Document VKxY5pxwpOev08bRDOkYnGoMg

PLAINTIFF'S EXHIBIT Asbestos Pleural Effusion I< EDWARD A. GAENSLER, M.D,, and ALFRED I. KAPLAN, M.D., Boston, Massachusetts i i The differential diagnosis of pleural effusion is large of slowly growing mesothelioma, and, incidentally, to but has not Included asbestos exposure. For 1 to 9 emphasize . that biopsyrproved chronic' interstitial i years we followed 12 patients with "idiopathic" pneumonitis caused by asbestosis may. be present effusions that were frequently recurrent, usually without radiologic, or evea physiologic abnormalities. bilateral, and often followed by continued chest pain. j 5* j The fluid was a sterile, serous, or blood-tinged exudate. Physical findings were limited to dubbing, dry rales, and signs of effusion. Asbestos exposure was from 3 to Selection of Patient* and Methods Our attention was first drawn to' impossible relation ship between asbestos exposure imd-pleureil'efinuioa by. 38 years, but often this history was elicited only with experiences with two patients (Cases. Lnd4)ri*bo ware. seen 8 years ago .after recurrent pleural, effusions arid difficulty. Usually, mechanics of breathing were who eventually required 'decortication; a diagnosis of; normal, lung diffusing capacity reduced, and asbestosis wa!s~made. from pleural arid lung biopsyvmato- alveolar-arterial Po. differences elevated. Decortication riaL For this report our computer program seaichrid for and lung biopsy specimens In seven patients and postmortem examination in one showed nonspecific pleuritis with rare asbestos bodies and fibers; ail had various degrees of chronic interstitial pneumonitis with simultaneous diagnosis of pleural effusion and asbestosis or asbestos'exposure among 4,077 : entries of patients seen in bur laboratories betweea-1951 and 1969. The re sults confirmed toe frequency-of this -relationship. Ex cluded from consideration were patients from our Sana asbestos bodies. One case of mesothelioma was torium Division, individuals seen'. in survey situations, recognized 9 years after the first documented effusion. With better understanding of the dangers of asbestos and better surveillance of workers, asbestos pleural and those wito pleural thickening'only, with empyema,, and with an unconfirmed history of effusion. Methods for evaluation.of:lung function and nonnaf values tried in our laboratories have been summarized (14). effusion will be recognized oftener. It occurred fn 21% r of all patients with asbestosis seen at our laboratory. Results ' Among thev4,077 patients, 91 Irad confirmed pleu Jt ral effusion (jabte 1) arid,57 hridfasbestosis or as-:, I bestos exposqre;"(Tabto 2);'24 oiKthese appeared in. Pleural disease, including thickening, plaque for both groups.-|por This tfridy; we `excluded 12 >f toe' mation, calcification (1-8), and mesothelioma (9- latter in whimr the effusion i OcccuTed in -relation to 13), are well-recognized manifestations of asbestos mesothelioma, bronchogeniccafdiioma, or congestive exposure. Benign pleural effusion related to such ex heart 'faiIttre:;..TTie; remaining 12?. patients, that- is; ! posure has not been reported.' During the past 8 21.1% of all those with .'asbestosis or asbestos.ex years we have seen an increasing number of patients j who had both an exposure to asbestos and pleural i effusion of undetermined cause which was frequently posure (Table 2), were thought to have "asbestos pleural effusion." This diagnosis was based on occu pational history, absence of any known disease that recurrent, usually bilateral, and often followed by has been- associated with pleural effusion, and patho continued chest pain. The purposes of this report are logic material in 8 of the 12 cases. to show that "asbestos pleural effusion" is not un * common, to call attention to an additional etiologic CLINICAL OBSERVATIONS * > agent to be considered in patients with "idiopathic" Most patients were referred because of recurring y pleural effusion, to suggest a possible precursor to pleural effusion of unknown cause and pleuritic chest i the development of mesothelioma or the possibility pain (Tabb 3). None had had respiratory problems before their present illness, and all but ode were cig * From tbe Tboradc Service*. Department* of Medicine and Sur gery* Boston University School oC Medicine. Boston, Mass. arette smokers. Abnormal physical' finding?; were 178 x ' 4- Amuls of Internal M*dldn74d78>191,1371  - J I r^8& ;ifll Tiblt 1. Etiology of Ptoural Effusions In 91 Pitknti - no. yv. ** *' '- Congestive failure* Malignant tumor Bronchogenic (no asbestos exposure) .Bronchogenic (with asbestoc exposure) Mesothelioma (with asbestos exposure) Metastatic Infections f Tuberculosis Viral ' Fungal' "Asbestoc pleural effusion" Asbestos only . -- Asbestos with talc Connective tissue disorders Rheumatoid arthritis Lupus erythematosus Progressive systemic sclerosis Pulmonary infarction Chronic interstitial pneumonitis Usual Desquamative interstitial pneumonia Laennec's cirrhosis Undetermined cause 2b 22 9 5 S 3 13 8 4 1 12 10 2 8 3 3 2 3 3 2 1 2 8 % 22.0 24.2 14.3 13.2 8.8 3.3 3.3 Z2 8.8 * Includeb two with asbestos- exposure, t Not including pyogenic end empyema. limited to variable evidence of pleural effusion, finger clubbing, and dry crackling rales with a "close-tothe-ear" sound in a few cases (Table. 3). The amount of pleural fluid was generally moder ate (Table 3). Mere blunting of the costophrenic an gle (1 -r) was seen only once (Case 12), and massive effusion (4+) was not observed. Documented effu sions occurred unilaterally in three patients, and bi laterally, either simultaneously or in .sequence, in the other nine. Six patients had but a single episode; five had from two to four episodes; and in. Case 10 bilat eral effusions never disappeared. No calcifications were seen on tomography. The fluid ranged from clear yellow to. bloody but was . usually serosanguinous; in the latter the RBC counts ranged from 5,000 to 50,000/mm1. Aerobic and anaerobic cultures for pyogens,- fungi, and tubercle bacilli always failed to. show growth. In most cases the fluid was an exudate. Sediment .and cell blocks showed no tumor cells. No thoracentesis was performed in Cases 6 and 11. The severity of parenchymal infiltration is indi cated in Table 3. Two patients had sufficient resid ual pleural thickening to rule out the presence of par enchymal infiltration (Figure 1). Five patients showed mottling and linear or reticular shadows in all or the lower two thirds of the lung fields (Figures 2 to 4). Eventually, honeycombing became evident in some of these. In three patients (Cases 4, 7, and 12) the lung fields appeared