POSTGRAD. MED. J. (1965), 41, 687.

Clinico- Pathological Conference

DIFFUSE PROGRESSIVE INTERSTITIAL FIBROSISOF LUNGS IN INFANCY

Held at the Royal Alexandra Hospital for SickChildren, Brighton, on Thursday,

November 19th, 1964.Chairman: MR. L. W. LAUSTE, M.B.E., T.D.,

M.D., B.Sc., F.R.C.S., M.R.C.O.G.Consultant Surgeon, Royal Alexandra Hospital for

Sick Children.MR. LAUSTE: Our guest speaker tonight is

Dr. Claireaux who is Morbid Anatomist at theHospital for Sick Children, Great OrmondStreet. He has recently been appointed to thatpost having been Pathologist at Queen Char-lotte's Hospital. He is an expert on neonatalpathology and takes a particular interest in lungdisorders. He is very well-known to pathologistsand paediatricians and I would like to extendto him a special welcome and thank him forcoming to take part in this Conference. I shouldlike to add that we are indebted to the NestleCompany who are giving support to this Con-ference and we do thank them for their gener-osity.

I will ask Dr. Mann to open the Conferenceand give details about two infants who weresiblings believed to be suffering from diffuseprogressive interstitial fibrosis of the lungs.DR. T. P. MANN: Mr. Chairman, it is appro-

priate that we should be discussing this conditiontonight because here we have an excellentexample of a clinico-pathological syndrome.Indeed, it is probably more this than an aetio-logical entity. This unique respiratory disorderwas first described briefly by Hamman andRich in 1935 as an acute and fatal affectionin adults. Since this original description, nearlythirty years ago, quite a considerable literaturehas been built up around this disorder. Themajority of reported cases have been adultsand the number of published examples mustnow be well over a hundred. The first accountof this condition in childhood was given byBradley from the United States of Americain 1956 who reported the clinical and autopsyfindings in a nine-year-old girl. Subsequentlyeighteen childhood examples of this syndromehave been published in the literature. Of theseeighteen, five have occurred in infants underone year of age and one of these is actuallyChristine, the first case we shall be consideringin a moment, (Mann, 1959). If, by the end of

this meeting, it is generally agreed that Chris-tine's brother, the second case to be presented,was also similarly affected-I might say herethat clinically this case does not conform to theaccepted clinical picture of diffuse progressiveinterstitial fibrosis of the lungs-but if, never-theless, you think that it fits into the samepattern then this will be the sixth example Iknow of occurring in the first year of life. It willalso be, as far as I am aware, the first instanceof sibling cases although this is now quitewell recognised in adults of the same parentage.Case No. 1.

Christine P. was admitted to this hospital inDecember 1953 at the age of seven months. Complaintswere food refusal, failure to thrive, paroxysmalcough and vomiting.

History: First child. Birth weight 6 lb. 8 oz. Twomonths before admission (age five months) coryzalasting two to three weeks. Simultaneously developeddry cough which slowly worsened and sometimes ledto vomiting. No whoop. Motions green during firstthree weeks of illness. Course of sulphatriad t-hreeweeks before admission.On Examination: Wasting, pallor, cyanosis, res-

piratory distress and repetitive cough (not likepertussis). Afebrile. Slight injection of throat andright tympanic membrane. Occasional added soundsover lungs. Liver normal in size. Admission chestX-ray: increased bronchial markings.

Clinical course: Steady deterioration in spite ofconsecutive courses of penicillin, chlortetracycline,erythromycin. Continuous oxygen required.Increasing pallor, cyanosis, dyspnoea and persistingdry irritative cough associated with progressive,diffuse, granular infiltration of lungs in serialradiographs. Body temperature normal except for aspike of 100'F. second day in hospital and range98°-100'F. just before death. Pulse range 100-180/min.respiratory rate varied between 30-80/min. Terminallyliver enlarged and neck veins 'became distended; noadded sounds heard over lungs. Died five weeks afterad-mission and three months after onset of symptoms.

Investigations: WR and Mantoux negative. Hb85-90%. WBC (8th day) 10,300. (polys 47%). (17thday) 14,200. (polys 64%), (29th day) 16,900 (polys.58%). Plasma Proteins: 6.9 g/lOOml albumin 4.5globulin 2.4. ESR (week before death) normal. ECG(four days before death) normal. No pathogens in

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POSTGRADUATE MEDICAL JOURNAL

serial nose and throat swabs. Virus studies not done.The clinical picture then was of a progressive suffo-cative pulmonary disorder with terminal right hear,tfailure. The following diagnoses were considered bythe clinicians during the baby's short stay in hospital:Pertussis, atypical virus pneumonia, miliary tuber-culosis, sarcoidosis, li.poid pneumonia, haemosiderosis.

