significance of lung function changes in...

Thorax (1960), 15, 109.

THE SIGNIFICANCE OF LUNG FUNCTION CHANGESIN ASBESTOSIS

BYROGER WILLIAMS* AND P. HUGH-JONES

Fronm the Department of Medicine, Postgraduate Medical School of London

(RECEIVED FOR PUBLICATION DECEMBER 21, 1959)

Asbestos is the name given to a series ofminerals composed of fibrous silicates ofmagnesium and iron which find widespread use inindustry. Inhalation of the dust may causeasbestosis, a crippling form of pulmonary fibrosis,which usually does not appear until many yearsafter the initial exposure. There is also anincreased incidence of carcinoma of the lung inpatients with asbestosis, and Doll (1955) estimatedthat the risk of lung cancer in asbestos workerswas approximately 10 times greater than in thegeneral population.The diagnosis of asbestosis at present depends

on the history of exposure to the dust togetherwith certain physical signs and radiologicalchanges. The most characteristic features of thelatter are a " ground-glass " mottling of the lowerzones of the lung fields with a shaggy border tothe heart. The physical signs are clubbing of thefingers and fine metallic crepitations on ausculta-tion of the lung bases. Unfortunately many caseseven with definite physical signs do not show thecharacteristic radiological changes, and the earlydiagnosis of the disease may be most difficult.The presence of "'asbestosis bodies" in thesputum simply proves that asbestos dust hasbeen inhaled and does not necessarily imply thatfibrosis is present.The purpose of the present work was to relate

the changes in lung function in asbestosis to theclinical and radiological signs of the disease andto try and determine the value of lung functiontests in assisting with its early diagnosis.

PREvious LUNG FUNCTION STUDIES

It has been known for some time that the mainfunctional defect in asbestosis is a reduceddiffusing capacity of the lungs. In early reports(Roemheld, Kempf, and Wedler, 1940; Baldwin,Cournand, and Richards, 1949; Gernex-Rieux,Balgairies, and Claeys, 1954; Bastenier, Denolin,*Present address: Medical Unit, Royal Free Hospital, Gray's Inn

Road, London, W.C.I.

de Coster, and Englert, 1955) this was inferredfrom the occurrence of arterial oxygen desatura-tion on exercise. Other changes noted weremarked hyperventilation on exertion, with rela-tively well-maintained tests of ventilatory capacity.This functional pattern, which was called byAustrian, McClement, Renzetti, Donald, Riley,and Cournand (1951) the syndrome of " alveolar-capillary block," occurs in a whole group ofuncommon diseases characterized pathologicallyby interstitial fibrosis. Wright (1955b) described aseries of 57 men with varying degrees of exposureto asbestos dust, who had been studied at theTrudeau Foundation. He found a reduced partialpressure of oxygen in the arterial blood despitenormal levels in the alveolar gas, and similarlyconcluded that the primary lesion was a reductionin diffusing capacity, though there was also amoderate reduction in the inspiratory capacityresulting from the fibrosis which often led to anappreciable reduction in maximum breathingcapacity. There was no consistent relation, how-ever, between the functional changes and theradiological appearances. More recently Bader,Bader, and Selikoff (1957) studied 18 patients withasbestosis and measured the diffusing capacity foroxygen by the method of Riley and Cournand infive of them. In only three of these was itsignificantly reduced.

SUBJECTS STUDIEDForty patients in all were seen. These were

divided into three groups.

GROUP 1.-This consisted of 21 cases ofasbestosis. They had all been seen and certifiedby the pneumoconiosis medical boards and werereceiving disability pensions ranging from 10 to80%.GROUP 2.-This comprised 10 men from the

same factory as the patients in the first group.They had been exposed to asbestos dust for vary-

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ROGER WILLIAMS and P. HUGH-JONES

ing periods of time but had shown no signs ofdisease and their annual radiograph had beenpassed as clear.

GROUP 3.-This consisted of nine men referredfor lung function tests in whom the diagnosis ofasbestosis had been questioned either because of:inadequate exposure, the absence of the charac-teristic physical signs, or the presence of atypicalradiological changes.

METHODSCLINICAL ASSESSMENT.-The patients were routinely

admitted to hospital for 36 to 48 hours. The clinicalassessment was done independently of the functiontests by one observer, and certain of the clinicalfindings which were later to be compared with thefunctional results were expressed quantitatively,dyspnoea being graded 0-5 according to the criteriaproposed by Fletcher (1952), and clubbing, crepita-tions, and wheeze as absent, slight, or marked. Aseparate study on a later occasion showed that thisobserver was probably biased towards finding thesigns of clubbing and crepitations when the patientswere seen in hospital. The laboratory investigationsthat were performed in nearly all the cases includeda blood count, E.S.R. (by the Westergren method),and serum protein and serum bicarbonate estimations.A 24-hour collection of sputum was examined forasbestosis bodies. The electrocardiogram wasanalysed particularly for evidence of right ventricularpreponderance.

RADIOLOGICAL APPEARANCES.-It was consideredthat the only radiological change in asbestosis capableof being graded was the degree of mottling. Thiswas assessed independently by a group of fourobservers using three standard films (grades 1, 2, and3) chosen to represent the range of mottling seen inasbestosis. Each zone of the lung field wasconsidered separately and the findings later addedtogether to form a total score (possible range 0->18).The mean of the readings of the four observers (threephysicians and a radiologist at HammersmithHospital), who had special experience in the readingof pneumoconiosis films, was taken as the radio-logical grade. Special note was also made of thepresence or absence of bullae which were defined astranslucent areas greater than 1 cm. in diameter. Fulldetails of the technique of radiological grading andthe effect of observer variability on the readings-obtained are given elsewhere (Williams and Hugh-Jones, 1960).LUNG FUNCTION TESTS.-The following tests were

carried out, all gas volumes being measured atambient pressure and room temperature.

