jclin chronic transmural bronchiolitis: a non-specific

J Clin Pathol 1992;45:993-998

Chronic transmural bronchiolitis: a non-specificlesion of small airways

C Edwards, R Cayton, R Bryan

AbstractAims: To investigate nine patients withhistological changes at open lung biopsycompatible with so-called "small airwaysdisease"; to define these changes anddistinguish them from other types ofbronchiolitis; and to correlate them withclinical features, respiratory physiology,and other laboratory investigations.Methods: The open biopsy sections andthe clinical records were reviewed.Results: There was chronic inflammationof the walls of centri-acinar respiratorybronchioles and peribronchiolar alveoli.Peripheral alveoli of affected acini werespared. Although lumens were narrowedand distorted, obstruction by granulationtissue plugs was not a feature. Clinicalbackgrounds included Hodgkin's disease,yellow nail syndrome, sicca syndrome,asthma and psoriasis. The main present-ing symptoms were cough, dyspnoea andwheeze, often associated with basal crack-les and basal shadowing. There was noconsistent immunological or haematolog-ical abnormality. Sputum culture wasnegative in six patients, and a variety oforganisms were cultured from three oth-ers. In most cases respiratory functiontests revealed an irreversible obstructivedefect (combined in some cases with arestrictive defect), gas trapping, and wellpreserved gas transfer. Lung volumeswere normal. Bronchodilators, with ste-roids and azathioprine in more seriouslyaffected patients, stabilised the diseaseprocess.Conclusions: The histological changesmay be distinguished from bronchiolitisobliterans and bronchiolitis obliteransorganising pneumonia by the absence ofintraluminal granulation tissue plugs, andfrom the obliterative bronchiolitis ofrheumatoid disease and diffuse peribron-chiolitis on clinical grounds. Althoughoften striking, this lesion does not repre-sent a clinico-pathological entity, and mayoccur in the distal lung in association witha number of different diseases. "Smallairways disease" is often used by clini-cians in a functional context, and maylead to confusion. It is suggested that"chronic transmural bronchiolitis" is amore appropriate term.

(3 Clin Pathol 1992;45:993-998)

Although asthma, chronic bronchitis andemphysema, bronchiectasis, and cystic fibrosisare the commonest causes of obstructive lungdisease, disorders of smaller airways may leadto similar clinical and physiological changes.These conditions have been classified by Kindtet al as bronchiolitis obliterans, bronchiolitisobliterans organising pneumonia (BOOP), dif-fuse panbronchiolitis and "small airways dis-ease".' Bronchiolar inflammation also occursin graft-versus-host disease,2 connective tissuedisorders,3 pulmonary and cardio-pulmonarytransplantation,24 T-cell leukaemia,' ulcerativecolitis6 and human immunodeficiency virus(HIV) infection.7 Xanthomatous bronchiolitisobliterans8 and follicular bronchitis and bron-chiolitis9 are also recognised.

"Small airways disease" is a somewhat illdefined chronic inflammatory condition ofbronchioles and distal bronchi, first describedin 1971 by Macklem et al.10 In a more recentstudy 11 of 16 patients with bronchiolardisease had biopsy specimens changes akin tothose reported by Macklem's group.' In thispaper we report a further nine patients, andsuggest that "chronic transmural bronchioli-tis" is a more appropriate term.

MethodsIn each case sections and paraffin wax blocksof the open lung biopsy specimens wereavailable, together with the clinical notes.Sections were stained with haematoxylin andeosin, and by the elastic van Gieson method.Measurements of lung function were obtainedfrom the clinical records. These includedforced expiratory volume in one second(FEV1) and forced vital capacity (FVC), FEV-1 :FVC ratio, total lung capacity (TLC), resid-ual volume (RV) and recordings of maximalexpiratory and inspiratory flow-volume loopstogether with diffusing capacity for carbonmonoxide corrected for alveolar volume(KCO). Lung functions were expressed as apercentage of the predicted values."The clinical and radiological details of the

nine patients are summarised in table 1. Case 1had had bronchiolitis as a neonate and hadspent several weeks in an oxygen tent. Case 2had been diagnosed as having stage IIa Hodg-kin's disease three months before presentation,and developed a series of respiratory infectionsafter starting a course of chemotherapy (mus-tine, vincristine, procarbazine and predniso-lone) and radiotherapy. Case 3 had beentreated with salazopyrin, tiaprofenic acid, dihy-