Well, these then are the details of the firstaffected child. Nine years later, in February1962, a second child in this family was founddead in his cot. This was an infant aged fourmonths and here now are the details basedon a retrospective history obtained from theparents two years after the event. I should addthat the mother and father are intelligentpeople and reliable witnesses. Thus, when Ispoke to them on this occasion I found theywere able to recall accurately clinical detailsconcerning Christine's illness, nine years pre-viously.Case No. 2.

John P. Birth weight 7lbs. Forceps delivery(November 1961). Cord round neck three times.Mother well during this fourth pregnancy. Johnnever robust from birith. Very difficult with thebottle. One feed would run into next. Seemed fullafter only two ounces. During winter of 1961-62 giventwo courses of antibiotics for chest infections(appeared to parents to have a common cold on bothoccasions but general practitioner found signs inchest.) Baby never short of breath. Not "a wheezer".Cough never a feature even with chest infections.For three to four days before death faint cyanotictinge round eyes and over bridge of nose. Lipsnever blue as with Chris-tine. Parents were pres-sing for hospital consultation for day or so beforechild's death. Father gave last feed before going tobed. This as usual took a long time but not due todyspnoea. Infant found dead in his cot next morning.Family History: Following Christine's death two

normal children born, now aged eight years andfour-and-a-half years. Latter prone to bronchitis;chest X-ray September 1963-normal. Paternal unclesuffers from asthma. No other relatives with chesttrouble. No family history of sudden deaths ininfancy or childhood.

This, of course, was a Coroner's case and itwas fortunate that the post-mortem was con-ducted by Dr. Elliott because on seeing thesurname of this child he realised that theremight be a possible link with a previouslyremarkable case in a family of this name-Irefer, of course, to Christine just described.MR. LAUSTE: Thank you very much. Per-

haps now Dr. Elliott would be kind enoughto give the pathology on these two cases?DR. R. I. K. ELLIOrr: In both these children

macroscopic abnormalities were confined to thelungs, so for the sake of brevity I will giveonly the positive findings.Autopsy on the elder child was performed

by Dr. R. W. P. Johnson. There was a smallleft pleural effusion, but no adhesions on either

FIG. 1.-Lung from case 1 (Brighton) Christine P.Cut surface of lung under slight magnificationshowing reduction in number of terminal airspaces and great increase of connective tissuebetween them. x6.

side. The main bronchi contained a smallamount of mucopus. The lungs were voluminousand felt very firm and slightly nodular. Thecut surfaces showed many small white flecks,somewhat 'suggestive of miliary tuberculosis,against an almost solid background. Viewedunder a hand lens, the lung tissues appearedalmost solid, with a few air spaces scatteredhere and there l(Fig. 1). Although the relativeproportions of air spaces and stroma variedsomewhat from one area to another, this re-markable change was present in all lobes of bothlungs.The younger child, which I examined myself,

had a deformed chest, the antero-posteriordiameter being much increased, producing a"pigeon-breast" appearance. There were nopleural effusions or adhesions. The trachea andbronchi contained a little frothy mucus, notpurulent. Both lungs were enlarged, and heavierthan normal, with the same increase of solidtissue and reduction of air spaces seen in thefirst child. The changes seemed more severein the lower lobes than elsewhere, but as beforeall the lung tissue was involved 'to some extent.There was a slight increase in pericardial fluid

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FIG. 2.-Lung from case 1 (Brighton) Christine P.Sparse air spaces lined by cuboidal epithelium.Marked increase of interstital tissue. H. and E.x 95.

and the heart was slightly enlarged, mainly dueto dilatation of the right ventricle.

