Journal of Arrhythmia 31 (2015) 47–49
Contents lists available at ScienceDirect
Journal of Arrhythmia journal homepage: www.elsevier.com/locate/joa
Case Report
Late onset interstitial pneumonia induced by bepridil: A case report Manabu Matsumoto, MDn, Masanobu Ohga, MD1, Shumpo Uemura, MD2 Department of Cardiology, Shun-yokai Uemura Hospital, Oaza-Fuchi 1903-1, Hyogo-machi, Saga 849-0913, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 23 November 2013 Received in revised form 8 March 2014 Accepted 13 March 2014 Available online 29 April 2014
A 63-year-old man was prescribed bepridil for paroxysmal atrial fibrillation in May 2011. He was referred to our hospital with the chief complaint of slight dyspnea in October 2012. Radiography and computed tomography indicated diffuse bilateral peribronchial infiltration. Since an examination of the bronchial alveolar lavage fluid revealed inflammatory lymphocytes and a drug lymphocyte stimulation test was strongly positive for bepridil, he was diagnosed with bepridil-induced interstitial pneumonia. In our case, the patient developed dyspnea 517 days after beginning bepridil treatment. Here, we describe an extremely rare case of late onset interstitial pneumonia induced by bepridil. & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
Keywords: Bepridil Drug-induced interstitial pneumonia
1. Introduction Bepridil is a Na þ , K þ , and Ca2 þ channel blocker that is effective for atrial fibrillation (AF), and is currently used as a second-line therapeutic agent for AF in Japan. Interstitial pneumonia (IP) is a well-known adverse effect associated with amiodarone, and sporadic cases of bepridil-induced IP (BIP) have been reported [1–6]. Previous studies have reported that the interval from bepridil administration to the onset of dyspnea due to IP was 4–60 days, except for the patient described by Suzuki et al. [5], who developed dyspnea 226 days after starting treatment. Here, we report the case of a patient with late onset BIP.
2. Case report A 63-year-old man was being followed up after coronary artery bypass grafting and left ventricular (LV) aneurysmectomy for extensive anterior myocardial infarction with an LV aneurysm. The patient had been taking aprindine at 40 mg/day for paroxysmal AF since August 2006; however, sinus rhythm (SR) was not maintained. Therefore, the patient discontinued aprindine, and was switched to bepridil at 100 mg/day on May 25, 2011. SR was maintained after a change to bepridil. The patient was referred to our hospital with the chief complaint of slight exertional dyspnea on October 22, 2012. n Corresponding author. Present address: Mouri Internal Medicine and Cardiology Clinic, Shime, 3-6-16, Shime-machi, Kasuya-gun, Fukuoka 811-2202, Japan. Tel.: þ 81 92 935 0595; fax: þ 81 92 935 9782. E-mail address: [email protected] (M. Matsumoto). 1 Present address: Mouri Internal Medicine and Cardiology Clinic, Shime, 3-6-16, Shime-machi, Kasuya-gun, Fukuoka 811-2202, Japan. 2 Tel.: þ81 952 33 0099; fax: þ 81 952 33 2370.
