAL FINDINGS IN FORMER ASBESTOS WORKERS WITH LONG CANCER Die Validitat der Rontgenologie und Histologie bei ehemals asbeststaub-gefahrdeten Beschaftigten mit Lungenkrebs THOMAS GIESEN Ministry of Labor and Social Affairs (former: Institut of Occupational Medicine, University of Giessen), FRG Einleitung und Fragestellung: Der Nachweis der fibrogenen Asbesteinwirkung als Asbestose der Lunge Oder der Pleura ist seit 1943 bzw. 1988 die entscheidende Voraussetzung fur die Anerkennung auch der krebserzeugenden Wirkung von Asbest (11,7]. Demnach mussen im Rontgen-Toraxbild eine Strukturvermehrung des Parenchyms von ^1/1 und/oder bestimmte ausgepragte Veranderungen an der Pleura (^2a) nach der ILOKlassifikation [1,2,7,12] und/oder im histologischen Praparat des Lungengewebes eine Asbestose bzw. Minimalasbestose [12] fur die Anerkennung einer Berufskrankheit in der Bundesrepublik Deutschland vorliegen. Wegen der erst kurzlich vorgenommenen Erweiterung des Begriffes "Asbestose** wurde in der Vergangenheh dem Pleura-Befund weder im Rontgenbild noch im histologischen Praparatugen gend Bedeutung beigemessen. Unter dieser Einschr nkung wurden Dignitat und Validitat der diagnostischen Verfahren bei Lungenkrebspatienten nach beruflicher AsbeststaubGefahrdung untersucht. Daruber hinaus stellt sich die Frage, insieweit die durch Asbest verursachte Fibrose weiterhin als pathogenetische Bedingung fur den Lungenkrebs gelten kann? Krankengut und Methodik Es wurden 122 Patienten mit Lungenkrebs nach einer zuriickliegenden, jeweils mehrjahrigen bekannten Astbestfaserstaub-Gefahrdung am Arbeitsplatz untersucht. Daz konnten u.a. das Alter bei Eintritt in die Gefahrdung, die Expositionsdauer, nach grober Schatzung die kumulative Staubdosis sowie das Alter bei Diagnose bzw. Tod bestimmt werden. Dabei erfolgte die Unterscheidung nach Patienten mit und ohne Begleitasbestose sowie danach, ob sie in der Produktion oder im anwendenden Handwerk besch ftigt waren. Bei 76 Personen dieser Gruppe (62,3%) lag sowohl ein auswertbares Torax-Rontgenbild wie auch ein histopathologischer Befund vor. Eine Strukturver-mehrung von ^1/1 im Rontgenbild [1,2] und der Nachweis einer histologischen Astbestose bzw. Minimalasbestose wurden als positiver Befund gewertet. Bei der Bestimmung der ValiditatmaPe der Sensitivital imd Spezifitat wurde einmal die Rontgenologie und zum anderen die Histologie als abhangige Variable verwendet. 520 Ergebnisse 1. Krankengut Tabelle I zeigt die verschiedenen Altersangaben. Auffallend dabei ist die Verschiebung von ca. 10 Jahren nach links bei den Personen ohne Begleitasbestose, die vorwiegend als Handwerker Asbeststaub ausgesetzt waren. In Tabelle II sind die "Asbestose-Parameter** aufgezeigt. Bei weitgehend gleicher Gefahrdungsdauer von 20 Jahren und gleichlanger Latenzzeit von etwa 26 Jahren findet sich der Hauptunterschied in der kumulativen Dosis. Die Per* sonen, die keine Begleitasbestose entwickelt batten, weisen im Median 70 Faser-jahre (F . lOfym3. Jahre) weniger auf als die Patienten mit Begleitasbestose. Abb. 1 veranschaulicht in Teil A), dap selbst bei einer Dosis von unter 20 bzw. 50 Faseijahren noch histologisch erkennbare Fibrosen--hier meist Minimalasbestosen-- auftreten. Im Teil B) erfolgt eine Unterscheidung nach den besonders gefahrdenden Tatigkeiten. Unter den Anwendem ist nur in der Gruppe der Isolierer eine Fibrose gefunden worden. 