(1) Resting Ventilation.-This was measured afterthe patient had been resting quietly for at least 20minutes using a vane anemometer which hasnegligible resistance (Wright, 1955a).

(2) Exercise Ventilation.-The standard exercisetest described by Hugh-Jones (1952) was used. Thestandardized ventilation (S.V.) was preferred to theexercise ventilation as a measure of the ventilatorycost of exercise, as it is valid even in patients who areunable to complete the full five minutes of exercise.

(3) Maximum Breathing Capacity.--This was esti-mated indirectly from the mean of three consistentreadings of the forced expiratory volume in onesecond (F.E.V.1.o) recorded as a tracing using a low-resistance spirometer (Bernstein, D'Silva, and Mendel,1952). The ratio of the F.E.V.1.o to the vital capacitywas calculated (known as the F.E.V. %). The testwas repeated after the patient had inhaled an aerosolof 1 % isoprenaline for five minutes in order to detectany labile air-flow obstruction.

(4) Lung Volumes.-These were determined by theclosed-circuit helium-dilution method (Gilson andHugh-Jones, 1949), the normal values being predictedfrom the simplified regression formulae derived byNeedham, Rogan, and McDonald (1954).

(5) Diffusing Capacity.-This was measured by thesingle-breath carbon monoxide method using thesimplified technique described by Ogilvie, Forster,Blakemore, and Morton (1957). Subsequent calibra-tion of the apparatus suggested a small systematicerror. This does not affect the validity of the resultsas the values for diffusing capacity have beenexpressed as a percentage of normal, the normalvalues being predicted from a regression on surfacearea derived from a group of normal subjects studiedusing the same technique.

(6) Arterial Oxygen Saturation.-This was measuredat rest using the spectrophotometric method in all thepatients in whom cyanosis was suspected clinically.Changes in oxygen saturation during the standardexercise test were measured using a Waters-Conleyear oximeter in the majority of patients in Groups 2and 3.

(7) Inequality of Ventilation, Perfusion, andVentilation-perfusion Ratio.-This was estimated bythe single-breath test devised by West, Fowler, Hugh-Jones, and O'Donnell (1957) using a suitable massspectrometer.

RESULTSGROUP 1.-The main clinical findings are given

in Table I. The average exposure was 14 years,but there was a wide range (three to 32 years) andtwo of the cases had only been exposed for threeand three and a half years respectively. Thedegree of exposure is more difficult to evaluate asthere were no satisfactory measurements of dustconcentration during this period, but the majorityof the patients in this group had worked inparticularly dusty departments such as the openingand crushing, weaving and sectional departmentsof the factory before modern methods of dustprevention had been introduced. One patient

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LUNG FUNCTION CHANGES IN ASBESTOSIS

AgeandSex

Expo-sure(yr.)

TABLE ICLINICAL DATA ON 21 RECOGNIZED CASES OF ASBESTOSIS (GROUP 1)

Gradeof

DyspnoeaClubbing Crepita-

tionsAsbestosis E.S.R.Bodies (mm./hr.)

PlasmaA/GRatio

ElectrophoreticPattern ofProteins

E.C.G.RadiologicalGrade ofMottling

1 50 M 16 3 + ++ Absent 9 1-4 Normal 62 48 M 10 2 + + + - 0 9 jincreased _ 53 50 M 18 4 + + + + Present 120 0-7 a2, N,yincreasedL 84 57 F 14 4 + + + - 61 1-6 Normal N 105 56 F 34 3 + + + + - 40 1.1 a21 6, y increased R 126 41 M 11 1 0 + Absent 2 1-3 a2, ,Bincreased N 67 37 F 3 2 + + 6 1-7 Normal N 48 45 M 9 3 + + + 7 1-0 ,, L 79 44 M 11 2 + ++ Absent 1 2-0 ,, N 610 46 M 12 4 + + + + 12 1-3 a2,p increased (R) 121 1 60 M 18 3 0 + + - 8 0-8 , increased N 1012 52 F 15 3 + + + + Absent 32 1.1 a2,9 increased N 413 59 M 14 5 + + + + 8 0-9 a2, , increased R 1414 46 M 22 4 ++ ++ 3 1.1 Normal R 1315 64 M 11 2 ++ ++ 15 1-4 ,, N 516 59 M 17 2 + + + 10 0-9 a2,B increased N 717 47 M 25 2 + + + 8 10 a2 8, yincreased N 218 54 M 32 2 0 ++ Present 2 1-3 Normal N 619 54 M 24 3 + + + + - 3 0-8 a2, ,B, y increased N 420 59 M 8 2 + ++ 38 0-5 Albuminreduced, (R) 1

a;, ,, y increased21 1 F 13 3 0 ± 5 1-2 V,yincreased L 6

Clubbing and crepitations graded absent (0), slight (+), or marked (+ +). For grading of dyspnoea and x-ray mottling see text.Electrocardiogram: N=Normal, L=left ventricular preponderance, R=right ventricular preponderance. (R)=borderline R.V.P.

