Celiprolol pneumonitisSecure Site  · The patient was treated with i. v. cefotaxime, spiramycin and methylprednisolone for 7 days. Considerable clinical and radiological improvement

Eur Resplr J, 1993, 8, 588-591 Printed In UK • all rlghta reserved

CASE REPORT

Copyright ~ERS Journala Ltd 1993 European Respiratory Journal

ISSN 0903 • 1938

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 Degat, L. Jeannin, Ph. Camus. @ERS Journals Ltd 1993.

• Service de Pneumologie et de R6an­imation Respiratoire, Centre Hospitalier Universitaire et Universit6 de Bourgogne, Dijon, France. •• Laboratoire d'H6mato· logic, Dijon, France.

ABSTRAcr: We report on a patient who developed bypersensitlvity pneumonitis during treatment with the ~-blocker, cellprolol. The clinical picture was a severe alveolltis, with compromised gas exchange. Inadvertent subsequent rechalleoge with cellprolol led to recurrence of the pneumonitis, 10 wee.ks after drug readmlnlstration. Again, the pneumonitis was fully reversible. Lymphocytes were elevated In broncboalveolar lavage, and progressively nonnallzed upon discontinuation of the drug. This case Is reminiscent of pneumonitis to other ~-blockers, which are reviewed here.

Correspondence: Ph. Camus, Service de Pneumologie et de R6animation Respira­toire, Centre Hospitalier Universitaire et Universit~ de Bourgogne, 21034 Dijon, France

Keywords: Beta-blockers; celiprolol; hy­persensitivity pneumonitis; interstitial lung disease (drug-induced)

Eur Respir J., 1993, 6, 588-591.

Beta-blockers can induce several types of adverse res­piratory reactions such as life-threatening asthma attacks, reversible interstitial pneumonitis, an oculo-mucocutane­ous syndrome, and pleural effusions with or without the lupus syndrome (1]. Celiprolol is a ~1-blocker, currently marketed in several European countries and in New Zealand. No untoward parenchyma! or bronchial effect has yet been reported with this drug (2]. We present the first case of celiprolol pneumonitis, and exhaustively review the literature on pleuropulmonary adverse effects to ~-blockers.

Case report

A 60 year old man was admitted on 10 November 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 accen­tuated 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%), eryth­rocyte sedimentation rate (ESR) was 90 mm in one hour, blood creatinine was 124 f.-llllOl·/'1, and blood urea nitro­gen (BUN) 9 mrnol·/'1• Fibrinogen was 7.7 g·/'1, alpha2-

globulin 11 g·/·1, aspartate amino transferase 51 IU·/'1

Received: November 9 1992 Accepted for publication January 31 1993

(normal (N) <40 IU·/"1), alanine amino transferase 47 IU·l·1 (N <21 IU·l-1), gamma glutamyl transpeptidase 116 IU·l·1 (N <28 IU·l-1), and alkaline phosphatase 102 IU·/"1 (N <63 IU·z-t). Bilirubin was within the normal range. Blood cultures were negative. Antinuclear (ANA) and anti-extractable nuclear antigen (BNA) antibodies were negative. An echocardiogram showed normal left ventricular function. Smears and cultures for Mycobacte­rium species in sputum were negative, as was serology against Aspergillus, Rickettsiae, Legionella, Mycoplasma pneumoniae, Leptospirae, Histoplasma capsulatum, Chla­mydiae, Myxovirus influenzae and parainfluenzae, Cox­sackie, Adenovirus, human immunodeficiency virus (I-nV) and respiratory syncytial virus (RSV). Precipitins against Thermoactinomycetes and avian antigens were also nega­tive.

Fig. 1. - Chest radiograph at the time of the first admission.

CEUPROLOL PNEUMONITIS 589

Administration of celiprolol and lisinopril was stopped. The patient was treated with i. v. cefotaxime, spiramycin and methylprednisolone for 7 days. Considerable clinical and radiological improvement ensued (fig. 2). The pa­tients was discharged asymptomatic at day 15, with a normal chest X-ray.

