J Clin Pathol 1981 ;34:129-137

Interrelationship of chronic eosinophilic pneumonia,bronchiolitis obliterans, and rheumatoid disease: ahypothesisTHOMAS P COONEY

From the Department ofPathology, University of Manitoba and Health Sciences Centre, Winnipeg,Manitoba, Canada

SUMMARY Three patients with histologically proven bronchiolitis obliterans are presented, two ofwhom had rheumatoid disease. All three patients had, in addition, clinical and radiological evidenceof chronic eosinophilic pneumonia; open lung biopsy in two showed coexistent features of chroniceosinophilic pneumonia and bronchiolitis obliterans. The association of both rheumatoid diseaseand chronic eosinophilic pneumonia with bronchiolitis obliterans in these patients may simply becoincidental, but the striking similarities between the cases suggest that a real interrelationship ofthese disease entities may exist.

The catalogue of respiratory complications ofrheumatoid disease has recently been extended toinclude airways obstructions 2 Although airwaysdisease in these patients is usually mild, a rapidlyprogressive form of bronchiolitis obliterans has beendescribed in five patients with rheumatoid disease3and a similarly rapid process was noted in twopatients with connective tissue disease (eosinophilicfasciitis and rheumatoid disease), possibly related tothe administration of penicillamine.4The association of chronic eosinophilic pneumonia

and rheumatoid disease has not, to my knowledge,been reported in the literature. Three patients withhistologically proven bronchiolitis obliterans arepresented, two of whom had rheumatoid disease. Allthree patients had, in addition, clinical and radio-logical evidence of chronic eosinophilic pneumoniawith histological confirmation in two. The data areexamined in the light of the hypothesis that theassociation in these patients of chronic eosinophilicpneumonia and rheumatoid disease with bronchio-litis obliterans is more than coincidental.

Case reports

CASE 1A 34-year-old woman had a six-year history ofallergy with positive skin testing for housedust,moulds, and various foodstuffs, recurrent nasalzpolypi,

Accepted for publication 14 July 1980

and peripheral eosinophilia. She was admitted on5 June 1979 for review of persistent disabling poly-arthritis. She had first noted generalised joint painswithout objective signs in 1974. In 1978 a clinicaldiagnosis of bilateral sacroiliitis was made; a latextest at that time was strongly positive on twooccasions. From December 1978 she developedaches in the fingers, ankles, and back, and rednessand swelling developed in the wrists, proximalinterphalangeal joints, elbows, knees, ankles, andfeet. Morning stiffness was pronounced. X-ray of thehands showed spindle-shaped prominence of the softtissues adjacent to the proximal interphalangealjoints of both index fingers and the left middle finger.No bony abnormality was seen. The patient, a non-smoker, also complained at that time of a hackingcough, productive of only small amounts of mucoidsputum. She experienced sweats and chills at nightbut was apyrexial. There was no history of inhalationof toxic fumes, nor had she been taking tetracycline,nitrofurantoin, or penicillamineOn admission she was not acutely ill. She had

obvious vitiligo of face, neck, arms, forearms,abdomen, and lower back. Blood pressure was120/80 mm Hg. She was afebrile. Examination of therespiratory system revealed bilateral soft inspiratoryrales, more marked on the right. Musculoskeletalexamination revealed tenderness and swelling ofproximal interphalangeal joints, metacarpophalan-geal joints, wrists, elbows, knees, ankles, and smalljoints of the feet. Synovial thickening and effusions

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were noted in the knees and ankles. There was limita-tion in the range of movement of elbows, shoulders,and knees.

Investigations revealed a sedimentation rate of55 mm in 1 hour. The peripheral eosinophil countwas 1428/mm3 on 14 June and this had risen to3210/mm3 by 20 June. Examination of stools for ovacysts and parasites was negative. Skin testing forcandida was negative. Mantoux test (5 TU) wasnegative. Rheumatoid latex test was positive 1:10240.Antinuclear factor was very weakly positive. Anti-deoxyribonucleic acid (anti-DNA) levels were nor-mal. Viral serology was negative. Serum immuno-globulin estimation was normal apart from amarginal elevation of IgG. Serum complement wasnormal. A chest x-ray on admission revealedmultiple peripheral pulmonary infiltrates, and reviewat this time of a routine chest x-ray taken in March1979 disclosed a peripheral zone of increased densityin the posterior segment of the left upper lobe.Marked progression in these peripheral infiltrateswas noted on a chest x-ray by 19 June. Pulmonaryfunction studies (Table 1) showed a restrictive patternof disease.

