(HR(O)NIC PUL (R)NARY (GRN L NI)Al \TOSIS OFBIERY'LLIUM \VORK\E~RS*:-

B'- GEORGE \W. \WRIGHT M\.D.:SARAN-AC 1AKE, N.N .

As early as 1(33, \Weher' l)resented eviIeIlce suggesting thaltpersons exl)osed to the inhalatioin of dust or funmes of berylliumcompl)oun(ls miglt develop severe l)tlmonary symptoms. A formiiof relatively acute pieinmonitis, similar to that reportedI by Weberaind occurring in workers expose(I to the fumiles of the berylliumextraction I)rocess, was first reported in this country by VanOrdstrand et al' in 1)43. Addlitional case rel)orts have lheenI)resented sul)sequently.

In 1942, a femiiale employee of a mainufacturer of fluorescentlamp)s was autopsiedl followinig a I)rolonged illnless characterize(dlby insi(lious onset, weiglht loss, extreme dysl)nea during physicalexertion an(l a p)ersistent nonprodluctive cough. A histologic diag-I1osis of Boeck's sarcoid( was accel)ted with the usual (legree ofal)athy. \Vhlein, however, it was sutbsequenitly learned that at leastten other workers of the same l)lant had become ill during thatand( the einsuino' year witlh clilical evidences anId roentgenograplhicappI)earances of ain abni0ormality very similar- or idlentical in natureto the auto)sie(l case, the dliagnosis of Boeck's sarcoi(l became lesstenable ain(I ani iIIdustrial factor was force(d in1to coInsi(leration.

In the interval snl1ce 1()42, it h1as beconme im1anifest that asystemic granuilomia, the earliest and most striking, evi(lences ofwhich appear in the Iuigs, is occurring in 1)ersOI1s who have ahistory in cotum111o1n of exposure to the ilnlhalatioin of berylliumcompounii(Is. 1From both a clinical and histologic standlpoint, itdiffers sharlAy fromii the acute clhelmlical pileutmoilitis rel)orted byVan Ordstrain( and( other earlier aind later- investigators. Thereis Ino crucial evidence to (late to iinldicate that the acute lpneutinonitis

1From the I )epartinenit of Physiology, E. I. Trrudeau Foundation.**Research suI)l)orte(l by a granlt from the U. S. Puhilic Healthi Service.

166

PULMONARY GRANULoMNIATOSIS

progresses into the chronic granuloma. Moreover, this granulomahas not been reproduced in experimental animals exposed in nu-merous ways to various beryllium compounds, in spite of repeatedand continuing efforts to do so. Because of its uncertain etiologyand still unproven clinical or histologic specificity, this particulargranuloma has been designated as pulnmonary gr(aldtloinatosis ofbervllizint1workers.

The following case exemplifies the salient features of pul-moniary granulomatosis of beryllium workers:

J. A. was a 58 year old white male of German descent, whosefamiiily history and past personal history has no apparent bearingupon the present illness. Until September of 1947, he had beenwell and vigorous but at that time he noted that he was losingweight in spite of a normal appetite, and in the ensuing threemonths his weight dropped from a previous stable level of 220pounds (height, 68 inches) to 150 pounds. No constitutionalsigns such as fever or night sweats, or even a feeling of illness,accompanied the loss of weight. In January of 1948, he firstnoticed breatlhlessness at an unusually low intensity of effort, andby February he was forced to stop in order to regain his breathat the top of one ordinary flight of stairs, climbed at a slow speed.At the same time, he began to have severe paroxysms of coughwhen he exerted himself and he raised about 4 tablespoons ofwhite tenacious material daily. Sudden changes of position, fromrecumbent to erect or vice versa, would also initiate a paroxysmof cough. Cyanosis of his nail beds was first nioticed by thepatient in January of 1948. A roentgenogram in Mlay of 1948showed a fine stippling in the lower two thirds of each lung field.From June of 1948 on, he rested at home. Nevertheless, he feltno l)etter even though he gained 25 pounds of l)ody weight. Hedenied chest p)ain, hemoptysis, palpitation, orthopnea, nocturia.edema, or gastro-intestinal symptoms.

His occupational history was irrelevant as to the inhalationof dust until 1943, from which time he was employed as anelectrician in a foundry that makes, among other things, beryllium

167

GEORGE W. WrRIGHT

copper castings. This mzani had anmple exposture to fumes andduist atten(Iing the manufacture and processing of beryllitum copper.

Physical exanmination in September of 1948 revealed the fol-lowing abnormalities: cyanosis of nail beds, ear and nose; respira-tory rate at rest of 26 per minute, each excursion being shallow;chest expansioin very limilitedI on b)oth sides; a few persistent raleswere audible at the base of both lungs posteriorly; the pulmonicseconid souind was louder than usuial; during miiild exercise, the

resp)iratory rate was markedlly augmented. ,A roentgenogramii ofthe chest showed a diffuse fine granulationi or stippling throtughoutboth lungs as is shown in Fig. I. The hilar regions appeared tobe the site of enlarged lymph nodes. A film taken at the endof force(d expiration indicatedl that the lungs emptied well (Fig. I).

