Thorax 1991;46:545-547

THORAX

Editorials

BOOP and COP

Pathological descriptions of rare lung diseases oftenprecede their clinical recognition and classification. Theconfusion this can cause is well illustrated in the story ofOB, COP, and BOOP, which came about in the followingway.

In the first place pathologists described some characteris-tic patterns of response to insult in the lungs: bronchiolitiswith or without obliteration was one and intra-alveolarinflammation and fibrosis was another. The former wasdescribed as a common feature in infections and was foundwith bronchitis and bronchiectasis but occasionallyoccurred in isolation.' The latter pattern was usually seenin the context of organising infectious pneumonia, andoccasionally the changes extended into the airways.' 2Thenthree papers were published by clinicians and these patho-logical features became clinical diagnoses. The first twowere essentially clinical descriptions of rare patterns ofdisease that were labelled according to the predominanthistological abnormality. Geddes et al3 described an airwaydisease and called it obliterative bronchiolitis (OB), whileDavison et al4 described an alveolar disease and called itcryptogenic organising pneumonitis (COP). The thirdpaper did not describe a clinical syndrome but started fromthe histology. Epler et al5 looked through 2000 reports ofopen lung biopsies in Boston spanning 30 years and pulledout those that contained the words bronchiolitis obliterans,94 in all. Fifty ofthese had no underlying cause and becausethe dominant pathological changes were in fact those oforganising pneumonia they were described under the titleof obliterative bronchiolitis organising pneumonia(BOOP). This histological pattern was essentially the sameas that described by Davison in the paper on COP and hadoriginally been described by Liebow and Carrington asbronchiolitis interstitial pneumonia.6

Partly because the paper on BOOP appeared in theprestigious New England Journal of Medicine, partlybecause it still has the largest number of patients, andpartly because BOOP is fun to pronounce, the name hasstuck even though the first two letters refer to a minor andpotentially misleading part of the disorder.

If all the patients in the three reports of OB, COP, andBOOP are considered together two quite different groupsemerge. Patients in the first (OB) have small airway diseasewith normal alveoli and hypertransradiant lung fieldswithout infiltrates and show little, if any, response totreatment. OB occurs in association with rheumatoidarthritis, in gr one marrowtransplantation, after viral infection, and as Dart of reiw,.tion in lung transplantation. Patients in the second group(BOOP) have an-alveolar disease with granulation tissuethat extends varia iways.Te nLents naveinfiltrates on the chest radlograph and, in general, a gooQdresponse -o This sccond group,-WNiclaccounts forthf blk of the patients of Epler et al, iscommoner than the first, has been the subject of manyrecent papers, and is discussed in more detail below.

PathologyThe original description of COP' emphasises buds ofconnective tissue in air spaces, indicating organisation ofpersistent exudate by fibroblasts and capillaries from thealveolar walls. Inflammatory cells that cluster in the centreof the buds include lymphocytes and plasma cells as well asa few neutrophils and eosinophils. The connective tissueextends into the alveolar ducts and occasionally intorespiratory bronchioles. There is a minor amount ofinterstitial inflammation and fibrosis. The reported findingsin COP are almost identical to thoseda J byEpler et al.5

Subsequent reports have used these pathologicalfeatures for diagnosis and so are largely repetitive. Aninteresting range of othTr feVaures, however, has beenmentioned. Cordier et al,7 in a review of 16 patients,

Cryptogenic organising pneumonitis, with buds ofgranulation tissueoccupying most of the alveoli. The appearances are those of organisingpneumonia, compatible, in the absence of infection and in associationwith characteristic clinicalfeatures, with cryptogenic organisingpneumonitis. Reproducedfrom Corrin"5 by courtesy of ChurchillLivingstone.