(Case 19) had never actually worked with asbestos,though, as works carpenter, he had been employedin many of the dusty departments. All exceptone (Case 6) complained of breathlessness on

exertion with serious limitation of their exercisetolerance. Another rather characteristic featurewas a distressing paroxysmal cough oftenprecipitated by exertion. Sputum was invariablyscanty and mucoid. Asbestosis bodies were

present in only two out of the 12 examined. Innine patients it proved impossible to collect an

adequate specimen of sputum during their stay inhospital.The most striking physical signs were clubbing

of the fingers and crepitations at the lung bases.Although crepitations were present in all, clubbingwas absent in four and marked in nine cases only.Usually these two signs went hand in hand, butthere was one patient (Case 16) in whom thedegree of clubbing was out of proportion to theauscultatory signs. Wheeze, though present innine cases, was marked in one patient only (Case20), who also gave a clear history of asthma. Thechest expansion was often reduced (mean 11 in.,range 3 in. to 2-1 in.), but this appeared to bearlittle relation to the radiological severity of thedisease. Arterial puncture in all patients thoughtclinically to be cyanosed showed that definitehypoxia was present in only two (Case 13 satura-tion 87.5%, Case 14 saturation 84.5%). In thesetwo cases and in one other (Case 18) the serum

bicarbonate level was slightly raised (33, 32, and 34mEq/1. respectively, upper limit of normal beingtaken as 31 mEq/l.

The main findings of interest in the clinicalinvestigations were the changes in E.S.R. andplasma protein fractions. The E.S.R. was increasedabove 10 mm./hr. in eight patients. In only twoof these (Case 3 with carcinoma of the lung, Case5 with rheumatoid arthritis) was there an obvious

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30

20

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VENTILATOPY LUNG KX&ES

MBC FEV7 rLc /C 9t RV.Xpred '*/I cded *4. /*ed

'/0v0I 6-! s ;~~~~~~~~~~~11im

Li IEmNorma/ range

D/IFFUSVCAPACITY

I

S*IS

FIG. 1.-The main change in lung function in 21 certified cases ofasbestosis (Group 1). The values for maximum breathingcapacity (M.B.C.), total lung capacity (T.L.C.), inspiratorycapacity (I.C.), residual volume (R.V.), and diffusing capacity(Dco) have been expressed as a percentage of the predictednormal.

Case

ill

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explanation other than the asbestosis. Electro-phoresis of the serum showed an abnormal patternin 13 with elevation of the a.2 and f8 peaks witha less marked increase in y globulin. One case inaddition showed a low albumin. The albumin-globulin ratio was reversed in seven of these 13cases.LUNG FUNCTION STUDIES.-The results are given

in Table II and the main changes illustrated inFig. 1.RESTING VENTILATION.-Six of the 12 cases in

which this was measured showed an increase in

minute volume, the upper limit of normal with theanemometer technique being 8 1. /min. for malesand 5 1. /min. for females (MacLeish, 1960). In fourof these it was due to an increase in respiratoryrate with a normal or small tidal volume. In theother two the hyperventilation was the result of anincrease in the depth of respiration, the rateremaining normal.

EXERCISE VENTILATION.-TwO were unable toperform an exercise test owing to physicaldeformities. The remainder showed an increasedstandardized ventilation (S.V.). In those who

TABLE IXRESULTS OF PULMONARY FUNCTION TESTS IN THE THREE GROUPS OF PATIENTS STUDIED

Ind. M.B.C.(1. 'mm.)

FENBefore After

Isoprenaline

Group 11 71 71 882 95 95 863 53 55 754 60 62 805 38 36 846 73 76 717 46 48 708 87 87 729 51 51 8610 67 66 83I1 87 87 8512 49 49 8013 25 27 3614 36 38 6715 91 96 7216 62 64 7217 88 88 8618 72 73 6619 92 94 6920 58 64 5521 49 53 76

Mean 64 66 74

M.V. sv(I. min.)

Restn. Exer-Ret cise

11.0 30i- 32

T 5570 50

35]- 4270 39

307.3 43- 484-5 40- 49

40100 426-8 398 5 35108 317.5 347-0 i 36140

8 5 40

Lung Vo

T.L.C. I.C.

3 53 1 704 45 1-753-26 1-273-39 1-472-44 0-984-63 2-203-17 0-985 28 1 752-78 0-603-79 0-924 82 2-012-92 11004.49 0943-96 1-13590 1-814-47 11514.45 2035*49 11996-51 2-114-67 1-732-97 1-23

4-16 1-48

olumes (I.)

R.V. TF

1 431-561-491-401-171-881 382 051 292 282 031-372-902-452-372-081-542-682-821 691 24

186

Inequality % per 500 ml.Dco Expired of:

(ml. Imm.Hg -R,.V./ min.) Ventila- Per - ValQcL.C. % tion fusion Ratio

41 11-6 17-0 10.1 8-735 13-1 79 111 6-946 11*2 14-1 5.7 9.941 9.9 16-2 4-3 13-148 9-8 221 7-3 17-141 16-8 8-6 -1-3 9.144 13-3 23-4 5 3 20 539 10-2 10 3 8 7 2-946 138 117 4-4 7.560 6-4 36-3 - 5.5 39.942 19-6 - - -

47 10-3 16-3 -2-4 17-865 - 358 21-9 18 662 8-7 30 0 17-5 18-240 9.4 11-8 80 7147 119 142 7-1 9-835 15-7 8-1 40 5I 149 18-4 103 7-9 3-643 12-8 11-2 9 0 4-336 21-6 152 6-4 12142 17-2 17 6 6-9 12-0