Table 1 Pulmonary function tests

Case I A B

TLC (1) 3-08 (66) 3-7 (79)FRC (1) 1-73 (69) 2-10 (84)RV (1) 0-98 (69) 1 50 (107)FVC (1) 2-11 (65) 2-20 (67)FEV,/FVC 84 80

Case 2 A B C

TLC (1) 2-07 (49) 4-02 (95) 7-53 (153)FRC (1) 1-34 (61) 2-92 (133) 5 03 (194)RV (1) 0-75 (53) 1-64 (116) 3-43 (203)FVC (I) 151 (54) 2 65 (95) 3-52 (109)

FEV,/FVC 84 80 55MMEFR(Q/s) 1-13 (49) 2-70 (114) 1-20 (51)

A = initial presentation; B = one month later; C = 7-12 monthslater.Values in parentheses are percent predicted.

Open lung biopsy was carried out two weeks afteradmission. This showed diffuse infiltration of lunginterstitium and flooding of alveoli by eosinophils(Fig. la). Central necrosis of these eosinophils wasseen in some alveoli. The alveoli also contained afibrinous exudate and numerous lipid-filled macro-phages. Multinucleate (Touton) giant cells werepresent within alveoli (Fig. lb), and these were seenalso within the lumina of some bronchioles, wheredestruction of adjacent bronchiolar wall with pro-liferation of fibroblastic tissue gave the lesion agranulomatous appearance (Fig. ic). More strikingwas the widespread obliteration of bronchiolar

4 :.

la

Fig. 1 Case 1. (a) Open lung biopsy. There is floodingof alveoli and infiltration ofpulmonary interstitium bynumerous eosinophils. To the left of centre a typicaleosinophilic abscess is seen. Lipid-laden macrophagesintermingle with eosinophils within the alveoli(Haematoxylin and eosin; original magnification x 160).(b) Multinucleate (Touton) giant cells lie in alveolarspaces. Eosinophils permeate all areas of the lungparenchyma (H and E; original magnification x 160).(c) Granulomatous destruction of the wall of a bronchioleby giant cell and fibroblastic infiltrates. This appearancewas seen quite frequently in different areas of the biopsy(H and E; original magnification x 63).(d) A polypoidfibroblastic proliferation protrudes into thebronchiole, partly obliterating the lumen. Eosinophils arepresent within the polyp. This histological variant ofbronchiolitis obliterans predominated throughout thespecimen (H and E; original magnification x 63).(e) Concentric constriction of the bronchiolar lumen bymucosal fibrous tissue. Constrictive bronchiolitisobliterans, as seen here, was noted infrequently in thebiopsy specimen. (Elastic van Gieson; originalmagnification x 63).

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lumina by polypoid masses of fibroblastic tissuemixed with eosinophils (Fig. Id). Occasionalbronchioles showed circumferential constriction ofthe lumen by mucosal fibrous tissue (Fig. le). Folli-cular bronchiolitis was noted focally in severalsections. The interstitium contained, together withmany eosinophils, a moderate infiltration of lympho-cytes and plasma cells. Vasculitis was not marked,although infiltration of the walls of some vessels byeosinophils was seen. Granulomas were not seen.Several small bronchi were included in the biopsyspecimen; these showed prominent goblet cellmetaplasia of the epithelium, plugging of thebronchi with mucus in which eosinophils weretrapped, thickening of the bronchial basement mem-brane, and mild hypertrophy of the bronchialmuscle. Special stains for organisms were negativesand cultures from the biopsy tissue were negative forfungi, acid-fast bacilli, and bacteria. Immuno-fluorescence studies for lgG, IgA, IgM, C3, C4, Clq,and fibrin showed only weak positivity for fibrinwithin alveoli.