On 15 December 1990, lisinopril and celiprolol were inadvertently reintroduced at home and continued on a daily basis. No adverse effect was observed over 10 weeks, but on 25 February 1991, the patient was read­mitted for recurrent but milder chest symptoms and X­ray changes (fig. 3). Paoz (room air) was 7.5 kPa. Blood chemistry was normal. Bronchoalveolar lavage showed increased cellularity (340 cells·!!l·1). Lymphocytes were 52%, neutrophils 12%, eosinophils 6% and alveolar mac­rophages 30%. The CD4+/CD8+ ratio was 2.3. Both drugs were again discontinued, but this time steroids were not used. Four days later, the patient was asymptomatic. He was discharged after 9 days, with greatly improved chest X-ray.

Fig. 2. - Chest radiograph at day 7, close to discharge.

Fig. 3. - Chest radiograph following 10 weeks of inadvertent rechallenge with celiprolol, showing recurrence of lung shadows.

As no case of pneumonitis to lisinopril had been pre­viously reported, and since there were only two reports of pneumonitis with the other angiotensin-converting enzyme inhibitor captopril (3, 4 ], the patient was re­challenged with lisinopril. There was no recurrence of the pneumonitis. The following months were unevent­ful, and the chest X-ray normalized. The patient is still being treated with lisinopril.

Repeat alveolar lavages in March and April 1991 showed persistent lymphocytic alveolitis, with figures around 50%. The CD4+/CD8+ ratio fell from 2.3 to 0.8. The last BAL in June 1991 showed a normalized cellular pattern (Iymphocytes 7%).

Discussion

We believe that this patient had drug-induced pneu­monitis, for a number of reasons. Firstly, there was no satisfactory alternative explanation for his lung disease. In particular, a thorough search for an infectious, en­vironmental or autoimmune aetiology was negative. Secondly, the pneumonitis improved following discon­tinuation of celiprolol. Although we concur that this was difficult to interpret during the first episode, since ster­oids were given, cessation of celiprolol during his sec­ond admission similarly improved the pneumonitis. Thirdly, rechallenge with celiprolol was temporally asso­ciated 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 will­ing to perform a rechallenge with such compounds should take this into account, as too short a re-exposure time 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 po­tential 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, BAL lymphocytes were still elevated 8 weeks after drug 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 6 Nadolol [20] 41/F 4 HSP N R 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 pleuropul­monary reactions showed 32 cases, implicating nine dif­ferent drugs (table 1). A relatively specific entity developed after exposure to practolol. Patients developed pleural thickening and/or effusions, encasting of lung bases, and a markedly restrictive lung function defect [7, 8-12). One patient developed constrictive pericarditis and pleural effusion [9]. Prognosis was often poor [11], and thus the drug was withdrawn from the market in 1976. In the 20 patients with pleuropuhnonary problems due to other ~-blockers, 11 developed hypersensitivity pneumo­nitis as seen in our case, 8 had a more indolent interstitial pneumonitis, 1 had the bronchiolitis obliterans with or­ganizing pneumonia (BOOP) pattern, and 2 had pleural effusions (table 1). Four patients had positive ANA. Duration of treatment ranged between 2-84 months. BAL was performed in seven cases, and showed lym­phocytosis in all six cases of hypersensitivity pneumoni­tis (range 45-85%). One patient had a purely neutrophilic alveolitis [17). Complete recovery was seen in 18 cases, there was one death [18], and in one case outcome was not stated [21 ]. Positive rechallenge was documented in three. cases [5, 6, 19).

Although marked lymphocytosis in BAL, and the notion of positive rechallenge in some patients suggest a hypersensitivity mechanism, the exact pathogenesis of ~-blocker pneumonitis remains unknown. Inspection of molecular structures of the different ~-blockers listed in table 1 shows no apparent similarity beyond their com­mon lipophilic and amphiphilic properties, and ~­blocking pharmacological activity.