45 13-1

Group 222 95 105 64 9 7 3123 109 117 75 10 0 3424 105 110 78 7-7 3625 82 82 74 8-7 2826 8 1 88 58 100 2927 86 83 74 11 0 3728 73 78 62 115 3529 56 66 66 9 5 3030 50 61 53 13-3 3931 54 64 77 37

Mean 79 85 68 10-2 34

5 91 195 2-09 35579 3-39 1-83 324 91 2 59 1-07 224 97 1-97 1-98 405-77 1-81 2-42 42

5e09 2-91 200 395 13 2-37 1168 335-22 2-49 2 57 496 02 2-03 2-77 463-63 1-61 108 30

5S24 231 1 95 37

Group 332 58 60 86 19 0 78 4-16 0 90 2-24 54 9 0 19.1 14-8 7 233 75 76 61 _ 46 5-13 2-21 1-92 37 12-4 15-4 12-0 7-634 39 43 46 9-8 59 5-51 1-65 3-64 66 144 119 0-3 11-835 63 68 68 _ 45 4-48 1.51 1-95 44 15 7 14-2 9 1 7-236 72 67 82 - 4-32 1-31 2-13 49 18 0 20-5 15-0 10 037 69 71 73 11-4 40 4 30 1-87 1-43 33 12-1 - _ _38 91 94 81 7-8 47 4 70 177 143 30 15-2 8-0 4-0 5 539 84 90 74 - 5-43 1-59 2-56 47 12-6 13-0 8-0 9 040 35 49 46 42 5-18 1-71 2-71 52 18-8 - _ _Mean 65 69 69 12-0 51 4-80 1-61 2-22 46 14-2

M.3.C.=maximum breathing capacity, F.E.V.Y-=forced expiratory volume (I sec.) as Y. of vital capacity, M.V.=minute volume, S.V.-standardized ventilation, T.L.C.-total lung capacity, I.C.=inspiratory capacity, R.V.=residual volume, Dm,-diffusing capacity for carbonmonoxide, Va'Qc=ventilation-perfusion ratio.

112

22-8 5426-4 2713-8 6-722-1 109213 64244 6-9295 7919-2 8 5210 13 121-4 -

222

1 6 4208 3-33-8 405.3 693.9 3-125 5.00-6 7 556 366-6 9-2_ _



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completed the full five minutes of exercise theS.V. was almost identical with the exerciseventilation (E.V.). This would be expected asthey had attained a steady state of exercise. Inthe four who were unable to complete the fullperiod of exercise, the S.V. was greater than theE.V. In two of these (Cases 4 and 7) it is likelythat they could have completed the exercise hadthey been prepared to tolerate the feeling ofdyspnoea as the ventilation achieved duringexercise had not reached the maximum of whichthey were capable. In the other two (Cases 5 and13) the S.V. was greater than their maximumventilatory capacity and represented a ventilatorydebt which continued to increase as long as exer-cise was continued and which was repaid duringrecovery.

MAXIMUM BREATHING CAPACITY.-It can be seenfrom Fig. 1 that this was reduced in many of thepatients, but in only five was it reduced to below50% of normal. The mean indirect M.B.C. was64 I./min., which is equivalent to 63% of thatexpected in a similar group of normal subjects.In the majority there was little or no response toisoprenaline inhalation, two cases only showingan increase in their M.B.C. of 5 I./min. or more.One of these was the patient with a history ofasthma and marked clinical wheeze onexamination.The F.E.V.% was reduced in the patient with

asthma and in one other (Case 13). This latterwas of considerable interest, for he also had thelowest M.B.C. of the group, and was the onlypatient who appeared to have a significant degreeof complicating emphysema. He died a fewmonths later, and at necropsy was seen to havewidespread centrilobular emphysema.LUNG VOLUMES.-The most striking change was

the reduction in inspiratory capacity. As a result,both vital capacity and total lung capacity(T.L.C.) were reduced. The residual volumeremained normal, and the ratio R.V. /T.L.C. %was increased-simply as a result of the reductionin T.L.C.DIFFUSING CAPACITY.-This was reduced in all

except two cases. One of these was the patientpreviously referred to with asthma. The other,whose diffusing capacity was right at the lowerlimit of the normal range, had minimal clinicaland radiological signs of the disease.

VENTILATION-PERFUSION RATIO INEQUALITY.-Five patients had ventilation, blood flow, andventilation-perfusion inequalities within normallimits. The other 15 (one was not tested) showed

abnormalities of one or other function. One hadan isolated abnormality of ventilation-perfusionratio. The remaining 14 can be divided into twogroups:

(a) The larger group consisted of 12 patients inwhom the ventilation blood flow relationship fellinto a remarkably constant pattern, consisting ofabnormal unevenness of ventilation in associationwith an even blood flow. This led to the ventila-tion-perfusion ratio inequality being of the sameorder as the ventilatory inequality.

(b) Two patients (Cases 13 and 14) had grossinequality of blood flow in addition to grossinequality of ventilation. The ventilation-perfusion ratio inequality in these cases was theresultant of the two disordered functions ofunequal ventilation and perfusion and did notbear the same close relation to unevenness ofventilation as in the first group. It is of interestthat these were the only two in the group whowere desaturated at rest.