Steroid therapy (prednisone 60 mg orally per day)was started on 11 July. Five days later the peripheraleosinophil count was normal. A chest x-ray threedays later showed considerable clearing of the in-filtrates. Pulmonary function studies the next day,showed some improvement (Table 1). Serial radio-graphs over the next two months showed almostcomplete clearing of the infiltrates. The latex test on10 October was negative. The patient remains wellapart from arthritis.

CASE 2A 58-year-old housewife was admitted from anotherhospital on 10 May 1971 with a presumptivediagnosis of pulmonary tuberculosis. She had firstpresented eight weeks previously because of a pro-gressive cough productive of one-quarter of a cup ofmucopurulent sputum per day, fever, increasingdyspnoea and fatigue, and a loss of 3.5 kg in weight.There was no history of wheezing or of arthritis.Past history was non-contributory. She had notinhaled toxic fumes. She had not been treated withnitrofurantoin or para-amino salicylic acid, but oninitial presentation she had received a short courseof tetracycline. The patient was a non-smoker andhad no allergies at that time. A nephew was reportedto have asthma.Examination on admission revealed a pyrexia of

38.80C, a respiratory rate of 24/min, and bloodpressure 110/70 mm Hg. There were signs of rightlung consolidation, and inspiratory rales werepresent over both lower lobes. No clinical evidenceof airways obstruction was found. A chest x-rayshowed bilateral pulmonary infiltrations, more

Cooney

marked on the right, with a suggestion of a peripheraldistribution (Fig. 2a). The peripheral blood eosino-phil count was 2400/mm3. Rheumatoid factor (latexfixation test) was positive 1:640. Antinuclear factorwas negative. Sedimentation rate was 124 mm/h.Skin tests for fungi were negative. Stool examinationfor ova, cysts, and parasites was negative. Allergy

F..

Fig. 2 Case 2. (a) Frontal radiograph 11 days afteradmissior. Patchy consolidation of both lungs is seen,more marked on the right. There is some suggestion of aperipheral distribution of the infiltrates. (b) Dramaticcleari,ng ofpulmonary infiltrates three weeks after theinstitution of steroid therapy.

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Interrelationship of chronic eosinophilic pneumonia, bronchiolitis obliterans, and rheumatoid disease

testing was negative at that time. Serological titresfor respiratory viruses and mycoplasma were nega-tive. Bacterial, mycobacterial, and fungal cultures onsputa were negative. Pulmonary function studiesshowed a restrictive pattern (Table 1). The patientwas treated with antituberculous drugs (isoniazid,streptomycin, and ethambutol) without improve-ment.Open lung biopsy was carried out two weeks after

admission. This showed diffuse thickening ofalveolar walls with an increase in interstitial collagen(Fig. 3a). Alveoli contained lipid-filled macrophagestogether with some eosinophils; in some regions,

flooding of alveoli by eosinophils was evident, andin these areas central necrosis of eosinophils was seen.Eosinophils and plasma cells widely infiltratedthe interstitial tissues, and lymphocytes werenumerous also in these areas. Isolated multinucleate(Touton) giant cells were present within alveoli.There was pronounced hyperplasia of alveolar typeIL cells, and foamy macrophages were seen alsobeneath the epithelium. No granulomas wereevident. A striking feature also in this biopsy speci-men was the presence of polypoid masses of granula-tion tissue, which extended into the lumina of smallbronchioles, partly occluding them (Fig. 3b).

Fig. 3 Case 2. (a) Open lungbiopsy. Tlhere is markedthickening of alveolar septa.Inflammation in this field ispr.edomtinantly interstitial. (H an1dE; original macgnification x 63).(h) Oh/iteration of the lumen of abr-onchiole by, polypoidfibr oblastictissue (upper centre) and acellular exudate (seen at Ihigherpower to be composed ofeosinophils andfoamynmacr.ophages). (H and E; originalmagnification x 63).

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Although the vessels showed marked sclerosis, therewas no evidence ofvasculitis.