2. Validitatsmpe Rontgenbefunde des Torax In Abbildung 2 ist die Bewertung des Rontgenbildes der histopathologischen Diagnose gegenubergestellt. Das Verhaltnis von negativen zu fraglichen, bis hin zu eindeutig positiven Befunden korreliert demnach gut. Unter den Lungenkrebspatienten mit einer histologisch eindeutigen Asbestose weisen zu Lebzeiten im Rontgen bild 40% (6:15) keinen positiven Beund auf. Unter den Patienten mit Minimalasbestose zeigen weniger als 1/4 (3:13) eine rontgenologisch eindeudge Asbestose. Histo-pathologische Diagnose Die histo-pathologischen Befundberichte aus Autopsie, Operation oder Endoskopie wurden in 30 verschiedenen Prosekturen erstellt. Mitunter ergaben sich divergierende Aussagen zum Vorliegen oder Fehlen einer Pneumokoniose, wenn zwei Posekturen zum gleichen Erkrankungsfall gehort wurden. Bei 44 der 76 hier besonders untersuchten Lungenkrebspatienten (58 %) fand Medical Methods Tabelle I Altersangaben ab Eintritt in die Asbestfaserstaub-Gefahrdung am Arbeitsplatz fur 78 Lungenkrebspatienten, den Zeitpunkt der Diagnose Lungenkrebs sowie des Todes an Lungenkrebs in Abhangigkeit vom histologischen Nachweis einer Lungenasbestose. Entsprechende Angaben fur 121 Lungenkrebspatienten in Abhangigkeit von den wichtigsten Tatigkeitsbereichen in der industriellen HersteUung und handwerklichen Anwendung von asbestprodukten. Lungenkrebs nach Asbestfaserstaub-Gefahrdung am A.rbeitsplatz: Altersangaben n Median Min. - Max. n Median Min. - Max. Median Diff. Histologische Diagnose: ASBESTOSE ODER MINIMAL-ASBESTOSE KEINE ASBESTOSE Alter [Jahre] bei - Eintritt in die Gefahrdurg - Diagnose LUNGENKREBS - Tod (Stichtag) 28 28 28 32,0 14,0 - 53,0 64,5 37,0 - 75,0 66,0 j 38,0 - 76,0 50 50 50 "...... 23,0 14,0 - 52,0 + 9, 0 55,0 34,0 - 78,0 56,0 36,0 - 79,0 + 9,5 + 10,0 TStigkeitsbereiche: 1 HERSTELLUNG ANWENDUNG VON ASBESTPRODUKTEN Alter [Jahre] bei - Eintritt in die Gefahrdung 58 39,0 14,0 - 55,0 63 - Diagnose LUNGENKREBS 58 64,0 34,0 - 80,0 64 - Tod (Stichtag) 58 65,5 36,0 - 81,0 64 22,0 14,0 - 50,0 54,5 36,0 - 78,0 55,5 37,0 - 79,0 + 17,0 + 9,5 + 10,0 zur Absicherung der histologischen Diagnose das lichtmikroskopische Zahlergebnis von sogenannten "Asbestk rperchen" nach Lungengewebsveraschung Verwendung. Validitatsmpe In Tabelle m sind die Validitatsmpe fur die gepriiften diagnostischen Methoden gegenii bergestellt. Unter A wurde der Rontgenbefund (R) als Variable und die Histologie (H) als gesichertes diagnostisches Verfahren eingesetzt. Im Rontgenbild betragt die Rate der falsch-negativen Diagnosen 57%, wahrend die Rate der falsch-positiven lediglich 2% ausmacht. Im Rontgenbild werden jedoch nur 43%, d.h. nur fast die Halfte der Patienten als eindeudge