Department ofHistopathologyC EdwardsR BryanDepartment ofRespiratoryPhysiologyR CaytonEast BirminghamHospital, BordesleyGreen East,Birmingham B9 SSTCorrespondence to:Dr C W EdwardsAccepted for publication18 May 1992

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Edwards, Cayton, Bryan

Table I Clinical details

Case No Age and sex Smoking Presenting symptoms Clinical findings Chest radiograph

1 F32 20/day Asthma 7 y, dyspnoea, dry cough, wheeze Bilateral wheeze Normal2 F34 20/day Hodgkin's disease, dyspnoea, dry cough, fever, Basal crackles, clubbing Basal shadows

arthralgia 3 months3 F40 Non-smoker Sicca syndrome 17 y, polyarthropathy, dyspnoea, Normal Normal

dry cough 18 months4 F42 Non-smoker Dyspnoea, malaise, arthralgia, pyrexia and rigors, 8 Basal crackles, splinter haem- Basal shadows

months orrhages5 F51 20/day Dyspnoea, productive cough 15 y Basal crackles, hepatomegaly Diffuse pulmonary shadows6 F63 20/day Dyspnoea, productive cough 12 months. Anorexia, Normal Right mid and lower zone

weight loss fibrosis. Apical fibrosis7 F66 Non-smoker Paroxysmal productive cough 4 y Fine crackles, wheeze Soft micronodular shadows,

left mid zone8 M42 Ex-smoker Asthma 7 years. Dyspnoea paroxysmal productive Basal crackles Bilateral basal shadowing

(4 years) cough. Occasional haemoptysis 4 y9 M45 Ex-smoker Dyspnoea, productive cough, malaise, myalgia 4 y. Normal Left basal shadowing

Yellow nail syndrome

drocodeine and paracetamol: she had neverreceived gold or penicillamine. Case 5 datedher symptoms from a pneumonic episode 15years previously. Case 6 had been treated fortuberculosis on the basis of the radiologicalfindings. Case 7 had had pleurisy 12 yearsbefore presentation, but had only been symp-tomatic for four years. None of the otherpatients mentioned any antecedent respiratoryinfection, and all denied contact with allergensor birds.Pulmonary function tests and the results of

laboratory investigations are summarised intables 2 and 3, respectively. In most cases therewas evidence of airflow obstruction, which waslargely irreversible. The FEVI was reduced incases 1, 4, 5, 6 and 8, and there was anassociated reduction in FEVI :FEV ratio below70% in cases 1, 5, and 8. TLC varied from61-116% of the predicted value, indicatingthat hyperinflation was not a feature. Residualvolume was high in cases 1, 3, 5, 6, 7 and 8,this being reflected in the increased RV:TLCratio in the same subjects. Case 4 was quitedifferent in that she had the features of a

Table 2 Respiratory function tests (All values % predicted)

Case No 1 2 3 4 5 6 7 8 9

FEVI 37 62 22 41 81 59 85FVC 71 31 62 41 62 88 80 89FEV1/FVC 54 97 54 72 100 21 88TLC 104 116 61 92 84 107 100 87RV 190 179 61 185 150 141 154 77RV/TLC 183 154 100 200 165 134 154 33KCO 78 71 72 114 75 84 85 91

restrictive ventilatory defect, with a low FEVI,FVC, andTLC. In case 9 the abnormality was

less severe, but the pattern also favoured a

restrictive ventilatory defect. Flow-volumeloops in cases 1, 7, 8 and 9 also showedchanges compatible with dysfunction of smallairways. Gas transfer was, in general, wellpreserved, the KCO ranging from 71-114%predicted. The lowest measurements were

recorded in cases 1, 3, and 6 with airflowobstruction, and in case 6 with a restrictivedefect. Pulmonary function testing was notcarried out in case 2.Immunological investigations (table 3) failed

to reveal any consistent abnormality. In case 2immunity to tetanus, diphtheria, Escherichiacoli and pneumococcal toxoids was impaired.In case 9 neutrophil function was normal, andthere was a normal response to diphtheria andtetanus toxoids: there was no abnormality ofT4:T8 function, or of lymphocyte response tomitogens and antigens. Serum IgA concentra-tions in case 8 were normal, and the normalquantity of IgA was present in a duodenalbiopsy specimen. Other laboratory tests alsofailed to reveal any consistent pattern. Thepancytopenia in case 2 was presumed to be theresult of chemotherapy for Hodgkin's disease.Blood cultures in case 4 were persistentlynegative, despite the splinter haemorrhages.