Turning to the histological findings, ithere waslittle of interest to report in organs other thanthe lungs, but one or two points need to bementioned. Neither child showed evidence ofpassive venous congestion in spleen or liver.Increased cellular infiltration in the portal tractsof the liver has been reported in some cases ofHamman-Rich syndrome, (Scadding, 1960;Davies and Potts, 1964), but there was no signof it in either of these. Knowing the familyhistory I was particularly careful to examinethe pancreas in the younger child; there was nosuggestion of fibrocystic change. Finally, com-parison of the heart muscle in the left and rightventricles showed, in the elder child, slighthypertrophy on the right side; in the youngerchild no appreciable change from normal; butthere was, as I have said, some dilatation of theright ventricle macroscopically. It is surprising,perhaps, that there should be so little change inthe heart in the presence of such gross damagein the pulmonary interstitial tissue.The histology of the lungs was not entirely

the same in both children; so I will describethe picture in the elder child in detail and thenindicate how the younger differed, the dif-

'1 a

I4

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FIG. 3.-Lung from case 1 (Brighton) Christine P.Hyaline membrane in air spaces. Mallory tri-chrome. x 95.

ferences being, I should add, of degree and notof kind; there can be no question that the samebasic abnormalities were present in both.The hand-lens view of the elder child's lung

showed solid tissue with a few air spacesirregularly scattered through it. Microscopicallythis solid tissue is highly vascular connectivetissue, full of ramifying capillaries and heavilyinfiltrated with inflammatory cells, mainlyplasma cells and lymphocytes, with neutrophilleucocytes in lesser numbers, and feweosinophils. Much of the collagen in the tissueis in the form of delicate fibrils enclosing spaceswhich presumably contain a great deal of tissuefluid, so that the texture appears loose (Fig. 2),but heavier fibrosis is often found lying con-centrically round the surviving air spaces.These air spaces are larger than ordinaryalveoli, are usually lined by cuboidal epithelium,and contain a good deal of cellular debris; quitefrequently hyaline material is seen lying againstthe epithelium, resembling the hyaline mem-brane of the newborn lung (Fig. 3). The freecells in the lumen are predominantly largemacrophages, which are sometimes aggregatedtogether to form giant cells. Larger air channels,the bronchioles and bronchi, contain little

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exudate and are not constricted or obstructedin any way.

In the younger child, air spaces are morenumerous, but are often flooded with anexudate of eosinophilic debris mixed witherythrocytes and neutrophil leucocytes;macrophages are fewer, but conspicuous whenthey occur because their cytoplasm is loadedwith eosinophilic material. Bronchioles andbronchi are often filled with this exudate andthe picture could be interpreted as pneumonicwere it not for the fact that, even in these areas,the normal alveolar network has already beencompletely replaced by the coarse trabeculaeand irregular spaces that seem to constitute thebasic deformity. The picture suggests an earlierstage of the disease, in which death has beenbrought about by superadded infection.MR. LAUSTE: I will now call upon Dr.

Claireaux to discuss this condition.DR. A. E. CLAIREAUX: I am very grateful

for the opportunity to be here and for yourkind hospitality before the meeting. This is asubject which interests me a great deal andcuriously enough, my arrival at Great OrmondStreet coincided with the first case they hadrecognised there. As you have heard Hammanand Rich described an acute pulmonary diseasein 1935 in which a diffuse fibrosis of the lungswas found at necropsy. They had met threeexamples between 1931 and 1933 in the medicalwards of Johns Hopkin's Hospital and twoyears later came across a fourth case. A furthermore detailed report was published by thesetwo authors in 1944 and this is the accountgenerally quoted. All the original authors'patients were adults. Since 1944 the conditionhas been reported by many investigators and itbecame obvious that it was not confined toadults. It occasionally presented in youngchildren but was rather rare in infancy. Thefirst childhood case, a five-year-old, to be seenat the Hospital for Sick Children, GreatOrmond Street, occurred in June, 1964 and asecond example came to light a few weekslater. At necropsy the lung in this condition hasa fleshy appearance and feels unduly firm. Onslicing there is little evidence of an aeratedstructure. Histological examination reveals amarked transudation of eosinophilic materialinto the air-spaces in the acute stage andhyaline membrane formation may be a pro-minent feature even in the older child or adult.This hyaline material is gradually organisedand young collagen appears. At the same timethere is a very extensive cellular infiltration ofthe interstitial tissue of the lung. The cells are

FIG. 4.-First Great Ormond Street case. H. and E.x 92. Lung showing numerous histiocytes andsome leucocytes in the alveolar lumen, thicken-ing and infiltration of alveolar septa andfibrinous membrane lining alveolar walls.

mainly monocytes but neutrophil and eosinophilleucocytes are also found. The latter appearsomewhat late in the disease process. Shouldthe patient survive sufficiently long, and manydie within four weeks of the onset of the disease,the fibrosis becomes more evident and even-tually a diffuse interstitial filbrosis of the lungdevelops. The alveolar walls gradually undergotransformation and become lined by cuboidalepithelium giving the lung a glandularappearance on histological examination. Thesurrounding lung shows pronounced atelectasis.