Asbestose-Kranke erkannt. Unter B gilt die Histologie als abhangige Methode. Dabei zeigt sich eine hohe diagnostische Sensitivitat. Die Rate der falsch-positiven Diagnosen "Asbestose" tiegt im Vergleich zum Rontgenbefund mit 25% jedoch revalit hoch. Die Rate der falsch-negativen Diagnosen betragt knapp 8 %. Diskussion und Schlupfolgerungen Als 1925 der Gesetzgeber das Recht fur Arbeitsunfalle und Berufskrankheiten geschaffen hat, sollten den Arbeitnehmem, die einen beruflich verursachten Gesundheitsschaden erlitten hatten, als Ersatz fur die verminderte Arbeitskraft eine Rente als Lohnersatz gezahlt werden. Mit diesem sozialen Gedanken sollte die moralische Verpflichtung des Arbeitgebers und der Gesellschaft umgesetzt werden, fur beruflich verursachte Schaden aufeukommen und den Arbeiter und seine Familie vor wirtschaftlicher Not zu bewahren und dieses--wegen der Lohnersatzfunktion-- moglichst zu seinen Lebzeiten. Vor diesem Hintergrund und der Tatsache, dap die Uberlebenszeit der Lungenskrebspatienten im Median 6 Monate betragt [16] ist bei strenger Auslegung der Gesetze 521 Medical Methods Tabelle U Kenngropen der Asbestfaserstaub-Gefahrdung am Albeitsplatz fur 78 Lungenkrebspatienten nach Unterteilung in Gruppen mit Oder ohne histologisch nachgewiesene Lungenasbestose einschieplich Minimalasbestose. KENNGROSSEN DER ASBESTFASERSTAUB-GEFAHRDUNG am arbeitsplatz FOR LUNGENKREBSPATIENTEN MIT HISTOLOGISCHEN DIAGNOSEN (MEDIANWERTE) Do sisSquivalente Mit Asbestose und MinimalAsbestose (n = 28) Kumulative Dosis [106 F/m3 Jahre]: 82,0 Alter bei Eintritt in die GefMhrdung [J.]: 32 GefShrdungsdauer [J.Js 19,2 Latenzzeit (Tod [J-] :*27,2 bzw. Stichtag) Ohne Asbestose (n = 50) 11 r 2 23 20,9 26,8 Diff. + 70,8 +9 " 1,7 + 0,4 nicht gewollt, bis zum Tod des Erkrankten zu warten, um erst an der Leichenlunge festzustellen, ob der Beschaftgigte zu Lebzeiten eine Berufskrankheit erlitten hatte. Das bedeutet, dap sich die medizinisebe Untersuchung zur Frage, ob der Asbeststaub eine Fibrose verursacht bat, auf das Rontgenbild stutzen mu{3. Invasive Eingriffe sind im Unfallrecht nicht duldungspflichtig. Die Untersuchung der 122 Patienten mit Lungenkrebs nach einer erwiesenen, teilweise relativ geringen Asbeststaubgefahrdung hat jedoch gezeigt, daP eine Begleitfibrose nur dann auftritt, wenn die kumulative Dosis einen bestimmten Schwellenwert, der nach BERRY und FINKELSTEIN zwischen 35 und 50 Faseijahren liegt [6], uberschritten hat. Fiir die karzinogene Wirkung von Asbestfasern gibt es aber keinen Schwellenwert. Das lapt die Schlupfolgerung zu, daP die Fibrose pathogenedsch keine Bedingung fur die Entstehung eines Tumors der Lunge darstellt, wie es am Beispiel des Mesothelioms nach Asbestgefahrdung bekannt ist [4]. Wie die Validitatsmafie in Tabelle m und die Abbildung 1 zeigen, kann auch durch die Einfuhrung der Begriffe "Minimalasbestose" Oder ``Pleura-Asbestose" diese Schlupfolgerung nicht verdrangt weden. Daruber hinaus gibt es weder in der Bundesrepublik noch international eine einheitliche N'omenklatur zur