Bronchiolitis obliterans organising pneumonia in patients ...Morritt GN, Corris PA. Bronchiolitis...
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Thorax 1989;44:711-715 Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone PHILIPPE CAMUS, JEAN-NOEL LOMBARD, MARIELLE PERRICHON, FRAN(OISE PIARD, JEAN-CLAUDE GUtRIN, FRANCOISE BEJUI THIVOLET, LOUIS JEANNIN From the Service de Pneumologie et de Re'animation Respiratoire, Centre Hospitalier Universitaire, and Laboratoire d'Anatomie Pathologique, Faculte de Medecine, Dijon, and the Service de Pneumologie and Service d'Anatomie Pathologique, H6pital de la Croix Rousse, Lyon, France ABSTRACT Two patients, treated with acebutolol and amiodarone respectively, developed a disease clinically, radiologically, and pathologically indistinguishable from bronchiolitis obliterans organis- ing pneumonia. In one case recovery followed discontinuation of acebutolol; in the other case cessation of amiodarone had no effect, and corticosteroids were required. In addition to these patients, several cases of bronchiolitis obliterans organising pneumonia have been reported during treatment with gold salts, amiodarone, and miscellaneous other drugs. Taken together, this information supports the view that bronchiolitis obliterans organising pneumonia may be a form of response by the lungs to insult by drugs. Introduction Case reports As a result of recent reports,' there has been renewed interest in the clinicopathological entity called bron- chiolitis obliterans with organising pneumonia. Patients with this condition usually present with mild constitutional symptoms that have lasted for several weeks.'"3 The chest radiograph usually shows bilateral asymmetrical, sometimes migrating, alveolar opacities.'-35 Pathologically, bronchiolitis obliterans organising pneumonia is characterised by buds of connective tissue obliterating alveoli, alveolar ducts, and bronchioles, associated with active interstitial inflammation.' On these grounds the disease differs from both pure bronchiolitis obliterans and classic interstitial pneumonia. Its cause or causes have not been clearly identified. The disease has been observed in the context of gastrointestinal disorders,6 certain lung infections,7 connective tissue disease,8 and inhala- tion of toxic fumes.9 In most cases, however, the exact cause remains obscure. We report two patients who developed bronchiolitis obliterans organising pneumonia while being treated with acebutolol and amiodarone respectively. Address for reprint requests: Professor Ph Camus, Centre Hospitalier Universitaire, BP 1543, F-21034 Dijon, France. Accepted 9 June 1989 CASE I A 59 year old man, who was employed in road construction, was admitted to hospital in January 1987. He gave a one month history of non-productive cough, increasing dyspnoea, a 4 kg weight loss, and moderate fever (< 38°C). He was a former smoker (30 pack years). For the past two years he had received acebutolol (Sectral, Specia, Paris) 200 mg/day for systemic hypertension (cumulative dose 219 g). On examination dry crackles were heard, mostly over the right lung. The chest radiographs (fig 1) showed numerous alveolar opacities, predominantly on the right side. The white cell count was normal; the erythrocyte sedimentation rate was 74 mm in one hour; serum electrophoresis displayed a normal pat- tern; and no precipitins against common avian, thermoactinomycete, or Aspergillus antigens were detected. Immunological investigations showed no circulating immune complexes and normal levels of complement C3, C4, and CHa,. Antinuclear antibodies and rheumatoid factor were absent. Pulmonary func- tion tests showed a restrictive pattern (total lung capacity (TLC; helium dilution) 62% predicted, vital capacity (VC) 63% pred, FEVj/forced vital capacity (FVC) 70%). Carbon monoxide transfer was near normal (81% pred). Arterial hypoxaemia and hypo- capnia were found (arterial oxygen tension (Pao2) in room air 7-3 kPa; carbon dioxide tension (PaCo2) 711 on May 23, 2021 by guest. Protected by copyright. http://thorax.bmj.com/ Thorax: first published as 10.1136/thx.44.9.711 on 1 September 1989. Downloaded from
Transcript of Bronchiolitis obliterans organising pneumonia in patients ...Morritt GN, Corris PA. Bronchiolitis...