Administration of prednisone, 40 mg/day, wasbegun on 28 May 1971. Within a few days dramaticclinical and radiographic improvement occurred,and this continued over the next few weeks (Fig. 2b).Pulmonary function studies one month later showeda return to normal (Table 1). The steroid treatmentwas gradually reduced and finally discontinued aftersix months.One month later (December 1971), however, the

patient noted a return of dyspnoea with wheezing.Clinical examination revealed hyperinflation of thechest, bronchovesicular breath sounds, and scatteredexpiratory rhonchi. Chest x-rays confirmed theclinical impression of hyperinflation. Lung functionstudies (Table 1) showed changes typical of obstruc-tive lung disease.The patient was seen once more in July 1975. She

had a cough productive of mucoid sputum and anexacerbation of dyspnoea and wheezing. Peripheraleosinophilia, 1055 eosinophils/mm3, was againpresent. Skin testing revealed positive reactions totrees, moulds, weeds, feathers, gum, and hog. Clinicaland radiographic evaluation showed little changesince December 1971. She returned finally in Decem-ber 1976 because of inflammation, swelling, andtenderness of metacarpophalangeal and proximalinterphalangeal joints of the left little and ringfingers. At that time rheumatoid factor (latex test)was negative.

CASE 3This 69-year-old woman had a history of rheumatoiddisease which dated back 33 years. The diseaseinitially affected shoulders, hands, and feet buteventually progressed to involve almost all thejoints, including the temporomandibular joints,Medical treatment had included acetyl salicylic acid,gold, and steroids but penicillamine was not given.She had had surgery to both knees and to the feet(excision of metatarsal heads). Biopsies of bothknees showed typical rheumatoid synovitis. Beforethis admission she had not had steroid treatment fortwo years. In the past she had had intermittentperipheral eosinophilia as high as 2400/mm3 (1974).Latex fixation test was negative in 1959 and 1974 andpositive 1:640 in 1972. Antinuclear factor wasrepeatedly negative; LE cells were repeatedly nega-tive; anti-DNA levels were normal. Radiographicexamination of the joints in 1974 showed changes ofrheumatoid disease in the cervical spine, knee, andshoulder joints. The metatarsal heads had been re-moved by that date. A chest x-ray was reported asnormal in 1973. Unfortunately, as the patient haddied two years before the preparation of this report

no x-rays were available for examination.The patient's terminal admission extended from

April 1977 to February 1978. She presented in April1977 with extreme breathlessness of four days'duration. Clinical examination of the respiratorysystem revealed bilateral crepitations. A chest x-rayon admission showed bilateral patchy upper lobeinfiltrates. Peripheral eosinophilia was again docu-mented (up to 13%); a polymorphonuclear leuco-cytosis was not observed. Mantoux test (5 TU) wasnegative. Repeated bacteriological studies of blood,sputum, throat, and urine were negative. In theabsence of specific proof of infection steroid treat-ment was begun. Serial radiographic examinationsshowed clearing of the upper lobe infiltrates overthe next five weeks. Pulmonary function studies onemonth after admission, however, showed evidenceof severe airflow obstruction. A chest x-ray inSeptember 1977 showed no evidence of pulmonaryinfiltrates, but the patient's clinical course fromadmission to the time of death in February 1978 wasone of slowly progressive respiratory failure.Examination of the lungs at necropsy revealed

bilateral hyperinflation. The bronchi containedmucoid secretions, and an established bronchiolitisobliterans (Fig. 4) was seen in a patchy distribution

* t > < ;+. L4

4~~~~~~~~0

I~~~~~~~~~~f

Fig. 4 Case 3. Established bronchiolitis obliterans seenin a patchy fashion throughout multiple lung sections atnecropsy. (H and E; original magnification x 25).

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Interrelationship of chronic eosinophilic pneumonia, bronchiolitis obliterans, and rheumatoid disease

throughout multiple sections of both lungs. Focalinterstitial scarring was also noted.Table 2 summarises the relevant features of the

above cases.