All these features are shown in the lung ofour first patient. The clinical history is that ofa girl, aged five years and nine months, whenshe was admitted to Great Ormond Street, whohad been ill since:the age of 18 months and haddyspnoea and cyanosis. She had had a recentrespiratory infection and was known to beanaemic. The liver and spleen were enlarged.Rhonchi were heard over the base of each lungand radiological examination revealed a com-bination of pulmonary coHllapse and consolida-tion. A biopsy specimen was removed from theright lung at operation and this revealed thechanges described above on histologicalexamination.As we were dealing with the first case of this

disorder in our hospital the slides were sent toDr. Lynne Reid at the Brompton Hospital whoagreed with the diagnosis.The lung was almos;t entirely consolidated

although some peripheral overdisitension wasnoted. Some areas of haemorrhage were pre-sent and many of the alveoli were lined bycuboidal epithelium. The interstitial tissue washeavily infiltrated with mononuclear cells and

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November, 1965 Clinico-Pathological Conference: Interstitial Fibrosis of Lungs

FIG. 5.-Second Great Ormond Street case. H. andE. x 93. Lung showing bronchiole lined byacidophil membrane. Surrounding lung collapsedand infiltrated with inflammatory cells.

eosinophils were also present in strikingly largenunmbers. A fairly dense interstitial fibrosis wasseen and a number of respiratory bronchioleswere lined by young fiibrous tissue and othersby hyaline membrane (Fig. 4).The patient is still alive and is being treated

with corticosteroids. A more recent biopsyshows a considerable dliminution in the oellularinfiltrate but the fibrosis, of course, persists.

Albout one month after the admission of ourfirst case another patient was admitted with asimilar history. The second patient was only18 months old and suffered from pronouncedrespiratory difficulty. A biopsy specimen oflung was obtained and the appearances arevery similar to those shown by Dr. Elliott thisevening. Distended respiratory bronchioles arelined by hyaline material and the appearanceis very akin to that of the lung of a newborninfant with the respiratory distress syndrome.The cellular infiltration is much less than thatseen in our first patient but there is widespreadiniterstitial fibrosis. Many air spaces havebands of collagen in their walls and many arelined by cuboidal epithelium. Some round cell

infiltration of the interstitial tissue is alsopresent but eosinophils which were such a pro-nounced feature in the lung of the older child,are absent (Fig. 5). This was obviously anotherexample of acute diffuse inrterstitial fibrosis ofthe Hanuman-Rich type. This underl"ines one ofthe difficulties in ascribing the Hamman-Richsyndrome to examples of obscure pulmonarydisease in children. There nmay be a number ofconditions, of widely different aetiology, whichresult in diffuse interstitial pulmonary fibrosis.Hamman and Rich stressed the acute natureof the disease process and the massive cellularexudate composed largely of mononuclearcells. The lining of non-fibrosed air spaces alsochanges. It becomes epithelialised and comesto resemble foetal lung tissue.Now that lung biopsy is becoming a more

frequent procedure, we are receiving an increas-ing number of specimens and interstitial fibrosismay not be such a rare diagnosis and not allof these are likely to prove to be examples ofthe Hamman-Rich syndrome.MR. LAUSTE: Will Dr. Nash now say some-

thing about the differential diagnosis?DR. F. W. NASH: There is naturally some

difficulty in attempting to discuss the differentialdiagnosis of a syndrome which has both clinicaland pathological components in its definition.The latter, which are regarded as distinctivecan only be established by histological examina-tion of the lungs. The clinical course of thedisease, reflecting a progressive interferencewith pulmonary function, is by no means dis-tinctive. Characteristically, the child developsa persistent irritant cough with breathlessnesswhich becomes progressively worse until thepatient becomes cyanosed, shows symptomsof anoxia, and ultimately dies from respiratoryinsufficiency, right heart failure (cor pulmonale)or some intercurrent infection. The course maybe spread over several months, even as longas a year or two, though a few patients havebeen known to succumb after a more acuteillness lasting only a few weeks.

This type of illness though uncommon inchildhood, particularly in infancy, is well recog-nised, and there are really only two maingroups of disorders that are likely to produceit-abnormalities of the heart and progressiverespiratory disease.