Grenzziehung, was eben noch eine Asbestose ist und wann eben keine Asbestose--trotz beruflicher Asbestgefahrdung-- mehr vorliegt. Die nach- folgende Ubersicht zeigt, in welchen Punkten eine einheitliche Normierung der Nomenklatur erforderlich erscheint: VORSCHLAGE ZUR DEFINITION UND DIAGNOSTIK DER "ASBESTOSE** 1. Rontgenologische Diagnostik --Lungenasbestose (Streuung ^ 1/0) und/oder --Pleuraasbestose als diffuse Verdickung und/oder hyaline oder verkalkte Pleuraplaques. 2. Histologisch-pathologische Diagnostik --Lungenasbestose nach Febrosegrad1* und/oder --Pleuraasbestose als dissufe Verdickung und/oder hyaline oder verkalkte Pleuraplaques. 3. Faserstaubanalytische Diagnostik --Anzahl der Asbestkorperchena) und/oder --Anzahl der Asbestfasern^. Konventiooen nach Priifung der methodiseben Zuverlassigkeitskriterien erforderlich. Daruber hinaus gibt es keinen erkennbaren wissenschaftlich begrundbaren Ansatz, wie ein Lungenkrebs nach beruflicher Asbeststaub-Gefahrdung mit oder ohne Begleitasbestose als asbestbedingt abgegrenzt werden kann. Demnach mufl eine Konvention erarbeitet werden, unter welchen Randbedin- 522 HISTOLOOE-BEFUND: LUNGENASBESTOSE ohne mit iooi%i * f Mji <20 20-50* sojooS >100 S >20 20-50 50-CO >100 < Medical Methods GO IcI 1001 tj V A 1 75- C I50- o d 25- 0- n=13 n=15 S0/1 vX'XvXvX 1/0 Ifggf Wwm iiil buy mmk mllllmlll kalna Minimal- Asbestos Asbestos* Asbestos* Hlto - Pathologl* Abb. 1. Histologische Diagnose der Lungenasbestose (einschlieilich Minimalasbestose) bei 77 Lungenkrebspatienten in Abhangigkeit von der fiber das Arbeitsleben kumuliert abgeschatzten Asbestfaserstaub-Dosis in 106 Asbestfasem einer La nge uber 5 pm prom3 Atemluft Jahre (= Faserjahre), Teil A) bzw. B) unterteilt nach den wichtisgsten industriellen Herstellungs- und handwerklichen Anwendungsbereichen von Asbestprodukten. Abk. der Tatigkeitsbereiche: AZ = Asbestzement, F + P = Filter + Pappen, RB = Reib* belage, IT/K = Gummi-Asbest u. Kunst-stoffe, Tex = Textilien, ISO = Isolierer, AZI = Asbest zum Isolieren Abb. 2. Rontgenbefunde des Thorax im Hinblick auf eine Lungenasbestose in Abhangigkeit vom histopathologischen Behind bei 76 Patienten mit Lungenkrebs nach Asbestfaserstaub-Gefahrdung am Arbeitsplatz. 523 Medical Methods Tabelle HI Vorschlage zur Definition und Diagnostik der Asbestose von Lunge und Pleura, einschlieplich der MinimalAsbestose und deren Faserstaub-analytischen Aquivalenten Lungenkrebs nach Asbestf^.serstaub-Gefahrdung am Arbeitsplatz: ValiditStsmaBe der rontgenolgischen (R) und histologischen (H) Diagnostik der Lungenasbestose^ A) R : H n B) H : R %n Sensitivitat 12 : 28 42,9 12 : 13 92,3 Rate der FalschNegativen 16 : 28 57,1 1 s 13 7,7 Spezifitat 47 : 48 97,9 47 s 63 74,6 Rate der FalschPositiven 1 : 48 2,1 16 : 63 25,4 PrSdiktiver Wert des - positiven Testes - negativen Testes 12 : 13 92,3 47 : 63 74,6 12 : 28 47 s 48 42,9 97,9 Positive Befunde:. - Histologie: Asbestose Oder Minimal-Asbestose - Rontgenstruktur: X 1/1 nach der ILO-Staublungen- klassifikation gungen--sei es die Dosis, sei es die Dauer der Gefahrdung-- ein derartiger Lungenkrebs als beruflich verursacht anerkannt werden soil. LITERATURE/RERERENCES 1. Bohlig, H., Hain, E., Woitowitz, HJ.: Die ILO U/C 1971 Staublungenklassifikation und ibre Bedeutung fur die Vorsorgeuntersuchung staubgefahradeter Aibeitnehmer. Prax. Pneumol. 