Thorax (1954), 9, 46.

PULMONARY MANIFESTATIONS IN THE DIFFUSECOLLAGEN DISEASES

BY

PHILIP ELLMAN AND LEON CUDKOWICZFrom the Rheumatism Unit, St. Stephen's Hospital, London, the Plaistow Hospital Chest Unit, London,

and the Department of Medicine, Dorking General Hospital

(RECEIVED FOR PUBLICATION MAY 28, 1953)

The aetiology of the diffuse systemic collagendiseases, embracing rheumatoid arthritis, sclero-derma, dermato-myositis, polyarteritis nodosa,and disseminated lupus erythematosus still re-mains obscure. The need persists for a widerconcept of their clinical picture, with less emphasison one particular system. Ellman (1947), inrespect of rheumatoid arthritis, suggested " rheu-matoid disease" as a more comprehensive desig-nation in view of the protean clinical manifesta-tions in certain of the more acute cases.Among the visceral manifestations of rheu-

matoid disease attention has already been drawnto the co-existence of joint and lung lesions(Ellman, 1947; Ellman and Ball, 1948; Hart,1948; Schlesinger, 1949; Leys and Swift, 1949),which have been regarded as hypersensitivitymanifestations in the sense suggested by the workof Rich and Gregory (1943).

Experience of the collagen diseases leads to therecognition of certain distinct clinical patterns,which histopathology fails to differentiate.Banks (1941), Rich (1946), Spuhler and Morandi

(1949), Miller (1949), and Kampmeier (1950)emphasized the unity of vascular pathologyevident in so wide a variety of clinically dissimilarconditions as disseminated lupus erythematosus,polyarteritis nodosa, dermato-myositis, sclero-derma, temporal arteritis, and the rheumaticdiseases. This clinical nosology is founded uponthe local or generalized manifestations of anapparently uniform and diffuse arteritis. Thebasic vascular lesion is regarded as a result offibrinoid degeneration of the ground substance ofthe arterial wall, leading to progressive occlusionor to aneurysmal dilatation of the vessel wall, withsecondary cellular infiltration and ischaemicfibrosis of the dependent structures or organs.Banks (1941), Klemperer, Pollack, and Baehr

(1942), Stokes, Beerman, and Ingraham (1944), andBaehr and Pollack (1947) postulated a unitaryconcept for the widely differing clinical mani-

festations of collagen disease, a view contested,however, by Kellgren (1952).The similarity of the histopathology of these

diseases may indicate a common pathogenesis.The various experimental studies of Bahrmann(1935), Rich (1942), and Rich and Gregory (1943),in which the injection of histamine or of a foreignprotein induced a necrotizing arteriolitis in theexperimental animal, sometimes accompanied byan acute carditis with myocardial Aschoff bodyformation, suggest that induced vascular hyper-sensitivity leads to necrosis of the vascular walland reactive cellular infiltration. This work lendssome support to the unitary theory of the under-lying pathogenesis, but fails to elucidate the iden-tity of the aetiological factors and does not explainthe curious specificity of the manifestations in sodiverse a group as the clinically separated collagendisorders. The different distribution of the majorlesions in these diseases suggests an undue tissuesusceptibility, primarily in the structures derivedfrom the mesenchyme or, perhaps, a geneticallydetermined tissue reaction pattern to a commonaetiological factor. The protean manifestationsof the vascular lesions frequently mask thediagnosis in the early stages. The clinical find-ings predominating in any one system or organoccasionally bring the patient to various out-patient departments (Bywaters, 1949) where thetrue nature of the widespread systemic disease maynot at first be apparent. Platt (1949) emphasizedin that respect the difficulty of differentiating be-tween a Type I nephritis and polyarteritis nodosa,and Miller (1949) mentioned the frequency of aperipheral neuropathy in polyarteritis nodosawhich introduces its own difficult problems indifferential diagnosis.Pulmonary manifestations in diffuse collagen

disorders are not uncommon and changes varyingfrom pleural effusions, partial consolidation,widespread reticulation, miliary mottling tochronic fibrosis and sclero-cystic lung disease have

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been described in the rheumatic diseases (Cheadle,1888; von Glahn and Pappenheimer, 1926;Masson, Riopelle, and Martin, 1937; Hadfield,1938; Gouley, 1938; Harkavy, 1941, 1943;Rakov and Taylor, 1942; Baggenstoss and Rosen-berg, 1943; Gregory and Rich, 1946; Jensen,1946; Klemperer, 1948; Ellman, 1947; Ellmanand Ball, 1948; van Wijk, 1948; and Lees, 1952);in polyarteritis nodosa (Weir, 1939; Elkeles, 1944;Miller and Daley, 1946; and Bergstrand, 1946);in disseminated lupus erythematosus (Tumultyand Harvey, 1949); and in scleroderma (Finlay,1891; Kraus, 1924; Matsui, 1924; Murphy,Krainin, and Gerson, 1941 ; Linenthal and Talkov,1941 ; Weiss, Stead, Warren, and Bailey, 1943;Jackman, 1943; Bevans, 1945; Getzowa, 1945;Goetz, 1945; Dostrovsky, 1947; Baehr andPollack, 1947; Lloyd and Tonkin, 1948;McMichael, 1948 ; Wigley, Edmunds, and Bradley,1949; Church and Ellis, 1950; Spain and Thomas,1950; Sante and Wyatt, 1951; Hayman and Hunt,1952).