Let us first consider diseases of the heart.Cardiac embarrassment in a young child soonleads to respiratory symptoms and episodes ofpulmonary infection with sometimes wheezyspells which may initially lead to the heartabnormality being overlooked. Acute heart

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failure is soon recognised and is not likely tobe confused with the progressive disease thatwe are discussing; but there are forms of cardiacdisorder which have a subacute or chroniccourse closely resembling that of the Hamman-Rich syndrome. In these children the heart isenlarged (though heart size is not always closelycorrelated with the severity of the symptoms)and the basic disorder is usually either dys-function of the myocardium, as in fibro-elastosisor the various forms of cardiomyopathy, or acongenital heart lesion with a large left-to-rightshunt leading to increased pulmonary bloodflow, as with some forms of patent ductusarteriosus and ventricular septal defect. Notrarely increased pulmonary blood flow is com-plicated by changes in the pulmonary vesselsand pulmonary hypertension, adding further todifficulties with respiration. But in all thesecases the primary heart abnormality should beestablished early in the course of the disease.Cardiac enlargement may be detected, perhapson clinical examination, certainly with the aidof radiological studies; characteristic heartmurmurs may be heard in some forms of con-genital heart disease, and there are usuallyabnormalities in the electrocardiogram. In somechildren there will be signs of right heart failurewith engorgement of neck veins, an enlargedliver and, rarely, oedema; though it is as wellto realise that in patients with laboured breath-ing from any cause distended neck veins anda readily palpable liver are difficult to interpret.The important point to make is that thoughrespiratory symptoms may dominate the picturein heart disease, a careful examination willestablish the cause early on. In diffuse pulmon-ary fibrosis right heart strain and then failureusually supervene after several months of ill-ness.Turning now to respiratory disorders, persis-

tant and progressive respiratory disease may bethe result of a large number of pathologicalprocesses, and they can be very difficult to dis-tinguish clinically. For convenience it is helpfulto consider the following broad groups:-a) Recurrent inhalation pneumonitis secon-dary to abnormalities of the upper respiratorytract, larynx and trachea; for example, severemicrognathos (a diagnosis which is immed'iatelyobvious), inco-ordination of swallowing,laryngeal obstruction (the various forms oflaryngeal stridor), tracheal obstruction due toa congenital web or tracheo-malacia or pres-sure from outside-not infrequently a vascularring. Finally, lung pathology may result froma small tracheo-oesophageal fistula, which may

for a long time be misdiagnosed as primarypulmonary disease.

In a few of these conditions the nature ofthe disorder is immediately obvious. In othersthe diagnosis will often depend on furtherinvestigations including a barium swallow and,if necessary, cine barium studies, directlaryngoscopy or bronchoscopy and perhaps theperformance of a tracheogram and broncho-gram.b) Disease primarily affecting the lungs, suchas-chronic unresolved pneumonia with, in thelater stages, fibrosis and bronchiectasis. Thissequence of events is nowadays only rarely metwith as a complication of the bacterialpneumonias, but one should of course considerother agents; for example, virus infectionlipoid and plasma-cell pneumonia, infectionwith pneumocystis carinii and with fungi.Examination of the sputum, if it can beobtained, or of stomach washings may help inthe identification of some of these diseases, butwhere the diagnosis remains obscure lungbiopsy would be justified. Idiopathic pulmonaryhaemosiderosis-a grealt rarity-should per-haps be mentioned here. It is thought to be dueto abnormal pulmonary capillaries allowing theescape of blood into the lungs, and affectedchildren develop progress-ive respiratorysymptoms with acute exacerbations. Thesepatients are usually anaemic and may developjaundice in the aculte phases, sometimes withenlargement of the liver and spleen. Blood iscommonly found in the sputum, vomitus andstools.c) Generalised diseases with predominantrespiratory symptoms. Fibrocystic disease ofthe pancreas (mucoviscidosis) is not a greatrarity in childhood and is one of the first con-diltions to be considered in the differentialdiagnosis. Helpful pointers may be obtained inthe history-other affected children in thefamily, meconium ileus in the patient in theneonatal period or coeliac symptoms later on.The most useful diagnostic test however is thefinding of abnormally high levels of sodiumand chloride in the sweat of these children.Infiltration of the lungs in miliary tuberculosis,leukaemia and the lipoidoses can producesevere respiratory symptoms, but the course ofall these illnesses in children is usually acuteand one soon finds ample evidence of diseaseoutside the respiratory tract. Finally, diseasesaffecting the small blood vessels and collagentissues of the body have to be kept in mind;polyarteritis nodosa, disseminated lupus,rheumatoid arthritis and sarcoidosis.