On examination, his blood pressure was 100/50 mmHg, pulse rate was 56 beats/min, respiratory rate was 20 breaths/minute (Hugh–Jones class II), and temperature was 36.0 1C, and fine crackles were slightly audible in the bilateral upper-to-middle lung fields. His white blood cell count was slightly elevated at 9000/μL, and his KL-6 and brain natriuretic peptide levels were elevated at 812 U/L (normal, o500 U/mL) and 219 pg/mL (normal, o18.4 pg/mL), respectively. Other routine hematological test results were unremarkable. Arterial blood gas analysis showed respiratory alkalemia (pH 7.461, PaO2 92.0 Torr, PaCO2 28.5 Torr; O2 free). Chest radiography and computed tomography (CT) revealed diffuse bilateral peribronchial infiltration located in the upper-to-middle lobes (Fig. 1A and B). Based on the hematological test results, there was no evidence of collagen disease or infection. Since several cases of BIP had been reported and the patient was not taking any other drug known to cause IP, we suspected BIP. We discontinued bepridil and followed him carefully in the outpatient department. One week after presentation, his chest radiographic findings slightly worsened. Therefore, he was admitted to our hospital on November 1, 2012. Bronchoscopy was performed after admission, with the bronchial alveolar lavage fluid (BALF) showing inflammatory cells (3.75 105/mL) and an increased percentage of alveolar lymphocytes (48.6%). The CD4 þ /CD8 þ ratio of the BALF was 0.70. Owing to warfarinization, a transbronchial lung biopsy was not performed. The blood drug lymphocyte stimulation test (DLST) was strongly positive for bepridil (stimulation index, 207%). Therefore, the patient was diagnosed with BIP, and steroid therapy with oral prednisolone at 40 mg/day (0.5 mg/kg/day) was initiated. The patient responded well to steroid therapy. After several weeks, his respiratory condition improved to Hugh–Jones
http://dx.doi.org/10.1016/j.joa.2014.03.007 1880-4276/& 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
48
M. Matsumoto et al. / Journal of Arrhythmia 31 (2015) 47–49
Fig. 1. (A) A chest radiograph taken on the 517th day after commencing bepridil administration. Diffuse bilateral infiltration is seen in the upper and middle lobes. (B) A computed tomography (CT) scan of the lungs taken on the 517th day after commencing bepridil administration. Diffuse bilateral peribronchial infiltration is seen in the upper and middle lobes.
Fig. 2. The clinical course. The patient was prescribed bepridil (100 mg/day) in May 2011. He developed dyspnea 517 days after commencing bepridil treatment, which was associated with an elevation of the serum KL-6 level (October 2012). His symptoms had not improved despite bepridil discontinuation; hence, we initiated steroid therapy. He responded well to steroid therapy, and his symptoms and the serum KL-6 level improved after several weeks.
Table 1 Patient number
Age (years)
Arrhythmia
Bepridil dose (mg/day)
KL-6 (U/mL)
DLST (S.I.%)
Treatment
Time intervala (days)
1 2 3 4 5 6 7 8
72 65 66 69 72 74 78 63
AF AF AF AF AF AF AF AF
400 150 200 200 200 200 100 100
Unknown 692 287 1230 3960 2745 1132 812
Unknown Borderline 160% Negative 93% Unknown Unknown Negative 05% Negative 90% Strong positive 207%
PSL 40 mg mPSL 500 mg 3 days, PSL 60 mg PSL 30 mg mPSL 1000 mg 3 days and tapering off Discontinuation of Bepridil PSL 60 mg mPSL 1000 mg 3 days, PSL 30 mg PSL 40 mg
21 14 30 60 40 226 4 517
Vasilomanolakis et al. Gaku et al. Okubo et al. Watanabe et al. (Case 1) Watanabe et al. (Case 2) Suzuki et al. Yokoi et al. Present case
a The time interval between the start of bepridil administration and onset of dyspnea. AF: atrial fibrillation, PSL: prednisolone, mPSL: methylprednisolone, and S.I.: stimulation index
class I. Since the imaging findings improved and the KL-6 level declined to 469 U/mL (Fig. 2), we gradually reduced the dose of prednisolone. On the 43rd day of admission, the patient was discharged. Prednisolone was tapered gradually on an outpatient
basis, and withdrawn in March 2013. Although the infiltrative shadow persisted on chest radiography and CT, his elevated serum KL-6 level had reduced and his respiratory function had improved. The patient did not have a recurrence of IP.