It is the puirpose of this paper to describe theclinical and radiological pattern of some pul-monary manifestations experienced in a variety of

TABLE IANALYSIS OF PRESENT SERIES

init- Clinical Radiological MainNo. |it- Age Sex Diagnosis Lung Respiratoryials iagnosis ~Manifestations Symptoms

1 A.S. 36 M Scleroderma Fine miliary Increasingmottling dyspnoea

2 B.R. 66 M Scleroderma Enlarged pul- Increasingmonary ar- dyspnoeateriet

3 K.R. 63 F Scleroderma Bilateral pleu- Dyspnoearal fibrosis

4 S.W. 31 F Dissemina- Left pleural Severe dysp-ted lupus effusion; bi- noeaerythema- lateral pleuraltosus fibrosis

5 V.A. 38 F Dissemina- Bilateral pleu- Exertionalted lupus ral fibrosis dyspnoeaerythema-tosus

6 A.E. 41 F Polyarteritis Miliary lung Attacks ofnodosa infiltration "asthma"

right upperlobe

7 D.E. 47 F Polyarteritis Increased vas- Attacks ofnodosa cular mark- "asthma"

ings; finemottling ofupper zones

8 J.S. 63 M Rheumatoid Left pleural Dyspnoeadisease effusion

9 J.D. 50 F Rheumatoid Right basal Severedisease opacity dyspnoea

10 R.G. 58 F Rheumatoid Basal pleural Exertionaldisease fibrosis dyspnoea

D

collagen diseases; to evaluate the response totherapy of the lung changes; and to review theseexperiences in the light of those recorded in theliterature. An attempt has also been made tointerpret these lung manifestations in terms ofischaemic changes secondary to pulmonaryvascular occlusions.

MATERIALThe present 10 cases represent a typical range

among a larger series of patients, who have comeunder the care of one of us (P.E.), falling into theseparate groups of the collagen diseases, and inwhom the pulmonary features were of majorimportance.

CLINICAL RESPIRATORY MANIFESTATIONSIN SCLERODERMA

The significant respiratory symptom in the firstthree patients was increasing dyspnoea, occurringafter the disease as a whole had already beenrecognized. All showed typical sclerodactylia,telangiectasia, and widespread skin sclerosis bythe time they became short of breath. In the firstcase it was not until the development of skinchanges over the thorax in the fourth year of thedisease that the effort of breathing became mani-fest. In the second and third patients dyspnoeawas experienced with the development of pleuralfibrosis at an even later date. There was no puru-lent sputum, and there were only a few variablephysical signs. With the development of thedyspnoea, chest expansions and vital capacitieswere found to be reduced. In the first patient thelatter fell from 4.2 to 2.6 litres within 18 months.Cyanosis or polycythaemia were not observed andno consistent laboratory findings were seen inrespect of alkali reserves or serum electrolytes.

RADIOLOGYCASE 1.-The radiographs of the lungs as from the

fourth year of the disease showed a progressivelyincreasing peripheral mottling spreading from thebases and hila towards the apices, leaving the latterfree. Fine honeycombing was present at the rightbase.CASE 2.-In the latter three years of this patient's

life the pulmonary arterial markings, particularly inthe right lower lobe, became increasingly more promi-nent (Fig. 1). A tomograph of the pulmonary arteryin the right lower lobe suggested early aneurysmaldilatation. The basal pleurae were thickened andadherent to the diaphragms.CASE 3.-In the sixteenth year of this patient's ill-

ness bilateral pleural thickening and increased vascularmarkings became visible. While receiving treatmentwith 3-hydroxy-2 phenlycinchoninic acid (H.P.C.).

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4PHILIP LLLMAN anid LEON CUDKOWICZ

diminished urinary chloride output, and a rapid risein serum sodium chloride.

Stopping A.C.T.H. rapidly restored the urinarychloride output, and was followed by a considerablespontaneous diuresis which caused the signs of hyper-volemic cardiac failure to subside.

In the interval of one year between the second andthird admissions in 1952 considerable cardiac enlarge-ment (Figs. 1 and 3) had taken place, suggestive ofboth right ventricular hypertrophy with pulmonaryhypertension and pericardial involvement. Theelectrocardiogram, the paradoxical venous neck pulse,and the inspiratory diminution in peripheral pulsevolume lend clinical support to the diagnosis of peri-cardial constriction.

Bilateral basal crepitations were audible, but theradiograph of the lungs at this stage showed littlechange in the fine nodular pattern which had been seenduring the previous admission (Fig. 2). A bronchogramwas normal.A course of 100 mg. of cortisone daily by mouth

produced no salt-and-water retention, and subjectiveimprovement was noted on the tenth day of the course.The thoracic skin was much looser and the vital capa-city increased by 0.8 litres. There were no changes inserum electrolyte levels, and the urinary chloride out-put increased slightly. At the end of the course ofcortisone occasional crepitations were heard, and therewas no change in heart size or lung pattern. Thepatient remained comparatively unchanged for threemonths and was able to enjoy a caravan holiday for

FIG. 1.-Case 2: scieroderma (twentieth year of disease). Radiograph five weeks.showing cardiac enlargement and prominent pulmonary arteries,particularly the right.

