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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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