chronic eosinophilic pneumonia - thorax · chronic eosinophilic pneumonia high and a modest...

Thorax, 1980, 35, 570-580

Chronic eosinophilic pneumoniaBERNARD FOX AND WILLIAM A SEED

From the Departments of Histopathology and Medicine, Charing Cross Hospital Medical School, London

ABSTRACT We describe three cases of eosinophilic pneumonia of unknown aetiology investigatedclinically and by lung biopsy. The illnesses lasted between six and 20 weeks and consisted of cough,dyspnoea, malaise, and in two cases prolonged pyrexia. All had blood eosinophilia and chestradiographs showing widespread bilateral shadowing; in two cases this had a characteristic per-ipheral distribution. One patient recovered spontaneously and the other two responded to steroids,with disappearance of pyrexia within 12 hours and radiological clearing within 14 days. Lungfunction tests during the acute illness showed volume restriction or gas transfer defects or both intwo cases. After remission all three showed abnormalities of small airways function. Lung biopsiesperformed during the acute illness were examined histologically and by transmission electronmicroscopy, and in two cases by immunofluorescence. There was both intra-alveolar and inter-stitial eosinophilic pneumonia with bronchiolitis obliterans, microgranulomata, and a vasculitis.Electron microscopy showed numerous eosinophils, many degranulated, and macrophages withphagocytosed eosinophilic granules and intracytoplasmic inclusions. In one case IgM, IgG, and IgAwere demonstrated in the bronchial walls and interstitium. No IgE or complement was present. Webelieve that eosinophil granules are responsible for the tissue damage and fever, and suggestmechanisms for this and for the response to steroid therapy.

Chest radiographic shadowing in combinationwith blood eosinophilia occurs in a number ofclinical contexts, and these have been dividedby Crofton et al,' on purely clinical grounds,into five categories: (1) simple pulmonaryeosinophilia (Loffler's syndrome); (2) prolongedpulmonary eosinophilia without asthma; (3) pul-monary eosinophilia witlh asthma; (4) tropicalpulmonary eosinophilia; (5) polyarteritis nodosa.However, cases occur which run a chronic

course and are difficult to fit into this classifica-tion, since they may or may not have asthma.Carrington and his colleagues2 3 have used theterm chronic eosinophilic pneumonia to describethese, and have demonstrated that lung biopsiesfrom such cases show a uniform histologicalappearance. Lung function, ultrastructure, andimmunofluorescent studies of biopsy materialhave rarely been reported. We describe threecases of chronic eosinophilic pneumonia in whichthese aspects were investigated.

Case reports

CASE 1A 72-year-old priest presented with a three-Address for reprint requests: Dr WA Seed, Department of Medicine,Charing Cross Hospital Medical School, London W6.

month history of worsening effort dyspnoea, drycough, malaise, fever with night sweats, andcccasional rigors. His appetite was poor and hehad lost 10 kg in weight. He had a history ofmild asthma for 12 years (treated with salbuta-mol and intermittent beclomethasone by inhala-tion), and myocardial ischa,emia (treated withdigoxin and frusemide).On admission he was febrile (38&10C) and un-

-ell. The only abnormal signs were in his chest,where there were widespread sparse wheezes, andcrackles confined to the left upper zone.

Chest radiography (fig 1) showed shadowingin the left upp.er and mid-zones, most markedperipherally, and patchy changes in the rightupper zone. Tests produced the following results:Hb-13-3 g/dl; WBC-12-3 X 109/1, with 52%yoneutrophils, 11 % lymphocytes, 7% monocytesand 30% eosinophils (absolute eosinophil count3X69 x 109/1); ESR-over 100 mm/hr; sputum-light growth of Candida albicans, but no sig-nificant pathogens isolated from many samples;serum immunoglobulins-IgG 21 g/l, IgA3-1 g/l, IgM 1l7 g/l, IgE 240 (later 94) IU/ml.The results of lung function tests are shown intable 1. Arterial blood gases with the patientbreathing air were p0, 55 mmHg, PCO2 33 5mmHg, pH 7-44. Skin test reactions to common

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Fig 1 Chest radiograph of case 1, showing shadowingin both upper zones

Table 1 Lung function tests during acute illness.Cases I and 3 were studied before biopsy, case 2 oneweek after biopsy. Figures in brackets are the valueexpressed as a percentage of the predicted normalvalue. Values more than 2SD from the predictednormal value are starred. Predicted normal values arederived from Cotes.4