M. Matsumoto et al. / Journal of Arrhythmia 31 (2015) 47–49
49
3. Discussion
5. Conclusions
Here, we have reported a case of late onset BIP (517 days after starting bepridil treatment). The Naranjo adverse drug reaction probability scale is useful for assessing adverse drug reactions, and a score of 5 points (probable) was assigned to our patient. There are 2 probably interdependent mechanisms involved in drug-induced IP: (1) direct, dose-dependent toxicity, and (2) an immune-mediated reaction. In the present case, we speculated that the mechanism of BIP might involve an immune reaction rather than pulmonary cytotoxicity for 3 reasons. The first was that IP was induced at a low dose of bepridil (100 mg/day). In our case, the dose of bepridil was lower than that reported in previous reports (range: 100–400 mg, median: 145 mg). The second was the strong positive DLST result for bepridil, although the sensitivity of the DLST for diagnosis of BIP was reported to be low (Table 1). The third was that cytotoxic pulmonary injury due to drugs is often steroid-resistant, whereas our patient responded well to steroid therapy. This was a rare case of BIP; however, IP should be kept in mind as an adverse effect of bepridil treatment, even if it occurs long after treatment initiation.
Here, we have described an extremely rare case of late onset of BIP.
4. Limitations The values of bepridil levels in serum provide very important information. Unfortunately, the bepridil levels were not measured from the onset of BIP.
Conflict of interest None of the authors have any conflicts of interest relevant to this manuscript. References [1] Vasilomanolakis EC, Goldberg NM. Bepridil-induced pulmonary fibrosis. Am Heart J 1993;126:1016–7. [2] Gaku S, Naoshi K, Teruhiko A. A case of bepridil induced interstitial pneumonia. Heart 2003;89:1415. [3] Okubo F, Ando M, Ashihara Y, et al. A case of drug-induced pneumonitis due to bepridil. J Jpn Respir Soc 2006;44:17–21 ([in Japanese with English abstract]). [4] Watanabe M, Takaya Y, Fukasawa S, et al. Two patients with bepridil-induced interstitial pneumonia. Circ J 2009;73:1352–5. [5] Suzuki T, Hanaoka T, Yokoyama T, et al. Gradual progression of interstitial pneumonia induced by bepridil. Inter Med 2009;48:2033–5. [6] Yokoi K, Yada H, Yoshimoto D, et al. A case of drug-induced interstitial pneumonia caused by repeated exposure to bepridil. J Arrhythm 2013;29: 39–42.
Contents lists available at ScienceDirect
Journal of Arrhythmia journal homepage: www.elsevier.com/locate/joa
Case Report
Late onset interstitial pneumonia induced by bepridil: A case report Manabu Matsumoto, MDn, Masanobu Ohga, MD1, Shumpo Uemura, MD2 Department of Cardiology, Shun-yokai Uemura Hospital, Oaza-Fuchi 1903-1, Hyogo-machi, Saga 849-0913, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 23 November 2013 Received in revised form 8 March 2014 Accepted 13 March 2014 Available online 29 April 2014
A 63-year-old man was prescribed bepridil for paroxysmal atrial fibrillation in May 2011. He was referred to our hospital with the chief complaint of slight dyspnea in October 2012. Radiography and computed tomography indicated diffuse bilateral peribronchial infiltration. Since an examination of the bronchial alveolar lavage fluid revealed inflammatory lymphocytes and a drug lymphocyte stimulation test was strongly positive for bepridil, he was diagnosed with bepridil-induced interstitial pneumonia. In our case, the patient developed dyspnea 517 days after beginning bepridil treatment. Here, we describe an extremely rare case of late onset interstitial pneumonia induced by bepridil. & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
Keywords: Bepridil Drug-induced interstitial pneumonia
1. Introduction Bepridil is a Na þ , K þ , and Ca2 þ channel blocker that is effective for atrial fibrillation (AF), and is currently used as a second-line therapeutic agent for AF in Japan. Interstitial pneumonia (IP) is a well-known adverse effect associated with amiodarone, and sporadic cases of bepridil-induced IP (BIP) have been reported [1–6]. Previous studies have reported that the interval from bepridil administration to the onset of dyspnea due to IP was 4–60 days, except for the patient described by Suzuki et al. [5], who developed dyspnea 226 days after starting treatment. Here, we report the case of a patient with late onset BIP.