normal after the effusion had disappeared. Patient 3 had massive hilar and super ior mediastinal adenopathy and coarse pulmonary nodulation (15). Most laboratory examinations were unrevealing. The-tuberculin skin test was .positive-in Patients 2 -andJL2, as was the histoplasmin test in Case 7. Lu pus erythematosus (LE) preparations were always negative, and the latex fixation test was positive only in Case 10. Evidence of respiratory tract infection preceding or with effusions, including, fever, elevated WBC counts, and growth of a predominant organism from sputum, was lacking. .Only Patient 8 had heart disease with a -myocardial infarction 1 .year earlier. Malignancy; did not^bccome evident during a follow up period that averaged 4 years; except for Patient 2 who developed a mesothelioma 11 years after his first effusion (Table 3.). ' OCCUPATIONAL HISTORIES (TABLE 4) Nine patients were engaged in occupations where significant asbestos exposure was easily documented; in the others the exposure was more'subtle. Patient 7, a;bricklayer who.had neyer used asbestos himself,, is reported below; Patient 8 was a body-shop man for 30 years and revealed only after lengthy questioning that he had done undercoating 1 day a week for many years. . Talc was used regularly by Patients i and 3 (15) and.was.an important nuisance in the section of the plant where Patient 12 was a pipefitter: ' The duration of'exposure was predictably long, from 20 to'38 years, in five patients and only 3 to 4 years in two patients.. Most had worked with asbestos until the time of their illness, but in three patients there was a 6- to .18-year interval between last ex posure and first effusion...... RESPIRATORY PHYSIOLOGIC STUDIES '" Eleven patients had respiratory physiologic stud ies, .usually on several occasions. La .an attempt to evaluate the severity* of' interstitial Idisease, we se lected' those studies rat mchisipnhi Table 5 that were Tabta 2. Pleural Dlmni'fe 57 (Mfentswith "AabastocJ*"* y . . . Pleural effusion V "Asbestoc pleural effusion" With mesothelioma With carcinoma With congestive failure. Pleural thickening Slight Moderate Severe With calcifications With tuberculosis Condition of pleura undetermined because of dense parenchyma! infiltrauon No pleural reaction no. 24 12 5 5 2 21 3 8 6 2 2 3 -v 9 -% 42.1 3d.8 5.3 15.8 * Docs oot include cadlvidrats tcca in survey situations only. _ Gmansler *nd KMpImn _Asbto*-P1ural Etfuslons 19. I Table 3. Clinical Data of 12 Mon with Aabastoa Maura! Effusion -Case Age Initial Complaint aubbing/. Rates; Dyspnea* -3 4 5. 6 7 8 9 10 yr 47 Recurrent pleuritic cheat pain, effusion 35 Severe progressive dyspnea, dif fuse infiltration 42 -Mediastinal mass, dyspnea, . pulmonary nodnladoa '58 - Recurrent pleuritic pain, effusion 50 . Progressive dyspnea 59 . Abaonsal survey film, progres sive dyspnea" ' 33 Pleuritic chest pain and dyspnea 58 ^Pleuritic chest pain and dyspnea 38 .Progressive dyspnea 48' -Joint pains, lumps' on elbows 1+/0 /1+ 2+/0 /3+ 2+/0 /!+ 0 /3+/1+ 2+/0 /1+ 0 /2+/2+. 0 /2+/0 0 /0 J\& 0 /0 /1+ 0 /2+/3+ 11 .53 -'. .Vv Progressive dyspnea, fatigue and ' . "heavy chest" 12 60 ` `-^.'Severe progressive dyspnea 0 /2+/3+ 0 /0 /3+' - * Dyspnea duanf/pcdodt ot Uttte or no pJcoral tfa4cm. t ChrooiCy-mtTcr cUy ctoee fnftlal Wfnrinci. Extent Right Left 3+ 2+ 2+ : - '0 . 1+ ' -2+ 3+ -. 3+. 2+ : 3+ 2+ Pleural Effusion' ' Number ' Right"--.'Left .* v>.. 'aOV . 2 . 2 Stnvr-coloced 40 4. -:^4r V 1 :i 1 -, .... ,}? 'aear^isnguinous Sabiwwanous . . Siirtgiiinbcs 'jduSow 'ij. obtained when there was WlsfEusion or the least posr sible residual : Mechanksiof breathing Were not greatly disturbed;: only three 'patients had significant "restriction" indi?. cated by reduced vital capacity. Obstructive disease, with reducddforced expiratory volume in 1 sec (FEVi) and'maximal voluntary ventilation (MW) and increased- residual Volume, was shown only in Patient 6, whd had bullous emphysema. One half of. the patients, however, had severely disturbed respira tory gas exchange: a sever degree of "alveolarcapiUary'&bck" Was' shown, in'Patients 2,3, 5, 6,11, from 23:tn'.44mm H^':Mbsf=patienti^j>Rvientihded during standard 'exercise,-; and tfaeir-^hywcilogk: dead space wai variably enlarged; Only Patient ;7 had'res-: piratory. studies thatwere entirellyy;Jwifhin.,the normal range. OPERATIVE FMDIHOsV'. -j) Patients' 1^-2; 4,ind. 7=iad pat^tfl/.aid' visceral a Figure I. Serial chest film* of Patient 1. IA. Initially there was marked blunting and thickening of the pleura laterally, and the left lung Reid appeared hazy,- Thereafter, 1*200 ml of straw-colored fluid was removed, end eventually a decortication was performed. IB. He was readmitted In November 1963. February 1964, again in May 1964 because of recurring pleural effusion on the right. IC. On follow-up examination In June 1970 he had been free at effusions for 5 years. Thera was bilateral slight pleural thickening and continued chest pain. ... 180 February 1971 * Annala of Internal M*dlcln * Volume 74 * Number 2 T*b< 3.!(Continuad) .'Parenchymal Infiltration f Fight ' * . .** Left Other Disease None... FoBow-ifp Sihce.'Fim Effusion " I . (See.also Table 6) :' -'! ' .- ... 8 yean; effud^nj^'^^^tna^hea severe chert paia'ooly^'.' ...Adv. 'Adv. . .* .. Nod. - 0.; . 'X - ' Adv. .0 0 Adv. Nooe b* -`i` TalconHcocis None ' None Bullous emphysema 9 yean i------^ ' ''--* ' v J . .r -bfiS?-?-.T^'.' <: 8 yean; severe KJatenffChistpain tv >.;=>&? -V, '-! W 7 yean; no further eGTouairt'; wph''mnd'?^orldas ' :~- 6 ; Min. Mod. ' Adv. . Mod. '- 0 0 Mod.Adv. Mod. None Arteriosclerotic heart disease None Rheumatoid arthritis None 1 year; no further difficulties; V:' 5 yean; progressive-dyspnea; died ofbilaleral empyema after intubation 3 months; ] i .o.;.. . None t Refers to redcotatlba nd linear ibadbas mnriind wttfc uttaoilt: Hod. -- obdulatlbt>..X -- no aUgnoab becauaa of orertyto* ptcnnl dwui. 4'y e1_a_n_;_o_netc cu-r_re_n_iv_e_ff_u_s_ib_G_^_se_v_e_re_'_'d_y_sp_n_e_a__ V *. M '% ' '.V % 3 ' diagnosis, to restore pulmonary function, and to pre vent further recurrences of effusions (Table 6). Sev eral lung biopsies.were obtained at each operation. Patient 3. was explored primarily because of superior mediastinal enlargement (15). Patient 9 had only a needle pleuraL biopsy, and Patient 12 had lung bi opsy because of progressive dyspnea. At operation irregular pleural symphysis was seen in-all patiehts^and serosanguinousfluid was found in all except mPatient; 12. Thecortex was quite vascu lar and. varied- in.thickness from a few .millimeters to 2 cm:Pleurat' calcifications or- asbestotic "plaques" were hot observed^ The lung-Vaa-often