Lung function tests Case I Case 2 Case 3

Airways measurementsPEVI (IBTPS) 2-10 (91) *1-35 (57) 3 40 (133)FVC (IBTPS) 2-90 (86) *1-45 (50) 4-15 (127)FEV1/FVC(%) 73 (113) 92 (115) 81 (100)PEFR (IBTPS S-') 5-3 (67) *2-9 (47) 8-5 (129)Volumes (He dilution) IBTPSFRC *2-20 (61) 2-0 (75) 3 25 (113)TLC 4 55 (78) *2.85 (64) 5 75 (115)VC 3-06 (91) *1-47 (51) 4-44 (136)RV (steady state) 1-49 (66) 1-40 (92) 1-32 (77)RV (single breath) *1j35 (60) 1 50 (99) 1-30 (76)Gas transfer (single breath)Dco (mmol CO min-l kPa'1) 4-98 (69) *3-14 (41) 9 13 (112)Kco (mmol CO min-I kPa-l 1-1) 1-34 (107) *1-25 (72) 1 72 (98)

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allergens, including Aspergillus sp, were nega-tive. Results of other investigations, listed below,were negative.During the next four weeks the patient re-

mained unwell and pyrexial, with a mild normo-chromic, normocytic anaemia (Hb 10-7 g/dl)and variabl.e eosinophilia (01 to 422XI09/litre).Serial chest radiographs showed some extensionof the shadowing in the left lung, but the upperzone changes in both lungs remained static.Bronchoscopy revealed small, pale nodules inthe left upper lobe and left apical lower lobebronchi, but was otherwise normal. Biopsies ofthe nodules revealed non-specific chronic in-flammation with plasma cell, neutrophil, andeosinophil infiltration.Four weeks after presentation, open biopsy of

the left upper lobe was performed. At operationthe lobe was consolidated, with fine adhesions tothe chest wall and pericardium and patchy con-solidation in the lower lobe. There was nopleural fluid. Postoperatively, fever and inter-mittent eosinophilia continued, and oral predni-solone, 30 mg/day, was started. The temperatureresolved within 12 hours (fig 2) and the chestradiograph after two we.eks was clear apart froma small area of scarring at the left apex whichantedated the present illness. Prednisolone wasgradually withdrawn over six months and thepatient remained clinically and radiologicallywell for several months. Lung function studiesduring this remission are listed in table 2. Fivemonths after withdrawal of steroids he relapsed,with fresh shadowing in the posterior part ofthe right lower lobe (an area previously spared)and eosinophilia of 3.4X 109/1. The principalsymptom on this occasion was dyspnoea, withclinical and functional evidence of gross airwaysobstruction (FEV1 0-85 1, FVC 1-6 1). He made

AA)V/lvFig 2 Temperature chartsfrom cases I (lower) and 2(upper) showing the effect ofstarting oral steroid therapy(P). ---- indicates anoutpatient period with nomeasurements,

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5 6 7 8 9 1 11 12 13 14 15 16 17 18DAYS

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Table 2 Lung function tests during remission andoff treatment. Notation and units (except wheregiven) as table 1. Predicted normal values for Vmax.,50% VC5; closing volume,6 phase 3 slope,7 mixingindex-our laboratory unpublished.

Lung function tests

Airways measurementsFIvtFVCFhVI/FVCPEFRVmax, 50% VC (IBTPSs-1)Closing volume (%VC)Phase 3 slope (%N2 IBTPS-1)

(single breath N2 test)VolumesFRCTLCvCRV (steady state)RV (single breath)Mixing index (RV/sBRVss x 100)

Gas transferDcoKco

Case I Case 2

2-10 (91)2-95 (89)

71 (111)7-01 (90)

*1-08 (33)28-8 (106)

2-10 (90)2-65 (93)80 (100)

5-43 (89)*2-68 (70)21-6 (132)

*2-1 (140) 1-2 (80)

4 25 (131)6-70 (117)3-14 (95)*3-56 (159)1-75 (78)*49

3 0 (128)4-8 (110)2-70 (95)2-12 (143)0-95 (64)*45

5-52 (79) 5-54 (73)1-29 (104) 1-66 (95)

a rapid response to oral prednisolone 60 mg/day, plus an initial continuous infusion of sal-butamol, and remains well on a tapering doseof prednisolone. The effect of steroids on theblood eosinophilia is shown in fig 3.