2. Case report A 63-year-old man was being followed up after coronary artery bypass grafting and left ventricular (LV) aneurysmectomy for extensive anterior myocardial infarction with an LV aneurysm. The patient had been taking aprindine at 40 mg/day for paroxysmal AF since August 2006; however, sinus rhythm (SR) was not maintained. Therefore, the patient discontinued aprindine, and was switched to bepridil at 100 mg/day on May 25, 2011. SR was maintained after a change to bepridil. The patient was referred to our hospital with the chief complaint of slight exertional dyspnea on October 22, 2012. n Corresponding author. Present address: Mouri Internal Medicine and Cardiology Clinic, Shime, 3-6-16, Shime-machi, Kasuya-gun, Fukuoka 811-2202, Japan. Tel.: þ 81 92 935 0595; fax: þ 81 92 935 9782. E-mail address: [email protected] (M. Matsumoto). 1 Present address: Mouri Internal Medicine and Cardiology Clinic, Shime, 3-6-16, Shime-machi, Kasuya-gun, Fukuoka 811-2202, Japan. 2 Tel.: þ81 952 33 0099; fax: þ 81 952 33 2370.
On examination, his blood pressure was 100/50 mmHg, pulse rate was 56 beats/min, respiratory rate was 20 breaths/minute (Hugh–Jones class II), and temperature was 36.0 1C, and fine crackles were slightly audible in the bilateral upper-to-middle lung fields. His white blood cell count was slightly elevated at 9000/μL, and his KL-6 and brain natriuretic peptide levels were elevated at 812 U/L (normal, o500 U/mL) and 219 pg/mL (normal, o18.4 pg/mL), respectively. Other routine hematological test results were unremarkable. Arterial blood gas analysis showed respiratory alkalemia (pH 7.461, PaO2 92.0 Torr, PaCO2 28.5 Torr; O2 free). Chest radiography and computed tomography (CT) revealed diffuse bilateral peribronchial infiltration located in the upper-to-middle lobes (Fig. 1A and B). Based on the hematological test results, there was no evidence of collagen disease or infection. Since several cases of BIP had been reported and the patient was not taking any other drug known to cause IP, we suspected BIP. We discontinued bepridil and followed him carefully in the outpatient department. One week after presentation, his chest radiographic findings slightly worsened. Therefore, he was admitted to our hospital on November 1, 2012. Bronchoscopy was performed after admission, with the bronchial alveolar lavage fluid (BALF) showing inflammatory cells (3.75 105/mL) and an increased percentage of alveolar lymphocytes (48.6%). The CD4 þ /CD8 þ ratio of the BALF was 0.70. Owing to warfarinization, a transbronchial lung biopsy was not performed. The blood drug lymphocyte stimulation test (DLST) was strongly positive for bepridil (stimulation index, 207%). Therefore, the patient was diagnosed with BIP, and steroid therapy with oral prednisolone at 40 mg/day (0.5 mg/kg/day) was initiated. The patient responded well to steroid therapy. After several weeks, his respiratory condition improved to Hugh–Jones
http://dx.doi.org/10.1016/j.joa.2014.03.007 1880-4276/& 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
48
M. Matsumoto et al. / Journal of Arrhythmia 31 (2015) 47–49
Fig. 1. (A) A chest radiograph taken on the 517th day after commencing bepridil administration. Diffuse bilateral infiltration is seen in the upper and middle lobes. (B) A computed tomography (CT) scan of the lungs taken on the 517th day after commencing bepridil administration. Diffuse bilateral peribronchial infiltration is seen in the upper and middle lobes.
Fig. 2. The clinical course. The patient was prescribed bepridil (100 mg/day) in May 2011. He developed dyspnea 517 days after commencing bepridil treatment, which was associated with an elevation of the serum KL-6 level (October 2012). His symptoms had not improved despite bepridil discontinuation; hence, we initiated steroid therapy. He responded well to steroid therapy, and his symptoms and the serum KL-6 level improved after several weeks.