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546 Geddes

Table 1 Clinical abnormalities in bronchiolitis obliterans organising pneumonia (BOOP)

Reference Davison4 Epler5 Bellomo9 Cordier' Miyagawa8n: 8 50 6 16 6

% with abnormality

Cough 88 75 100 56 83Fever 25 33 33 - 83Breathlessness 88 50 83 88 50Weight loss 75 - 33 63 -

Crackles 75 68 100 17 -Erythrocyte sedimentation rate increased 100 - 100 100 100Chest radiograph:

Local - 10 33 25 -

Multiple 100% 69 33 44 100Diffuse 50 10 33 - -

Steroid response 100 - 100 - 83

confirmed the predominantly alveolar distribution of theabnormalities. All patients showed some degree of inter-stitial inflammation and fibrosis but this was intense in onlytwo patients. In three cases multinucleate giant cells werefound. Miyagawei et al8 reported 11 patients with fleetinginfiltrates on the chest raaiograpn and divided them into sixwith the above featue no and flve witheosinophils in te1DIopsy materiat.-Tnese latter patientshad peripheral blood eosinophilia and fall clearly into adifferent clinical group of cases ofpulmonary eosinophilia.Although the small airways were relatively unaffected inthis eosinophilic group, pathologically the alveoli hadmany features in common with those ofBOOP/COP, albeitwith a greater predominance of eosinophils. In all of thesereports the blood vessels were spared and there was noevidence of infecting microorganisms.The pathological features ofBOOP are essentially those

of organising pneumonia and are therefore in no wayspecific. They may be tounc witn Iviral and od1L1 ULganslng,infmions, allergic alveolitis, irradiation pneumonitis, anddrug reactions. In the idiopathic group overlap and diag-nostic difficulty may also occur witi n rr i-matosis, and eosinophilic pneumonia when vasculitis andeosinophilia are th stg aracteristics.

Table 2 Associations of bronchiolitis obliterans organising pneumonia(BOOP), excluding infections

Collagen vascular diseaseRheumatoid arthritis 10Polymyositis I IDermatomyositis I IChronic thyroiditis 12Wegener's granulomatosis 13

DrugsGold 14Amiodarone 15Cephalosporin 16Acebutalol 15Sulphasalazine 17Sulindac 18Cocaine 19

Aspiration 20Irradiation 21Ulcerative colitis 22AIDS 23(Infection)*(Extrinsic allergic alveolitis)*

*The pathological changes of BOOP may be found, though the clinical pictureusually differs.

Clinical featuresThe classical clinical presentation as described by Davisonis of a subacute influenza like illness, with cough, malaise,fever, and dyspnoea and with chest radiographic abnor-malities and no response to antibiotics. Other reports haveemphasised a wider spectrum of both symptoms andradiographic ch nn table 1.Three points emerge from a comparison of the reports

summarised in the table. The first is that the clinicalspectrum cannot be completely defined when the conditionrequires histology for diagnosis. Transbronchial biopsyspecimens are too small to be reliable and as only the moresevere cases come to open lung biopsy the milder cases mayremain undiagnosed. this is wellboughtout by ordiee'ssubgroup7MEth localised disease that was removed toexclude neoplasm. If these patients had been given a shortcourse of corticosteroids or possibly if they had beenobserved for a little longer the condition would haveresolved and therefore never have been diagnosed. Theremay be many such patients and this clinical group remainsundefined. The second issue is the range of radiographicabnormalities. Although peripheral fleeting shadowssimilar to pulmonary eosinophilia are characteristic it isnow clear that localised disease may occur as well as diffusechanges. The Is wsare de-seftbed as alveolar infiltrates whereas the diffuse changeshave an interstitial appearance, and these changes appearmore resistaiiTo eroid treatment. Whether thesediffuse interstitial changes are the result of fibrosis fromprevio a ds is not clear, bu tnis appearsunlikel A few shadows have cavitated and in a fewpatients pleural effusions have developed. The third pointconcerns the serological findings. Almost all patients havehad a raised erythrocyte sedimentation rate and some havehad autoantibodies. No reports have mentioned anti-neutrophil cytoplasmic antibodies.