In seven cases the disease was stabilised withvarious combinations of oral and inhaledbronchodilators, steroids, azathioprine andantibiotics (table 4). Two cases have been lostto follow up. Case 5 died in respiratory failurefour years after presentation; permission for

Table 3 Laboratory investigations

Serum protein Autoantibodies Precipitin Other Sputum bacteriology

1 Normal ANA negative N/A H influenzaeB catarrhalis

2 Low IgA ANA, RA latex, Rose Waaler Aspergillus negative Pancytopenia H influenzae, Klebsiellanegative species, S aureus

3 Normal ANA, RA latex, Rose Waaler N/A ESR 20 mm/h Normal floranegative

4 Raised IgM ANA negative; RA latex, Rose N/A Iron deficiency anaemia. Normal floraWaaer, IgMab positive Hepatitis B negative

5 Slightly raised IgM, IgG ANA positive; RA latex, Aspergillus, pigeon, chicken Hepatitis B negative Normal floraDNAab negative negative; budgerigar weakly Hepatitis A positive

positive6 Normal N/A N/A N/A Normal flora7 Raised IgG ANA, RA latex negative Aspergillus positive Raised EST, low serum iron. Normal flora

Thyroxine 9-l, TSH 7-68 Raised IgG, IgM, IgE, IgG, N/A Pigeon positive Raised orosomucoid S aureus

Aspergillus, budgerigar, chickennegative

9 Normal ANA, RA latex negative Raised C-reactive protein Normal floraILeukocytosis

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Chronic transmural bronchiolitis

Table 4 Treatment and follow up

Treatment Follow up

1 Steroids, bronchodilators, antibiotics, Stable 3 yearsazathioprine

2 Chemotherapy antibiotics Well 5 years later3 N/K N/K4 Steroids, azathioprine Stable 2 years5 Steroids, antibiotics, bronchodilators Died 4 years after presentation6 N/K N/K7 Steroids, bronchodilators Improved after 1 year8 Steroids, bronchodilators Symptomatic improvement after three years9 Steroids, azathioprine Improved after 2 years

necropsy was not obtained. Cases 4 and 8 havedeveloped non-specific chronic gastritis con-firmed by biopsy. A computed tomogram ofcase 8 showed changes compatible with bron-chiolitis, and case 9 was shown to havebronchiectasis.

Pathological findingsThe specimens submitted consisted of wedgesof lung tissue varying from 2-6 cm across themajor axis. In seven instances the specimenhad been injected with formalin to distend theair spaces and avoid artefact due to post-operative collapse.Although no abnormality was noted on gross

examination of the specimens, in five casescentriacinar and sub-pleural mottling wasapparent in the sections to the naked eye (fig1). Microscopically, the walls of a variableproportion of terminal and proximal respira-tory bronchioles were thickened and infiltratedby lymphocytes, plasma cells, and a fewneutrophils (figs 2 and 3). The bronchiolarmuscle was either disrupted or entirely des-troyed. In two cases there were scattered,somewhat ill defined lymphoid follicles amongthe inflammatory cells (fig 2).

As the airways extended into the centre ofthe acini, where the inflammatory process wasmaximal, the lumen narrowed, often abruptly,breaking up into a series of smaller, distortedpassages lined by cuboidal, non-ciliated epi-thelium (figs 2 and 3), reminiscent in someways of the bile duct proliferation of chronicliver disease. The walls of adjacent alveoli werealso thickened and infiltrated by chronicinflammatory cells: those towards the periph-ery were normal. The lumens ofmore proximalbronchioles were often dilated to a maximumdiameter of 750,um, were lined by apparentlynormal ciliated epithelium, and frequentlycontained a small quantity of muco-purulentmaterial.The inflammatory process often extended to

the pleural surface from adjacent airways, andwas associated with reactive change in theoverlying mesothelium. Muscular pulmonaryarteries also showed reactive change, withintimal fibrosis and medial hypertrophy (fig 3).The vasculature in the unaffected areas of thebiopsy specimens was normal: there was neverany evidence of pulmonary hypertension.