partially ate lectatic but'reinflated readily after decortication. The lung, tissue!was`described as? normal to excessively Arm biff without distinct nodulation except in Patient 3; "no -differences'in texture were noted between up per and lower,regions. . LUNG PATHOLOGY. Large biopsies from both upper and lower lobes were available for six patients, from both sides in one patient, and from autopsy in a seventh patient (Table 6). Biopsy specimens were fixed in inflated condition (16)', and, in addition to routine treatment, 12 serial sections were stained with Peris' ferrocyanide; atypi cal lung regions immediately beneath the pleura and from the tip of the lingular segment were ignored. Chronic interstitial pneumonitis of various degrees was seen in all cases. The mildest reaction consisted of a diffuse, chronic, low-grade inflammation with in JSs.s_._- terstitial edf^^'ilnE^tooyric.'reachpni increased rcriculin, and o^sibr^^yaliite m^nbranes~ (Figdr'5^ and 6). Thiclamihg^and^fedeina^of the..interlobular septa were often striking (Figured6). Sometimes.pleu ral fibrosis extend^ into ithe; luiog septa. At a more advanced stagej; the reaction'.-was more diffuse, ;with the intexsriri^ -.mpdarately thickened, by increased 'collagen formatibhi;(Hgare JA.')'i:'ln the most severe form fibrosis'.praibminated- and-!, was' at first - focal ^mai^^jhp^eycomtHhg .(Figure r9^'iMacfof^g^^j^;^h;^^gl^rgCTnil;were . seen in ffl s^q^Sh&ihi^pjiBmiclgrmuies; were often bii^t^,OMip7&ro^is^fiefracriie.:aiid'gave. a-Trtrongly pOsidyie^?e^^toEvhpn (Figare;7C)i In some instances ich ceiis^together with desquamated granular pneumocytes, .were denscly packed and filled many alveoli (Figure 71^);..whereas elsewhere they were more scattered (Figure 5-ii)'. In the more severe cases'fdreign-body; giant cells often contained both fibers and asbestos bodies. The lungs of Patient 3 also showed a moderate interstitial pneumonitis, but alveolar septa were filled with talc crystals, and there were many whorled silicotic nodules (15). Asbestos or ferruginous bodies were seen in all lungs. However, their number varied greatly (Table 6). In 3 patients -only a-few were seen in 12 serial sections (1 + ); in 4 patients several were seen in each section (2 + ), and in Patient 10 innumerable asbestos bodies.were seen in every field (4-r) (Figure 9). Qaanatmr and kaplmn Asbstot Effusions . 181 `if I 1fV Z 'jl i z t s t< 't *e lS} ! i I* I f X Figure 2. Serial chest fltma of Patient 2. l 2A. In 1961 there was diffuse, fina-modulation and reticulation. Vfhan. we first nw-htm. In I9S2J;thare'was;,In addition, blunting of the right costophrenlc angle. ' t-E 2E. Effusions recurred, and by 1964 both the pleural residual and ths parenchymal reticulation had progressed. Decortication and lung biopsy were performed In 1965, and he was readmitted In 1967 and agalrr In 1969 for recurrent affusions and increasing dyspnea. 2C. In 1969 there was a thick cortex and early honeycombing. 2D. During his last admission In 1970 plaural thickening had Increased, and there was a 2-cm nodulo protruding from the pleura Into tho lung field, better scan In Figure 3. - * PLEURAL PATHOLOGY granular material (Figures 75 and 8A). There was often regenerating proliferating mesothelium, exten The pleural cortex varied from barely 1 mm to 15 sive collateral circulation, and, sometimes, hemor mm in thickness. When lung was attached, the wavy rhage. Granulomas or other more specific lesions line of the original pleura could be readily identified were not seen. Twelve serial sections failed to show i (Figure 75). In all cases there was a marked "pleu asbestos bodies or fibers in two cases; there were fi ral drift" of carbon, other dust, and iron-posiriye bers alone in Case 1 (Figure 7C) and fibers inter- 182 February 1971 * Annohs of Internal Medlcfna * Volume fiumbor 2 i < vjsw'Vy--' spaced among'raze asbestos bodies in others (Figure SB):: There were only 2 or 3 asbestos bodies in all . 12 sections in 3 cases (Table 4). Whenever bodies S V ' and fibers were found,.they were less than 1 mm out' side of the original pleura. A mesothelioma developed eventually in Patient 2, whose case is described below. Case-Reports CASE 1 This 47-year-old Banbury machine operator and_ tile- maker wa* first referred in August 1962 for evaluation of dyspnea, pleuritic chest pain, and recurring left pleu- ral effusion of 1 month's, duration. Past and family his- ill< tones were unremarkable.: He had earlier worked-as a cook in the merchant marine and as an elevator oper ator. For. the past 12 years he had been a tilemaker op erating a Banbury machine, mixing asbestos, sand, and other materials into a blender and then pouring, and moulding the mixture to produce vinyl-asbestos and fire- retarding tile. . .. :*V Examination.- showed slight dubbing and decreased breath sounds at the left base. Vital signs were normal, and he was afebrile. The' chest roentgenogram showed haziness over the entire left lung field with marked pleu ral thickening laterally (Figure 1A). Blood and urine were normal. Skin tests for tuberculosis and common fungi were negative. About 1,200 ml of straw-colored exudate were removed. Bacteriologic and cytologic ex aminations were negative.-.: - Parietal pieurectomy was eventually performed be cause of recurring effusion and persistent pain.and' be- . cause tumor was suspected. The pleura was markedly thickened (Figure IB), and the lung was excessively Figure': 3. Patient 2. A spot'film of. the rlghFupper lung ernphs--. sized the nodular lesion,'the thick .cortex;' reticulation, and honey; combing not so well .seen In Figure 20. firm-and partiallysatelectatic. Biopsy specimeni from up-. per and lower lobes showed- diffuse interstitial -pneumo nitis 'with thickened alveolar-septa; .many alveoli were filled with granular pneumocytes and macrophages con taining large orange-yellow granules'' that stained in tensely blue for iron (Figure.'7.^). Occasional asbestos bodies were seen.. The pleural; cortex was quite vascular (Figure IB), and the.-loose-rissue just outside of.'lhe original pleura contained occasional 'granule-laden mac-.' rophages and asbestos fibers (Figure 7C) i-. - After thoractomy "hand-like''; chest pain and dyspnea persisted. Subsequent admissions in November 1963' and February and. May. 1.964 were,'prompted "by. increased .Vr V* Xt. f a- -;t:* Figure 4.`Chest films of Patient 11, a store controller In an asbestos products plant since 1950. 4A. Annuel roentgenograms showed slight basal reticulation for the first time in 1962. 48. By 1968 the Infiltration had progressed somewhat. *j 4C. A film from January 1970, taken during an admission for evaluation of mild hypertension, was then obtained and showed a marked right pleural effusion. 