Table 2 Relevant clinical and histological data

Case CEP BO Rheumatoid Rheumatoid Peripheraldisease factor eosinophilia

I + + + (definite) 1:10240 +2 + + - 1:640 +3 ? + + (classical) 1:640 +

CEP = chronic eosinophilic pneumonia; BO = bronchiolitisobliterans; + present; - not present.

Discussion

The association of chronic eosinophilic pneumonia(CEP) and rheumatoid disease with bronchiolitisobliterans as documented above may simply becoincidental. It is possible that the associateddiseases merely increased the risk and severity ofbronchiolitis obliterans in these patients. Thesimilarities between the cases are such, however,that the hypothesis of a more than coincidentalassociation of CEP, bronchiolitis obliterans, andrheumatoid disease merits exploration.The clinical courses of cases 1 and 2 conform well

to those described in several published reports on

CEP.5-"1 A history of allergy, night sweats and chills,the abrupt onset of the illness, peripheral bloodeosinophilia, peripheral infiltrates on chest x-rays,failure of antibiotic and antituberculous therapy,and the dramatic clinical and radiographic responseto steroid therapy are all features typical of CEP as

it has been delineated. The absence of fever anddyspnoea in case 1 is usual, but individual cases ofCEP without these features have been reported.7 910The radiographic picture in case 2 does not have theclassical 'photographic negative of pulmonaryoedema' appearance, but Gaensler and Carrington"have noted that 24% of the cases in their serieslacked the typical appearance. Case 2 also was givena short course of tetracycline early in her illness.CEP is known to occur in association with severaldrugs,6 7 and Ho and his associates'2 have implicatedtetracycline in this context. Both of their patients,however, had a typical hypersensitivity skin rash andimproved on withdrawal of the drug, neither ofwhich features was seen in this case.The finding that first attracted attention to cases

1 and 2 was the very marked bronchiolitis obliteransthat was evident in the lung biopsy of each patient.This was far more severe and widespread than isusually seen in CEP.6 710 Supporting the severity ofbronchiolitis obliterans in case 2 was the florid

obstructive pneumonitis seen in the related paren-chyma. After a dramatic response to steroids in thispatient, with reversal of the restrictive pattern ofdisease seen on admission, the later development ofa clearly obstructive picture apparently related tosmall airways disease (MMEFR = 1-20 I/s; Table 1)is striking. In the published series of CEP in whichfunctional studies are provided, four patients arerelevant in this context: one patient6 had a picture ofcombined restrictive and obstructive disease (histo-logical features not specified); one patient8 withhistological evidence of CEP and (mild) bronchiolitisobliterans continued to have obstructive diseaseafter resolution of CEP; and two patients7 de-veloped, respectively, moderate and marked ob-struction after CEP (neither of these had bronchio-litis obliterans on lung biopsy). In the light of theseobservations, the subsequent course of case 1 will beof extreme interest regarding the development of anobstructive picture.Case 1 is of interest in two further ways. By the

criteria of the American Rheumatism Association13she has definite (but not classical) rheumatoiddisease. The association of CEP and rheumatoiddisease has not previously been suggested. However,some patients with rheumatoid disease developperipheral eosinophilia, which is both sporadic andunexplained.14 Further, such patients have a higherincidence of extra-articular manifestations of rheu-matoid disease (including pulmonary fibrosis).14Patients with rheumatoid disease are known to bemore liable to pulmonary infection.15 It is con-ceivable that, in such a population (often steroid-treated), fleeting pulmonary infiltrates attributed toinfection, together with peripheral eosinophilia,might in fact represent 'silent' CEP. One of 16patients with CEP reported by Liebow and asso-ciates6 was noted incidentally to have a latex fixationtest positive 1:320. Examination of the lung biopsyin that case showed a granulomatous reaction in thewall of bronchioles (their Fig. 30) identical with thatseen in Fig. ic in this paper. This appearance wasnot seen in any other patient in the group. Onepatient with CEP in the series of Gaensler andassociates1" later developed arthritis and scleroderma(serology is not reported).The second point of interest in case 1 is the

relevance of histological bronchiolitis obliterans tothe rheumatoid disease. Geddes and associates3documented five patients with rheumatoid diseasewho developed rapidly progressive bronchiolitisobliterans. In their cases the bronchiolitis obliteranswas of the less common constrictive variety de-scribed by Gosink and colleagues,16 one of whosepatients also had rheumatoid disease. A similarhistological pattern was seen in the rheumatoid

