Copyright ~ERS Journala Ltd 1993 Eur Resplr J, 1993, 8, 588-591 European Respiratory Journal Printed In UK • all rlghta reserved ISSN 0903 • 1938

CASE REPORT

Celiprolol pneumonitis

J.N. Lombard*, B. Bonnotte*, M. Maynadie**, P. Foucher*, 0. Reybet Degat*, L. Jeannin*, Ph. Camus*

Celiprolol pneumonitis. J.N. Lombard, B. Bonnotte, M. Maynadie, P. Foucher, 0. Reybet • Service de Pneumologie et de R6an­ Degat, L. Jeannin, Ph. Camus. @ERS Journals Ltd 1993. imation Respiratoire, Centre Hospitalier ABSTRAcr: We report on a patient who developed bypersensitlvity pneumonitis Universitaire et Universit6 de Bourgogne, during treatment with the ~-blocker, cellprolol. The clinical picture was a severe Dijon, France. •• Laboratoire d'H6mato· logic, Dijon, France. alveolltis, with compromised gas exchange. Inadvertent subsequent rechalleoge with cellprolol led to recurrence of the pneumonitis, 10 wee.ks after drug readmlnlstration. Correspondence: Ph. Camus, Service de Again, the pneumonitis was fully reversible. Lymphocytes were elevated In Pneumologie et de R6animation Respira­ broncboalveolar lavage, and progressively nonnallzed upon discontinuation of the toire, Centre Hospitalier Universitaire et Universit~ de Bourgogne, 21034 Dijon, drug. This case Is reminiscent of pneumonitis to other ~-blockers, which are France reviewed here. Keywords: Beta-blockers; celiprolol; hy­ Eur Respir J., 1993, 6, 588-591. persensitivity pneumonitis; interstitial lung disease (drug-induced) Received: November 9 1992 Accepted for publication January 31 1993

1 Beta-blockers can induce several types of adverse res­ (normal (N) <40 IU·/" ), alanine amino transferase 47 piratory reactions such as life-threatening asthma attacks, IU·l·1 (N <21 IU·l-1), gamma glutamyl transpeptidase 1 reversible interstitial pneumonitis, an oculo-mucocutane­ 116 IU·l·1 (N <28 IU·l- ), and alkaline phosphatase 102 ous syndrome, and pleural effusions with or without the IU·/"1 (N <63 IU·z-t). Bilirubin was within the normal lupus syndrome (1]. Celiprolol is a ~ 1-blocker, currently range. Blood cultures were negative. Antinuclear (ANA) marketed in several European countries and in New and anti-extractable nuclear antigen (BNA) antibodies Zealand. No untoward parenchyma! or bronchial effect were negative. An echocardiogram showed normal left has yet been reported with this drug (2]. We present the ventricular function. Smears and cultures for Mycobacte­ first case of celiprolol pneumonitis, and exhaustively rium species in sputum were negative, as was serology review the literature on pleuropulmonary adverse effects against Aspergillus, Rickettsiae, Legionella, Mycoplasma to ~-blockers. pneumoniae, Leptospirae, Histoplasma capsulatum, Chla­ mydiae, Myxovirus influenzae and parainfluenzae, Cox­ sackie, Adenovirus, human immunodeficiency virus (I-nV) Case report and respiratory syncytial virus (RSV). Precipitins against Thermoactinomycetes and avian antigens were also nega­ A 60 year old man was admitted on 10 November tive. 1990 for severe dyspnoea of recent onset, dry cough and constitutional symptoms. He had formerly smoked but had stopped in 1960. For the past 20 months, he had received lisoprinosil (20 mg·day-1), and celiprolol (200 mg·day-1; total dose 122 g) for mild systemic hypertension. At admission, the patient had fever (38.7°C), and crackles were heard over both lungs. Chest X-ray showed accen­ tuated lung shadows and considerable loss of volume (fig. 1). Arterial oxygen tension (Pao~ (breathing room air) was 6.3 kPa, and arterial carbon dioxide tension (Paco~ was 4.5 kPa. After oxygen, 10 /·min·1 via nasal prongs, Pao2 rose to 7.9 kPa. No bronchoalveolar lavage (BAL) was performed. Complete blood count showed 15,300x1()9 white cells·/'1 (neutrophils 85%; eosinophils 2%), eryth­ rocyte sedimentation rate (ESR) was 90 mm in one hour, blood creatinine was 124 f.-llllOl·/'1, and blood urea nitro­ 1 1 gen (BUN) 9 mrnol·/' • Fibrinogen was 7.7 g·/' , alpha2- globulin 11 g·/·1, aspartate amino transferase 51 IU·/'1 Fig. 1. - Chest radiograph at the time of the first admission. CEUPROLOL PNEUMONITIS 589