40. He was referred in June 1970 because of dyspnea of recent-onset? The film at that time~showed marked pleural thickening. I 't'Gaatiefar andjtaptan JAsb^etoe Pleural Effulona- 1*83' 5 1 Table 4- Occupation*! History of 12 Man with Asbestos Pleural Effusion Cue Occupation Job Description . Asbestc*. Interval* Exposure' - Other Jobs i Banbury machine operator; : rile manufacture 2-: .. Stiram fitter and gas fitter; (private and navy yard)'- ft *.* p ,"3V " Span grinder,, rubber company * "4V ' - Shipfitter, boiler insulator 5 Asbestos Worker** Unions 6 . ' Pipccovcrer, new naval ship construction 7 Bricklayer 8 Auto body shop man 9 . Asbestos Worker's Union 10 Mill grinder in asbestos products plant 11 General laborer and store controller in asbestos products plant 12 Pipe fitter in-various com panies using asbestos and talc Muted sand, asbestos, vinyl, and so forth; moulded vinyl asbestos and fire-retarding brick; talc exposure Covered new pipe 12 yean; naval ship.re- fitting (removed old covering) 10 yean; gas fitter working near pipecovcrtra since then 5 ' Shredded rubber tire, tile scrap; sprinlddjl with talc; mixed material for battery eatings' Insulated boilers with magnesia block and asbestos cement; removed old insulation General insulation work, "mostly fiber !- glass" , ' Fitted prefabricated insulation; made and shaped segments in shop Laid bricks in high-rise office buildings . immediately below laggera who sprayed cement-asbestos-glass mixture on steel Undercoaring with asbestos mixture 1. - .day/week General insulation work, mostly fiber glass; - joints and boilers covered with asbestos . Mixed raw materials for fire-retarding brick ;! and sheets Swept floors, piled fiber, racked sheets,- - worked on veneer press, unloaded freight cars Pipe fitter in brake lining plant 7 years; pipe fitter in chemical plant mnlring meteorological balloons 26 years, much talc exposure yr 12 -0 38.'. -8 * v :- ; v.* 22; .O'. yr . ' * 13f/ , : 6' * r . V' . 4- 6 12 ...O' ' - .- 8 . -0 v 30 .... * ` *' L3>, .V . / >V.; -3-6'' *. , 20 K. V* .--* . 0- ' i*- V* ** CdOfea* - elevator --operator ' ' -' -->>0- ' '.y : : t.;* :r . * ' *' .*.. . f- . RuIhnan ' ` attendant . Chemical' worker" . Granite , cutter -Lumber !' * ' cutting 0 0. 'Stockboy, ' .:U. S. Anny . Draftsman Icterr&l between tut ubestos exposure and first pkurxi effusion. pain and repeated pleural effusions, now. on the right side (Figure Iff). The fluid remained sterile and had a benign cytology. - - Chest pain has persisted to the present and has been unresponsive to intercostal nerve blocks arid .resection of .the costal- arch. His last chest roentgenogram, in June 1970, showed minimal pleural thickening bilaterally (Figure ,1G). Pulmonary function in. 1966 (Table-5) and 1970, when there was no effusion, was'normal-ex cept for a slight increase of. the alveolar-arterial Pot dif- ' ference, .. ' *'- .^J-- '-Si-'.. :. - ` ' case .. - : This- SS-^ear-oid plmhlUfiw*S; first seen Jn/1962 bccause, of progressive dvfpnca anAf-fatigueJoThae"symp-! `toms, together .with iriterriritten'tirright-;ipldmtic- chest 'A," ......... TaWe 5. Salectad Respiratory Studies .of 11 Hw with Asbestos-Pleural Effusion. During Periods of;L***t PWiaal jnvofvemaot Case Date ' (Month/Year) Pleural Condition at Time of Study Maximum / Vital " . /.si Vital-. . .,;. Residual Breathing .;!/' Capacity*. . Capacity -S?Z; Volume* Capacity* - .:;-.-'.iscet- .'.V i 6/66 Slight fibrothorax, right 2 10/62 None 3 3/6J Blunted costophrenic angles t_. 4 10/63 Slight fibrothorax, bilaterally 5 9/63 Bilateral effusion, 1 + 6 7/66 Bullous emphysema only 7 11/69 Minimal blunted angles, bilaterally 8 6/69 Blunted costophrenic angle, right 9 11/69 Bilateral effusion, I + 11 4/70 Fibrothorax, right 2+ 12 4/66 None 100 normal subjects, our laboratory * " 88 178 .'. 73 128 84 -- 123 89 80 92 116 118 % 95 100 62 87 ' 52 89 104 93 80 ' 69 . 94 108 74 81 72 96 68 41 83 58 63 86 71 . 82 > 123 135 127 155 55 -- 97 121 125 . 49 75 115 * Percent prediaed from Baldwin, quoted by Gaensler and Wright (14). t Percent of total vital capacity delivered in one second. Jg4 Fmbrunry l$71 Annala of Internal Medicine Volume 74 Number 7 cfO^IuMl led to his first admission 15 years earlier. A \.^di^~roratgenogram then showed "a form of silicosis," 7-'a^'bronchoscopy showed "coal dust." Cough increased' ' Oirith smoking' between 2 and 4 packs a day. A right '^euralyeffusibn was first noted 1 month before. He be-rgintbfwork with his father as a steamfitter in 1923 and 7' ilway*-covered ail work with asbestos. From 1935 he >'irornsS'if a- nary yard at refitting. He did no covering [ ^butrbkd-lo strip old insulation 1 day each week before .Tnsstailmg new work. Since 1945 he had been a gas fit' *ter,ilWorking side by side with pipccoverers in an usually . {idinty'-eavironment. :7. Examination showed marked clubbing and obvious hyperpnea but was otherwise unremarkable. The first available chest roentgenograms from 1961 showed fine .mottling and reticulation throughout both lung fields ..(Figure 2*4). In 1962 there was also blunting of the right costophrenic angle. Pulmonary function studies showed normal mechanics of breathing, severe hyper ventilation,, an elevated alveolar-arterial Po, difference, Wverely . reduced diffusing capacities, and an elevated ^physfblogic dead space (Table 5)1 .'IT'-Two years later he was admitted twice because of ''dyspnea and right pleural effusion (Figure 2B). Thora centeses yielded sterile, blood-tinged fluid with negative cytology.. Dyspnea progressed, and in 1965 he stopped work and was readmitted-once more. Physical findings were unchanged, and an intermediate tuberculin gave a "barely positive" reaction. Slightly pink pleural fluid contained 5,000 RBC and 250 WBC/mm1, with 64% polymorphonuclear leukocytes, 36% lymphocytes, 5.9 g/100 mi protein, and a lactic add dehydrogenase of 113 units/100 ml. All cultures- were negative. An explora tory thoracotomy for persistent pain and recurrent effu sions showed a thickened cortex, which was removed to gether with two wedges from the right upper lobe. The parenchyma felt resilient, offered considerable resistance to sutures, .and showed severe interstitial pneumonia with fibrosis, honeycombing, and many asbestos bodies (Figure 8A). The pleura showed nonspecific fibrosis with focal hemorrhage, mesotheiiaP proliferation, and two asbestos bodies in serial sections. Chest pain and effusions continued, requiring anal gesics for relief and hospitalizations in 1967 -and again in 1969 (Figure-2C). His inost recent admission, in 1970, was 23 years after onset of dyspnea and pleuritic chest pain and probably 12, and certainly 9 years after, his first effusion. Cyanosis and dyspnea at rest were now present The roentgenogram-was'largely unchanged but. now showed a 1.5-cm nodule protruding lateraljy. frcm the' thickened pleura into the ltihg (Figures 2D,' 3). At thoracotomy a firm .pleural tumor was founditd encase ..the;lung and extend into thq interlobar fissures. lt was . a malignant mesotbclial tumor with large cuboid*! edit ' with eosinophilic'granular cytoplasm .