250 mg. thrice daily, the patient developed a rightmiddle lobe abscess and interlobar effusion, whichresolved after large doses of penicillin and cessationof H.P.C.

CLINICAL RESPONSES OF LUNG LESIONS TO TREATMENTCASE 1.-An ex-R.A.F. N.C.O., aged 33 years, was

admitted under the care of one of us (P.E.) on threeseparate occasions.On his first admission in 1950 there was no cardiac

enlargement, but a palpable impulse in the pulmonaryarea was noted.A course of A.C.T.H., 100 mg. daily for 21 days,

was given. While there was some evidence, both sub-jectively and objectively, of a decrease in skin tight-ness and improved mobility of the fingers, the radio-logical opacities in the lungs remained unchanged.The vital capacity was not influenced.On his second admission in 1951 3-hydroxy-2

phenylcinchoninic acid, 1 g. a day, had to be dis-continued on the eighteenth day on account of flatu-lence, anorexia, and later diarrhoea. The clinicalresponse to this substance was inconclusive and the -lung changes remained uninfluenced.A second course of A.C.T.H. had to be abandoned

on account of a rapid rise in jugular venous pressure FIG. 2.-Case 1 scieroderma (fifth year of disease). Lower zone ofand bilateral basal crepitations, hepatomegaly, a bightlung showing prominent pulmonary artery and fine" honey-andbiaterabasa creptation, heptomegly, a combing" at base

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CASE 2.-A man aged 66 years, whose sclerodermastarted at the age of 44, developed exertional dyspnoeain the eighteenth year of his illness, which a year laterbecame aggravated by angina of effort and slighthaemoptysis. He manifested obvious sclerodactylia,widespread skin sclerosis, multiple telangiectasia, andsome dysphagia for solid food.The lung fields at this stage showed a very large

right pulmonary artery and bilateral pleural fibrosis.In the twentieth year of the disease the above-men-tioned symptoms became worse and the heart sizeincreased. The apex beat was in the mid-axillary line.The blood pressure was 220/110 mm. Hg. The electro-cardiogram suggested a right bundle branch block, andcardioscopy indicated that although there was someright ventricular enlargement most of the increase insize of the heart was due to left ventricular hyper-trophy.

Cardiac catheterization was undertaken at Hammer-smith Hospital at this stage by Professor J. McMichael.The right auricular pressure was -2 mm. Hg, and theright ventricular and pulmonary arterial systolic pres-sure 50 mm. Hg. These pressures were regarded asbeing compatible with systemic hypertension.

After repeated episodes of congestive heart failurethe patient died in the twenty-second year of his illness.

Unfortunately a necropsy could not be obtained.Tomography (Fig. 3) showed that there was aneurysmaldilatation of the right main pulmonary artery.

CASE 3.-K.R., a housewife, aged 63: this patient'slung features, particularly the basal fibrosis, remaineduninfluenced by prolonged courses of A.C.T.H. orcortisone. While receiving 750 mg. H.P.C. she devel-oped a right middle-lobe abscess, which necessitatedhigh doses of penicillin and cessation of H.P.C. onthe thirty-fifth day.

FIG. 4.-Scleroderma: radiograph of the left lung showing increasedvascular marking and small cystic areas in midzone.

FIG. 3.-Case 2: scleroderma. Tomograph ofright lung showing greatenlargement of pulmonary artery.

The patient tolerated H.P.C. very well and showedobjective improvement. A gangrenous scab on theright middle finger separated and the skin healedcompletely, in spite of having been present for twoyears.

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In addition she had suffered from intractable diar-rhoea over the previous 19 months, having as manyas 20 stools a day. The frequency of the stools andthe hypochromic normocytic anaemia with which thiswas associated showed no improvement on eitherA.C.T.H. or cortisone. While on H.P.C. the stoolssoon became well formed, and on the sixteenth dayof the course they were fewer than three a day.Four months after the course of H.P.C. the patient

still had no further diarrhoea, and her stools, two aday, were normal. The lung fields now showed wide-spread reticulation and areas suggestive of sclerocysticchanges (Fig. 4).

RESPIRATORY MANIFESTATIONS INDISSEMINATED LUPUS ERYTHEMATOSUSThe three cases falling into this group presented

acute pulmonary disease at the inception of theirillness.

CLINICAL COURSECASE 4.-A typist, aged 31, was seized by a sudden

severe inspiratory pain in the left chest, becamerapidly dyspnoeic, and developed a high pyrexia. Inaddition the left knee became swollen. A period ofobservation showed the pyrexia to be uninfluencedby chemotherapy, and attempts at thoracentesis wereunsuccessful. The diagnosis of pericarditis was made,and a shadow in the region of the left lower lobe,with some elevation and poor excursions of the leftdiaphragm, suggested either a left lower lobe atel-ectasis or a pulmonary infarct.