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FIG. 6.-Christine P. aged 6 months. Diffuse progressive interstitial fibrosis of lungs.

To conclude one can say that in establishingthe diagnosis of the Hamman-Rich syndromeone may have to go through a process ofdetailed investigation and exclusion; first, ofprimary heart disease, then of a whole host ofrespiratory diseases and general disorders withrespiratory involvement. The stage will then bereached where *the child will be seen to besuffering from severe ventilation difficultiesapparently due to primary lung disease ofunknown aetiology. The final step would be toexamine some lung tissue under the microscopeand demonstrate the characteristic histologywhich has already been described.MR. LAUSTE: Now we must hear about the

radiological aspects from Dr. Rubin.DR. J. RUBIN: In radiology one is concerned

to see how the pathology is shown on the X-raypicture. Christine had a series of three radio-graphic examinations showing progressive X-raychanges, which I think mirror the pathologythat we have heard described. On the first X-rayexamination very soon after admission whenthe suggested diagnosis was broncho-pneumonia,the X-ray picture was that of an ill-defineddiffuse generalised increase of the broncho-vascular markings and of lung striations bilater-ally, and all I could suggest at that time wasbronchiolitis. The odd feature was that it wassuch a uniformly diffuse clouding throughout

- .l:... l. .:.. ..

FIG. 7.-Letterer-Siwe disease in an 8-month-oldinfant.

both lung fields. Secondly two weeks later, afurther X-ray examination with screeningshowed a progressively increasing generalisedinfiltration. There was definite fine mottlingdiffusely throughout both lung fields withevidence of spasmodic respiratory movementson screening. The possibility of miliary tuber-culosis was particularly in my mind becausethe X-ray picture simulated it, and also haemo-siderosis. The Hamman-Rich syndrome wasnot considered because at that time we hadno knowledge whatever of this condition occur-ring in infancy. Finally the diffuse mottled in-filtration became coarse and granular after afurther two weeks interval (Fig. 6) and againI considered that the appearances were indis-tinguishable from miliary tuberculosis. We hadto think also of sarcoidosis, an acute collagendisease and other conditions which might givea similar appearance. For example, we havetwo radiographs here for comparison with theone under discussion which bear some similarityto each other. There is one of reticulosis, orgeneralised histiocytosis (Letterer-Siwe) whichis relatively common in this age group as faras diffuse pulmonary infiltration is concerned(Fig. 7), and another of miliary tuberculosis(Fig. 8). We have a different type of X-raypicture when we come to the kind of case Dr.Claireaux has described in older children which

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FIG. 8.-Miliary tuberculosis in a child aged 6months.

may resemble this film of fibrocystic diseaseof the pancreas (Fig. 9). Also in the radiologicaldifferential diagnosis we must consider malig-nant infiltration. Thus, our next film shownhere (Fig. 10) is one of a malignant invasionfrom a rhabdosarcoma. Incidentally, it seemsto me that the radiological picture in olderchildren and in the adult cases of Hamman-Rich fibrosis described in the literature is notalways the same as that found in infants withthis type of disorder. Outside infancy we donot see the early clouding of the lung fieldsprogressing from a -fine to a coarse diffusegranularity. In older children, unlike infants,we tend to see scattered consolidations andcollapse and no uniformity. One cardinal featureto conclude with in the radiological differentialdiagnosis is that in the Hamman-Rich syndromeof diffuse interstitial fibrosis we do not haveemphysema or honeycombing in the lung fieldsbecause the alveoli are obliterated.

DR. MANN: It may be of some interest tomention tha-t Hamman and Rich published anaccount of their first case (a coloured man aged47 years, admitted to Johns Hopkin's Hospitalin 1931) as long ago as 1933 in the form of aClinico-Pathological Conference. Could I askDr. Claireaux to tell us a little more about theclinical aspects of the two Great Ormond Streetcases? I am particularly interested in the firsitchild he mentioned who, I believe, he said

i

Fic. 9.-Fibrocystic disease of the pancreas in a 3j-year-old child.

had survived now for over four years. Thisseems surprising because diffuse interstitialpulmonary fibrosis is a very lethal condition,especially in children, although admittedlyadults have been descrilbed who have been keptgoing for several years with the help of steroids.Inciden-tally, in the first Great Ormond Streetcase, I thought the pulmonary changes Dr.Claireaux demonstrated were noticeablypatchy, there being a lot of reasonable lookingalveoli in the section. I am surprised it is notthe diffuse affection one would expect in thisdisturbance.