-and vesicular, nhcle& arranged in. pseudotnhules qr</papillaty fashion. Few. mitotic figurrs-.were seen (figure 8F). . / . CASE 7 ' - .`This 33-year-old bricklayer .was referred.for cvalua- 'tkm for pleuritic-pain, recurrent bilateral pleural effu sions,' and dyspnea.,of. 9 mqnthsV-duration. During two previous hospitalisations he ^was | afebrile, and physical examination was unremarkable .except- for signs of fluid bilaterally. Examination of blood and.urine was normal, a histoplasmin :ikih. test wasipositive,;and intermediate' tuberculin negative^Two thoracenteses yielded- clear yel low' fluid with' a specific gravity ;of -1.030; glucose, 82 mg/100 ml; ancf2,430 RBQ;and 840 WBC/mm',7with 23% polymorphonuclear leukocytes and .77% lympho cytes. Cultures ; and ' cytologic studies were'1 negative. Bronchoscopy, right scalene txiangle exploxatiqn,.:and pleural needle biopsies were-unrewarding. The past hn- torywas unremarkable. " '. -. He had spent 2 years in Panama with the Navyl Soiris then, for 9 yeafs, he had worked as a bricklayer on high-rise office buildings. Detailed questions and spe cific, reference to asbestos eventually revealed.'that he had been continually exposed-to-a fine, white, wooly dust that came from the-floors immediately above-him where laggers sprayed steel beams with a fireproofing com pound. The -material consisted of short fibers of asbes tos, fiberglass, and cement that often coated the floors and clothing of the bricklayers. The laggers wore masks but the bricklayers did not*.", * This type of laatar prohibited to New York City by Mayor John. T.lrvUay at this writing (Boston GJ0&*,;Juac 17, 1970).': Tcbfe 5. (ContSmwd) Exercise Ventilation Lung Diffusing Capacity S.B* s.aj Arterial Po, ' AlveolarArterial Po, Difference <7 .v r;.. -Arterial Pco, -Physiologic -Dead'' Space:- Hun/mix per m* % ml 11.9 18.7 13.4 119 10.4 -- 14.0 10.8 13.9 12 12.7 91 91 23 41 9.1 66 10 100 -- 57 12.5 60 7.1 87 15.1 -- -- 112 11.7 53 ' 9.8 59 9.0 100 14.8 ---------------- mm Hf--------------- 77 " * ' 70 84 32 40 23 -- 75 29 -- -- 82 12 ---- 82 24 63 43 65 44 91 14 39 38 37 -- 43 27 42 -- 38 39 31 39 ml 126 450 135 . -- 191 193 193 -- 141 405 166 y 150 t Single breath diffusing capacity, % predicted from Gacnsler And Wright (14). i Steady state diffusing capacity, mi/min per mm Hg, standard temger*U_*ad pressure, dry. -- -Gan*/*r and Xapfan PleuraI,,Effoakjn* 85 -ftt' . TabU 6- Surgwy and Pathology In So112 Man with Asbaatoa Plaural Effusion Case 1 10 12 Date (Month/ Year) 8/62 Operation Left decocticatioa and lung biopsy 5/65 Right decortication and lung biopsy 2/70 Right resection mesothelioma 1/62 8/62 3/63 Right biopsy of pleural nodule, lung, and. mediastinal node Left decortication and lung biopsy Right decortication . ' and lung biopsy 10/68 Left decortication and lung biopsy 2/ 6/ffl Right needle .. pleural biopsy Bilateral closed ' thoracotomy; '' autopsy 2/66 Right lung biopsy Long Pathology Frequency V of Asbestos''1. Bodies' i Pleural Pathology 'Frequency J ' -V of.Asbestos Vv'""-'.'If''?:-' Bodies* '-' Diffuse interstitial pneumonitis with moderately thickened septa; dumps of macrophages with iron-positive granules fill most alveoli (Figure 7A) Severe chronic interstitial fibrosis and honeycombing Papillae and branching tubules of large cells without anaplasia (Figure SB). SQicotic nodules in lung and pleuia, thickened interstitial tissue filled with talc crystals 2-f? r '}. 1-3-tmn cortex; pleural .a.- c . fibrosis; many/ubestos? :^ r. "/. fibers (FteureTfl'and ;.; ;lj .t s-Tv, V- "p-:... 2-f '.'Il-d-mm plehta Twt&matt^d.^f . i-.- henidnhage and mesotfiettal. -y proliferation (Figure 8A)/ri^.' F: 'i+ 14- v-j Pleuremoderatclythlckcbcd ; and studded with silicotic . nodules ... ' , . (3)' Both sides: diffuse,-chronic, low grade inflammation with interstitial edema, histiocytic reaction, and increased. reticulin; many dust-laden macrophages; severe edema of interlobular septa (Figures 6A and B) Pleural fibrosis extends into lung along sepue; slight diffuse interstitial pneumonitis (Figure 5A) '; Very severe, diffuse organi zation; fibrosis and ,' obliteration of alveolar structure and bronchioles; many nests of asbestos bodies * with giant cells, some aneriolitis (Figure 9A) Focal interstitial pneuthpoitis with much increased'collagen; lymphocytic infiltration and .' with germinal centers. 24- ... . Chroidipleuritl* and fibrosis, . 3-fflta hyalinrrtsj.coctex " fft /. s-sv '-1\ *./y ` ' if*.*. >.v.' 14- ;/ 2-mra cortex; regenerated .. / . J. proliferating mesothelioma*' . . extensive collataal'ciitu-.,. latioa-(Figure .&) - -- . - ;. Chronic pleuritixiod fibrosis, incteitsed'coll&teral.cucur'- ' lotion C V- 44- : J-to-Ts-mm vsecular cortex F covered by fibrin, original pleura well demarcated, innumerable asbestos bodies -V . - and fibers on inner border `j.'* *V*. , , > - 0) F . -09 1+ F 24- . ' Slightly thickened and marked vascularity ' '- ' \1\ . ' - - c. .fr **- 0 5 ' F -- fiben; number* la jwtcathMea huHcne total number of mbqtoi bodie* foundin 12 ratal toetfeoa.' ^ . / The chest roentgenogram.showed blunting of both, costophrenic angles with thickening of the left lateral'/ pleura. This was the only patient who had entirely nor- mal lung function (Table 5): Persistent pain and recurring effusions led to left ex- -ploratory thoracotomy. A thin pleural cortex was re--, moved, and two biopsy specimens were obtained from a effusion is well krtriwiL Fewr. studies, of large .numbers of patients have beSdn/ published in. recent years; and the. reported; frequencies , of. [various .causes axe not comparable.