Aetiology and differential diagnosisThere is some confusion about whether the label ofBOOPshould be used when the cause is known or whether itshould be confined to cryptogenic cases, as suggested by thelabel COP. The above clinical, radiological, and patho-logical features have now been described in associationwith many different events (table 2). The fact that the samepattern occurs as a result of infections, drugs, and connec-tive tissue disorders confirms that BOOP is not a singleclinicopathological entity but rather one way in which thelung mounts an inflammatory response to a range ofdifferent insults. The term BOOP is probably best restric-ted to those cases of unknown cause.The idiopathic cases are likely to prove no more

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BOOP and COP

homogeneous than those with known cause. Some may becaused by an external antigen, inhaled or ingested, that hasnot been identified, whereas others may represent a re-sponse to a host antigen. Not surprisingly therefore thereappears to be overlap with other idiopathic conditions,such as Wegener's granulomatosis and pulmonary eosino-philia. Presumably the same cause (for example, a drug)may provoke predominantly eosinophilic inflammation inone individual and a predominantly granulomatous orvasculitic response in another. BOOP appears to be anothervariant of such reactions.

Clinical decisionsThe usual clinical problem is that posed by a patient with apneumonic illness that fails to respond to empiricalantibiotic treatment. The questions are then how far toinvestigate and whether to start corticosteroids in a patientwho may still have an untreated infection. The results ofserological investigations are not conclusive, though thepresence of antinuclear antibodies or rheumatoid factormay be a clue and the absence of antibodies to organismsthat cause pneumonia is a useful negative finding. Radio-graphic findings are not diagnostic and, although fleetigperipheral shadows are reiatively cnaracteristic and seldomoccur in infectious pneumonia, the radiographic patternsare too variedand imprecise to make this distinction.Computed tomography may provide interesting pictures,24but cannot confirm or refute the diagnosis.The central issue is whether to obtain biopsy material

and if so how. Bronchoalveolar lavage has been performedin some patients but too wide a range of cell counts havebeen reported to be of any diagnostic value. The onlyexception to this might be the finding of a high eosinophilcount in the lavage fluid, which would suggest an eosino-philic infiltrate even without peripheral blood eosinophilia.Nevertheless, lavage for bacteriological examination isstrongly recommended. Sterile lavage fluid is HldaLUtryfor excluding infection if empirical corticosteroid treat-ment is intended. Transbronchial biopsy specimens areworth taking at the same time, though te diagnostic ratemay be low. Suffici.iL t it 1 fbr dia , y wever,be obtained, especially if multiple sections are cut. Openlung biopsy provides a better specimen but at greater costto the patient. Wner Lthe clinical picture is typical andinfection has been excludedisome clinicians may be con-fident enough of the diagnosis to give a therapeutic trial ofsteroids. If, however, there are unusual features-forexample, cavitation, haemoptysis, or suspicion of neo-plasm-empirical treatment is risky and has the addeddisadvantage of modifying the histological features.Once the diagnosis is secure and a response to cortico-

steroid treatment has been obtained, the steroid dose maybe reduced over months and in most patients may bestopped altogetheraIter612 montns. More rapid With-drawal may lead To relapse, and in a few patients progres-sion or a chronic relapsing course despite treatment maysuggest a systemic disorder with a vasculitic component.Such cases should be further investigated for the possibilityof systemic vasculitis and immunosuppressive drugs con-sidered.

SummaryBOOP and COP are essentially the same condition andrepresent one ofmany ways in which the lung may respondto an inflammatory stimulus. Some underlying causes ofBOOP have been identified but in many cases no cause canbe found. The clinical and radiological features are of apneumonic illness that responds to corticosteroids ratherthan antibiotics, but as milder cases are being identified theclinical spectrum is widening. Most cases can be confidentlydiagnosed only by open lung biopsy, but bacteriologicallavage and transbronchial biopsy followed by a trial ofsteroids may sometimes be considered.

DUNCAN M GEDDESRoyal Brompton and National Heart HospitalLondon SW3 6HP

Reprint requests to: Dr Geddes

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