Atelectasis was the more likely, since the shadowhad never resolved even 13 years after this episode.The patient has had a series of remissions since then,and while being investigated for recurring knee effu-sions in 1948, it was thought that the left lower-lobebronchi were dilated. Her vital capacity is now only2 litres. She remains dyspnoeic at rest, and the leftdiaphragmatic excursions are very restricted.CASE 5.-L.A., a housewife, aged 38, had an acute

onset resembling the above. The illness started witha sudden pyrexia of 104° F., rigors, dyspnoea, andpain in the lower dorsal spine and both sub-costalmargins.The patient appeared cyanosed, and the dyspnoea

necessitated nursing in an oxygen tent. Blood cul-tures remained consistently negative, and the illnesswas in no way influenced by high doses of sulphon-amides or penicillin. A shadow at the right base wasregarded as being due to a sub-phrenic abscess, andthis was explored surgicaliy on the seventeenth day ofthe illness, but no pus was found (Fig. 5). In spiteof some cyanosis and cough there was no sputum.During the sixth week of the disease the patient wastransferred to a chest unit, still extremely ill. Clinicalexamination of the chest at this stage showed dull-ness and diminished air entry at both bases. Radio-graphs showed a diffuse opacity at the right base andmottling in the area of the left lower lobe. Onscreening it was noted that the left diaphragmatic

movements were impaired by an opaque mass underthe left dome. The left subphrenic space was exploredsurgically and again no pus was found. The spleen.however, was considerably enlarged.

This patient gradually improved without any speci-fic therapy (Fig. 6). The acute lung lesions in thiscase were probably instances of pneumonitis" as de-scribed by Rakov and Taylor (1942) associated withdisseminated lupus erythematosus or variants ofrheumatoid disease (Bywaters, 1949), since the facialerythema of lupus erythematosus appeared threemonths later.

RESPONSE OF LUNG LESIONS TO TREATMENTAn opportunity to observe the response to cor-

tisone and A.C.T.H. occurred in Case 4 during anacute flare-up in the twelfth year of the patient'sillness.CASE 4.-The patient was admitted to St. Stephen's

Hospital under the care of one of us (P.E.) with ahigh swinging fever, tachypnoea, and with swollenknees. She was very wasted, her face and her breastsshowed erythematous patches and many small telangi-ectases. Her lips and fingers were cyanosed. Therespiratory movements were almost entirely thoracic.Both bases appeared to be dull, and there was nobasal air entry. Rales were present throughout bothlung fields. With the exception of a tachycardia therewere no abnormal findings in the cardiovascularsystem.The temperature often reached 104° F., but blood

cultures were sterile. A polymorphonuclear leuco-cytosis of 14,000 was present. A course of penicillinon empirical grounds, and a similar course of sali-cylates had no effect on the course of the illness. Asternal marrow puncture yielded lupus erythematosuscells.

Radiography of the chest at this stage showed eleva-tion of the diaphragm, bilateral basal reticulation.and apparently a right basal effusion (Fig. 7). Thora-centesis, however, produced no fluid.

In view of the grave condition of the patienit shewas given a course of A.C.T.H. (90-60 mg. per day)which had to be discontinued on the ninth day inspite of subjective improvement, because of a purpuricrash with raised blebs over the lumbar spine andbuttocks. Her temperature rose at once to 103° F.and she became very ill and toxic.

It was then decided to try the effect of 100 mg. ofcortisone per day. Her rash disappeared rapidly. Thetemperature gradually settled and the patient, afterbringing up some bloodstained sputum for a few days.improved to a very remarkable degree. The lungchanges, however, remained both clinically and radiologically the same. The use of cortisone in this in-stance was probably life-saving, but its action is notunderstood.The two patients just discussed subsequently

developed episodes of joint effusions and thetypical facial erythema. Exertional dyspnoea is

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FIG. 5.-Case 5: disseminated lupus erythematosus. Right lung FIG. 6.-Case 5: the same, showing resolution of the right para-showing para-cardiac shadow cardiac shadow.

Ficv. 7.-Case 4: disseminated lupus erythematosus postero-anterior radiograph of chest showing elevation of diaphragm,right basal pleural effusion and reticulation at the bases, particularly the left.

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their main disability. Radiography in eachinstance shows marked basal pleural thickening,and diaphragmatic movements, particularly inCase 4, are impaired.

THE RESPIRATORY MANIFESTATIONS OFPOLYARTERITIS NODOSA

The outstanding earliest respiratory symptomsof the seventh and eighth patients were attacks ofwheezing and the production of frothy sputum.

CLINICAL COURSECASE 6.-A housewife, aged 41, four years after

childbirth developed attacks of wheezing, and repeatedbouts of diarrhoea, with blood and slime in the stools,occurring more or less simultaneously, began to in-capacitate her. This was soon followed by loss ofweight, continuous malaise, and mild pyrexia, un-influenced by sulphonamides. A radiograph at thisstage showed a right upper zone miliary pattern (Fig.8). A blood count showed: Hb 92%, R.B.C. 4,600,000,W.B.C. 33,000 (eosinophils 61%), E.S.R. 41.Although treated on a sanatorium regime, no im-

provement in the severity of the illness or frequencyof the asthmatic attacks could be achieved.Widespread joint pains, particularly affecting the

knees, shoulders, wrists, and fingers, and crops ofred spots on the skin of the face, chest, and fingersdeveloped later, in addition to the bowel and chestsymptoms. A diagnosis of polyarteritis nodosa wasmade on clinical grounds.