4

BLOODEOSINOPHIL

COUNT(X 109I1itre)

Bernard Fox and William A Seed

CASE 2A 47-year-old female filing clerk presented witha six-week history of prog.ressive dyspnoea, weak-ness, and 7 kg weight loss. Her previous historywas healthy. On admission she was thin and ill,with pyrexia to 39°C. Abnormal signs were con-fined to the chest, with dullness to percussionand sparse crackles at the right base anteriorly.

Chest radiography (fig 4) showed extensivepatchy shadowing throughout the right lung, andmore localised linear shadowing in the left midand lower zones. T.ests produced the followingresults: Hb-111 g/dl; WBC-14-3X109/1, with91% neutrophils, 4% lymphocytes, and 5%monocytes; ESR-92 mm/hr; sputum-lightgrowth of penicillin-sensitive coagulase-positiveStaphylococcus aur eus; serum immunoglobulins-IgG 11P0 g/l, IgA 3-8 g/l, IgM 1P5 g/l, IgE<30 IU/ml. Arterial blood gases with thepatient breathing 40% oxygen were pO2 128mmHg, PCO2 38 mmHg, pH 7-38.The patient was treated with ampicillin and

flucloxacillin, 500 mg six hourly, for eight dayswithout clinical or radiological improvement.Repeated sputum cultures were sterile apartfrom occasional isolations of Candida albicans.Blood counts showed a progressive fall in haemo-globin to 7 9 g/dl, and leucocytosis (12-0-14-8X l09/l) with 84-86% of neutrophils and 4-5%eosinophils (absolute eosinophil counts 0 56-0-59 X 109/1).She remained severely ill and after two weeks

was started on antituberculous chemotherapy.However, she continued to deteriorate, andfurther chest films showed extension of shadow-ing throughout the left lung and in the rightupper zone. ESR and white blood count remained

2 4 6 8 10 12

TIME (HOURS)

Fig 3 Case 1: effect of oral steroid therapy onblood eosinophil count.

Fig 4 Chest radiograph of case 2, showing bilateralperipheral shadowing.

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Chronic eosinophilic pneumonia

high and a modest eosinophilia (up to 1-10 X109/l) persisted. After four weeks in hospital shewas transfused with three units of blood andopen biopsy of the left upper lobe was per-formed. At operation, the whole left lungappeared inflamed, with a few pleural adhesionsbut no effusion. Post operatively she remainedpyrexial until prednisolone 30 mg a day wasstarted, when her temperature rapidly settled(fig 2) and she improved clinically. The eosino-phil count was normal five days later, and chestradiograph after two weeks showed only a smallarea of shadowing in the right mid-zone and left-sided pleural changes secondary to the thora-cotomy. Tomography of the lesion in the rightlung showed a 1 cm area of shadowing consistentwith localised fibrosis. Prednisolone was gradu-ally withdrawn and then stopped after sixmonths, and the patient remains well. Lungfunction tests performed six days after the startof steroid treatment, and one week after with-drawal of steroids, are tabulated in tables 1and 2.

CASE 3A 46-year-old beautician presented with a two-month history of dry cough, followed by anor-exia, weight loss (3 kg), and night sweats. Forone week before admission she had noticed mildeffort dyspnoea. Her previous health had beengood. On admission she appeared well and wasafebrile; abnormal physical signs were confinedto the chest, where there was evidence of con-solidation in the right upper zone.

Chest radiography (fig 5) showed extensive peri-pheral shadowing in the right upper and midzones and similar but more localised changes in

Fig 5 Chest radiograph of case 3, showingperipheral shadowing in upper and mid zones.

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the left mid-zone. Tests produced the follow-ing results: Hb-11-4 g/dl; WBC-11-6X 109/l, with 40% neutrophils, 10% lympho-cytes, 3% monocytes, 47% eosinophils (absoluteeosinophil count 5-36 X 109/l); ESR-79 mm/hr.The sputum was extremely sparse, mucoid, andcontained no pathogens. Lung function testsproduced normal results (table 1). Arterialblood gases with the patient breathing air wereP02 89 mmHg, pCO2 32 mmHg, pH 7-41. Serumimmunoglobulins were IgG 20 8 g/l, IgA 1-5g/l, IgM 1-8 g/l, IgE 91 IU/ml. Skin testing waspositive to a number of common allergens,though not to Aspergillus. She remained afebrile,with only minor symptoms, but blood eosino-pdiilia persisted with absolute counts between3-42 and 7 0x 109/l. Chest radiography showedextension of the shadowing in the left lung tothe upper zone, and slight clearing on the right.Two weeks after admission transbronchial biopsyof the right upper lobe was performed via afibreoptic bronchoscope, and shortly after thisshe was allowed home. Three weeks later, herchest film showed complete clearing, and hasremained normal during six months follow-upthough a mild blood eosinophilia persists (0-6-0-9 X 109/litre).