In summary, patients on ~-blockers can develop dif­fuse interstitial lung disease. Acute hypersensitivity pneu­monitis with BAL lymphocytosis is the most common pattern, and the overall prognosis is good. On the basis of this report, celiprolol should be added to the list of ~-blockers capable of inducing hypersensitivity pneumo­nitis.

References

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Lahiri B. - Captopril-induced hypersensitivity lung disease. Chest 1989; 95: 685-687. 5. Akoun GM, Herman DP, Mayaud CM. - Acebutolol­induced hypersensitivity pneumonitis. Br Med J 1983; i: 266-267. 6. Akoun GM, Milleron BJ, Mayaud CM, Tholoniat D. -Provocation test coupled with bronchoalveolar lavage in diag­nosis of propranolol-induced hypersensitivity pneumonitis. Am Rev Respir Dis 1989; 139: 247-249. 7. Marshall AJ, Barritt DW, Griffiths DA, Laszlo G. -Respiratory disease associated with practolol therapy. Lancet 1977; 2: 1254-1257. 8. Fleming HA, Hickling P. - Pleural effusions after practolol. Lancet 1975; 2: 1202. 9. Dyer NH, Varley CC. - Practolol induced pleurisy and constrictive pericarditis. Br Med J 1975; i: 443. 10. Mackay AD, Axford AT. - Pleural effusions after practolol. Br Med J 1976; ii: 89. 11. Erwteman TM, Braat MC, Van Aken WG. - Interstitial pulmonary fibrosis: a new side-effect of practolol. Br Med J 1977; ii: 297-298. 12. Hall DR, Moraison JB, Edwards FR. - Pleural fibrosis after practolol therapy. Thorax 1978; 33: 822-824. 13. Burgess Record N. - Acebutolol-induced pleuropulmo­nary lupus syndrome. Ann Intern Med 1981; 95: 326. 14. Legett RJ. - Pleurisy and pulmonary granulomas after treatment with acebutolol. Br Med J 1982; ii: 1425. 15. Wood GM, Bolton RP, Muers MF, Losowsky MS. -Pleurisy and pulmonary granulomas after treatment with acebutolol. Br Med J 1982; ii: 936. 16. Akoun GM, Touboul JL, Mayaud CM, Gauthier-Rahman S, el Gbarbi N. - Pneumopathie d'hypersensibilite ~ l'acebutolol. Rev Fr Allergo/1985; 25: 8.5-86. 17. Camus Ph, Lombard JN, Perrichon M, et al. - Bronchi­olitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44: 111-715. 18. Husebye E, Hausken T, Holmboe JH, Ovreberg K. -Betablokkere og penisfibrose, lungefibrose og positiv anti­nuklear faktor. Tidsskr Nor Loegeforen 1985; 105: 972-974. 19. Vacher D, Aumaitre 0, Mignot P, Lavarenne J, Molina C. - Alveolite allergique medicamenteuse et syndrome de Parsonnage et Turner chez un malade traite par labetalol. Presse Med 1987; 16: 539-540. 20. Levy MB, Fink JN, Guzzetta PA. - Nadolol and hy­persensitivity pneumonitis. Ann Intern Med 1986; 105: 806-807. 21. Musk AW, Pollard JA. - Pindolol and pulmonary fi­brosis. Br Med J 1979; ii: 581-582. 22. Bensaid J, Aldigier JC, Gualde N. - Systemic lupus erythematosus syndrome induced by pindolol. Br Med J 1979; ii: 1603-1604. 23. Abroad S. - Sclerosing peritonitis and propranolol. Chest 1981; 79: 361-362. 24. Thompson RN, Grennan DM. - Acebutolol-induced hypersensitivity pneumonitis. Br Med J 1983; 286: 894.