Thorax 1989;44:711-715
Bronchiolitis obliterans organising pneumonia inpatients taking acebutolol or amiodaronePHILIPPE CAMUS, JEAN-NOEL LOMBARD, MARIELLE PERRICHON,FRAN(OISE PIARD, JEAN-CLAUDE GUtRIN, FRANCOISE BEJUI THIVOLET,LOUIS JEANNIN
From the Service de Pneumologie et de Re'animation Respiratoire, Centre Hospitalier Universitaire, andLaboratoire d'Anatomie Pathologique, Faculte de Medecine, Dijon, and the Service de Pneumologie and Serviced'Anatomie Pathologique, H6pital de la Croix Rousse, Lyon, France
ABSTRACT Two patients, treated with acebutolol and amiodarone respectively, developed a diseaseclinically, radiologically, and pathologically indistinguishable from bronchiolitis obliterans organis-ing pneumonia. In one case recovery followed discontinuation of acebutolol; in the other case
cessation of amiodarone had no effect, and corticosteroids were required. In addition to thesepatients, several cases of bronchiolitis obliterans organising pneumonia have been reported duringtreatment with gold salts, amiodarone, and miscellaneous other drugs. Taken together, thisinformation supports the view that bronchiolitis obliterans organising pneumonia may be a form ofresponse by the lungs to insult by drugs.
Introduction Case reports
As a result of recent reports,' there has been renewedinterest in the clinicopathological entity called bron-chiolitis obliterans with organising pneumonia.Patients with this condition usually present with mildconstitutional symptoms that have lasted for severalweeks.'"3 The chest radiograph usually shows bilateralasymmetrical, sometimes migrating, alveolaropacities.'-35 Pathologically, bronchiolitis obliteransorganising pneumonia is characterised by buds ofconnective tissue obliterating alveoli, alveolar ducts,and bronchioles, associated with active interstitialinflammation.' On these grounds the disease differsfrom both pure bronchiolitis obliterans and classicinterstitial pneumonia. Its cause or causes have notbeen clearly identified. The disease has been observedin the context of gastrointestinal disorders,6 certainlung infections,7 connective tissue disease,8 and inhala-tion of toxic fumes.9 In most cases, however, the exactcause remains obscure. We report two patients whodeveloped bronchiolitis obliterans organisingpneumonia while being treated with acebutolol andamiodarone respectively.
Address for reprint requests: Professor Ph Camus, Centre HospitalierUniversitaire, BP 1543, F-21034 Dijon, France.
Accepted 9 June 1989
CASE IA 59 year old man, who was employed in roadconstruction, was admitted to hospital in January1987. He gave a one month history of non-productivecough, increasing dyspnoea, a 4 kg weight loss, andmoderate fever (< 38°C). He was a former smoker (30pack years). For the past two years he had receivedacebutolol (Sectral, Specia, Paris) 200 mg/day forsystemic hypertension (cumulative dose 219 g). Onexamination dry crackles were heard, mostly over theright lung. The chest radiographs (fig 1) showednumerous alveolar opacities, predominantly on theright side. The white cell count was normal; theerythrocyte sedimentation rate was 74 mm in onehour; serum electrophoresis displayed a normal pat-tern; and no precipitins against common avian,thermoactinomycete, or Aspergillus antigens weredetected. Immunological investigations showed nocirculating immune complexes and normal levels ofcomplement C3, C4, and CHa,. Antinuclear antibodiesand rheumatoid factor were absent. Pulmonary func-tion tests showed a restrictive pattern (total lungcapacity (TLC; helium dilution) 62% predicted, vitalcapacity (VC) 63% pred, FEVj/forced vital capacity(FVC) 70%). Carbon monoxide transfer was nearnormal (81% pred). Arterial hypoxaemia and hypo-capnia were found (arterial oxygen tension (Pao2) inroom air 7-3 kPa; carbon dioxide tension (PaCo2)
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Camus, Lombard, Perrichon, Piard, Gu&rin, Thivolet, Jeannin
Fig I Patient 1: Chest radiograph at the time ofadmissionshowing bilateral, predominantly right sided alveolarshadows.