Other investigationsThe following investigations were carried outon all three patients and were normal or nega-tive: serum electrolytes, urea, creatinine, calcium,phosphate; liver function tests; serological testsfor syphilis; Widal test; immunofluorescent testsfor antibodies to thyroid colloid, thyroid epithe-lial cell cytoplasm, gastric parietal cell cytoplasm,nuclei (ANF), mitochondria, and smoothmuscle; serial complement fixation tests againstthe following respiratory pathogens-adenovirus,cytomegalovirus, influenza A, B, and C, para-influenza 1 and 3, psittacosis, respiratory syncy-tial virus, Mycoplasm, Coxiella burneti; serumprecipitins to Aspergillus; filarial fluorescentantibody test; microscopy and culture of faeces;culture of throat swabs, MSU, and blood; urineand sputum culture for mycobacteria.Apart from the drugs mentioned in case 1,

none of the patients had been on any treat-ment in the months preceding their illness. Case1 had travelled to Australia in the early stageof his illness, without leaving the aircraft enroute; neither of the others had been abroadwithin the previous 12 months.

EXAMINATION OF LUNG TISSUEThe open biopsies (cases 1 and 2) were divided

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into four. One piece was used for transmissionelectron microscopy and fixed in Karnovskyfixative for four hours at 4°C. It was thenwashed overnight in cacodylate-sucrose buffer at4°C and then post-fixed in 1% aqueous osmiumtetroxide for one hour at 4°C. After rinsing indistilled water it was dehydrated to absoluteethanol, then placed in epoxypropane and freshwarm Araldite, and finally embedded in freshAraldite. Sections were stained with uranylacetate and lead nitrate, and examined in aPhillips 201 electron microscope.Another sample was cultured for bacteria,

fungi, and viruses and nothing was grown. Afurther piece was frozen for immunofluorescentstudies, and the remainder of the tissue was

fixed in 4% neutral formaldehyde for histology.In case 3 (fibreoptic biopsy) observations werelimited to histology and electron microscopy.

HISTOLOGYThe findings in cases 1 and 2 were similar. Themost striking change, which was diffusely dis-tributed throughout the lung, was consolidation,with alveoli filled by macrophages and eosino-phils, and widespread thickening of the alveolarwalls, lobular septa, and visceral pleura by oede-matous loose vascular conective tissue infiltratedby eosinophils, plasma cells, and macrophages(fig 6). There were many "cosinophilicabscesses"3 composed of masses of eosinophilicgranules, eosinophils, macrophages-some con-

9~' Fig 6 Case 1: lung biopsy showingintra-alveolar consolidation and cellular

<#.!t> M infiltration of alveolar and lobular septa.,.tS H anl E, original magnification x 100.

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Fig 7 Case 1: bronchiolitis obliteranswith ulceration of mucosa andinflammatory granulation tissue in

* ~~ lumen. H and E, original magnification

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taining eosinopihilic granules-and fibrin, oftenwith areas of necrosis, the whole lesion frequentlysurrounded by macrophages. There were areasof intra-alveolar organisation with vasculargranulation tissue infiltrated by plasma cells,eosinophils, and a few macrophages. Many ofthe alveoli were lined by cuboidal cells and con-tained oedema fluid. There were a few micro-granulomata, some related to bronchioles. Therewas bronchiolitis involving most of the bron-chioles and in some there was ulceration of themucosa; and the lumen was partly and in placescomlpletely occluded with granulation tissuecontaining eosinophils, macrophages, multinu-cleated giant cells, plasma cells, and fibrin(bronchiolitis obliterans) (fig 7). Some of thebronchioles were filled by mucus containingeosinophils, macrophages, plasma cells, and oc-casional multinucleated giant cells. In areasthere was an obstructive type of pneumonia withalveoli containing many lipid-filled macrophages(fig 6).