Administration of celiprolol and lisinopril was stopped. As no case of pneumonitis to lisinopril had been pre­ The patient was treated with i. v. cefotaxime, spiramycin viously reported, and since there were only two reports and methylprednisolone for 7 days. Considerable clinical of pneumonitis with the other angiotensin-converting and radiological improvement ensued (fig. 2). The pa­ enzyme inhibitor captopril (3, 4 ], the patient was re­ tients was discharged asymptomatic at day 15, with a challenged with lisinopril. There was no recurrence of normal chest X-ray. the pneumonitis. The following months were unevent­ On 15 December 1990, lisinopril and celiprolol were ful, and the chest X-ray normalized. The patient is still inadvertently reintroduced at home and continued on a being treated with lisinopril. daily basis. No adverse effect was observed over 10 Repeat alveolar lavages in March and April 1991 weeks, but on 25 February 1991, the patient was read­ showed persistent lymphocytic alveolitis, with figures mitted for recurrent but milder chest symptoms and X­ around 50%. The CD4+/CD8+ ratio fell from 2.3 to 0.8. ray changes (fig. 3). Paoz (room air) was 7.5 kPa. Blood The last BAL in June 1991 showed a normalized cellular chemistry was normal. Bronchoalveolar lavage showed pattern (Iymphocytes 7%). increased cellularity (340 cells·!!l·1). Lymphocytes were 52%, neutrophils 12%, eosinophils 6% and alveolar mac­ rophages 30%. The CD4+/CD8+ ratio was 2.3. Both drugs were again discontinued, but this time steroids were Discussion not used. Four days later, the patient was asymptomatic. He was discharged after 9 days, with greatly improved We believe that this patient had drug-induced pneu­ chest X-ray. monitis, for a number of reasons. Firstly, there was no satisfactory alternative explanation for his lung disease. In particular, a thorough search for an infectious, en­ vironmental or autoimmune aetiology was negative. Secondly, the pneumonitis improved following discon­ tinuation of celiprolol. Although we concur that this was difficult to interpret during the first episode, since ster­ oids were given, cessation of celiprolol during his sec­ ond admission similarly improved the pneumonitis. Thirdly, rechallenge with celiprolol was temporally asso­ ciated with recurrence of the pneumonitis, and we feel that this is a strong argument for the implication of this drug. Lisinopril alone probably played no significant role, as selective readministration of that compound produced no adverse effect. Time to recurrence of celiprolol pneumonitis in our patient was 10 weeks. Thus, the clinician who is will­ ing to perform a rechallenge with such compounds should take this into account, as too short a re-exposure time Fig. 2. - Chest radiograph at day 7, close to discharge. may erroneously lead to the conclusion that the test is negative. Likewise, in two patients with acebutolol [5), and propranolol pneumonitis (6], rechallenge led to an increase in BAL lymphocytes after 5 [5), and 6 weeks [6], respectively. In contrast to our case, these patients remained asymptomatic during drug rechallenge, and did not develop chest opacities. Whether BAL lymphocytes increase during drug rechallenge before clinical recurrence takes place remains unknown. If BAL lymphocytosis indeed represents an early marker of recurrence, the po­ tential risk of drug rechallenge might be reduced if its effects could be monitored at a preclinical stage by BAL. For the time being, however, optimal timing of BAL, and modalities of follow-up during rechallenge, remain an unsettled issue. Following cessation of celiprolol, the return of BAL lymphocytes toward normal took 16 weeks, in our case. Similarly, in a patient with propranolol pneumonitis, who was not taking steroids, AKoUN and eo-workers [6] found near normal BAL lymphocytosis 9 weeks after cessation of the drug. In a patient with acebutolol pneumonitis, Fig. 3. - Chest radiograph following 10 weeks of inadvertent BAL lymphocytes were still elevated 8 weeks after drug rechallenge with celiprolol, showing recurrence of lung shadows. withdrawal (5]. VI 8

Table 1. - Summary of literature on ~blocker-induced pleuropulmonary adverse effects