In two specimens (cases 2 and 7) there werescanty foci of organising exudate in alveolarspaces, and in one of these (case 2) a smallquantity of exudate was present in a singlebronchiole. The alveoli in four cases (2, 7, 8and 9) showed some evidence of obstructivechange, with an excess of intra-alveolar macro-phages and a little proliferation of type IIalveolar lining cells; in cases 2 and 8 there wereneutrophils in occasional alveoli, and in case 9the subpleural lymphatics showed the charac-teristic dilatation of yellow nail syndrome. Theseverest changes were present in case 8, wherefibrosis was extensive, and associated withearly "honeycombing" (fig 4).

Figure 1 A whole sectionof an open lung biopsyspecimen showingcentriacinar mottling: case7 bar: 5 mm.

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DiscussionThe histological changes in the airways of thisgroup of patients share certain features incommon with diffuse panbronchiolitis,'2 13 theobliterative bronchiolitis of rheumatoid dis-ease3 14 and "small airways disease".' 10 Dif-fuse panbronchiolitis is a disorder of the"transitional zone" of the lung, which islocated just distal to the terminal bronchiole, at

the point where the air passage assumes a

respiratory as well as a conductive function.'2Bronchiolar walls are infiltrated by histiocytes,

Figure 3 An inflamedterminal bronchiole(arrow) enters the fieldfrom the left andterminates abruptly. Theadjacent muscularpulmonary artery showsreactive mural thickening(arrowheads): case 4, bar:500 pm.

lymphocytes, and plasma cells. The infiltrateextends into the adjacent pulmonary inter-stitium; proximally, terminal bronchiolesdilate, and distally foamy cells accumulate inthe peribronchiolar parenchyma. In necropsy

tissue bronchiolar lumens are occluded bygranulation tissue. 3

Diffuse panbronchiolitis seems to be ende-mic in Japan, but has a low prevalence gen-

erally.'2 A single European case in an Italianman was reported in 1990' and further cases

have been reported from North America.'6 It

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Figure 2 A terminalbronchiole (arrow),surrounded by fibroustissue and inflammatorycells, runs into the fieldfrom the left, and breaksup abruptly into smallerairways. Scattered, illdefined aggregates oflymphocytic cells arepresent: case 9, bar:500pum.

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Chronic transmural bronchiolitis

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affects men more commonly than women andgenerally presents after the age of 40: over 75%of patients have chronic sinusitis. Initially thereis wheeze, cough, dyspnoea and hypoxaemia;later the sputum becomes purulent, and cul-ture yields Pseudomonas aeruginosa in over 60%of cases. Pulmonary function tests show severe

obstructive and slight restrictive defects. Bron-chiolar lavage fluid contains a higher percen-tage of neutrophils and macrophages than inchronic bronchitic and normal subjects.'7Death usually results from respiratory failure.The aetiology of diffuse panbronchiolitis is

unknown. Smoking is not a factor; there isnever a history of exposure to toxic gas or a

preceding infection, or of chronic bronchitis,bronchiectasis, emphysema or asthma. Serumsecretory IgA is high, but this is probably a

non-specific expression of chronic airwayinflammation.'8 A chronic increase in coldhaemagglutination titre has also been repor-ted.'9 In some cases there is a familial inci-dence.9There seems to be an association withT-cell leukaemia, a disease cased by HTLV-1which is frequently complicated by pulmonaryinfiltration and fibrosis.5 20`22 It has been sug-

gested that HTLV-1 may affect the bronchiolesas well as lymphocytes and the central nervous

system.5 22

The obliterative bronchiolitis of rheumatoidarthritis and other connective tissue dis-eases3 14 21 is characterised by destruction ofbronchiolar walls by a mixed inflammatoryinfiltrate. Luminal plugging by granulationtissue is not a feature 14; the appearancesconform to the less comon "constrictive"pattern of bronchiolitis as defined by Gosink etal.24 Lung function tests indicate airflowobstruction with air trapping and normal gastransfer. 14 25 Steroids are of little value, and theprognosis is poor. The pathogenesis is uncer-

ill '17*

tain; penicillamine has been proposed as a

factor, but its exact role is uncertain.26 27The concept of small airways disease was

proposed by Macklem et al,'0 who described a

series of seven patients with chronic obstruc-tive disease of small airways, but with no

evidence of severe or extensive emphysema.Three were found to have bronchiectasis atnecropsy, and two others were thought to havebronchiectasis, although this was never proved.Bronchiolar inflammation and mucous plug-ging were features in all cases, the importantpoint being that it was more extensive than thebronchiectasis itself. A somewhat similar het-erogeneous group of 16 patients with smallairway lesions was reported more recently.' Infive the biopsy specimens showed the featuresof bronchiolitis obliterans. In the remainderbronchiolar inflammation without obliterationwas the most consistent finding; in three theinflammatory process had spread to the inter-stitium. Overall, there was a severe, irreversibleobstructive defect and occasionally a restrictivedefect, with a high percentage (greater than25%) of neutrophils in bronchoalveolar lavagefluid.