-because they depend on the reporting in stitution and the interests of the observer (17-22). - Tuberculosis, although decreasing, has- remained normal-appearing lung. There was some focal interstitial important and, during the last 15 years, has ac pneumonitis with irregular thickening of alveolar septae (Figure 5A). The alveoli contained many macrophagesrfilled with irregular, coarse, yellow granules and 16 as-, bestos bodies in 12 sections. The cortex was vascular, counted for from 6 to 81% of all cases of pleural effusion (17, 18, 21, 22). Pleural effusion without apparent cause but with a positive tuberculin reac showed regenerating proliferating mesothelium, three tion still must be considered of tuberculous origin, asbestos bodies, and occasional fibers (Figure SB). One and the term "pleural effusion (presumably tubercu year after thoracotomy pleural effusion had not re-;, lous)" should replace the- term "idiopathic" (23). %% currcd, intermittent pain continued, and pulmonary function remained normal. Indeed, among young adults with "idiopathic" effu sion and a positive tuberculin te$t followed for 5 or Discussion more years, 66% developed active tuberculosis (19). The breadth of diagnostic possibilities witiTjpIeural PleuraT'effusion of-undetermined cause in patients nq 186 February 1971 Annatwf lntrnakjfctttcln ; Voluma-74 - Number 2 j .......... ?v -'"'if.1. Figure 5. 8iopsy xpcdmen from Patient 7. 5A. The lung showed focal Interstitial pneumonitis with thickening of alveolar septs;. many alveolar spaces contained macrophages tilled with coarse yellow granular- material; .asbestos bodies were rare. (Hematoxylin and eosin; microscopic magnification, X 60, X 1.9.) SB. A 2-mm pleural cortex showed regenerating proliferating mesothallum 'and extern ' siva collateral circulation, it contained occasional asbestos fibers and only 3 .asbestosbodies In 12 serial sections. High magnification shows two large asbestos, fibers sur-. rounded by broken segments of an asbestos body. (Peris' ferrocyanlde; microscopic, mag nification, X 1,500, X 1.9. partially polarized.) with a series of negative tuberculin skin tests remains a problem. Asbestos exposure has never been men tioned in the differential diagnosis (12, 13, 17-23). Pleural thickening or calcifications have been noted in various pneumoconioses (24) and in recent years have been identified particularly with asbestosis (1-8). Indeed, pleural thickening and calcification are con sidered characteristic radiographic signs of asbestosis (I;_7 j. In surveys of asbestos workers with 20 or more years of exposure Frost, Georg, and M0ller (2) found only 39% with a normal pleura, Selikoff (6) found only 44%, and in our patients who were re ferred because of their symptoms, only 16% had a normal pleura radiographically (Table 2). Benign pleural effusion was mentioned once by Eisenstadt (25), who described an insulation worker who pre sented with pleuritic pain and a left effusion that was brown, sterile, and had benign cytology. Despite anti tuberculous drugs, the effusion recurred twice on the opposite side, and decortication and lung biopsy were performed. The lung showed thickened alveolar walls with occasional asbestos bodies, and the pleura was fibrosed but without bodies. differential diagnosis A diagnosis of "asbestos pleural effusion" must be^ jkUu. made with caution. It may be an error to attach too much significance to the mere coexistence,of two dis eases, and the commoner the two diseases, the greater the likelihood of error (26). Careful study was made to exclude other- known causes of pleural effusion. The negative cytologic examinations, lung and pleu ral biopsies, and follow-up have ruled out malignant tumor. There was. no evidence of .cbngestive heart failure, cirrhosis^' thrombbembbHc.disease, or trauma. The tuberculin'test was negative in all but two pa tients, and in these tuberculosis was effectively, ex cluded by open-pleural.biopsy. Only Patient 3 had an acute illness with his effusions, and- neither clinical nor laboratory- studies were indicative of bacterial, viral, or mycoplasma infection. Only'Patient 10 presented a somewhat nosologic problem that will be discussed in more detail else where. Bilateral effusion and parenchymal infiltration were discovered when he presented with arthritis and nodules. The fluid persisted for 5 years despite multi ple thoracenteses (Table 3). Numerous latex fixation tests were positive to 1:8,192 dilution, and LE prep arations were always negative. His 3-year asbestos exposure, 20 years before his illness (Table 4), was discounted until he died of respiratory failure. Then .the lungs were largely destroyed by massive fibrosis --- -^Gaciio/of and Koptan ** Aiixrotoa Ptsurol Effusions f M -v.-'ituS .' -" Figure 6. Umg biopsy spsdmen .from Patient 4, obtained In'August 1962 from the anterior segment of;the left'upperJobe- (A) and in ' March 1963 from the right lower lobe <S). Alt sections showed diffuse, chronic, low-grade Inflammation .with intersdtUi edema, histio cytic reaction, increased rtUculIrt, and occasional hyaline membranes; there were many dust-laden macrophages endian occasional lym phoid fotfida. Marked thickening and edema of the Interlobular septa* ara well seen In the right upper comer of A.and the right lower comer o< B: other sections from all five lobes were similar. (Hematoxylin and eosln; microscopic magnification, X 50, X 1.9.) and honeycombing, spaces were filled with clumps of less than that (Cases'!, 4 to 6, and.8 to 10), inter asbestos bodies (Table 6.and Figure 9), and a num mittent,' (Cases S' and 12), or to "dusts containing ber of these bodies were-in-the thick cortex. Although much talc. (Casesr.3 and 12). The relationship of. as the relationship between; pleural effusion and- rheu bestos amphiboies'tb talcia3 been-.discussed recently matoid arthritis has been questioned by some (26; (13, l5).Tt is thought that asbekdsrpleural effusion 27), other studies appear to confirm the increased may-develop with dust 'exposures^that may 'be.: less frequency of effusion,in this disease (28). In this than .those that have been '.associated -with the devel case die rheumatoid abnormality of tissue reaction opment of'.asbestosis, Perhaps "asbestos pleural effu may have had a modifying effect on asbestosis. In sion": resembles^;jhcsothelioma more-'than asbestosis deed, two. patients with-asbestosis and rheumatoid in this regard. ?*'' ' \ 'Ti. 7V arthritis have been described, although their disease 'm was nodular and not associated with effusion (29, . REXATKINSHiP;''TO. ASBESTOSIS - Jj' - I 30). I . Pleural?plaques and calcifications.;from asbestc exposure "lire said to occur without'parenchymal as k RELATIONSHIP TO ASBESTOS EXPOSURE ' . bestosis: We tried to determine whether this is tea 'I The prevalence of asbestosis is related to both the concerning asbestos pleural effusionl The command concentration and duration of dust exposure. A do^e- criteria for a clinical diagnosis of asbestosis are dysp times-time relationship could not be established in nea, basilar dry rales, dubbing of the fingers, a rc our patients because, (heir work was largely unsuper duced vital capacity, and a roentgenogram consists: vised and their exposure often unsuspected. There with moderate or advanced asbestosis. Previous!; fore, the duration of exposure indicated in Table 4 we defined the presence of at least three of these cr has little meaning. Until recently it was believed that, teria as necessary for an epidemiologic diagnos with a recommended threshold value for dust of 5 million particles/ft5, clinically recognizable asbestosis (31). Tables 3 and 5 show that by this definition s of the present patients had "asbestosis" (Cases 2, rarely developed in less than 20 years (31). In sev eral of our patients the total exposure was.