Subsequently she went to Oxford, and after a periodof observation at the Radcliffe Infirmary under thelate Sir Arthur Hurst and Professor Witts, a courseof N.A.B. was tried, which produced some benefitand a drop in the eosinophil count. No evidence ofgastro-intestinal infestation could be found. Althoughthe diarrhoea improved somewhat following thecourse of N.A.B., the asthmatic attacks persisted. Insubsequent years she was found to be sensitive to mosthouse dusts, but desensitization was never accomp-lished.The last radiograph showed resolution of the miliary

pattern in the right upper zone (Fig. 9).CASE 7.-A housewife and part-time factory hand,

aged 47, had as first symptoms attacks of " asthma "in increasing frequency, which responded to ephedrineand adrenaline at first. Two years following the onsetof these attacks she lost some 6 stones in weight, andbegan to experience paraesthesia, and later numbnessin her hands and feet. Her stools became loose,containing blood and mucus, but there was no colicor tenesmus.

She was admitted under the care of one of us (P.E.).The chest expansion at first was good, the lung fieldswere hyper-resonant, movements at the bases werediminished, and coarse rales were audible at the bases.A chest radiograph revealed a miliary or fine nodu-

lar infiltration of the upper zones. The leucocytecount was 27,000 per c.mm. with 54% eosinophils.

No pathogens were found in the faeces. Biopsy of apectoral muscle was normal.

In the central nervous system there was evidence ofhypoalgesia of all fingers with weakness of the musclesof the hand and forearm. The anterior tibial and theperoneal muscles were weak and wasted. Posteriorcolumn proprioception was impaired in toe and anklejoints.

Although the muscle biopsy was negative thispatient was regarded as having polyarteritis nodosawith an eosinophilic lung infiltration, and she wastreated with a course of neoarsphenamine. The re-sponse to this was disappointing and she went down-hill rapidly, developing a right knee effusion, a leftHorner's syndrome, and finally succumbed to rapidcongestive heart failure.The post-mortem examination showed widespread

myocardial fibrosis and patchy consolidation through-out both lungs. The blood vessels in the lungs showedonly simple intimal thickening.

RESPIRATORY MANIFESTATIONS ASSO-CIATED WITH RHEUMATOID DISEASEThe last three patients in this series suffered

from rheumatoid disease for some years beforethe onset of respiratory symptoms, which differedin their clinical course and severity.

CLINICAL COURSECASE 8.-A retired jeweller, aged 63, had a history

of rheumatoid disease for 17 years, with the principalarthritic manifestations in the knees, wrists, andankles. In the last seven years of his illness exacerba-tions of joint swellings were ushered in by cough,dyspnoea, and purulent sputum. While these attacksof " bronchitis " lasted his joints were always swollenand painful, and remissions with a fall in the E.S.R.occurred as the chest symptoms subsided. In theeighteenth year of his disease he was admitted underthe care of one of us (P.E.) on account of increasingdyspnoea, loss of weight, swollen and painful joints,crops of nodules, and a painful left eye.On examination the patient appeared very wasted

and pale. He was dyspnoeic at rest. The left eyeshowed a patch of episcleritis on the lateral cornealscleral margin with a raised phlycten in the centre.

Painful nodules, the size of cherries, covered theback of his head, the left olecranon process, the ulnarborders of both forearms, and the ischial tuberosities.The wrist and the metacarpo-phalangeal and kneejoints were very swollen.The heart was enlarged, with the apex beat 4+ in.

from the mid-sternal line. The sounds were normal.and the blood pressure was 105/65 mm. Hg. Thepulse rate was 45, and an electrocardiogram showed2:1 heart block, with right axis deviation.

In the lung fields there were dullness and no airentry at the left base, and bilateral rales.

Radiography of the chest confirmed the cardiacenlargement, and cardioscopy showed this to be dueto right ventricular hypertrophy. There was an effu-

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FIG. 8.-Case 6: polyarteritis nodosa. Right upper zoneshowing analmost miliary pattern.

FiG. 10.-Case 8: rheumatoid disease with widespread rheumaticnodules. Postero-anterior radiograph of chest after prolongedcortisone therapy, showing persistence of left pleural effusion.

FIG. 9.-Case 6: polyarteritis nodosa. Right upper zone four yearslater, showing resolution of miliary pattern.

FRo. I 1.-Case 9: rheumatoid arthritis. Postero-anterior radiographof chest showing right para-cardiac shadow with increased basalreticulation.

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sion at the left base (Fig. 10). Aspiration of fluidfrom the left base showed a transudate. No malig-nant cells were seen, and cultures were sterile. Aguinea-pig inoculation remained negative. Nothingabnormal was found in the urine, and renal functionwas normal. The E.S.R. fluctuated throughout hisstay between 80 and 100 mm.

After a period of observation he was given digitalisand also "mersalyl" twice weekly. This had noeffect on the pleural effusion and the adventitioussounds.

Accordingly he was given cortisone for 71 days,starting with 100 mg. per day. On this regime thejoint swellings and nodules regressed and the dys-pnoea became less distressing. The effusion remaineduninfluenced. There was no change in serum electro-lytes, and at no time was oedema or a rise in jugularvenous pressure noted.