In bronchiolitis obliterans, bronchioles are

occluded by granulation tissue, and laterreplaced by fibrous tissue. Alveoli are notaffected. This type of lesion occurs in marrowor heart-lung transplant recipients,27 28 inpatients with rheumatoid arthritis who may or

may not be receiving gold or pencillaminetreatment, other collagen diseases, and afterviral infections or inhalation of toxic fumes.25Some cases seem to be idiopathic. A somewhatsimilar condition affecting larger bronchi hasbeen described in Stevens-Johnson syn-drome.2930

The entity now generally referred to as

BOOP, following a report of 57 cases by Epler

Figure 4 An area of early"honeycomb" change incase 8. Bar: 500 um.

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et al in 1985,3' was first described by Davisonet al in 1983,32 who used the term "crypto-genic organising pneumonitis". This condi-tion, which may be idiopathic or associatedwith exposure to fumes, drugs, or an infection,or with a connective tissue disorder25 27 ischaracterised by proliferation of granulationtissue alveoli as well as bronchioles ("burgeonsconjunctifs" or Masson bodies). Response tosteroids is usually favourable.25 33

Clinically, our patients are also a heterogen-eous group. None fulfilled the clinical criteriafor diffuse panbronchiolitis, and none hadclear-cut evidence of a connective tissue disor-der. The histological changes, however, weresimilar throughout, and appeared to be iden-tical with the "small airways disease" des-cribed by Macklem et al'° and Kindt et al.'"Small airways disease" therefore seems to benon-specific, and may arise as a result ofdifferent insults. It does not represent a distinctand definable clinico-pathological entity.

Despite the disparate clinical backgrounds,and non-specific histology, our patients doshare certain features. This type of lesion seemsto be commoner in women in the fourth or

fifth decade of life. Presenting symptoms are

cough (which may be paroxysmal), dyspnoeaand wheeze, frequently associated with myalgiaor arthralgia. On auscultation there are basalcrackles, and opacities, usually basally situ-ated, are seen on chest radiographs. In some

cases there may be no radiological abnormal-ity. Respiratory function tests reveal a

predominantly obstructive ventilatory defectwith little hyperinflation but considerable gas

trapping, similar to that described in a clinicalseries of patients with disease of small airwaysby Turton et al.34 The airflow obstruction islargely irreversible, and the RV and RV:TLCvalues indicated gas trapping at the levelexpected in emphysema, but without the cor-

responding increase in lung volume. There isno gross impairment of gas transfer. Labo-ratory tests are unhelpful, and serologicalinvestigations for connective tissue diseasetend to be negative or inconclusive. Althoughthere may be a history of smoking, the changesare more severe than those described in cigar-atte smokers.35 The disease process may bestabilised with bronchodilators alone, but ste-roids or azathioprine may also be needed. Thenature of the changes, however, suggests thatcomplete return to normal morphology andfunction is unlikely to occur.When reporting biopsy material, this type of

lesion must be distinguished from bronchiolitisobliterans and BOOP, and from other more

specific conditions such as diffuse panbron-chiolitis and the bronchiolitis of rheumatoidarthritis. The term "small airways disease" isimprecise, and may also lead to confusionbecause it is often used by clinicians in a

physiological rather than a morphological con-

text. We suggest that "chronic transmuralbroncholitis" is a more appropriate designa-tion-adding the caveat that it is a histologicalchange, and not a clinico-pathological entity.Its presence in biopsy material should signalthe need for further investigation.

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3 Hakala M, Paakko P, Sutinen S, Huhti E, Koivisto 0,Tarkka M. Association of bronchiolitis with connectivetissue disorders. Am Rheum Dis 1986;45:656-62.

4 Yousem SA, Paradis IL, Dauber JH, Griffith BP. Efficacy oftransbronchial lung biopsy in the diagnosis of bron-chiolitis obliterans in heart-lung transplant recipients.Transplantation 1989;47:893-5.

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