I

Roenitgennogram of chest.illspirationl.

FIGURE IA. At maximum expiration. B. At maximum

Roenitgenogranms of the hands, feet and abdomen were normal.The laboratory provided the following data:

168

PULMONARY GRANULOMATOSIS

Heniiatology-October 1, 1948Red cells: 5.8 Mill. 'White cells: 9000Hemoglobin: 116%o(100% ~14.5 gr.) 16.82 grams Diffcrenitial couint (200 cells)Color Index: 1.00 Polys 57% 5130Volume Index: 0.91 Lymphs 27% 2430Satur. Index: 1.09 Monos 13% 1170

Fosins 2.5% 225Hematocrit: 50% Basos .5% 45

Van Allen: normal values)men 47%o non-fil. 22% 1129women 42% filament. 78% 4001

Blood Sedimentation Rate (Cutler tube) : 14 mm. in 1 hour

Blood Chemiiistry-October 2, 1948Total Serum Proteins ........................... 6.10 grams/100 cc.

(normal range: 6.3-8.0)Serum Albumin . ........................... 3.72 grams/100 cc.

(normal range: 3.8-5.2)Serum Globulin ................ ........... 2.38 grams/100 cc.

(normal range: 2.0-3.5)Albumin/Globulin Ratio ....... ....... 1.5

(normal range: 1.45-2.2)Serum Non-protein Nitrogen ........................23.6 mg./100 cc.

Alkaline Phosphatase ...................... 3.8 King-Armstrong Units(normal range: 4-12)

Blood Cuiltirc-September 30, 1948Aerobic and Aiierobic-in Phosphyptose broth zith 0.1 agar

October 8-No growthOctober 12-No growth

Broinisuliphalein Liver Functioni Test(intravenous injection of dye: 5 mg./kg)5 minutes-more than 60%45 minutes-about 7%

Vant dcn Bergh Scrunm Biliru-lbinlDirect reaction: NegativeIndirect reaction: 0.3 mg./100 cc.

(normal range: 0.1-0.3 mg.)

Urinal,ysis-September 30, 1948Color-yellow Reactioni-acid Sugar-neg.Character-clear Sp. Gr.-1.018 Albumen-neg.MIicroscopic (cenitrifuged specimen)Few calcium oxalate crystals; few ammonium urate crystals; 1 to 7rbc/HPF; 2 to 4 wbc/HPF; few squamous epithelial cells and mucousthreads. Few epithelial cell plaques, no casts observed.

169

10(LEORGE, \W. \W RIGHT

Spnthzm E.i-(am niacztiloni Septemil)er 330, 1')48Character-mucopurulent.Gram Stain-Gramn pos. cocci anid (lip)1o. gram neg. cocci.Z.N. Stain No acid fasts foun(l.Fontania Stain No spirochetes.20% KOH monnlt No fungti or cvasts.October 2, 1948Onl blood agar Gramii neg. cocci predominwat-Stapyx l aureus strep

alplha.October 8, 1948No diplhtheroid coloniies grown.Sal). agar-No funlgi grown.

.SPtnohim ,Somcars and(i C(nltnrie--October 5, 1948Character mucopurulent, greyish xwhbite lasses.Gram Stailn-maniy graimi pos. cocci an(l diplo., gramii neg. cocci ani(l bac.

gramii neg. filamenits with granules.Z.N. Stain No acidI fast bac.-No acicl fast diphtleroids.Fonitania Stain No spiroclhetes or fusiformiis.20% KOH mount- No fungi or yeasts.October 7, 1948On blood agar: ( 1) granm neg. cocci colonies pre(l. (2) Staph. albus

(3) Staph. aur. (4) Strep. alpha (5) Gramnieg. bac. -No diphtheroilcoloniies.

October 9, 1948No (liplhtheroid colonies.

Reni(al Finntion Shtndy -PSP OOctober 5, 1)48TiIIeC 1 (oll)c1W15 minutes 100 cc. 19%30 ninu1ttes 195 cC. 381 hour 320 cc. 22%2 hours 315 cc. 17.57,

96.55c%itnbercn1lin Tcst: Negative to 1 mgm1. (O. T. ).