-probably 6, and 9 to 11). Only two had a vital capadty of k than-80%, which is surprising because the pleui 1S8 February 1971 Annate of Intom^-Mgdlclna * Voofumo 74' Number Z- ~ __ 3 'I :' vORfum 7i' Biopsy section* from Patient l.? \ ` .-V -i.. ____ .. . v^t^.The.kmg biopsy shows diffusa interstitial pnaumonltis with mod*rata .thickening ofCalvaoiar septa;. many-' alveoli wara .flilod with -,/nacroph*ge* containing largo yellowish granules that stained Intensely (or. Iron. Occasional asbestos bodies ware seen In.'itllraections. ' ' ^(Periodic add-Schlff and light green; microscopic magnification, X 12S, X 1.9.) =, .. vj7B. The pleural cortex was moderately thick and quite vascular; the wavy line of. the original pleura was well-seen. On the lung side '.-there was a marked "pleural drift" of carbon and Iron-containing granular material. (Peris' ferrocyanide: microscopic magnification, X . 50, X 1.6.) " * - -- . 7C- Just outside tha original pleura there: were occasional macrophages containing Irregular large brown granules. Within some of these cells, and sometimes around them, were asbestos fibers well seen In this partially polarized high magnification. One end of,a fiber (ar row) has begun to stein for Iron. (Peris' ferrocyanide; microscopic magnification. X 1.250._X ,1.9 partially polarized.) thickening has usually been thought to cause a rc.duced vital capacity and reduced compliance (4, 3234)1 Among the six patients without these criteria ' .for clinical asbestosis, two (Cases 1 and 12) had both 1 impaired respiratory gas exchange (Table 5) and mod erate interstitial pneumonitis (Figure 7A). Patients .:-4- and .7 had no signs or symptoms of "asbestosis" ..and.essentially normal respiratory function (Table :5), but their biopsy specimens showed early inter stitial pneumonitis (Figures. 5A~ and 6)'. These obser vations suggest that [1] among the clinical criteria for "asbestosis" the chest roentgenogram is..'the. most sensitive--a conclusion that we have also reached from an epidemiologic survey' (31); [2] studies of respiratory gas exchange, particularly of: diffusing capacity and alveolar-arterial .oxygen gradients, may show additional patients with asbestosis who have no clinical signs and symptoms---a finding that has been ! ncura : 8. Tissue from.-Pattent 2. 8A. Decortication and Tung .biopsy ' In' 1965 showed a thlcktpteuret cor- tax'-with'marked hemorrhage' and .. mesdthelUl ,proliferation:/Asbestos ' bodies are seen withinV cortex and lung; there was severe' chronic In terstitial fibrosis and honeycomb ing. (Peris' ferrocyanide;' micro scopic magnification, X 50, X 1.9.) 8B. A second exploration in 1970 showed a firm pleural tumor encas ing the lung. This epithelial type of malignant mesothelioma. consisted of single layers of well-formed, large, regular cuboldal cells with eosinophilic granular cytoplasm and vesicular nuclei arranged In loosely formed tubules,, epithelial folds, end papillae. Mitotic figures were very rare, and Jfiere was no epithelial mucin. (Hematoxylin and eosln; microscopic magnification. X 125, * 1-6.) - -Qanntlat and Kaplan *-Astu>to Pleural Effusion* 89 ,'V# f . ' ' ' r TFIguro 9. Lung from no- . cropsy of Pztiant 10. Tbr was ~ .severe diffuse organization, mas-' :.;'sJva fibrosis, .and obliteration of' .'Vahmolar structures, and broncftloies;- .".all sections were-, filled with, nests .'Vcontaining Innumerable -asbestos .(arrows),-:-- Many .asbestos; 4v": ,, were within' macrophages'' giant.cells, Tir other areas there. .'.''f.was- mariced - arteriofitisL (Hematox- -"` yiin and eosln; '.miaoscopic rasg- / r nification. X 31.2; X 1.6.) . . suggested previously (4, 32); [3] early interstitial^' . pneumonitis may be present without either clinical or. physiologic abnormalities; and [4] asbestos pleural effusion occurs together with some.degree of paren chymal asbestosis oftener than not, in this series in 10 of 12 cases. failed to show, such 'a ksion. Unilateral pleuritic pain for 12r years before the development'of a mesothe lioma has been reported (25); and an unconfirmed history of self-limited pleural effusion years before clinical evidence of mesothelioma has. been recorded among South African asbestos miners (9). PATHOGENESIS, AND RELATIONSHIP CONCLUSIONS ' TO MESOTHELIOMA The mechanisms of pleural adhesions, basilar pleu- ral thickening, and plaque formation have been stud-r ied extensively, but remain unexplained. Kiviluoto (3) has suggested that, asbestos fibers advance into. . ' the lung periphery to penetrate the visceral pleura;' / with lung movement* the sharp points are said to > traumatize the parietal'pleura, inducing minute hem?' '.-vi orrhages that are later transformed into fibrous, cat-, lagenous, and, finally; calcified plaques. Others have proposed an inflammatory reaction or possibly hyper sensitivity (4). The implication of these theories, if any, for asbestos pleural effusion are not known. The role of asbestos exposure in the development of mesothelioma has been explored extensively since the initial report by Wagner, Sleggs, and Marchand (9). Recent editorials have expressed different bfit not conflicting viewpoints (12, 13). Our Patient 2 developed clinical evidence of a mesothelioma prob ably 12 years after his first of many effusions (Fig ures 2, 3, and 8B). This may.have been coincidence, or asbestos pleural effusion may be a precursor to the development of mesothelioma years later, or it may have been a very slowly growing tumor from the be ginning, even though thoracotomy 5 years^eariier The diagnosis .of asbestos pleural effusion must rest on an effusion that remains otherwise unex plained. and a history of exposure to asbestos dust that may. have been'brief, intermittent, and in the im- mediate:or distant- past. An exhaustive occupational history may be required to elicit such exposure. The - diagnosis can be-Confirmed:'by openbiogsy' material showing'nonspecific pleuritis' andi thickening withbut or with .rare asbestos bodies' and!'fibers