Four months after cortisone was stopped the physi-cal and radiological signs were unchanged.

CASE 9. A housewife, aged 50, in the six yearspreceding an acute chest illness, had episodes of jointpains and swellings, leaving a limited range of move-ment, with stiffness at both wrists, prominence ofthe metacarpo-phalangeal joints, with early ulnardeviation of both fingers. The left knee could not befully extended.

She was admitted to hospital with a pyrexia of104° F., dyspnoea, and joint pains, without obvious

FIG. 12.-Case 9: the same, showing resolution in seventh montof illness.

swellings. The only abnormalities outside the loco-motor system were crepitations at the bases of bothlungs.A chest radiograph showed a right paracardiac

shadow with increased basal reticulation (Fig. 11).The E.S.R. was 11 mm. A white blood count showeda polymorphonuclear leucocytosis of 13,000 per c.mm.All blood cultures and agglutination reactions werenegative. A search for tubercle bacilli and all othertests were negative, and the pyrexia did not respondto chemotherapy.

In the second month of the illness a course of sali-cylates was started, which at first controlled the pyrexiarapidly. At the end of the second month the tempera-ture climbed again and the E.S.R. was 52 mm. Whiteblood cells were 6,000 per c.mm. with a normal differ-ential count.A chest radiograph showed no change in the right

basal shadow. The cardiovascular system appearednormal.

In the fourth month the E.S.R. had climbed to86 mm. and the patient began to improve. The pyrexiasettled slowly and the shadow at the right base, aswell as the basal reticulation, resolved, leaving noabnormal signs at the time of her discharge at thebeginning of the seventh month of the illness (Fig. 12).CASE 10.-A housewife, aged 58, developed bilateral

pleural effusions in the sixth year of her illness. Thiswas ushered in with widespread arthralgia, loss ofweight, and high swinging fever. With the establish-ment of the effusion the wrists and the metacarpo-phalangeal and proximal phalangeal joints becameswollen, and she also developed severe left episcleritis.The episcleritis and the effusions gradually subsidedand she is now left with bilateral basal pleural fibrosis,and a typical rheumatoid arthritic lesion.

DISCUSSIONThe respiratory manifestations in these 10 cases

seemed to present rather different clinical andradiographic patterns in the four diagnosticgroups. In the three cases of scleroderma, pro-gressive dyspnoea developed late in the course ofthe disease, with radiographic changes at thebases of the lungs in two cases, and an enlargedpulmonary artery and evidence of pleural fibrosisin the other: the course was unaffected by treat-ment. In the two cases of disseminated lupuserythematosus, dyspnoea developed at the begin-ning of the disease with basal shadows in theradiographs; the course was remittent, but irre-versible lung changes developed and were un-influenced by treatment. In the two cases of poly-arteritis nodosa, asthma was the presentingrespiratory symptom, and radiographically a finemottling was seen in both upper zones in one caseand in the right only in the other; dyspnoea wasprogressive, and one of the patients died from

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pulmonary heart disease. Of the three cases ofrheumatoid disease, one had unilateral and anotherbilateral pleural effusions, and the other an acutefebrile illness with dyspnoea and a right para-cardiac shadow; the lung changes were unaffectedby treatment.

Cortisone, although life-saving in Case 4, cer-tainly had no effect on the clinical and radio-graphic signs seen before or subsequently. It isour belief, therefore, that these lung changes wereprogressive in nine patients and self-limiting in thetenth case.

THE LITERATURE IN RELATION TO PULMONARYSCLERODERMA

Finlay (1891) recognized the association betweenpulmonary fibrosis and generalized scleroderma.Matsui (1924) described three patients with pul-monary fibrosis and scleroderma in whom thetotal pulmonary artery bed was reduced, and theright ventricle enlarged. Kraus (1924), in a histo-logical study of sclerodermatous lungs, observedsome pulmonary emphysema with right ven-tricular hypertrophy. The alveolar septa wereincreased in width and " arteries " showed markedintimal proliferation. Their tunicae mediae wereinfiltrated with round cells. The first report ofradiographic changes in sclerodermatous lungswas made by Murphy and others (1941), whorecognized fibrosis spreading from the hila. Bron-chography was normal. Linenthal and Talkov(1941) and Wigley and others (1949) alsodescribed cases of scleroderma in which pul-monary fibrosis preceded skin lesions. Weiss,Stead, Warren, and Bailey (1943) found mottlingof the lungs in six out of nine cases. At necropsyalveolar fibrosis with reduction in calibre of thebronchi and pulmonary arteries was seen. Theyalso described myocardial involvement.Getzowa (1945) gave a more detailed patho-

logical account of the lung lesions in sclerodermaand described diffuse fibrosis of the alveolar wallwith thickening, leading to obliteration of capil-laries and alveolar spaces. Large coalescing isletsof compact fibrous tissue alternated with areas ofhyaline degeneration of the alveolar walls. Thelatter were sometimes thinned and ruptured,causing cyst formation under the visceral pleura.Getzowa believed that the collagen change pre-cedes the obliterative vascular changes. Goetz(1945) emphasized the interstitial nature of thepulmonary fibrosis, and also referred to vascularnarrowing. Baehr and Pollack (1947) regardedthe primary abnormality in scleroderma as anendarteritis, with fibrinoid necrosis of the vesselwalls and of the surrounding collagen tissue.Macroscopically, sclerodermatous lungs were