Histopl(asninl 7Tcst: Negative 1 :1000.Flcct rocardiorapo n

WN'itlin niormlal limllits.Basal 1ctiabo/ic RNate (open circuit metlo(l )

+14, +11 (duplicate runs)._I. 1JX [lltR.11 . ITI CAPA.P CITY Petermined Predicted

No inicrease after vaponiephrinl 138 L/IIimm. 122 L/min.L UX.VG (UOLU J.1I:, NEC(lIIUFNT I)ctermiced Predicted

Total Volume. .3.90 L. 5.10 L.Vital Capacity .2.75 3.86Mid Capacit .2.15 1.91lReserve Air ........ 1.00 0.67IResi(lual .\ir . 1.15 (307c) 1.24

I170

PUMINA1R\ cGRANUI.oMlATO(ISIS1

L -A-(; II'I ( 1L'Il'I\CL'CYttimes Mid Cap)acity 71% (Normal 885%1/c

F1'/COkOSC( fBotlh lheilidiaphragnis move quite well (lutriig (Iiiet b)reathlig l)ut thle

excursi"ils seemiis somes chat limited during deep breathing. Rif) motion i_sslightly limite(l (luriing (leel) b)reathing oni botlh si(les. 'ITlhe lun, fields appearto fill alnd eml)ty very well. There is nio deviationi of the iedilastintuill durilngthe phases of resl)iration ai(l nio evidence of regional trapp)ing in the lung.The lheart seems niormiial ini conitour, size anid pulsations, except for the pul-mloniary colnus which perhal)ps pulsates in a somnexhat exagg,erated manner.

A1'RTlI.4L BLO01) f 1S'ES'-?E.S TINA-CO.. Cointenit ....... ....... 44.35 vol.%S'02 Con1telt 2.2 .26 -(-vo%l ) 02. ............%p .34 mmin. I-l,g02 Capacit .... 21.86 Vol.po0()2 ............667 Immtil. H-HbO2 Saturation .......... 92.7% 1)H ............... 7.48Calculated Alveolar p02...... 103 miml.Alveolar-Arterial (Gra(lient ...... 36 mIm.

IR7'EJRI.-IL 1,001) (;.- iSIsFS') R1AN; 1.1X I'AICISSSample obtained (luring the 5th miniute of exerci se by imieanls of anl

in(clxxellinig arterial ia.c(lde, the subject walking on thle trea(dmiill at 2 milesper lhour oni tlle level, oxygen consumlption being (1.88 lite-s per miniute atthe time the samlple was (draxxvn.CO2 Cointenit .............. 41.84 vol.%//02 Conitenit ....... 15.78 vol.%pCO.............. 41 iiimm . Hg02 Capacity . 23.14 vol.%7pO2 ..............33 innm. HgHb()2 Saturationi ..........68.2%7 ptH ........ .. 7.45Alveolar-Arterial Gradient ...... 63 nmm.

111'T4IB0L IC A.l) C1RC('(!01TIORY Tk PSPVIAI' )1'.YIXRCINF(The maximiiumtl exercise of which this imiani was capable xx as a level walk

at 2.5 miles per lhour for a perio(l of five minutites.)l)uriiog the 5th iiiiniite, the folloxviiig data xxere obtained:

Miniute Ventilation 76.3 litersOxygen Consumption 1.00 L/',imm.Carbon I)ioxide ()utiput 0.98 /mlli.0xyg-en Ventilation Equivalent 76.3 L. (Normial 25 L.)Dy)spnea TIl(lex ().551D)yspnea 4MaximumllPiul se Rvate (Itiriing exercise 140/mM aximutni Respiratory Rate during

exercise 68 /inPulse, 10tlh imiitite of recoverv 100/ImResp., 10th miniitite of recovery 42/in

It xxwas notable that this patient (leveloped severe cyanosis during this stilnt ofexercise.

171

12EORGE W. WRIGIIT

Oin AMay 20, 1949. he entered a hospital l)ecause of extremedvspnea, cyanosis and a temperature of 102 F. His capillaryblood at this time contained 6.54 million red cells, 18 grams ofhemoglobin and 18.5 thousand leucocytes per cimiml. He expiredon M\ay 21, 1949, approximately 21 months after the onset ofsymptoms. At necropsy. the examiner noted that the body didnot show signs of wasting but appeared to be that of a wellnourished man. The spleen was enlarged. The right pleuralsac contained 1.0 liter of amber fluid. Both lungs were moderatelyadherent to the chest wall. The tracheobronchial and mediastinalnodes were enlarged. The heart appeared enlarged, weighing390 grams. The left ventricle wall measured 16 mm. in thicknessand the right ventricle wall measured 7 mm. in thickness, the latterchamber appearing to be dilated. No abnormality of heart valvesor coronary vessels was noted. There was a firm laminated andpartially recanalized clot attache(d to the wall and occluding themain left pulmonary artery. No site of origin of an emboluscould be discovered, but it is worthy of note that the patient gavea definite history of phlebitis with edema and varicose ulcers tenyears and again two months before death. The occlusion of thepulmonary artery was obviously not a recent event. The cutsurface of the lungs after fixation showed an excess of solid tissuethroughout the entire parenchyma, the alveoli being relativelyscarce and coarse. There was marked thickening of the inter-lobular tissue. Both lungs were involved throughout with no grossevidence of focal areas of normal lutng tissue. The most strikingthink about the autopsy was the extensive distribution of the ab-normality as compared to the roentgenographic evidence. Thegross anid histological report of the lunigs andl tracheobronchiallymiiph nodes by Dr. A. J. Vorwald* is as follows:

GROss DESCRIPTION

LEFT LUNG: The left lung is of about normal size, and the lobesappear of normal relative sizes. Over the upper half, anteriorly and laterally,the visceral pleura is thickened and pearly white and smooth. It measures

*Director of the E. L. Trudeau Foundation, Saranac Lake, N. Y.

172

PI't _1)NARY (GRAN'L1\IATO't)SIS 17,)1 mmn. in thickness. ( )x cr the lowx er lobes, the x isceral ain(I parietal pleuralsurfaces are tsed l)y (Icli'cate fibhious tissue. The interlohular fissure i-Similarly OhlitrCIatel. pinlulImonary tissUeie Smlahat fi in 6ut olPlo -

getiic'ols ill C(1I1s tc'iitv, 1l11d crieplitailt. ()11 -SCCtioIl tl' uIpper l(Al) aplplarseconitaini ani excess of tissues, alld the alveoli are fexver tlhaln niorm-ial ill litilli-bler, hut thex- aci- evcnix dlistril)butel tlhroughlouit an1( are emipiity. 'T hey arie

c-try coarse. lcTre is i1do(ler-ate accentuation of the secondary loblulationl y

hlack piw mllent. The loxx\cr lobe oii sectioln resemhles the upper, x-itll hlieexceptionl that tlhirc is ani irregtular zoiie of difftse fibrocis tisstie depositiolnjust bleneath the interlb)har pleura. Thlis zoine is 1 cmii. ill greatest depth anidextenids ahiout .3 ins. '[lie ilntral)ullionarv bronc hi arei of lliorm-al size anldtaple nInornally, tlieir iling l)being slmiootlh alnd lpale. '1'lle imaini lIlmInonaryartery to tlis IIo)e clontains a firmii, lamiinlated hroxvn and wx bite thrombus.Tlhis is firmly attached to the xx all, alld seemlls to he at least plartially coy-ci-ccl hx inltima. Steral hranclhes of the x essel are simiiilariv InvonIxlved.

RIt'N T 1 ( \' (;: lic right IlunIg including the middle lobe, -enerallxresemhles the left. A zo/le of scarrinag is iiotedc heieath the HitecrloIbar pletiraIof the loxxcr lohe, as i tlc lctft. Tle putilmiloary artery to tlis Iliung is emiptyaicl its iiitimit is sIlo 1thl.

7K.1n'1('111'()1k/X() \ C 11.1/I\ (1)I)S: Thliese are c((isiderahlv nl1argc(l.gethe largest heiiig 3 cmis. ii greatest dimension. Theyt are soft an(I (Iii sectiIappear miottle( xxith giraxfoci, stirroutii(lecl hx linear black jIgnicltatioln.

Mi 101wxoli I sc rioriIIN (Se Fig. I I)

I NA'(J.S : All sectiwis exhlilit a diffuise, graililoniiatouhs iilflaiuniatiliicliai-acterizecl )v scattcircdl, stellate lesions xhic'h arclocalizcel iii the alxvel<Iarxalls and(I wxlichilistort aiid Iften obllliterate the acljacent alveolara spaccs.Ini addition, the alvelIar xx alIls arc generally thickened, and thc aIx-colarspaces freqtuently clltai looscly scatteredI macrllphag,s. 1Ilic spaces areninttsuallx lisplroIPortiioalI and ire-gtilar iii size. Mlanly are (reatly dilatedanid giv,e alatoIllical evi(dence (If emphysema.

The goraninlloailatoins inflaainmation is predomlliiinaitly ccl lular colisistilio-oIf a coIml)act internal arca of large iionontuclear cells xith scattcercd lyxi-phocytes,fewx pllasma c''lls, aiid aii Ilceasional giaiit cell. Th1le c\t(flasm(Ifthe mIi(lIiiniclea1r cclls isofteil foamiy aiicl freqiciitIv coiitainis large vactiolesstiggestix-c of fatglo-ni( s. 'I'lic giant cells are giencrallI of the I anghanstxype, thlat is xit initclei arranged about the peripheryIof the cell. 1'le eto-plasim (If manix- If tliesc cellsis alsos-actiolatecl( Cichiloi(alloies are Wiotasiiiierotis as ill sMICl' casc',oflptillmonarygr-antilomiatosis sti(ie(l prex'iotisly.Thc'e' are sitnatedl xxithliii te o-raiiulomatous lesions, and( usuiall' otitsi(le ofgianit cells. Th1e majoritx'consistof a central core surrounie(ld by onic orm orelaminiatedI rings of bluish-black substance suggestive of calciutm. Thin re-