In summary, the functional changes seen in thisgroup of 21 patients who were thought to havedefinite clinical and radiological evidence ofasbestosis were remarkably constant and consistedof: a lowered overall diffusing capacity of thelungs; a reduced inspiratory capacity; hyper-ventilation on exercise and a lack of evidence ofair flow obstruction as shown by a normalF.E.V.% unless the disease was complicated, asin two ctases, by asthma or emphysema.GROUP 2.-The changes in lung function in this

group are best considered in relation to the clinicaland radiological findings. Although the averageexposure in this group was 14 years, the same asin Group 1, the exposure was not comparable asthese men had been employed to a much greaterextent in less dusty departments, e.g., Case 26 hadspent most of his time working in the laboratorytesting various compositions of asbestos. In TableIII the cases have been arranged according to thechanges found in their diffusing capacity.There were two patients with a normal diffusing

capacity. Their radiographs were normal andthey had no symptoms or signs. This was despitethe fact that one of them had been working withasbestos for 23 years though he remarked that hehad always been particularly conscientious aboutwearing a mask.There were four patients with a reduced

diffusing capacity. Three of these had normalradiographs and only one suggestive signs ofasbestosis with the combination of slight clubbingof the fingers and crepitations at the bases. Thepatient (Case 24) with the most marked reduction

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in diffusing capacity to 47% of normal had nosymptoms or signs but did appear to us to showsome radiological changes. The last three casesalso showed significant desaturation on exercise.One case only showed a reduced inspiratorycapacity.The remaining four patients had diffusing

capacities at the lower limit of the normal range.Three showed minimal radiological changesaccording to the grading of the independentobservers though elsewhere their radiographs hadbeen passed as normal. One had slight clubbing.Other changes in lung function in these cases werea reduced inspiratory capacity in three andabnormal inequality of ventilation in two.These were the only two in this group withabnormal ventilation-perfusion relationships.Blood flow inequality remained within normallimits in both and consequently the ventilation-perfusion ratio inequality was of the same orderas the ventilatory inequality.

It is of interest that six of the eight patients whohad functional evidence of asbestosis also showedsimilar though less marked changes in their plasmaprotein fractions to those described in the firstgroup. Two of the six had reversed albumin-globulin ratios and one an unexplained elevationof E.S.R.The changes in ventilatory capacity in this

group bore no relation to the changes in diffusingcapacity or radiological appearances. Althoughthe mean M.B.C. was higher than that found inGroup 1, when this is corrected for age and thevalues expressed as percentages of predictednormal, the reduction in M.B.C. is very similar inthe two groups (66% of normal in Group 2 ascompared with 64% in Group 1). The patientsin the present group, however, had much moreevidence of airway obstruction, perhaps empha-sizing that Group 1 (certified asbestosis) hadremarkably little. Eight of the 10 cases showedan increase of 5 1./min. or more in their M.B.C.

TABLE IIIRELATION BETWEEN CLINICAL FINDINGS AND CHANGES IN DIFFUSING CAPACITY IN GROUP 2 CASES

Case andSAge Exposure Grade of Electrophoretic Radiograph Diffusing CapacityCae and Sex (yr.) SgsDyspnoea Pattern ogah (% of Normal)28 48 M 23 None 0 Normal Normal 100 t Nosmal23 40 M 14 ,,9 0 5

30 53 M 17 Clubbing 3 Normal Mottling (grade 3) 7931 43 M 14 Crepitations 1 P increased ,, ( ,, 2) 79 ?Redud25 44 M 14 ,, 1 a2, 8 increased ,, ( ,, 8) 75[euce22 45 M 16 ,, 0 P increased Normal 74

26 41 M 21 Crepitations 0 VBy increased Normal 7327 52 M 10 ,,1 6, yincreased *

eue29 48 M 1 5 Clubbing and crepitations 1 Normal *69 Reduced24 43 M 11 None 0 a2, P increased Mottling (grade 5) *47)

* These patients showed arterial oxygen desaturation on exercise.

TABLE IVREASON FOR REFERRAL AND OTHER CLINICAL DATA ON NINE CASES WITH QUESTIONABLE ASBESTOSIS

(GROUP 3)

Age Expo- Grade Club- Crepita- Asbes- E.S.R. Plasma Electrophoretic RadiologicalCase and Reason for Referral sure of bing tiosa tosis 'm/hr A!G Pattern of Grade ofSex (yr.) Dyspnoea bg tions Bodies (mm./br.) Ratio Proteins Mottling

32 55 M Atypical radiologicalappearances,unusual exposure 16 4 + + + Absent 13 1-0 a2 ,t increased 4

33 45 M Medico-legal assess-6ment .. .. 12 2 + + + + - 6 16 Normal I1

34 52 M Mitral stenosis, cys-tic lung .. .. 21 5 + + + + Absent 30 0-7 y increased + + 9

35 36 M Normal radiograph 17 3 + + + Present 0 1-3 a2 p increased 136 45 M Carcinoma lung,

? attributable .. 2 2 0 + ,, 66 0-7 a2 , y increased 237 63 M ? Carcinoma lung.. 19 3 + + + + Absent 44 0-8 a2 Pt increased 1238 39 M No physical signs,

normal radiograph 22 3 0 0 , 6 1-0 a2, f increased 439 47 M Ascites due to meso-

thelioma of peri-toneum,? attribut-able .. 21 1 0 + Present 45 0-5 Albuminreduced,

a2, ,B increased40 65 M Chronic bronchitis 4 2 + + Absent 11 1-4 increased

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after inhalation of isoprenaline and the meanF.E.V.% was 68% (cf. 74% in Group 1). It seemslikely that the disability in Case 30, who was theonly patient in this group who admitted to asignificant limitation of his exercise tolerance, wasrelated more to airway obstruction than to adiffusion defect as he had a low F.E.V.% andshowed a good response to antispasmodics.GROUP 3.-The main clinical findings together

with the reason for referral are shown in TableIV.These were difficult patients to evaluate, as

might be expected. But in six (Cases 32, 33, 35,37, 38, and 40) it seemed possible to arrive at afairly firm conclusion since they showed thefunctional pattern of an interstitial fibrosis: areduced diffusing capacity and relatively well-maintained ventilatory capacity. Exerciseoximetry was performed in four, three showedmarked desaturation (Cases 31, 37, and 40). Intwo of these six cases (Nos. 33 and 40) therewas also evidence of some degree of airwayobstruction. Many of these patients were of con-siderable interest, and two are illustrated in moredetail in Figs. 2 and 3. Case 33 had one of themore bizarre presentations of asbestosis, his firstcomplaint being that he was unable to play cardsowing to the clubbing of his fingers.