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136 Cooney

patient with bronchiolitis obliterans described byEpler and associates.4 Disease in this patient wasattributed possibly to penicillamine (although twoof Geddes' patients were not treated with this drug).A further case of bronchiolitis obliterans in a patientexposed to cleansing agents'7 was more likely relatedto that patient's rheumatoid disease.18 Bronchiolitisobliterans in cases 1 and 2 was predominantly of themore common polypoid type, but occasionalbronchioles in the biopsy specimen from case 1(Fig. le) showed circumferential constriction bymucosal fibrous tissue identical with that seen inFig. 12 of the paper by Geddes and associates.3 Theappearance in the same patient of both polypoid andconstrictive bronchiolitis obliterans is distinctlyunusual16 and raises once more the question of therelevance of this patient's rheumatoid disease.

It is clear that case 2 does not have rheumatoiddisease. However, the positive latex fixation testnoted during her CEP and the transient episode ofsmall joint inflammation in December 1976 may yetprove to be of significance. Pulmonary complicationsof rheumatoid disease are known occasionally toprecede the arthritis by months or years.'920 Thispatient had histological bronchiolitis obliterans in1971 and now has clinical evidence of this disease.Case 3 incorporates many of the speculative issues

raised thus far. This patient with classical rheumatoiddisease was noted at necropsy, after a progressiveterminal illness of 10 months' duration, to haveestablished bronchiolitis obliterans. There is circum-stantial evidence to suggest that the illness thatinitiated her terminal admission was an episode ofCEP: acute onset of dyspnoea, failure to demon-strate an infective aetiology, peripheral eosinophilia,bilateral upper lobe radiographic infiltrates, and aradiographic response to steroid therapy. This mayin effect have been a clinically 'silent' CEP, as sug-gested above, with subsequent progression to thebronchiolitis obliterans seen at necropsy.The aetiology and pathogenesis of CEP and of

many cases of bronchiolitis obliterans are unknown.Certainly the common infectious agents have beenruled out in many cases. In support of an immuno-logical basis for pathogenesis in CEP, Kanner andHammar21 have identified within the dilated roughendoplasmic reticulum of large plasma cells ahomogeneous intracisternal electron-dense materialwhich they presume to be immunoglobulin. Theysuggest that this may act as an eosinophilic chemo-tactic factor. In this regard, the cases reported hereare contributory only in that once again an infectiouscause seems unlikely, and an immune one seems atleast possible.Accepting an association between bronchiolitis

obliterans and rheumatoid disease,3 the cases pre-

sented here raise three que. tions. Firstly, is there anassociation between CEP and rheumatoid disease?Secondly, can CEP progress to bronchiolitisobliterans? And, finally, in rheumatoid disease, isbronchiolitis obliterans on occasion a late mani-festation of CEP? The evidence provided here is byno means conclusive, but it is hoped that the de-scription of these cases may stimulate further obser-vations in this field. Parallel studies of CEP, bronchi-olitis obliterans, and rheumatoid disease will berequired to provide the answers.

I thank Dr WM Thurlbeck, who reviewed themanuscript; Dr CB Carrington for encouragementand helpful discussion of the cases; Drs FD Barager,W Kepron, and RH McFarlane for clinical details;Erika Jahnke for help with the photographs; andBetty Minton and Kathy Braun, who typed themanuscript.

References

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3 Geddes DM, Corrin B, Brewerton DA, Davies RJ,Turner-Warwick M. Progressive airway obliteration inadults and its association with rheumatoid disease.Q J Med 1977;184:427-43.

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Requests for reprints to: Dr TP Cooney, Department ofPathology, University of British Columbia, Acute CareHospital, 2211 Wesbrook Mall, Vancouver, BC, V6TIWs.

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