174 (;IGEO(R E W. \X }RI( i- Ij

Fl(;t R II

Phlotoinli1cI )-g rap)hs of gramll(millatolls leisinS pre selt ill tile ltillg-s 1.Atrea demolnstratillg tilt scatterel stellate lesinils, SoIne (if which hiave coal-lesce(d. ie al v(olar spac is are (listol tt(i aild tile inlterveIninlg w alls arctlickele(l. B. (,reater inagnificationi thanl I to sihowx (letail of leiiions. N(teiallt cells. Incinsii 11 l)( lies are nllot present ill tils sectiI 1.

fractile itedles arfott( 1( mllvl )ccasi(1llvx n ad(ditioiin tilere is fiilie liackiarticulate substatce filnlyx scattctre(l tillhnighliot tlhe grailnionlatons reaction,blut esit acilly ill tile ocal I esnIlIS.

SoIille of the focal 1 sli ls exhibjit Iild cellular degeleiration, xw hileothers reveal aii apprecialeli dexelopmltllet of lowIselyxx0oen' straldls of conl-nlectivc tisstie. Tlhe latter illuost proinlitleIlt as tilill collars ahilit tile ceilt-alfoci of large iiioioiltielear cells. An ilccasillilal lesioll irexeals coilsidlerahlefihrosis anii( livalinizatiill. Sich1 lesiolils are iinteripreted Is tle IlliOst Illatinrereactiom. The aIr-aligeiictlilt if tile fibrosis atlol llx aliile is limllike that xhllichcllaracterizes tilc reactiill to free c(rstalliIlt silica.

Studv uif tlhe xascular trnilks is iilterestiilg. Ilt ar-terics allcI arteriolesembileddlecd iil tilte g-railnlulllatotIs reactioii ai-e tlliclk-xalleil alni tileir Itiilleilsallplear nlarrwxei. 'I'lle lar(er vascular cllailtel s of tile eapillary system areofteitldistended xw ithl bihl l aiiul souilmetilmles po-Oj cct iiltii tile alxeolalr spaces.Thli.s is snggestixe if plassive coilogestioll. hloxwextcr, (ellellatouns precipitate is

PUL-MONARY (RANUL( MATI1)SIS 175

conspicuous by its abseiice. h siiialler calpillary sy stems w ithin tile alveolarwalls are dliffictilt to ideitif. Although solile siMall m11icroscopic clalnsls aredetected, many xxalls appear axvascular. Tli.s o)bservatio is subject to criti-cisll Silcinej ection sttl(lies (of tle vascular chaniicls w\ crc nlot carric(l oit inthis case.

\Witil 1-fcl-elCtc the thlrlllll)obsis of tie let1t 1)1l1111rllars artery, miainiiyof tile larg- iiitralobar arterie s coitaini c millpact 11 lllIgeneouC0tIs IllaX.SS ofcorpuiscular imiateri-al. These ar tci ies are plrstiahlll 1v)b ranchles (f tlee aillplulImloniary trunk. Ill conltrast (tilci arteris, espIcI ially tho)se x l11iiI follo0tile ilmajoi-a1ii pIassages dll1)1acrsumldlably lid5 1(1i-l-Oil tilev hr(onlichlial artery,ai-c oftteil emtlilts (ol fillI xw itlh scatteredl 1)1(1(c1 rpuscl c ill (-)()(I state (ofprese-ixatioll. \\hetiher tlhese arteries are actually ioi-o liial that haxe as-sutiledl tlhc iua'j Ir circulatory hltldeli 11y reasoll (If tIlhrOlll(Isis (If the pullilo-arv artery to tilis tlung, callillt 1) (lcteriiiiic(l frI 111 tile pireparatiIlls iild(lerrcxviexxw. \ erificati hI of this Iminlt Illighit he acco mpdlished iy iiljo.ioh1 studies(If the xvasctilar ti-iuilks (f hsothi thle pulmli vdalr l lrolbllihal sy stelil.

1 .if lIP()I.k() V .111. II I Y M>.11P1A 1)1ES: TIle iio(les dtie 1yper-plastic. ill silitises are (listeil(liel N1 itll large 1o11(ill nuclear cells. li ad(li-tioIl, tlhrC arc xw idely scattei ed focal lesions (If comIll)pact ildnIlluiclear cellssiluilaroItlios plresent iil tile lu111-. ( udilat cells cIe scatteirei tlii ltighlolt111(1 main eollltaill cIlclloidilal lbmlics. Simillar- Idlies are foulnd dilso x ithlillthe girditilml(IliilatIls ieectiollii Iitside tile gid-ilt cells. In ogeiieral, the l)Idiesare less illacks t111a1n tliosc in the ltiiig. Frequently, thlcy are lar-ge ( estilliated51)-100 llicrI ills ill (lialileterl) 'I'lTis olserxvatil stilil)l)prts tilCe ilesis tilatsiclh odlies foiilil ill itti aic(i e-x-cludes the pwsibiilitv (i thiri- bciiig (Ii-a'iietlfroIil the lung.

