Late onset interstitial pneumonia induced by bepridil: A case report

Abstract

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.

1. Introduction

Bepridil is a Na⁺, K⁺, and Ca²⁺ 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.

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 °C, 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, <500 U/mL) and 219 pg/mL (normal, <18.4 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).

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.

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⁺/CD8⁺ 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 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.

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.

3. Discussion

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.

Table 1.

Patient number		Age (years)	Arrhythmia	Bepridil dose (mg/day)	KL-6 (U/mL)	DLST (S.I.%)	Treatment	Time intervala (days)
1	Vasilomanolakis et al.	72	AF	400	Unknown	Unknown	PSL 40 mg	21
2	Gaku et al.	65	AF	150	692	Borderline 160%	mPSL 500 mg×3 days, PSL 60 mg	14
3	Okubo et al.	66	AF	200	287	Negative 93%	PSL 30 mg	30
4	Watanabe et al. (Case 1)	69	AF	200	1230	Unknown	mPSL 1000 mg×3 days and tapering off	60
5	Watanabe et al. (Case 2)	72	AF	200	3960	Unknown	Discontinuation of Bepridil	40
6	Suzuki et al.	74	AF	200	2745	Negative 05%	PSL 60 mg	226
7	Yokoi et al.	78	AF	100	1132	Negative 90%	mPSL 1000 mg×3 days, PSL 30 mg	4
8	Present case	63	AF	100	812	Strong positive 207%	PSL 40 mg	517

^aThe time interval between the start of bepridil administration and onset of dyspnea. AF: atrial fibrillation, PSL: prednisolone, mPSL: methylprednisolone, and S.I.: stimulation index

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.

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.

5. Conclusions

Here, we have described an extremely rare case of late onset of BIP.

Conflict of interest

None of the authors have any conflicts of interest relevant to this manuscript.