In the other three patients it was impossible toprovide a definite answer. Case 36 had beenexposed to asbestos for two years only from1936-38 but during this time developed breath-lessness and wheezing which persisted despiteleaving the industry. Radiological changes overthe years were minimal until 1958 when hedeveloped a carcinoma of the lung and wastreated with radiotherapy, the problem then beingwhether this was attributable to asbestosis.Although the diffusing capacity was reduced itmight equally have been caused by post-radiationfibrosis. In Case 39 some of the reduction indiffusing capacity might have been due to areduction in lung volume consequent on the highdiaphragm and ascites. The problem was com-plicated in Case 34 by the presence of mitralstenosis and incompetence. He also had functionalevidence of emphysema with a low M.B.C.,reduced F.E.V. %, and considerably increasedresidual volume (157% of predicted normal).

CORRELATION BETWEEN CLINICAL, RADIOLOGICAL,AND FUNCTIONAL CHANGES

The findings in the first 38 patients have beenanalysed statistically. In the correlations with

CASE 32 LI/NO FUNCTION TESTS/. I VNCG VOLLIMES MORNAL

2. MAXIMUM BSEATHIU.; CAPACITY(IialTct)

-60 A AA4i WItnudS3. FEY. ,% V.C.

#6;; (# -{n

4. EXE_RC,Sf OX/METRY9-4 g2 %e/ saAfZoi

s. DiFflsitW cApCAPACIbJY,9 - hl,, flt "I'm./MrfUts(J/ 3 z

6. INfEqU4LItYOFA) VENTIL2. rO(Nt

i~94s) EN7T/LA TION/IPERRFUSION RA-/V7% ('NVPtoS%)

(a)

(b)

FIG. 2.-The functional changes (a) in a patient (Case 32) withunu3sual radiological appearances; (b) the radiograph showinglarge bullae and coarse fibrotic scarring at the right base. Expo-sure was for 16 years when the patient was covering electricwelding rods with asbestos yarn.

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CASE 50 LUNitG FUNCTION TESTS

I CLING VOLLIMEEF

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94 ktrcs 4/ev 4tispAsc,t

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grade of dyspnoea, those with grade 5 dyspnoeahave been excluded as there were only two patients(Cases 13 and 34) in this group and both thesewere complicated cases with functional evidenceof emphysema.The results are given in Table V. It can be

seen that there was highly significant correlationbetween reduction in diffusing capacity and theseverity of dyspnoea which is illustrated in Fig.4. There was no correlation between grade of

TABLE VRELATION BETWEEN DIFFERENT LUNG FUNCTIONTESTS AND SEVERITY OF CLINICAL AND RADIOLOGICAL

CHANGES

Correlation Between:

Dco and grade of dyspnoeaS.v.

Dyspnoeic index (S.V. M.B.C.%) andgrade of dyspnoea

M.B.C. and grade of dyspnoeaVentilatory inequality and grade ofdyspnoea

R.V. T.L.C.% and grade of dyspnoeaDco and grade of clubbingDco and years of exposureDco and grade of mottling (radiological)T.L.C.,,I.C. .. .R. V.R.V. T.L.C. °',M.B.C.

Correlation Coefficient (r)

-0-67 p<0O001+0-60 p<0O001+0 61 p<0001-0 30 p>0 05

-0-69 p<0 001-0-56 p<0O001-0 66 p<0 001+0 08 p>0 10-0 74 p<0 001-0 31 p0-05-0 39 pm002-0-09 p>0I10-042 pm00t0 24 p>0l10

dyspnoea and reduction in maximum breathingcapacity. The standardized ventilation anddyspnoeic index, which is the ratio of standardizedventilation to the maximum ventilatory capacity,were also closely related to the grade of dyspnoea.It was of interest to find such a good correlationbetween reduction in diffusing capacity and thegrade of finger clubbing (Fig. 5).

There was a highly significant correlationbetween reduction in diffusing capacity andradiological grade of mottling (Fig. 6). Reductionin inspiratory capacity and total lung capacitywere also related to the severity of radiologicalchange but at lower levels of significance. As withdyspnoea, there was no correlation betweenchanges in maximum breathing capacity andradiological grade.

FIG. 3.-Functional changes (a) in a patient (Case 38) whose radio-graph (b) had been passed as normal. Exposure was for 22 years

as a lagger.

DISCUSSION

An " alveolar-capillary block" or diffusiondefect appears to be a remarkably constant find-ing in established cases of asbestosis. There were

only two patients in this series who appeared to

2.

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FIG. 4.-The relation between diffusing capacityand grade of dyspnoea.

FiG. 5.-The relation between diffusing capacityand the severity of finger clubbing which wasgraded absent (0), slight (1), or marked (2).

FIG. 6.-The relation between diffusing capacityand grade of radiological mottling.