'il'e} nole alsIo exhlilbit slattv-ereci ltllulms (If iliac k plartictulate materialI' a/elizIe l inlcilally ahblit tile xvasclilar tritiilunks cll ill tile tialbectilac. Mtaily

slicli lo(calizatioiis are accl pilllmiid(l by an aplprecialle Ipl iferatioIi (If con-nleetive tisstie, but wxitilmltt theIlatteril xhichl cllaracterizes the reaction to(IlIai-tz.

T here are Fill latho-noilliic siglls or cvillp)tol s of thlisgrantulonl t. The exact i1ui.Eb11e1r of cases is nitkliownil. It is YeCasolf-alhlv certain that at least miior-e tlhani 100 lionaflllde exainlmles arekinowIn. In otr own lalioratorv, we hax e stti(lie(l 16 cases con-si(lere(l to qutalify as geniuine examllles of this ,ran )tilolia. \A1gYave a historv ()f tlvs-s lea oin exertioll as oile of the earliestex idlences of illness. Striking, loss of xweit, inot alwavs ac-Conill)ilie(l 1by loss of apll)petite, aci] sexvere par)Xvsimal, relatixelv

17EO(ERGE \W. \W iJ1(;1i1'

ioIll)r(m)dllctiVe COUl"h is alimiost as coinstanit as is (lvspnea. \Weak-ness or ease of fati,te is prominent, eslecialIv ill thlose witlhsevere pullmonlary changes. IPhysical sins are qtuite varial)le;evidences of weigllt loss, lililite(l th(oracic excur'sionls, rapid respira-torv r.ate at rest and (htirillng exercise, iTh(llerate to sexere cvanosis,clubbing of the fingers, genieralize(l a(leiop)Iathy and skin papules*beilc l)resent 'With a frequencv (c )rresp)ondning to the order inwllichi they have been liste(l. Evi(lences of conyestive failure arecomimilCoii terinallIv. Thle absence of reaction to initracutanieotustuboerculiin was ol)serve(l in every case of our series. Iolycythemia.electrocar(liographlic evidence of right x-enitricle prepon(lerance,changes in )1o00( protein concentration and( electr()phoresis l)atternand elevation of the serui lplhoslphatase wN-er-e also fotuni(d to bepresenit, thotugh not in each case.

As indicated by mieasturemiienit of the total lutng- volume, theniaj()ritv of otur cases showed a limitation of the size to whiclthe luIg cotildI be disten(led by imcaxitiulim phvsical effort. Insl)ite of thlis, the Maximum Breathing ('apacitv rem-eainiedI nlormiialor onily slightly re(luced uniless the Iluingo became extremely tin-dlistensil)le or developel dliffuse olbstrtictive emphysema. A highlevel of Aximitinuml Breathing Cal)acity was inaintaine(l in thelresence otf a reduced stl-roke volutme liv a rapid resl)iratorv rate.Most strikinlg of the physiologic mleasulr-emiienits was the presenceof severe overbreathing (luring exercise in eaclh of otur cases.WNhereas the niornmal lpersonl resl)ires 25-5 liters of air for eaclliter if oxygen remox ecl froml the inslpired -as, those cases ofulmonary grrantilomatosis who complain of exertionial (lv-spnieawil breathe two to tlhree timies that volume. This is indicatedin the patient l)resente(l her-ein bv the very higs-h oxy(gen veintilatioileqluivalent. ( )verbreathing w"as associated in eaclh case witlh aniabnornallv l()w 1() of the arterial blood sam1pled (luring(, exercisea1t(l could be overcome to a large extent by the inlhalationl of pureo)XVgeil (luring exercise. The differenice between the p02 ()fthe alveolar air am(i the arterial 1)1o0(1 was g-reater tlhanl normiial

Biopsy reveals leshim idenitical w itlh that of the lu100Z.