4-6 kPa. Bronchoalveolar lavage fluid had normalcellularity (total cell count 160 x 106/1) and anincreased proportion of neutrophils (15% of all lavagefluid cells). A transbronchial lung biopsy specimenfrom the right middle lobe showed the combination oforganising pneumonia and obstruction of small airpassages by buds of connective tissue (fig 2). Afterdiscontinuation of acebutolol the fever remittedrapidly. Lung volumes and the chest radiographimproved more slowly over two months, at the end ofwhich the fluid from a second lavage showed a normalneutrophil count and a shift in the cells towardseosinophils (12%) and lymphocytes (24%). By the
* 7 ;/-
Fig 2 Patient 1: Transbronchial lung biopsy specimenshowing the combination ofincreased cellularity, organisingpneumonia, and alveolar and ductalfibrosis (left).(Haematoxylin-eosin-safranin.)
eighth month lung volumes were normal (VC 1001%pred), but slight airflow obstruction persisted (FEV,/FVC 69%). When last evaluated in March 1989 thepatient was symptom free and had a normal chestradiograph.
CASE 2An 81 year old retired turner was admitted to hospital
Fig 3 Patient 2: Chest radiographs showing (left) retractile alveolar shadows in the right upper lobe at admission and (right)clearing ofthe right upper lobe, lesions ofthe right middle and lower lobes, and a moderate pleural effusion one month afterwithdrawal ofamiodarone.
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Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone
in October 1987 because of moderate weight loss andfever, persistent dyspnoea, and a cough productive ofyellowish sputum. The symptoms had developed overseveral weeks and had not changed after a 10 daycourse ofamoxycillin. A chest radiograph in July 1987had been normal. He was a former cigarette smoker.In 1984 a permanent pacemaker had been implantedfor the control ofcardiac arrhythmia, and he started totake amiodarone (Cordarone, Clin-Midy-Labaz,Montpellier) 200 mg/day, five days a week (cumulativedose 190 g). He was also receiving isosorbide dini-trate, aminophylline, canrenone (an antialdosteronediuretic), and frusemide. On examination dry crackleswere heard over the right upper lung field. A mildleucocytosis was noted (12 x 109/l); the erythrocytesedimentation rate was 20 mm, in the first hour. Thebiochemical profile was normal. The chest radiographshowed retraction and shadowing of the right upperlobe (fig 3, left). Pulmonary function tests showedsubstantial airflow obstruction (FEV,/FVC 42%);TLC was 74% and VC 55% of predicted. Mildhypoxaemia (Pao2 79 kPa) and slight hypocapnia(Paco2 4 8 kPa) were present. Bronchoalveolar lavagefluid had increased cellularity (1.5 x 109/l) and asubstantially increased neutrophil count (80%). Asimilar pattern was found in lavage fluid from the rightmiddle lobe, though this area was not affected on thechest radiograph. Amiodarone was discontinued butthe remainder of the treatment was kept unchanged,and the patient was discharged. One month later hereported similar symptoms. On the chest radiographthe right upper lobe had spontaneously cleared, andalveolar opacities had migrated toward the right lowerlung field (fig 3, right). A moderate pleural effusionwas also noted, which proved to be an exudate. Fluidfrom a second lavage again showed neutrophilalveolitis, but this was less severe (15%). Lung biopsyspecimens obtained by thoracoscopy showed severeinterstitial pneumonitis and extensive obliteration ofalveolar ducts and alveoli by typical "bourgeonsconjonctifs" (fig 4). Occasional foci of foamy alveolarcells were also present. Prednisolone 40 mg/day wasstarted in December 1987, with considerable symp-tomatic improvement and the chest radiographcleared progressively; pulmonary function test resultsremained unchanged. Prednisolone was progressivelytapered and stopped in August 1988, with norecurrence of the disease.
Discussion
Both patients presented with a history of malaise,dyspnoea, moderate fever, asymmetrical alveolaropacities, and increased neutrophils or lymphocytes inbronchoalveolar lavage fluid. Extensive obstruction of
._..- -. . -II. ..L7 A '. .lel ,-p:.g X... .' ....4-b.w.