Drug Ref DO. Age/sex Duration of IT Pulmonary Pleural involvement ANA Histopathology Rechallenge Steroids Outcome YIS months involvement

Acebutolol (13] 55/M 8 Effusion (DI-LE) + N R (14] 57/M 18 liD Pleuritic pain + y R (15] 47/F 24 IID Effusion and thickening OIB N R [5] 69/M 6 HSP + N R [16] 49/M 13 HSP N R (17] 59/M 24 BOOP 1BB N R [$] mF 12 IIDIBOOP? TBB ? R 65/F 6 HSP y R 68/F 23 HSP OIB y R 73/F 9 HSP Effusion + y R Alpreoolol [18] 58/M 36 IID y D Ateoolol [18] 64/M 11 liD N R ... Celiprolol • 60/M 20 HSP + Y/N R ?! Labetalol [19] 55/M 2 HSP + N R Nadolol [20] 41/F 4 HSP N R 6 Pindolol (21] 55/M 84 liD Ol.B N ? [22] 63/M 24 Effusion (DI-LE) + y R Practolol [8] 53/M 38 Effusion + thickening N ? ~ (9] 65/M 36 Thiclcening N ? ~ [10] 66/M 36 Effusion + thickening + DI-LE + Pleural biopsy y R ~ [11] 43/F 18 liD Effusion + 1BB N D (7] 53/M 41 HSP Effusion + thickening Pleural biopsy y s 67/F 37 Thickening Pleural biopsy N ? 65/F 15 Thickening N s 77/F 32 Effusion N A 54/M 17 Thickening N A 66/M 43 Thickening N A [12] 57/M 12 Effusion + thickening N ? 60/M 17 Effusion + thickening N ? Propranolol [23] 56/M 24 Effusion N R [24] 56/F 3 HSP N R (6) 59/M 30 HSP + N R (18] 40/F 24 IID 1BB y R

•: presellt report. TI': treatmeDl; A; aggravation; ANA; antinuclear anb"bodies; BOOP: bronchiolitis obliterans and organizing pneumonia; D: death; DI-LE: drug-induced lupus erythematosus; HSP: hyperseDSitivity pneumonitis; lLD: interstitial hmg disease; Ol.B: open lung biopsy; R: reoovery; S: sequelae 1BB: trambronchial bmg biopsy; -: DOt present; ?: DOt stated. S: the case histories of these four patients have been kindly given to ~ by the Drug Safety Unit of the Manufacturer (Specia, Paris, France). Only for acebutolol were unpublished reports of adverse effects ina>Iporated into this table. CELIPROLOL PNEUMONITIS 591