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There was a mild arteritis with eosinophils,plasma cells, and macrophages involving theadventitia and media but there was no evidenceof necrosis nor w,ere the veins involved. Smallpulmonary arteries showed narrowing of thelumen by vascullar connective tissue and therewas also moderate hyperplasia of the media.

In case 3, thelre was marked peribronchial con-solidation with macrophages (some containingeosinophilic granules), plasma cells and oc-casional clusters of eosinophils. There was alsointra-alveolar organisation and obstructive lipidpneumonia similar to that seen in cases 1 and 2.Howev,er, there was no evidence of bronchiolitisobliterans, eosinophilic abscesses, or vasculitis inthe small amount of tissue available.No organisms or fungi were seen in any of

the cases.

ELECTRON MICROSCOPYThe findings were similar in all three cases.There were many eosinophils and macrophages

n _ _ AN.

Fig 8 Case 3: eosinophil with normal (small arrow) and degranulated (large arrow) granules in alveolarcapillary. Electron micrograph, bar mark 2 ,m.



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in the alveolar spaces and interstitial tissue.There were three main types of eosinophil. Onecontained normal granules composed of a densecentral core surrounded by a less dense matrix8;in the second the central core of the granuleswas translucent and the surrounding matrix wasmore dense. Finally there were some eosinophilswhich contained both types of granules, and incase 3 thes,e were also present in an alveolarcapillary (fig 8). Many of the macrophages con-tained eosinophilic granules and some fragmentsof eosinophils. There were cytolysosomes con-taining irregularly shaped translucent bodies(fig 9), and one macrophage in case 1 containeda rectangular shaped body surrounded by amultilayered membrane. Some of the macro-phages contained odd shaped cytoplasmic inclu-sions with a pentalaminar wall (fig 10).Within the interstitial tissue there were nor-

mal plasma cells, lymphocytes, and mast cells;some of the latter were degranulated. There wasfocal oedema of the alveolar capillary wall and

in places the alveoli were lined by type 2 cells.Deposits of immunie complexes were not seen.

IMMUNOFLUORESCENCEIn cases 1 and 2 the lungs were examined forIgA, IgG, IgM, IgE, fibrinogen, and Clq frac-tion of complement using commercially preparedFITC conjugated sera. Case 1 was negative; incase 2 IgG, IgA, and IgM were present in plasmacells and macrophages in the interstitial tissueand in the bronchial wall, and as irregular flecksin the connective tissue of the bronchial wall.Fibrinogen was present within alveoli in bothcases. In neither case was there evidence ofiimmune complexes.

Discussion

Our three cases demonstrate well the clinicaland pathological spectra of chronic eosinophilicpneumonia. We have found 60 published caseswith biopsy or necropsy histology which matched

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Fig 10 Case 3: macrophage (nucleus N, cell membrane CM, and mitochondria M) with pentalaminarinclusions (arrows). Electron micrograph, bar mark ,r,m.

that in our cases. Apart from two patients (onewith bronchopulmonary aspergillosis3 and onetreated with nitrofurantoin2) no aetiology wasestablished.2 3 8-23 Clinical details are only com-plete for about half these cases, but a remarkablycoherent picture emerges which is well illus-trated by our cases and summarised in table 3.The age distribution has a peak in the fifthdecade, and decays symmetrically about this;but no age group is exempt. Females preponder-

Table 3 Presenting clinical features in 63histologically confirmed cases of chronic eosinophilicpneumonia

Feature Incidence% Comment

Radiographic shadowing 100 Typical pattern in 60%(see text)

Blood eosinophilia 81 May be intermittent;absent throughout in 13 %

Fever 94 May reach 40°CCough 94 Productive in 80%Dyspnoea 84Weight loss 82 Up to 24 kgMalaise 83

ate by two to one. Asthma was present in 53 %,usually with a short history (m,ean duration sixyears, and less than five years in 70%); onsetin childhood has been described only once.Eosinophilia was occasionally gross (up to 25X 109/litre) but much more commonly wasmodest or intermittent (cases 1 and 2), and in asmall proportion of cases it is never seen.2Not suprisingly, severe cases (which comprise

about two-thirds of the total, and present withall the features listed in table 3) were oftentr,eated initially as bacterial pneumonia and sub-jected to lung biopsy because of a downhillcourse, as in cases 1 and 2. However, in 60-70%of all cases, the chest radiograph showed a peri-pheral pattern of shadowing (the "photographicnegative of pulmonary oedema") which has re-cently been demonstrated to be virtually diag-nostic. 23 Gaensler and Carrington23 recom-mended that, in view of the rapid response tosteroids which is typical of this disease (seebelow), a trial of steroid therapy is appropriate