and, usually, an interstitial pneumonitis.of various.severities, with - asbestos bodies. The pleural fluid.is. a.'sterile exudate and:may be dear yellow to blood-tinged. Examina tion -for sugar, hyaluronic add, and asbestos bodies . or fibers probably will not be helpful. Similarly; be cause of the nonspecific pleural changes and the rar ity of asbestos bodies, pleural needle biopsy is likely "to be of interest only to exclude other disorders. The importance of asbestos pleurisy cannot be judged from our own data, which are not representa tive; oar laboratories are oriented primarily to symp tomatic ambulatory referrals. Nevertheless, the 12 cases presented here emphasize that asbestos pleural effusion may not be an uncommon manifestation of asbestos exposure. These cases represent more than 2056. of all patients.with recognized asbestos expo- 190 February 1971 * Annate of Internal Medicine Voiuiu+.7<^. - --- _- - " IT* X ^Sfrfuclied in oar-laboratories. The Increased myr,'tse#of asbestos'(12,13, 35), together with -in- '^^ireasing clinical, and' radiographic surveillance of '\'vaibestos; workers,'iilalce it likely that benign pleural .' diffusion' associated .with asbestos exposure will be ^ _________________ ___________ indebted- toDr. J. j'^Clitlsteipher Wagner.Faihologist, Pneumoconiosis Research Unit, gjrr'lPttartfe, Glamorgan/IT. K,- and to Dr. Charles B. Carrington, Professorof-1 Pathology. Yale University Medical ^"--.-jflchotd. New Hnvext, '-.Conn,dor review of some pathologic ma- .. .v-ttriai.-ia these cascai.D'f.-. Irving M. Madoil kindly referred Pa- ! and .4; Dr. SarmselOivo Cohen, Patient 2; Dr. John W. ' iSufcder! Patient ffp'Dr.'.&agio A. Conte,. Patients 7 and 9;. and - -jjjK Jphin B- Cadigan, Patient 12:- 'i,>Supported' in part, fcx research grant HE-05933, training giant VHT3-S562, and research career-, award 5-K6-HE-1173, National .".^IJeterand Lung Institute,-.U.S. Public Health Servico/Washing- e'Son;--D.C. : '. r- - ; ' "!$^Received 27 July l970;'revision accepted 16 October 1970. . :V- ^Requests for. reprints should' be addressed to Edward.A. Cairmirr. MJD, Boston rUniversity School, of Medicine, 80 B. ;-iygJGSotfnb;:cocd St, Boston; .Mass. 0211S ^ttfsrences cification among insulation workers. Danish Mad Butt 3:202- 204, 1936. ,;: - r . f. 3. KtvtluoTO R: Pleural calcification as a roentgenologic sign "of non-occupational..endemic anibropbyllito-gsbcstoais, Acta *^:^r.'-'-Radiol {Stockholm}; 194' (suppl):1-67,1960 J-t. HEtm BE, Wn.uaus- R: Tho pathology of asbeatosls with ; reference to lung limctibn. Thorax 16:264-281, 1961 .. ">5.':Lswsoh JP: Pleural-calcification as a sign of asheatosis. Clin IRadiol 14:414-417, 1963- . . U: Tho 'occurrence-of pleural calcification among Jfi&fT'tsbestos insulation' workers. Annals NY Acad Set 132:351- f-1?<$37, *965 ' V;V ' ^^. Stuis-CaeMa* GK.1' Ttaabtr CP: Radiological and-patho- g-V- ' logical correlations'-la .ssbestosis in. the Republic 'of. South g\`* ~ "rS^'Aftica- and the United. Kingdom. L A: proposed radiological >-41 ''^^-..classification of ssbestosu. Ann NY Acad Set 134:373-378, ' 5v .MruastAK L: Asbestos .bodies and pleural plaques in a Fla- :v=p" nish series of.autopsy cases. Acta Path Microbiol Scand .^'^^SmCsuppU :8-107, .1966 '. . . 1 ^-.'.^f^WjuwE*. JC,' Suaoca CA,MaaaUAD P: Diffusa ' pleural 53- mesothelioma and-'asbestos exposure on the Northwestern J^V.Cape Province. BrtfJ.lnduitr.'Med 17:260-271,1960 ` X;-WsGEa JC: Experimental production, of mesothelial tumor Sslt- tempt to identify asbestos within some. of. the tumors, vun NY Acad Set 132:647-673, 1963 ' , 12.SEUKOFr U. Bans* RA, Bangs ME. et aJ: Asbestostrimd neoplasia. Amcir 1 Mad 42:487-496, 1967 :.' s ' 13. Wtzottr GW: Asbestos and health ia 1969. Amor Re* 'Reap Dis 100:467-479, 1969 ' ", 14. Gaenslek EA, WaiGor GW: Evaluation of respiratory!,im pairment. Arch Environmental Health (Chicago) 12:146489, 1966 13. Giahxvc WGB, GtiwtJtt EA:.'Talco-tilicosn fai.e* rubber worker. Mad Thoracalls 22:390-604, 1963 .` '\r, 16. Gantry r EA, BaLb-Motsm MV;. Halos J: Opea:lmig - biopsy In' diffuse pulmonary disease.- New Eng J -Mad- -270: * 17. J319-133L 1964 ' Therapy of pleural affusion. A ststoment by the ?&''*, Committee ;. :.a; a Therapy of the American, Thoracic, SodDiy.' Aniar.;Rev Reap Dis 97:479-483, 1968 . 18. LeuaiXEN EC, Cats. DTrPleufcal effusibn. NawlSftt'Jj&ad ' 32:79-84, 1933.,-;.' ' "bM 19. Rofeu WH, Waatso.'JJ: Primary aetofibriDOUs piooral;ffbi.. don in military', personnel: Atrter Rem^Tubarc :7t;6W^3l, \JS5S .. ' V ; ` .- :J:-` 'Ji- 2GuSaaEss J, Hjuuson HN, Wrest Jr The role of thpateoiomy'-la tisa differeorial ''diagnosis vot..pleurair<afiusion. VS'i-AJnia'd forces Mad J 10:1935-1978, .1939 ' 2L SochocxY S: Pleural- effusion:' a review:of- 632 caaeeBrtt:/! Cltn Proct 20:619-62^,1966.- ,: 22. Csnt&xvEn J, Aio.atBouoajtaifc:j:. ut" pBhcuoa-SipiQij^pSla : piiure parietafe' i faiguitle ^dana le dtsgnostic ^SoE$iim|^e.-' % Ipauchemenrs j^eoranx. Etude', dc 847 pcejettTrvrara^'Jtt^i&e-:-: Mad Bop Portal18: E143-1134,1967' t " 2X Htwtartw HCr.'.'jDTsaurj of yha Chascl-Philadd^aiS'KsiR' ' Saundcn Co, 1969. pi 641 ' . - 'V 24. SsarrH AR: Pleural criciflcatipm'resulting'fromnaxposute& certain dusts. Amar-J Roentgen 67:375-382; 1932.'s>fi, 25. EtSEKSTaDT HB:.AJbeswe pieiutisy. DliChajt 46r3WJ(^ll^4. . 26. Editorial: RhriimatofaLylettritBijl Ltee^:135113i?T9<iiPfrp1-''^27.- Stack BKR, Gaajff" IWBb.-Rliewns.tnt^ nagrstatt4ttii^8-':- .. / i? ,'ease. Brit J Dts Cfieji"59':262^fl;:l?6Sii.V;^'' Vv 28. Wauxa WC, Wvosf V: Rheumatoid'' Dir.26:467-474, 1967 . ' 29. RKxaaus AG, Baaazrr CMr -Rhenmatbid lung ^tanges' asao- '. X gated with asbestos&TAonia:-13:185-193, 1958 - 30. Tar.l fasott WG: B hnimatoid,pneumoconiosis (Cafilsn's syo-. drome ) ia sn asbestos workcr- Thorax 16:372-377, -1961 .'.i#-,-. 3L Moswnr RLH J*. Fkaus'BG'-ja, Buxoess WA, ct'-aU'A obo- `trolled study of the.effects oLJow. coneeatrationa'jbf;asb<^toa. . .1 CHniral. environmental, radiologic, and tpirographlc obsm- , - 'ovations. Unpublished' otmxvitioDS '-^ i 's : . ' 32.jWn.usus R,Tiwm-JoMW;Pei,-Tha;4iiru&anca o(')Usc^fuih>: "Son changes in/astiessosi's. Thorax, 15:109-lI9,."19rt^MjXlj.^i'.'' 33. "Esdzjl M, Bsia R,;>SMJicbiwilI: Pulnitmaty'fnnct>on:lrL;pa-' - Jbestosis of thejung. ^LmariJ tjbdjlQ:233;.242,.. 3a7Ganxlj EAi Lung displacement: abdominal lyilargwaajl; `pieursj space "disorders and dbfonintlcs' id the' raifitc;ca*^.- . a. Handbook of Pftys&>/bgy,".^ectidn'-3}cRe*piratia^iVoljiH, ' N* edited, by Ftkw 'WQ,:R*hh.H. Wsthiiifton, DjE^tnifejin ' Physiological Soc5ety;;1963, p:il623 . 35. BaocEUg.P: Magic mmetaL'.'.TAe Nina.-Torker;-ii''Oc&et 4968, p. 117 & % s.` !'/l