found to be firm, inelastic and reduced in size.Dostrovsky (1947) described "pulmo-sclerosiscystica" with scleroderma occurring later in thedisease. Pagel, Woolf, and Asher (1949) did notthink that the lung pathology was specific. Lloydand Tonkin (1948) described the clinical sequencein scleroderma lung disease as exertional dysp-noea, dry cough, and reduction in vital capacity.Radiologically this was associated with diffusefibrosis. Church and Ellis (1950) referred tofibrocystic changes in the lungs, and foundbronchiectasis in one case, and migrating lobarconsolidation, not responding to chemotherapy, inanother. They regarded the fibrosis as the resultof pulmonary endarteritis. McMichael (1948)mentioned a case of widespread scleroderma withdiffuse fibrosis, particularly accentuated at theright apex. In the last five years of the patient'sillness dyspnoea became crippling, and the electro-cardiogram showed right ventricular hypertrophy.Spain and Thomas (1950) recognized radiologic-ally cystic lesions and extensive fibrosis of thebasal pleurae. They thought that dyspnoea wasdue to impairment of gas exchange at the level ofthe alveoli, as no evidence of ventilatory insuffi-ciency could be found. They noted fibrousreplacement in the musculature of smallerbronchi, and referred to Bevans (1945), who notedmarked narrowing of " pulmonary " vessels nearthese bronchi, notably in the smaller arteries.The literature, therefore, recognizes diffuse

pulmonary fibrosis, fine nodulation and cyst for-mation, as well as pleural fibrosis as the mainabnormality in this disease. Bullous emphysemahas not been described, and according to Baehrand Pollack (1947) the lungs, if anything, weresmaller than normal. Interstitial thickening ofthe alveolar basement membranes is repeatedlyemphasized. Although Church and Ellis (1950)referred to true bronchiectasis in one of theircases, dilatation of the bronchi does not appearto have been emphasized elsewhere, and it was notfound in the bronchogram carried out in Case 1.The major clinical symptom in the patientsrecorded was progressive dyspnoea.

THE LITERATURE OF LUNG CHANGES IN DIS-SEMINATED LUPUS ERYTHEMATOSUS

Multiple opacities in the lungs of patients withdisseminated lupus erythematosus were noted byTumulty and Harvey (1949). Baggenstoss (1952)believed that no pathognomonic lesions had beendescribed in the lungs, although clinically pul-monary involvement was remarkable for itsfrequency and atypical course. Rakov andTaylor (1942) described a chronic interstitialpneumonitis leading to atelectasis and respiratory

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PHILIP ELLMAN and LEON CUDKOWICZ

failure. They found basophilic mucinous oedemaof the alveolar walls, peribronchial and peri-vascular tissues, and alveolar haemorrhages.Baggenstoss believed that these interstitial lesionsmight be of considerable significance in clarifyingatypical pulmonary symptoms in some cases ofdisseminated lupus. Robertson (1952), in a reviewof 58 cases of pleural effusion in adults over 40,found that four suffered from collagen diseases,and in one necropsy identified this as disseminatedlupus erythematosus.The acute symptoms at the onset of the disease

in Cases 4 and 5 of this series are perhaps a littleunusual, but the subsequent course, and in par-

ticular the exacerbation of similar illnesses laterin the course of the disease, as in Case 4, addssupport to the view that the lung lesions are clearlypart of the progressive disease process. The sub-sequent changes in the lungs were permanent.

THE LITERATURE OF POLYARTERITIS NODOSA AND

LUNG CHANGESThis disease was first described by Kussmaul

and Maier (1866). In discussing the pathologyMiller (1949) spoke of necrotizing panarteritiswith fibrinoid necrosis affecting all coats, andemphasized the fact that eosinophilia seems com-

mon only in patients who have asthma. Harkavy(1943) demonstrated vascular lesions in the lungsof asthmatics. Bergstrand (1946) referred to theresemblance of the vessels in asthmatic lungsto those in polyarteritis nodosa. Migratingopacities in the lungs of patients with poly-arteritis nodosa have been noted by Weir (1939),Elkeles (1944), and Miller and Daley (1946).

THE LITERATURE OF LUNG CHANGES IN

RHEUMATOID DISEASE"Rheumatic pneumonias " have long been

recognized in relation to rheumatic fever. Cheadle(1888), Naish (1928), Rabinowitz (1926), Muir-head and Haley (1947), and van Wijk (1948) spokeof lower lobe consolidation of variable duration.Paul (1928), Neubuerger, Geever, and Rutledge(1944) and Jensen (1946) refer to multilobarinvolvement. Von Glahn and Pappenheimer(1926) found arteritis in 20% of rheumatic feverlungs with concentric thickening of vessels, andrevascularization of the intima. Masson and others(1937) described an alveolar fibrin coagulum andwidened alveolar ducts lined by an eosinophilicmembrane. Gouley (1938) thought that chronicdiffuse fibrosis was a sequel to the lung involve-ment in rheumatic fever.Changes resembling those seen in rheumatic

"pneumonia" were produced experimentally byGregory and Rich (1946), who considered that an

anaphylactic angiitis affected the pulmonary capil-laries. While lung changes in rheumatic fever arewell known, the association of lung changes withrheumatoid arthritis has only recently been appre-ciated (Ellman, 1947; Ellman and Ball, 1948;Hart, 1948; Leys and Swift, 1949; Schlesinger,1949; and Lees, 1952). The radiographic picturevaried from basal consolidation to widespreadbilateral reticulation. Ellman and Ball (1948)recorded interalveolar exudation with collapse ofalveoli and thickening of the interalveolar septa intwo of their cases at necropsy.