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in such patients without biopsy. We accept thiswith reservation, since it will hinder explorationof a pathogenetic process which is still largelyobscur,e; and we would recommend fibreopticbiopsy whenever possible, since we have shownit to be an effective approach (case 3).The natural history of the diseas,e is reason-

ably well-established. Many of the reported caseshad *a protracted course before diagnosis andtreatment, and permanent spontaneous remis-sion (as in case 3) was seen in less than 10%.The vast majority were treated with steroids,and our experience in cas,es 1 and 2 is typical.There is dramatic resolution of pyrexia andblood eosinophilia followed by a rapid clinicaland radiological remission. The radiographusually clears completely within two weeks.Howuever, when steroids are withdrawn, one-thirdof cases sooner or later relapse (as did case 1),often with infiltrates in the same areas of thelungs.23 Such relapses, which have been recordedup to eight times in a single patient, continue torespond to steroids, and appear to be preventedby low dose maintenance therapy (< 10 mg pred-nisolone daily).Our patients all had lung function studies

during the acute illness (table 1). The mostsevere case (2) had both restrictive and gas-transfer defects, the latter more severe thancould be accounted for solely by the reduction ofalveolar volume. Case 1, of moderate severity,had a borderlin,e restrictive defect only duringthe first attack; the recurrence 15 months laterwas dominated by gross airways obstruction.Case 3, which was very mild, retained normallung function.There are few detailed reports of lung func-

tion during the acute untreated illness.2 12 15 19These are in keeping with our findings, and wecan summarise the acute situation thus: mildcases may have normal lung function; withincreasing severity volume restriction and a truedefect of gas transfer appear. In patients with aprevious history of asthma, airways obstructionmay occasionally be the dominant abnormality.Hypoxaemia caused by disturbed ventilation-perfusion relationships may be severe (p02 <50mmHg). Three deaths have been reported.3 16 23Our cases also illustrate the reversibility of

these lung function abnormalities with steroidtreatment; in particular, gas transfer defects areeliminated2 and fixed volume restriction is un-usual except in those patients with a severe,protracted course before treatment or with re-peated recurrences after steroid withdrawal. Theresponse to steroids suggests that resolution,

rather than organisation, of the pneumonic pro-cess occurs. This would be in keeping withthe dominance of cellul-ar and exudative changes,rather than necrosis, in biopsy specimens, and issupported by the observation of Perrault et al,12who repeated a needle biopsy of their patientduring remission. The only abnormality seen,in what had previously been a florid and typicalpicture, was minimal peribronchial fibrosis anda single healed granuloma.However, we disagree with the impression

given in many reports that the process is entirelyreversible. Both our open bi-opsies showed bron-chiolitis obliterans. In view of this, we includedtests of small airways function in the remissionstudies (table 2). In all three cases at least twoof these tests were abnormal. We, therefore,believe that an irreversible residuum of smallairways disease exists in our patients. probablycommensurate with the severity of the originalepisode, and that this may be a common featureof the disease. Tests of small airways functionhave not been reported previously, but bronchio-litis obliterans was a feature of a third of thebiopsi,es reported by Gaensler and Carrinigton."The histological changes in cases 1 and 2 were

characteristic of those described by Liebow andCarrington.3 In case 3 only a small amount oftissue was available but it was possible to con-firm the clinical diagnosis of eosinophilic pneu-monia. Although only a few eosinophils werefound in the histological sections many morewere seen by electronmicroscopy. The explana-tion for this disparity is that on electronmicros-copy it is easy to identify both normaland degranulated eosinophils whereas onlyeosinophils with normal granules will be readilyidentified in histological sections.24We have no direct evidence as to the cause

of eosinophilia in chronic eosinophilic pneumo-nia. Eosinophilia can accompany all four typesof immune reaction.24 In type 1 reactions mastc,ell degranulation appears to be the trigger. How-ever it is unlikely that this could play a signifi-cant role in a disease with such a prolongedand stable pulmonary reaction, and all ourpatients had normal serum IgE levels. Activa-tion of complement appears to be the stimulusfor eosinophilia in types 2 and 3 reactions butwe found no evidence of complement activationin our cases. In type 4 (cell-mediated) reactionsblood eosinophilia may be caused by the releasefrom lymphocytes of eosinophilic stimulatingand chemotactic factors.24 We interpret thepresence of microgranulomata as evidence of acell-mediated immune reaction and we favour