/ 2GRADE OF DYSPNO0

FIG. 4

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RAD/OLOG/CAL GRADE oF A4Pi@. 6

have a significant degree of compli-cating emphysema and these stoodout in clear contrast to those with apure diffusion defect. This is in con-

' I trast to the findings of Bastenier et al.3 4 (1955). They concluded that there

was no specific physiopathologicalpicture in pulmonary asbestosis, and

although the fibrosis and vascular lesions causeda diffusion defect this was accompanied to avariable extent by the changes of secondaryemphysema. In six of their eight cases ofasbestosis there was an increase in residualvolume and deficiency of pulmonary mixing. In

x our patients, with one exception, there was noincrease in residual volume, and the rise in theratio of residual volume to total lung capacity(R.V. /T.L.C.-%) is simply due to the reduced totallung capacity consequent upon the loweredinspiratory capacity, and does not indicateemphysema. It is of interest that both the patientsin this series with functional evidence of emphy-sema gave a history of recurrent purulentbronchitis which appeared to be rare in those withuncomplicated disease.The results in our second group suggest that

2 changes in pulmonary function, particularly thediffusing capacity, may precede clinical or radio-

logical signs. Wright (1955) alsofound in his series cases showingwell-marked functional changes inthe absence of any clearly recog-nizable abnormality in the radio-graphs. He suggested that in theseeither the earliest radiologicalchanges had been missed or thedisease process was so diffuse in itsearly stages that there was poor

x x contrast between normal andx * . diseased areas and hence no defi-

nitely abnormal shadow on theradiograph. On the other hand, healso found patients in whom thedisturbance of function was mini-mal despite the presence of definite

9 /0 HI /2 / x-ray changes, and in these he sug-'OTTLiNG gested that the disease process was

focal in nature with large volumes

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of normal lung tissue remaining. In the presentseries there were no patients in whom the radio-logical appearances appeared to be out ofproportion to the functional changes found, thosewith minimal radiological changes tending to haveminimal functional changes also.The finding of detectable changes in pulmonary

function at an early stage in asbestosis is clearlyof great importance, for it is at this stage thatobserver variation is so marked in the assessmentof both physical signs and radiological appear-ances. The problem of observer variability in theradiological diagnosis of asbestosis has beendiscussed in detail elsewhere (Williams and Hugh-Jones, 1960). It is not only in early cases thatdisagreement occurs, and one of the most surprisingfindings in the study just referred to was themarked disagreement between the observers inreading the films from certified cases.The presence of large bullae is not usually

regarded as one of the characteristic radiologicalfeatures of asbestosis, yet these were present in sixof the present series (Cases 8 and 10 from Group1, Case 24 from Group 2, and Cases 32, 33, and34 in Group 3). The presence of these bullae didnot appear to affect the functional changes. Onepatient had an increase in residual volume, but wehave referred earlier to his functional evidence ofemphysema.The changes in the plasma protein fraction were

of considerable interest, for similar changes hadbeen observed in silicosis (Vigliani, Boselli, andPecchiai, 1950) and have been part of the evidenceput forward in favour of an immunological originof the hyaline tissue of the silicotic nodule (Viglianiand Pernis, 1958). Possibly a similar mechanismis of importance in asbestosis. The exact causeof the fibrosis in this disease remains unknown.Knox and Beattie (1954) suggest that a fibrogenicagent is released from the breakdown of asbestosisbodies. They found that the severity of thelesion at necropsy was not related to the mineralcontent of the lung but was associated with alengthening of the combined exposure and survivaltime, the survival time being the interval betweenthe last exposure to dust and death. The mineralcontent of the lung tended to decline withincreasing survival time. In the present series,however, there was no correlation during lifebetween the changes in diffusing capacity andeither the years of exposure or the total numberof years between first exposure and time of study.Individual susceptibility to the disease is undoub-tedly an important factor. Wright (1955b) notedthat there were some patients with prolonged andintense exposure who failed to show any change

in radiological or physiological tests. In thepresent series it was possible to compare individualpatients in the various groups, e.g., Cases 11 and22 had both worked unloading crude asbestos fora comparable period of time (18 and 16 yearsrespectively), yet one (Case 11) had definite clinical,radiological, and functional signs of the diseasewhereas the other had a normal radiograph, nosymptoms, and only minimal functional changes.The severity of breathlessness in our patients

was related to the degree of diffusion defect andnot to reduction in ventilatory capacity. If it isaccepted that the sensation of dyspnoea can berelated to the ratio between the air requirementsfor a given amount of exercise and the maximumpossible ventilation or maximum breathingcapacity (Baldwin et al., 1948; Warring, 1949;Hugh-Jones, 1952), then it is clear that thebreathlessness of asbestosis is related to theincreased air requirement consequent on thediffusion defect rather than to the reduction inventilatory capacity. This is in contrast to thefindings in coal-workers' pneumoconiosis, wherethere is little increase in the ventilatory require-ment of exercise and the severity of breathless-ness is closely related to the fall in maximumbreathing capacity (Gilson and Hugh-Jones, 1955).Another factor besides hypoxia from the

diffusion defect which may cause exercise hyper-ventilation in interstitial fibrosis may be excessstimuli from stretch reflexes in the lungs resultingfrom the excessive lung "stiffness." Unfortun-ately it was only possible to measure the stiffnessof the lung in one case where it was increasedas seen by a reduced compliance.The finding of a large ventilation-perfusion ratio

inequality in many of the cases in this series wasof considerable interest. This has been discussedin more detail elsewhere (Read and Williams,1959) where the changes found in 28 patients withvarious interstitial diseases, including a numberwith asbestosis, are reported. Two patterns ofdisturbed function were described. That in whichthe ventilation-perfusion ratio inequality wassimply the result of ventilatory inequality, per-fusion remaining normal, and that in which therewas gross unevenness of perfusion in addition touneven ventilation. It was suggested that unevenperfusion was due to superadded cysts orgeneralized emphysema, for the second patternwas found only in those patients with a lowF.E.V.% or radiological evidence of cystformation.The ventilatory inequality in apparently pure

examples of interstitial disease, i.e., where there isno evidence of airway obstruction, may possibly