Case 8 in the present series was perhaps unusualin that pleural involvement alone was suspected.Baggenstoss and Rosenberg (1943) and Raven,Weber, and Price (1948) have, however, recordedinstances of pleural nodulation associated withnecrobiotic nodules elsewhere. In Case 9 therewas basal consolidation, which remained un-influenced by chemotherapy, and ultimately re-

solved leaving no disability.Rich, in the 1946-47 Harvey Lectures, empha-

sized the overlap between the systemic collagendiseases, rendering the differential diagnosis notonly difficult but often impossible. Miller (1949)believed that the vascular changes were essentialto all these disorders, producing clinical featuresas variable as the Henoch-Schoenlein type ofallergy at one end of the scale, and chronic poly-arteritis nodosa at the other. While the vascularpathology is well established the curious speci-ficity of lesions in certain tissues remains un-explained. The vascular changes which have beendescribed in the lungs in all these diseases is ofinterest, in that the vessels involved need still to beproperly identified. Matsui (1924), Weiss andothers (1943), Bevans (1945), and Church and Ellis(1950) considered that the vascular changes inscleroderma were in the pulmonary artery. In thesame disease Kraus (1924) referred only to intimalproliferation in " small arteries "' near the alveolarsepta. Goetz (1945) spoke of " vascular "' narrow-ing. Von Glahn and Pappenheimer (1926)observed concentric thickening of " vessels " andrevascularization of the intima in rheumatic pneu-monias. It appears, therefore, that the identity ofthese vessels is by no means clear. In ordinarylung sections it is nearly impossible to distinguishbetween bronchial or pulmonary arterioles, unlessone of these circulations has been previously in-jected with a contrast medium too coarse totraverse the capillary beds. Using such a mediumit is possible to inject the bronchial circulationand study the intra-pulmonary distribution of thebronchial arteries (Cudkowicz and Armstrong,1951). In normal lungs the bronchial arteries

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DIFFUSE COLLAGEN DISEASES

supply all pulmonary supporting structures, thebronchial tree, interalveolar septa, visceral pleura,all intra-pulmonary nerves and plexuses, the lymphnodes at the hila, and furnish the vasa vasorum tothe pulmonary arteries.The pulmonary lesions of the systemic collagen

diseases appear to be confined to the pleura, theinter-lobular septa and the alveolar-supportingmembranes, the smaller bronchi and peribronchialtissues and, as in Case 2, to the walls of the pul-monary artery. This suggests that the wide,diffuse changes seen throughout both lung fields(at least in scleroderma) are in the exclusive terri-tory of the bronchial arteries, and that the lesionsrecorded by Bevans (1945) in the wall of smallbronchi affected occluded bronchial arteries. Totalocclusion of the bronchial arteries would deprivethe lungs and the visceral pleura of their onlyarterial blood supply at least until such time as ittakes for pleural adhesions to form, and to con-

vey new parietal pleural arteries into the occludedbronchial artery bed. This is seen in pulmonarytuberculosis (Cudkowicz, 1952). Miller (1949)believed that a panarteritis underlies the mani-festations of collagen disease. The lung lesionsin these diseases, because of their characteristicpathological localization, suggest involvement ofthe bronchial circulation in its wide distribution.As this circulation is responsible for the nutritionof all lung structures except the respiratory epith-elium of the alveolar capillaries, it is reasonableto suppose that the variable degrees of pulmonarysclerosis seen in scleroderma and disseminatedlupus have resulted from the deprivation of theonly arterial blood supply available to the support-ing structures of the lungs.

SUMMARYThe clinical and radiographical features of

lung involvement in 10 patients suffering from thesystemic collagen diseases have been described.The response of these lesions to treatment, includ-ing hormonal therapy, was very disappointing, andin only one instance was the lung disease self-limiting.The literature in respect of the pulmonary mani-

festations has been reviewed. Histologically,variable degrees of vascular occlusion have beenfound, probably in the territory of the bronchialarteries. The lung changes in this disease groupmay represent the effects of progressive pulmonaryischaemia resulting from the loss of a bronchialarterial blood supply.

We are indebted to Professor J. McMichael for hishelp in Case 2, to Professor L. J. Witts in Case 6, andto Dr. A. Wingfield and Mr. W. P. Cleland respec-

tively for referring Cases 4 and 5 to one of us. Finally,we should like to express our indebtedness to Profes-sors Sir Henry Cohen and Alan Kekwick for havingso carefully perused the manuscript, and to Mr. K.Moreman, A.R.P.S., for his reproduction of the radio-graphs.

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