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this as the cause in our cases.The eosinophil appears to play a crucial role

in the pathogenesis of this disease; it is the pre-dominant cell in the tissue reaction, blood eosino-philia is usually present in the active stage, andwhen remission is produced by steroids eosino-philia rapidly disappears. It has been suggestedthat the damage to the (heart in Loffler's cardio-myopathy is caused by the eosinophilic gran-ules;25 cardiomyopathy is not a feature ofchronic eosinophilic pneumonia but this may bebecause the eosinophilia is milder and much lessprolonged. However it is possibl,e tihat the releaseof eosinophilic granules locally and in high con-centration in the lung, which we have demon-strated in our cases, is responsible for the tissuedamage. The substances present in the eosino-philic granules which could be implicated arehydrolases, myloperoxidases, or the basic proteinof the crystalloid internum,26 prostaglandins,27and thromboplastin.28 The cause of degranula-tion is not clear; however it seems likely thatagain an immunological mechanism may be im-plicated. Eosinophils can be stimulated to de-granulate in vitro by immune complexes,26aggregated IgG,29 and foetal calf serum,30 andit is possible that a similar type of stimulus mayhave been acting in these cases. In one case wefound IgG in the lung but we did not identifyimmune complexes. Eosinophils also produce apyrogen" and its release may be the explanationof the pyrexia seen in these cases. The dramaticresponse to steroids could be caused by theireosinopenic effect and by the stabilising effecton cell membranes which would prevent degran-ulation occurring.The crystalline cytoplasmic inclusions within

macrophages are probably the early intracellularstages of the formation of Charcot-Leydencrystals,32 which are often present in chroniceosinophilic pneumonia3 although they were notseen in histological sections in our cases. Thepentalaminar inclusions, which have not pre-viously been found in chronic eosinophilic pneu-mona,'9 20 resemble the intracytoplasmic in-clusions seen in histocytosis X,33 Langerhanscells of th,e epidermis,34 and macrophages in thelungs in the usual type of interstitial pneumoniaand bronchioalveolar carcinoma. 5 These in-clusions are probably formed from the surfacemembrane as the result of endocytosis.36The histological features of the pneumonic

process are not unique to this form of pulmonaryeosinophilia. An eosinophilic pneumonia may bepresent in Loffler's syndrome,'7 allergic broncho-pulmonary aspergillosis, polyarteritis nodosa,

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and tropical eosinophilia.38 The diagnosis, there-fore, depends upon clinical as well as histologicalfeatures, and a search for aetiological factors iscrucially important. This needs particular em-phasis in asthmatic patients, since all the present-ing features in table 3 (with the exception of thetypical radiographic pattern, whioh is not alwayspresent) may occur in allergic bronchopulmonaryaspergillosis or tropical eosinophilia. In this con-text, our finding of normal serum IgE levels inall our patients is interesting, since very highlevels are typical of the latter two diseases. How-ever, IgE levels have not been reported pre-viously in chronic eosinophilic pneumonia,and their value as a discriminant requiresconfirmation.

Crofton et all emphasised that cases of pul-monary eosinophilia form a continuum, and thattheir classification was arbitrary. Our cases illus-trate this. Criteria based on the duration of theillness or the presence of asthma may be trans-gressed both by cryptogenic cases like ours, andby cases where an agent such as a drug orparasite is incriminated. At pr.esent chroniceosinophilic pneumonia appears to be a genuineentity on clinical and histological grounds. Thisis useful therapeutically but exploration of itspathogenesis is overdue.

We are indebted to Dr RA Parkins and Dr PSnashall for permission to publish details of theircases. We would like to thank Mr RA Barnettand Mr TA Bull for technical assistance.

References

1 Crofton JW, Livingstone JL, Oswald NC,Roberts ATM. Pulmonary eosinophilia. Thorax1952; 7:1-35.

2 Carrington CB, Addington WW, Goff AM et al.Chronic eosinophilic pneumonia. N Engl J Med1969; 280:787-98.

3 Liebow AA, Carrington CB. The eosinophilicpneumonias. Medicine (Baltimore) 1969; 48:251-85.

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