DR. CLAIREAUX: I am sorry I said so littleabout the clinical picture in our cases but Ihad to watch the clock. The first child Imentioned presented at the age of 18 monthswith dyspnoea and cyanosis, subsequentlyfinger clubbing appeared. She is now aged sixyears old. I should have mentioned that theslide I demonstrated (Fig. 4). is the secondlung biopsy after steroid therapy and so theprocess has been modified by treatment. Mysecond slide (Fig. 5) was a primary lung biopsyfrom our second case and showed the picturewhich Dr. Elliott has shown us tonight in theBrighton babies.DR. MANN: Coming back to our cases, the

history in Christine was typical of that describedin diffuse interstitial pulmonary fibrosis. How-ever, her sibling died a sudden and unexpectedcot death and there were quite definitely nopreceding symptoms to suggest progressive pul-monary dysfunction although admittedly thisinfant had not behaved normally from birth.May I ask Dr. Claireaux if he is satisfied ourtwo children had the same basic disorder.

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~~~.:'.g.:::=.,-......., ,

FIG. 10.-Diffuse pulmonary infiltration due tometastases from rhabdomyosarcoma of rightforearm. Aged 7 years.

DR. CLAIREAUX: Yes, I think both childrenhad a diffuse interstitial fibrosis of the lungs.Whether this is really the Hamman-Rich syn-drome is another question. I believe that certainsevere virus infections of the lung may befollowed by interstitial fibrosis. Your secondcase seemed to show a brisk polymorphonuclearleucocytic reaction in the bronchi and it wouldseem possible that the second child, althoughsuffering from a similar underlying disorder,had a terminal acute infection which provedfatal.

DR. MANN: In view of what you say, areyou not surprised our second child had norespiratory symptoms right up until death?DR. CLAIREAUX: Not entirely. This absence

of respiratory symptoms is not all that unusualin cases of sudden death in infancy, e.g., cotdeaths. Nevertheless a number of such infantsshow inflammatory changes in the lungs at-necropsy.

DR. MANN: I am thinking in view of thebasic pathological changes we saw in this child'slung, are you not surprised by the absence ofrespiratory symptoms?DR. CLAIREAUX: Yes. This was a point I

found very difficult. The cellular infiltrate inyour two cases seemed to be less pronouncedthan is usual in a typical Hamman-Rich syn-drome. The infiltrate in our first case was sopronounced that a diagnosis of histiocystosiswas considered.MR. LAUSTE: Now there is a little time left

for anybody else who wishes to contributeto the discussion.DR. F. MEADE: I think there is probably no

condition which better illustrates the utterdependence of the clinician on the pathologistwhen it comes to making a diagnosis. However,it is the aetiological factors which I find of thegreatest interest in this syndrome. We may bedealing with a viral or chemical cause. We haveheard of a possible relationship to rheumatoidarthritis and that there may be a genetic factoroperative. I think it is worth mentioning thatwe now believe there is a genetic factor at workin some cases of bronchitis. There is one otherfactor that may be relevant to the secondBrighton case-I noticed that John was a verydifficult feeder. He seemed full after only twoounces. I would like to ask was there anythingin the history to suggest regurgitation of feeds?Also, was there any evidence of any oesophagealabnormality at post-mortem?DR. MANN: Clinically there was no evidence

of vomiting or regurgitation. There was nohistory of choking attacks; just this greatdifficulty of getting feeds into the baby.

DR. ELLIOTT: I would like to say thatpathologically there was no evidence of anyoesophageal abnormality nor did the appear-ances in any part of the lung really resemble thesort of lipoid pneumonia you get in childrenwho inhale milk feeds. With milk inhalationthe lungs present a fairly typical picture andthey are certainly much less cellular lookingthan the ones we saw here.MR. LAUSTE: Well, we are now very short

of time as our speaker has to return to London.I propose, therefore, asking Dr. Mann to saya few words about the aetiology and treatmentof this condition.DR. MANN: Considering first the treatment

of diffuse interstitial pulmonary fibrosis, thisis, of course, most unsatisfactory. Our firstcase, Christine, improved dramatically whenfirst placed in oxygen and this sort of responsehas been noted by most authors. Physiologicalstudies indicate that amongst other things, weare dealing with a reduced diffusing capacityin this affection and one would therefore expectoxygen to help, at least initially. The onlyother therapeutic agents of value are thecorticosteroid group of drugs. These may leadto symptomatic improvement and occasionallyprolong life for several years. I must emphasisethat once started the patient's life usuallybecomes dependent on the drug.Turning now to pathogenesis, there are one

or two points to bear in mind. Firstly, there isthe familial occurrence of cases to which Dr.Meade has just referred. This I would havethought had happened too often to be coin-