Fig 4 Patient 2: Thoracoscopic lung biopsy specimen.Upper panel: lowerpower view showing widespreadatelectasis and extensive obliteration ofairspaces by buds ofconnective tissue with a branchedpattern typical ofairwaydichotomy. Part ofthe atelectasis may resultfrom a crushingartefact. Lower panel: Higher magnification view showingsubstantial interstitial infiltration by mononuclear cells,organising pnewnonia, and buds ofconnective tissue.(Haematoxylin-eosin-safranin.)
air passages and alveoli by buds of connective tissue,and increased interstitial cellularity were present inboth specimens (figs 2 and 4). The outcome was goodin both cases. These findings are not specific, but takentogether strongly suggest bronchiolitis obliteransorganising pneumonia." '°As bronchiolitis obliterans organising pneumonia is
a non-specific and patchy pattern oflung reacticn thatmay be found in the vicinity of more specific proces-ses,7 a large biopsy sample is clearly preferable toestablish the diagnosis. In a given patient, however, ifthe clinical features and radiographs pattern stronglysuggest bronchiolitis obliterans organising pneumoniaand the pathological material obtained by transbron-chial biopsy, even if small, is unequivocally character-
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Camus, Lombard, Perrichon, Piard, Guerin, Thivolet, Jeanninistic, we believe that the risks of an open lung biopsyare not justified. In such instances a therapeutic trial ofcorticosteroids should be considered.
Bronchiolitis obliterans organising pneumonia hasbeen observed in the context of exposure to toxicfumes,9 Nocardia asteroides infection,7 gastrointestinaldisorders,6 and connective tissue disease.8 Our patientsfitted none of these categories, and apart from theirexposure to drugs their disease was entirely similarto idiopathic bronchiolitis obliterans organisingpneumonia.
Patient 1 developed bronchiolitis obliterans organ-ising pneumonia while receiving acebutolol, a drugpreviously associated with lung infiltrates." As with-drawal of the drug without addition of corticosteroidsled to prompt and lasting recovery, we believe thatacebutolol was implicated in this patient's illness. Thehistological changes in drug induced lung disease dueto acebutolol have been described briefly" as con-sisting of granulomas; the presence of bronchiolitisobliterans organising pneumonia was not reported.
Patient 2 was receiving several drugs in addition toamiodarone, but none of them has been previouslyassociated with pulmonary side effects. 2 In contrast topatient 1, withdrawal of the possible offending drughad no effect on his disease. This does not rule outamiodarone induced lung disease, as this drug isknown to sequester in the lung for a long time.'3Several reports on amiodarone pneumonitis havementioned bronchiolitis or alveolar fibrosis, or both,in addition to the classic pattern of interstitialpneumonitis with foamy alveolar macrophages.'l'9 Inaddition, we are aware of two unpublished observa-tions of typical bronchiolitis obliterans organisingpneumonia in patients taking amiodarone (FGalateau, personal communication, 1989). Usually,however, bronchiolar or alveolar fibrosis is lessprominent than in our patient.'9 On the other hand,cases of amiodarone pneumonitis have been reportedin which lung opacities recurred months after with-drawal of the drug, at a time when corticosteroids werebeing gradually tapered.0 Although this observation isconsistent with the known persistence of amiodaronein the lung,'3 it is very reminiscent of bronchiolitisobliterans organising pneumonia.Our cases should also be viewed in the light ofearlier
reports of bronchiolitis obliterans organisingpneumonia in patients treated with other drugs. It wasobserved in single patients treated with barbiturates2'and D-penicillamine.8 Williams et aP' and Swinburn etaP6 independently reported the condition in patientswith ulcerative colitis treated with sulphasalazine andmesalazine respectively. In the latter paper bron-chiolitis obliterans organising pneumonia wasascribed to ulcerative colitis on the basis of an earlierreport of this association.6 Typical histological
features have also been observed in open lung biopsyspecimens of three patients with rheumatoid arthritisand gold induced pneumonitis.2"25 Given that all thesedrugs are known to induce classic drug inducedinterstitial pneumonitis,'2 we may speculate that incertain patients bronchiolitis obliterans organisingpneumonia represents a pattern of response by thelungs to insult from drugs.
In summary, our observations, coupled with severalpublished reports, suggest that bronchiolitisobliterans organising pneumonia may develop inpatients treated with various drugs. To establishwhether a connection exists between exposure to adrug and bronchiolitis obliterans organisingpneumonia, we believe that a careful history of drugintake should be recorded in every patient with thiscondition.
We thank Drs Fausser and Philippe for referring thesepatients to us.
References
I Davison AG, Heard BE, McAllister WAC, Turner-War-wick MEH. Cryptogenic organising pneumonitis. Q JMed 1983;52:382-94.
2 Epler GR, Colby TV, McLoud TC, Carrigton CB,Gaensler EA. Bronchiolitis obliterans organisingpneumonia. N Engl J Med 1985;312:152-8.