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be related to local abnormalities of expansion.Motley (1958) has recently suggested that ven-tilation-perfusion ratio imbalance is the cause ofthe arterial oxygen desaturation on exercise ininterstitial diseases. It is worthy of note thereforethat the three cases in the second group whichshowed desaturation on exercise had a ventilation-perfusion ratio inequality within normal limits.

It is of course impossible to say that a man hasasbestosis without pathological confirmation, butthe other diseases which cause a similar functionallesion, such as scleroderma, some cases ofsarcoidosis, the Hamman-Rich syndrome, lymph-angitis carcinomatosa, are rare. The finding,therefore, of changes in diffusing capacity withoutany airflow obstruction in a patient with a historyof exposure to asbestos is strong suggestiveevidence of asbestosis whatever the radiologicalappearances.

SUMMARYA study is described of the lung function in 40

patients who had been exposed to asbestos dustin their work for varying periods of time. Theseincluded 21 certified cases of asbestosis, 10patients with a prolonged exposure but no definiteradiological signs, and nine in whom the diagnosisof asbestosis was in doubt.The functional changes of asbestosis were

those common to other interstitial fibroses, andconsisted of a lowered diffusing capacity togetherwith a reduced inspiratory capacity, hyper-ventilation (often accompanied by arterialdesaturation) on exertion with no evidence of air-flow obstruction except in cases complicated byasthma or emphysema. Many patients alsoshowed inequality of ventilation and ventilation-perfusion ratio.These functional changes were related to an

independent grading of physical signs and radio-logical appearances Changes in lung function,

specific for- an interstitial fibrosis, often precededefinite changes in the radiograph, so that theirfinding in patients with a history of exposure toasbestos is suggestive evidence of asbestosis what-ever the radiological appearances.

We would like to thank the Cape Asbestos Co. Ltd.for their wholehearted co-operation, Dr. W. J.Smither, Works Medical Officer, without whose helpmuch of this study would have been impossible, Dr.R. M. McGowan, of the London PneumoconiosisMedical Panel, and Dr. J. C. McVittie, of the Ministryof National Insurance, who initially suggested theinvestigation. We are indebted to Dr. John Readfor the mass spectrometer findings and Miss HeatherMacLeish for valuable help, including the measure-ments of resting ventilation.

REFERENCESAustrian, R., McClement, J. H., Renzetti, A. D., Donald, K. W.,

Riley, R. L., and Cournand, A. (1951). Amer. J. Med., 11,667.Bader, M. E., Bader, R. A., and Selikoff, I. J. (1957). J. clin. Invest.,

36, 871.Baldwin, E. DeF., Cournand, A., and Richards, D. W., Jr. (1948).

Medicine (Baltimore), 27, 243.(1949). Ibid., 28, 1.

Bastenier, H., Denolin, H., Coster, A. de, and Englert, M. (1955).Arch. Mal. prof., 16, 546.

Bernstein, L., D'Silva, J. L., and Mendel, D. (1952). Thorax, 7, 255.Doll, R. (1955). Brit. J. industr. Med., 12, 81.Fletcher, C. M. (1952). Proc. roy. Soc. Med., 45, 577.Gernez-Rieux, C., Balgairies, E., and Claeys, C. (1954). J. franC.

Mid. Chir. thor., 8, 193.Gilson, J. C., and Hugh-Jones, P. (1949). Clin. Sci., 7, 185.-- (1955). Spec. Rep. Ser. med. Res. Coun. (Lond.), No. 290.Hugh-Jones, P. (1952). Brit. med. J., 1, 65.Knox, J. F., and Beattie, J. (1954). A.M.A. Arch. industr. Hyg.,

10, 23.MacLeish, H. (1960). Personal communication.Motley, H. L. (1958). Dis. Chest, 33, 581.Needham, C. D., Rogan, M. C., and McDonald, I. (1954). Thorax,

9, 313.Ogilvie, C. M., Forster, R. E., Blakemore, W. S., and Morton, J. W.

(1957). J. clin. Invest., 36, 1.Read, J., and Williams, R. S. (1959). Amer. J. Med., 27, 545.Roemheld, L., Kempf, H., and Wedler, H. W. (1940). Dtsch. Arch.

klin. Med., 186, 53.Vigliani, E., Boselli, A., and Pecchiai, L. (1950). Med. d. Lavoro,

41, 33.and Pernis, B. (1958). Brit. J. industr. Med., 15, 8.

Warring, F. C. (1949). Amer. Rev. Tuberc., 60, 149.West, J. B., Fowler, K. T., Hugh-Jones, P., and O'Donnell, T. V.

(1957). Clin. Sci., 16, 529.Williams, R., and Hugh-Jones, P. (1960). Thorax, 15, 103.Wright, B. M. (1955a). J. Physiol. (Lond.), 127, 25P.Wright, G. W. (1955b). A.M.A. Arch. industr. Hlth, 11, 196.

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