An exhaustive review of ~-blocker-induced pleuropul­ Lahiri B. - Captopril-induced hypersensitivity lung disease. monary reactions showed 32 cases, implicating nine dif­ Chest 1989; 95: 685-687. ferent drugs (table 1). A relatively specific entity 5. Akoun GM, Herman DP, Mayaud CM. - Acebutolol­ developed after exposure to practolol. Patients developed induced hypersensitivity pneumonitis. Br Med J 1983; i: 266- 267. pleural thickening and/or effusions, encasting of lung 6. Akoun GM, Milleron BJ, Mayaud CM, Tholoniat D. - bases, and a markedly restrictive lung function defect [7, Provocation test coupled with bronchoalveolar lavage in diag­ 8-12). One patient developed constrictive pericarditis and nosis of propranolol-induced hypersensitivity pneumonitis. Am pleural effusion [9]. Prognosis was often poor [11], and Rev Respir Dis 1989; 139: 247-249. thus the drug was withdrawn from the market in 1976. 7. Marshall AJ, Barritt DW, Griffiths DA, Laszlo G. - In the 20 patients with pleuropuhnonary problems due to Respiratory disease associated with practolol therapy. Lancet other ~-blockers, 11 developed hypersensitivity pneumo­ 1977; 2: 1254-1257. nitis as seen in our case, 8 had a more indolent interstitial 8. Fleming HA, Hickling P. - Pleural effusions after pneumonitis, 1 had the bronchiolitis obliterans with or­ practolol. Lancet 1975; 2: 1202. ganizing pneumonia (BOOP) pattern, and 2 had pleural 9. Dyer NH, Varley CC. - Practolol induced pleurisy and constrictive pericarditis. Br Med J 1975; i: 443. effusions (table 1). Four patients had positive ANA. 10. Mackay AD, Axford AT. - Pleural effusions after Duration of treatment ranged between 2-84 months. practolol. Br Med J 1976; ii: 89. BAL was performed in seven cases, and showed lym­ 11. Erwteman TM, Braat MC, Van Aken WG. - Interstitial phocytosis in all six cases of hypersensitivity pneumoni­ pulmonary fibrosis: a new side-effect of practolol. Br Med J tis (range 45-85%). One patient had a purely neutrophilic 1977; ii: 297-298. alveolitis [17). Complete recovery was seen in 18 cases, 12. Hall DR, Moraison JB, Edwards FR. - Pleural fibrosis there was one death [18], and in one case outcome was after practolol therapy. Thorax 1978; 33: 822-824. not stated [21 ]. Positive rechallenge was documented in 13. Burgess Record N. - Acebutolol-induced pleuropulmo­ three. cases [5, 6, 19). nary lupus syndrome. Ann Intern Med 1981; 95: 326. Although marked lymphocytosis in BAL, and the 14. Legett RJ. - Pleurisy and pulmonary granulomas after J ii: notion of positive rechallenge in some patients suggest a treatment with acebutolol. Br Med 1982; 1425. 15. Wood GM, Bolton RP, Muers MF, Losowsky MS. - hypersensitivity mechanism, the exact pathogenesis of Pleurisy and pulmonary granulomas after treatment with ~-blocker pneumonitis remains unknown. Inspection of acebutolol. Br Med J 1982; ii: 936. molecular structures of the different ~-blockers listed in 16. Akoun GM, Touboul JL, Mayaud CM, Gauthier-Rahman table 1 shows no apparent similarity beyond their com­ S, el Gbarbi N. - Pneumopathie d'hypersensibilite ~ mon lipophilic and amphiphilic properties, and ~­ l'acebutolol. Rev Fr Allergo/1985; 25: 8.5-86. blocking pharmacological activity. 17. Camus Ph, Lombard JN, Perrichon M, et al. - Bronchi­ In summary, patients on ~-blockers can develop dif­ olitis obliterans organising pneumonia in patients taking fuse interstitial lung disease. Acute hypersensitivity pneu­ acebutolol or amiodarone. Thorax 1989; 44: 111-715. monitis with BAL lymphocytosis is the most common 18. Husebye E, Hausken T, Holmboe JH, Ovreberg K. - Betablokkere og penisfibrose, lungefibrose og positiv anti­ pattern, and the overall prognosis is good. On the basis nuklear faktor. Tidsskr Nor Loegeforen 1985; 105: 972-974. of this report, celiprolol should be added to the list of 19. Vacher D, Aumaitre 0, Mignot P, Lavarenne J, Molina ~-blockers capable of inducing hypersensitivity pneumo­ C. - Alveolite allergique medicamenteuse et syndrome de nitis. Parsonnage et Turner chez un malade traite par labetalol. Presse Med 1987; 16: 539-540. 20. Levy MB, Fink JN, Guzzetta PA. - Nadolol and hy­ References persensitivity pneumonitis. Ann Intern Med 1986; 105: 806- 807. 1. Rosenow EC Ill. - Drug-induced bronchopulmonary 21. Musk AW, Pollard JA. - Pindolol and pulmonary fi­ pleural disease. J Allergy /mmuno/1981; 80: 780-787. brosis. Br Med J 1979; ii: 581-582. 2. Van Zyla AI, Jennings AA, Bateman ED, Opie LH. - 22. Bensaid J, Aldigier JC, Gualde N. - Systemic lupus Comparison of respiratory effe.cts of two cardioselective beta­ erythematosus syndrome induced by pindolol. Br Med J 1979; blockers, celiprolol and atenolol, in asthmatics with mild to ii: 1603-1604. moderate hypertension. Chest 1989; 95: 209-213. 23. Abroad S. - Sclerosing peritonitis and propranolol. 3. Kidney JC, O'Halloran DJ, Fitzgerald MX. - Captopril Chest 1981; 79: 361-362. and lymphocytic alveolitis. Br Med J 1989; ii: 981. 24. Thompson RN, Grennan DM. - Acebutolol-induced 4. Schatz PL, Mesologites D, Hyun J, Walker Smith GJ, hypersensitivity pneumonitis. Br Med J 1983; 286: 894.