3 Guerry-Force ML, Muller NL, Wright JL, et al. Acomparison of bronchiolitis obliterans with organisingpneumonia, usual interstitial pneumonia, and smallairways disease. Am Rev Respir Dis 1987;135:705-12.
4 Katzenstein AL, Myers JL, Prophet UD, Corley LS,Shim MS. Bronchiolitis obliterans and usual interstitialpneumonia. Am J Surg Pathol 1986;10:373-81.
5 Chandler PW, Shin MS, Friedman SE, Myers JL,Katzenstein AL. Radiographic manifestations ofbron-chiolitis obliterans with organising pneumonia vs.usual interstitial pneumonia. AJR 1986;147:899-906.
6 Swinburn CR, Jackson GJ, Cobden I, Ashcroft T,Morritt GN, Corris PA. Bronchiolitis obliteransorganising pneumonia in a patient with ulcerativecolitis. Thorax 1988;43:735-6.
7 Camp M, Mehta JB, Whitson M. Bronchiolitis obliteransand Nocardia Asteroides infection of the lung. Chest1987;92:1107-8.
8 Yousem SA, Colby TV, Carrigton CB. Lung biopsy inrheumatoid arthritis. Am Rev Respir Dis 1986;131:770-7.
9 Patel RC, Dutta D, Schonfeld SA. Free-base cocaine useassociated with bronchiolitis obliterans organisingpneumonia. Ann Intern Med 1987;107:186-7.
10 Anonymous Case records of the Massachusetts GeneralHospital: case 24-1986. N Engi J Med 1986;314:1627-35.
11 Legett RJE. Pleurisy and pulmonary granulomas aftertreatment with acebutolol. Br Med J 1982;285:1425.
12 Cooper JAD, White DA, Matthay RA. Drug-induced
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Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodaronepulmonary disease. Part 2: Noncytotoxic drugs. AmRev Respir Dis 1986;133:488-505.
13 Camus Ph, Mehendale HM. Pulmonary sequestration ofamiodarone and desethylamiodarone. J PharmacolExp Ther 1986;237:867-73.
14 Marchlinski FE, Gansler TS, Waxman HL, JosephsonME. Amiodarone pulmonary toxicity. Ann Intern Med1982;97:839-44.
15 Gefter WB, Epstein DM, Pietra GG, Miller WT. Lungdisease caused by amiodarone, a new antiarrythmicagent. Radiology 1983;147:339-44.
16 Olson LK, Forrest JV, Friedman PJ, Kiser PE, HenschkeCI. Pneumonitis after amiodarone therapy. Radiology1984;150:327-30.
17 Colgan T, Simon GT, Kay JM, Pugsley SO, Eydt J.Amiodarone pulmonary toxicity. Ultrastruct Pathol1984;6:199-207.
18 Adams PC, Gibson GJ, Morley AR, et al. Amiodaronepulmonary toxicity: clinical and subclinical features. QJ Med 1986;59:449-71.
19 Myers JL, Kennedy JI, Plumb VJ. Amiodarone lung.Hum Pathol 1987;18:349-54.
20 Joelson J, Kluger J, Cole S, Conway M. Possiblerecurrence of amiodarone pulmonary toxicity follow-ing corticosteroid therapy. Chest 1984;85:284-6.
21 Bense L, Wiman LG, Steiner E, Hjerpe A. Pulmonaryside effects after treatment with barbiturates. Eur JRespir Dis 1986;69:61-2.
22 Williams T, Eidus L, Thomas P. Fibrosing alveolitis,bronchiolitis obliterans and sulfasalazine therapy.Chest 1982;881:766-8.
23 Autran P, Garbe L, Pommier de Santi P, Baralis G,Charpin J. Un cas d'accident rare de la chrysotherapie:une miliaire pulmonaire allergique.Rev Fr Mal Respir1978;6:183-90.
24 McCormick J, Cole S, Lahirir B, Knauft F, Cohen S,Yoshida T. Pneumonitis caused by gold salt therapy:evidence for the role of cell-mediated immunity in itspathogenesis. Am Rev Respir Dis 1980;122:145-52.
25 Fort GJ, Scovern H, Abruzzo JL. Intravenous cyclophos-phamide and methylprednisolone for the treatment ofbronchiolitis obliterans and interstitial fibrosisassociated with chrysotherapy. J Rheumatol1988;15:850-4.
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