176)

PULIMONARY GRANULOMATOSIS

in each case both during rest and exercise. This was true evenin the two cases who were completely asymptomatic at the timeof our examination. It is obvious that a significant proportiollof the pulmonary artery blood flow enters the left atrium in-completely arterialized. There is no evilence of an anatomicalshunting of blood around the alveolar capillaries and except ina very few, there is no evidence of a poor dlistribtution of gasesin the alveoli. Furthermore, the alveolar P02 is consistently high.These facts, together with the appearance of the alveolar wallwhen examined histologically, strongly favor the view that thereis an impediment to the passage of oxygen across the membraneseparating the gas from the blood phase. The imIpediment tooxygen diffusion across the alveolar wall appears to be the criticaland fundamental abnormality of this disease. In essence, thesepatients behave at sea level as would a normal man at an elevationof 10 to 15 thousand feet. If the lung becomes sufficientlysclerosed and resistant to distention, the already overblrdenedrespiratory apparattus becomes even less able to cope with thestress of exercise. It is as though a normal man went to anelevation of 15,000 feet, tightly bound his chest and abdomenin the position of quiet inspiration, and then proceeded to exercise.

The prognosis of these cases seems good for those with mildsymptoms, in that though they retain an abnormal roentgenogram,their symptoms (lo not tend to progress. Those having sev-eresymptoms tend to progress to a fatal outcome. Five of our caseshad relatively mild symptoms and are still living andl able to workat sedentary occupations. Eleven had severe symp)toms, and ofthese, six are dead, one is alive hut requires oxygen continuously,the remaining four are scarcely able to be even mildly active.

From the standpoint of diagnosis, these cases seem to fallinto a fairly well defined pattern. Careful clinical, roentgenologicand physiologic study will exclude most of the conflicting diag-noses. A history of exposure to the inhalation of beryllium com-pounds then categorizes the patient as belonging to the granulomaof beryllium workers. There is no question but that cases char-acteristic in every detail for pulmonary granulomatosis, lacking

1717

178 GEORGE WV. \WRIGHT

only a history ot expostire to herylliuim, (lo exist. The authiorhas three stich cases. 'Moreover, inI some of the cases believedto he hona fihde the miiagniitudcle of exposuire to l)ervllium is v-ervfleeting as to timiie ain(l almost ridiculous as to intensity. Lackingain experimental (lelmohnstration of this "><ltloma ianimlicals cx-

l)osed to l)eryllituil- cCOMpounds in the many ways uitilized to (late;and kniowling that man- heavily exposed1persons fail to acquire the(lisease tthat those wlhc) have (levelol)e(l it frequently wvere onilyslightly exl)ose(l, that cases )erfect in every (letail excel)t for ahistorv of bervilitim exposuire (1) exist onemicay properly questionthe role of bervIlitim colmioun(ls as thle sole cauise of the -rai1t1-loma. It appears more logical that, as exl)resse(l l)v Dr. Gardner,the beryllium is butt one component of a compl)lex etiologYic milechi-amismIl. It is etquallv possible thait berylliuim may be but oneof several substances calp)able of setting ofl the mechanism wlichlea(ds to the (levelo[)ment of this granima.li.

RT L14ER FENC FIS

1. Wr-imor 11i. 1f. and( FINGL:IIARDr, WN. '. : . \nmvendting h)ei (cler Unter-suchtig, n01 Stacubn atis (lcr BIcrvllitnio-ewimng, Zenitralblat. f.(Gewcrhchv-. 10: 41, 1933.

2. VA ()RDSTRA Ni), H. S., H RamEs,K. and tARM(MY, 'M. G. ClhemicalPneuCo1nia in NV' )r1crs 14xtractin-g Iervllitim ( )xicde, (leveland Clini.Qnart. 10: 10-18, 1943.

)ISCtUSSIT)\N

IR)R. JosFPur LARLI;1 noORm [Baltinmore, MarylanvaI: Mr. Presidcnt,aonong the salts which have b)een suggcste(d for parenteral inljection1 islenlicilliii. Thle informati Ii is that inj ection 0f b)eryvllinnm by the parentcral- mite w( l(l prodnee a svn(lr()le of tlils niatnire.

IRe. Jn , BAREoow YoV aM A.Ns [Ch1icago, Hllin0ois]: I was go()ing(y toin(jnlirc mnltclh along the same lince, wlhether the localize(d graniolmatouslesions whichloccnr whlen l)crvllitim( is inij'ectc(l cast ano light uipon hieinieclhaniisnii.

D)R. IRANCi.S C. W( nD [Philadelphia. Penisylvanlia]: Arc there anyorannioiatons lesios in the eve, snichi as we see in sarcotld

I'PI,AM).N ARY (GRAN VI'D)MATOSIS 179

DR. MAVRIC E FRI.xtO\ I-S xIIi Boston, Mlass. ]: It woul(l like to<askwhether it is true that the hreaking of one of those lutinlous tuhe lights issuIfficiet to expose ani individual to heryllium to the extenlt that lhe imightget this syndrome.

l)i. MAtRiCE ti. PtNC('IF s [ialtilimiore, -Maryland 1: I should like toa-sk Dr. WN-riglht if hie would nlamlle a few of the indulstries, otiler thlaln lamllpm.Nakinig, in wxhieh beryllium is use(l.