26:688-700 (1972). 2. Bohlig, H.t Hain, E., Valentin, H., Woitowitz, HJ.: Die Weiterentwickhing der Intemationalen Staublungenklassifikation und ihre Konsequeozen fur die arbeitsmedizinischen Vorsorgeuntersucbungen staubgefahrdeter Arbeitnehmr (ILO 1980/Bundesrepublik). Prax. Pneumol 35:1134-1139 (1981). 3. Cookson, W.O., Musk, A.W., Glauck, J.J., De Klerk, M.H., Yin, R., Mele, R., Carr, M.G., Armstrong, B.K., Hobbs, M.S.T.: Com pensation, Radiographic Changes and Survival in Application for Asbestos-Compensation. Br. J. Iod. Med. 42:461-468 (1985). 4. Craighead, J.E., Mossmann, T.B.: the Pathogenesis of AsbestosAssociated diseases. N. Engl. J. Med. 1446-1455 (1982). 5. Giesen, T., Woitowitz, H.J.: Rbntgenologische und histologische Befunde bei Lungenkrebspatieriten nach Asbestfaserstaubgefardung am Arbeitsplatz. Verhandl. 26. Jahrestagung derDtsch. Ges. f. Aibeitsmed., Gentner., Stuttgart, 289-294 (1986). 6. Giesen, T.: Asbestverursachter Lungenkrebs ohne Asbestose--Die Asbestfaserstaub-Gefahrdung amArbeitsplatz als wesentlich mitwirkende Ursache? Inauguialdissertation, vorgelegt bd derJustus-Liebig-Uniyersit t Giessen (1988). 7. Giesen, T.: Anderung der Liste der Berufskrankbehen (An!. 1 BeKV)-- List of Occupational Diseases hat changed. Zbl. Aibeitsmed. 38: in printing (1988). 8. Hillderdahl, G. Lindgren, A.: Pleural plaques: Correlation ofautopsy findings to radiographic findings and occupational history. Eur. J. Resprir. Dis. 61:315-319 (1980). 9. Kannerstein, M. Chnig, J.: Pathology of Carcinoma of the Lung associated with Asbestos Exposure. Cancer. 30:14-21 (1972). 10. Lidell, F.D.K., McDonald, J.C.: Radiological findings as Predictors ofmortality in Quebec asbestos workers. Br. J. Ind. Med. 37:257-267 (1980). 11. Nordmann, M.: DerBerufskrebs der Asbestarbeiter. Z. Krebsforsch.: 4:288-302 (1938). 12. Otto, H., Bohlig, H.: Morphologie und Rontgenologic der Asbestose. Radidoge. 25:9-21 (1985) 13. Roedelsperger, K., Woitowitz, H.J., Manke, J., Biuckel, B., Giesen, T.: Probleme des asbestfasemachweises im fjingan^nh Atemw.Lungenkrkh. 11:236-238 (1985) 14. Whitwell, F., Newhouse, M.L., Bennet, D.R.: A Study of Histological Cell Types ofLung Cancer in Workers Suffering from Asbestos in the United Kingdom. Br. J. Iod. Med. 31:292-303 (1974). 15. Woitowitz, H.J., Lange, H.J., Beierl, L., Rathgeb, M., Schmidt, K., Ulm, K., Giesen, T., Woitowitz, R.H., Pacbe, L. Rodelsperger, K.: Mortality rates in the Federal Republik of Germany following previous occupational exposure to asbestos dust. for. Arch. Occup. Enviom. Health. 57:161-171 (1986). 16. Woitowitz, HJ., Giesen, T.: Lungenkrebs nach AsbestfaserstaubGefahrdung am Arbeitsplatz--Aibeits-und Sozialmedizinische Aspekte. Die BeiufsgenossenscbaR. 10:600-607 (1986). 524