Table 1 Patient number
Age (years)
Arrhythmia
Bepridil dose (mg/day)
KL-6 (U/mL)
DLST (S.I.%)
Treatment
Time intervala (days)
1 2 3 4 5 6 7 8
72 65 66 69 72 74 78 63
AF AF AF AF AF AF AF AF
400 150 200 200 200 200 100 100
Unknown 692 287 1230 3960 2745 1132 812
Unknown Borderline 160% Negative 93% Unknown Unknown Negative 05% Negative 90% Strong positive 207%
PSL 40 mg mPSL 500 mg 3 days, PSL 60 mg PSL 30 mg mPSL 1000 mg 3 days and tapering off Discontinuation of Bepridil PSL 60 mg mPSL 1000 mg 3 days, PSL 30 mg PSL 40 mg
21 14 30 60 40 226 4 517
Vasilomanolakis et al. Gaku et al. Okubo et al. Watanabe et al. (Case 1) Watanabe et al. (Case 2) Suzuki et al. Yokoi et al. Present case
a The time interval between the start of bepridil administration and onset of dyspnea. AF: atrial fibrillation, PSL: prednisolone, mPSL: methylprednisolone, and S.I.: stimulation index
class I. Since the imaging findings improved and the KL-6 level declined to 469 U/mL (Fig. 2), we gradually reduced the dose of prednisolone. On the 43rd day of admission, the patient was discharged. Prednisolone was tapered gradually on an outpatient
basis, and withdrawn in March 2013. Although the infiltrative shadow persisted on chest radiography and CT, his elevated serum KL-6 level had reduced and his respiratory function had improved. The patient did not have a recurrence of IP.
M. Matsumoto et al. / Journal of Arrhythmia 31 (2015) 47–49
49
3. Discussion
5. Conclusions
Here, we have reported a case of late onset BIP (517 days after starting bepridil treatment). The Naranjo adverse drug reaction probability scale is useful for assessing adverse drug reactions, and a score of 5 points (probable) was assigned to our patient. There are 2 probably interdependent mechanisms involved in drug-induced IP: (1) direct, dose-dependent toxicity, and (2) an immune-mediated reaction. In the present case, we speculated that the mechanism of BIP might involve an immune reaction rather than pulmonary cytotoxicity for 3 reasons. The first was that IP was induced at a low dose of bepridil (100 mg/day). In our case, the dose of bepridil was lower than that reported in previous reports (range: 100–400 mg, median: 145 mg). The second was the strong positive DLST result for bepridil, although the sensitivity of the DLST for diagnosis of BIP was reported to be low (Table 1). The third was that cytotoxic pulmonary injury due to drugs is often steroid-resistant, whereas our patient responded well to steroid therapy. This was a rare case of BIP; however, IP should be kept in mind as an adverse effect of bepridil treatment, even if it occurs long after treatment initiation.
Here, we have described an extremely rare case of late onset of BIP.
4. Limitations The values of bepridil levels in serum provide very important information. Unfortunately, the bepridil levels were not measured from the onset of BIP.
Conflict of interest None of the authors have any conflicts of interest relevant to this manuscript. References [1] Vasilomanolakis EC, Goldberg NM. Bepridil-induced pulmonary fibrosis. Am Heart J 1993;126:1016–7. [2] Gaku S, Naoshi K, Teruhiko A. A case of bepridil induced interstitial pneumonia. Heart 2003;89:1415. [3] Okubo F, Ando M, Ashihara Y, et al. A case of drug-induced pneumonitis due to bepridil. J Jpn Respir Soc 2006;44:17–21 ([in Japanese with English abstract]). [4] Watanabe M, Takaya Y, Fukasawa S, et al. Two patients with bepridil-induced interstitial pneumonia. Circ J 2009;73:1352–5. [5] Suzuki T, Hanaoka T, Yokoyama T, et al. Gradual progression of interstitial pneumonia induced by bepridil. Inter Med 2009;48:2033–5. [6] Yokoi K, Yada H, Yoshimoto D, et al. A case of drug-induced interstitial pneumonia caused by repeated exposure to bepridil. J Arrhythm 2013;29: 39–42.