I )1. FIT.xNIS slINOT RAxKEi \NANN Boston, Mas-s.]: I wouldi liketo ask I)r. Wriglt if these people xheeze xxitli dyspuca.

DR)i. \WRIGHT [ul singl : rTe injection of salts, ill animiials at least,lhas heen pretty iuitichi of a failure; xx C have nlot heeni ahle to rep roducethe (liscase at all.

I)r. (ar(ldncr was ahble ti) prod(uee a Isme sarcomia, xith groeat regtularity,fromll the imijectl ii of f have f i)rgitten wx hich compoi)und.

It has blen su'ggeste(l that the Sol uhle he l- lium11 C'll)OuIpils x illproduce the acuite disease, and it is the insolublle ones wx hich proiduce thegranuiloima. Thlait is heing sai(l s(o)IClel on the hasis of the history f expi)surein thlcse individuals, and iiot in the hasis of reprod(hciing the disease inanlinlals. I thinlkl on uvlld he safe to coimtintiC using hervIlliu andpeiiicillin unltil solime flirtlher evidences are hroti-glt forth, to the contrary.

We have not hlao, in in oxvii series, army eve s5-miptomis at all nordo I kinxx of aiy in the publ ished cases.

TIlc mlatter- If hreakil, a single fluorescent tuhe, or iii)I-e .L'han asingle flulorescenit tuhc, is, I heliexe, oAf coii(leeral)le inlmportance becaise,as von kinoxx, there xx as a stateiiement seiit out by the lamipl) inld(ustries,x ariliig indixiduals ahoiut that practice. 'I'lere are txvo (lanigers involvedone is tlhat, if yon cuit yoir skini xxith a piece of g'lass haxingg tlis duistpoxxwder on it, vyoi are alit to dcxvelq) a granuilonma xhich is an exact replicaif the lesioni seeln ii the ltun-s. As far as I kiioxx, a granuilonma of thlattype, of xwhich tlhere aire several cases in existence, has niot gonle on0 Lo someleplace clsexwlhere in the 1ladv

The seconid tlliiig, of cutirse, is the matter of dust coming frolml thetuhe xx lien you hreak it p1.)

I (Io iiot kinoxx hio xixmici cxie osire it takes to develop tlis granuilomlaif, indeed, it is a specific graiiulona. One or txio ofitiur cases, as I iiien-tionie(l hefore, hax e a ridiculously sIiiall exposure, aii(l I asstunie, fromthe sini-le laiiii) hbeitg hroketi, olle coulddcxll chip lesioni. I do kiioxvtwxxo of our cases developed ill m1enl xvhose jo1) it xx-as to hreak upl) aniddestrov the rejecte(d fluiorescenit tuhes. Tlese tuhes xxvre )ut iilto a Oigiron0 harrel, and(i a man stood oix ei it aiid hiroke tIlelii upl) xvitli anl i-onpipe. They, ioif coulrse, hiad Imassive exposurs.

180 (;EO)R(;E \. \WRI(HT

Ihcideltally, the lamiii) indlllstrv in'w has a fltlrescelnt P)o)\\ er perfectliad(lcqCoiate in all respects, wNlhilhl (ho)s I1ot contain l)ervIlilm. It -\ill beinterestig to see if xx e still get granilomia fromi those lamiii) plants.

Industrv is sin l)ervllitim it is a very x i(le lx seti material a

very critical one in nor p)reseiit- e(colycnoniv and( I tliliik it is a shiam11e thatit has heen inicriminlated( So xv i(ldlv (0n stic h a teutons hasis, l)Ccause a

lulmll)er (of iuln(tistries arc refu.sinigioox to manufacture sclnCh imp)rtant iteml1sas hei-N 111m C)1)l)1pr., ad(I herv Iliutm steel.

Thrte fluOr-escent lamill) industrv, the neon Xign industrv, *Lhe v%ario(u)shaxvv metal casting inidinistb ise, ilmake uise (o) loeryllinml comillounds, and(I Imight sav it is, if not the 1110st critical, at least one of the Imiost criticalelm vs u.sedl inl atomlic enlergy pro(lndction andl, for that reason is a verxcritical material and cannot he ahandmhed to(lav.

Nxoxx (lo they wheeze Those xho heco me extremelx ill and hav -e

very severe sxymaptoms (1() xwhecze. TIhose wxxlo haxve the svx(nrome, in giienral,(10 not xheeze unitil thev reach thleir terminial plhase. I thilnik the x\-leezill(

probahly represents early congestive failure, because xxe haxve ilot beeihble to aholislo thle xxheezing 1! the tise of ilnhalation anld the otther hling

xx hich commonnlOIv xx-ork. in hronchial spasm or imntucosal eeledema.