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696 POSTGRADUATE MEDICAL JOURNAL November, 1965

cidental although as far as I know ours is thefirst description of the disorder in siblings. Theother point Dr. Nash has spoken about, is thatthis sort of diffuse pulmonary pathology maybe found in association with other well defineddisorders, such as disseminated lupus erythe-matosis, rheumatoid arthritis, rheumatic feverand even polyarteritis nodosa. In discussingaetiology we must also bear in mind the verywide age range of cases which stretches frominfancy right up to the seventies. Lookingthrough the literature, many causes for diffuse.interstitial pulmonary fibrosis have beenadvanced. Thus, it has been suggested that thisaffection may result from the inhalation ofsome toxic chemical substance (this is unlikelyin children), that it may be a response to a yetunidentified infection, virus or otherwise, thatit may be a localised manifestation of a collagendisease. Lastly, the concept has been putforward that we are dealing here with ahypersensitivity state. In this connection severalauthors have wondered whether this conditionmight arise from sulphonamide sensitivity andit is of interest to note that Christine hadsulphatriad before she was admitted to hospitaland sulphadimidine was given subsequently.I am afraid I was unable to get any preciseinformation about drug administration in thesecond child.May I conclude by saying that reading

through the literature one gets the impressionthat we may well be dealing here with theend-result of the activities of a very wide rangeof aetiological agents but probably the mostfavoured theory today is this one of a hyper-sensitivity state, possibly an auto-immunereaction. There are several features in supportof this hypothesis. For instance, Dr. Claireauxhas told us about the presence of eosinophilsin the lung lesions; then there is the raisedlevel of globulins in the blood found in somecases (not in Christine, though) and I supposeit couild be said that the familial occurrence of

cases perhaps favours a genetically influencedmode of tissue response. Also supporting thistype of mechanism is the favourable responseto steroids in some instances and the fact thatthe serum globulins, when raised, fall withsuch treatment. Finally, I must mention brieflythe experimental work of Read in Australia.(1958). He prepared an "anti-rat-lung serum"in rabbits which when injected into the tracheasof rats produced a range of pulmonary lesionswhich were interpreted on an allergic basis andwhich had a counterpart in the spectrum ofhistological changes seen in diffuse progressiveinterstitial pulmonary fibrosis.

I wonder if Dr. Claireaux can add anythingabout aetiology from the pathological side?DR. CLAIREAUX: I would only like to say that

I think there is a possibility that some patientsmay have a dysgammaglobulinaemia. Also, thatfluorescent antibody studies on our materialhave so far proved negative.MR. LAUSTE: I am sure you will agree that

this has been a most interesting and valuableconference. I would like to thank all those whohave taken part, especially Dr. Claireaux.

REFERENCESBRADLEY, C. A. i(1956): Diffuse Interstitial Fibrosis

of the Lungs in Children, J. Pediat., 48, 442.DAVIES, G. M., and Porrs, M. W. (1964): Chronic

Diffuse Interstitial Pulmonary Fibrosis in Brothers,Guy's Hosp. Rep., 113, 36.

HAMMAN, L., and RICH, A. R. (1933): Clinico-pathological Conference, Int. clin. Series 43, i, 197.

HAMMAN, L., and RICH, A. R. (1935): FulminatingDiffuse Interstitial Fibrosis of the Lungs, Trans.Amer. clin. climat. Ass., 51, 154.

HAMMAN, L., and RICH, A. R. (1944): Acute DiffuseInterstitial Fibrosis of the Lungs, Bull. Johns Hopk.Hosp., 74, 177.

MANN, T. P. (1959): Diffuse Progressive InterstitialFibrosis of Lungs in Infancy, Proc. roy. Soc. Med.,52, 638.

READ, J. (1958): The Pathological Changes Producedby Anti-lung Serum, J. Path. Bact., 76, 403.

SCADDING, J. G. (1960): Chronic Diffuse InterstitialFibrosis of the Lungs, Brit. med. J., i, 443.

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