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Figure. Chest radiography, thoracic computed tomography, and hematoxylin-eosin staining in 2 patients receiving dronedarone. A, Chest radiograph obtained at admission of a 72-year-old woman with a 3-week history of dyspnea, who had been receiving dronedarone for 11 months. There are diffuse irregular pulmonary infiltrates over both lung fields. B, Thoracic computed tomography with contrast on the ninth admission day. There are bilateral diffuse ground glass opacities with more prominent changes over the right lung field. C, Hematoxylin-eosin staining of transbronchial biopsy specimen obtained on the 13th admission day (original magnification ×400). There are cellular infiltrates in the alveoli with tufts of young fibroblasts growing into the airspace, compatible with the diagnosis of bronchiolitis obliterans with organizing pneumonia. D, Chest radiograph obtained at admission of an 83-year-old man treated with dronedarone for 12 days. There are bilateral diffuse pulmonary infiltrates. E, Thoracic computed tomography 17 days after dronedarone. There are diffuse fine interlobular septal thickening with bilateral ground glass opacities with more prominent changes over the right lung field.

Figure. Chest radiography, thoracic computed tomography, and hematoxylin-eosin staining in 2 patients receiving dronedarone. A, Chest radiograph obtained at admission of a 72-year-old woman with a 3-week history of dyspnea, who had been receiving dronedarone for 11 months. There are diffuse irregular pulmonary infiltrates over both lung fields. B, Thoracic computed tomography with contrast on the ninth admission day. There are bilateral diffuse ground glass opacities with more prominent changes over the right lung field. C, Hematoxylin-eosin staining of transbronchial biopsy specimen obtained on the 13th admission day (original magnification ×400). There are cellular infiltrates in the alveoli with tufts of young fibroblasts growing into the airspace, compatible with the diagnosis of bronchiolitis obliterans with organizing pneumonia. D, Chest radiograph obtained at admission of an 83-year-old man treated with dronedarone for 12 days. There are bilateral diffuse pulmonary infiltrates. E, Thoracic computed tomography 17 days after dronedarone. There are diffuse fine interlobular septal thickening with bilateral ground glass opacities with more prominent changes over the right lung field.

1.
Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey.  N Engl J Med. 2009;360(18):1811-1813PubMedArticle
2.
Hohnloser SH, Crijns HJ, van Eickels M,  et al; ATHENA Investigators.  Effect of dronedarone on cardiovascular events in atrial fibrillation.  N Engl J Med. 2009;360(7):668-678PubMedArticle
3.
Quaglino D, Ha HR, Duner E,  et al.  Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.  Am J Physiol Lung Cell Mol Physiol. 2004;287(2):L438-L447PubMedArticle
4.
Malhotra A, Muse VV, Mark EJ. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities.  N Engl J Med. 2003;348(16):1574-1585PubMedArticle
Research Letters
Mar 26, 2012

Fatal Lung Toxic Effects Related to Dronedarone Use

Author Affiliations

Author Affiliations: Divisions of Cardiology (Drs Siu and Tse) and Respiratory Medicine (Drs Ho and Lam), Department of Medicine (Drs Siu, Ho, Lam, and Tse), and Department of Pathology (Dr Wong), Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

Arch Intern Med. 2012;172(6):516-517. doi:10.1001/archinternmed.2011.1681

Dronedarone is a derivative of amiodarone that aimed to reduce the extracardiac adverse effects while preserving its antiarrhythmic effects for treatment of atrial fibrillation (AF).1 In the ATHENA trial (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter),2 dronedarone reduced cardiovascular hospitalization and death in patients with nonpermanent atrial fibrillation (AF) with other cardiovascular risk factors. However, an experimental study3 suggested that dronedarone might have toxic effects on the lung greater than or equal to amiodarone. We describe 2 cases of fatal and near-fatal lung toxic effects associated with dronedarone use.

Report of Cases
Case 1

A 72-year-old woman was hospitalized with progressive dyspnea for 3 weeks. She had symptomatic paroxysmal AF, and amiodarone was initiated 2 years ago. Ten months before admission, she was enrolled into the ATHENA trial,2 in which amiodarone therapy was stopped for 1 month prior to switching to dronedarone. At the time of admission, she had already been using dronedarone for 9 months. Chest radiography on admission showed bilateral diffuse pulmonary infiltrates, and thoracic computed tomography revealed diffuse ground glass opacities involving both lungs (Figure, A and B). Treatment with empirical board-spectrum antibiotics failed, and she developed progressive respiratory failure necessitating mechanical ventilation 20 days later. All microbiological examination findings were negative. Trans-bronchial biopsy revealed features compatible to bronchiolitis obliterans with organizing pneumonia (BOOP) described in amiodarone-induced lung toxic effects (Figure, C).4 Pulse methylprednisolone therapy was tried, but she subsequently died 4 days later.

Case 2

An 83-year-old man with history of hypertension and diabetes mellitus presented with new-onset AF. He was treated initially with 6 days of intravenous and then 4 days of oral amiodarone (a total of 4.6 g), which was subsequently switched to oral dronedarone for 4 days. He was transferred to our hospital for management of AF. On admission, dronedarone therapy was stopped, but he developed progressive dyspnea 2 days later. Chest radiography and thoracic computed tomography revealed diffuse ground glass opacities over both lungs, compatible with BOOP (Figure, D and E). Treatment with broad-spectrum antibiotics failed, and he developed respiratory failure necessitating mechanical ventilation. All the microbiological investigation findings were negative. His condition improved with pulse methylprednisolone therapy, and he was successfully weaned off from the ventilator.

Comment

Although it is arguable that both patients were treated with amiodarone before switching to dronedarone, the temporal sequence of their onset of respiratory symptoms as well as similar radiological features would suggest that dronedarone may in fact play an important role in the pathogenesis. Furthermore, the lung toxic effects appear to occur both after the short- and long-term exposure to dronedarone. Our observations suggest that serial monitoring of chest radiography is needed in patients receiving dronedarone, especially in those with prior exposure to amiodarone.

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Article Information

Correspondence: Dr Tse, Division of Cardiology, Department of Medicine, The University of Hong Kong, K1929B Queen Mary Hospital, Pokfulam, Hong Kong (hftse@hkucc.hku.hk).

Author Contributions:Study concept and design: Siu and Ho. Acquisition of data: Siu, Ho, Lam, and Tse. Analysis and interpretation of data: Wong, Lam, and Tse. Drafting of the manuscript: Siu and Tse. Critical revision of the manuscript for important intellectual content: Siu, Wong, Ho, and Lam. Administrative, technical, and material support: Siu, Wong, and Lam. Study supervision: Siu and Tse.

Financial Disclosure: None reported.

References
1.
Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey.  N Engl J Med. 2009;360(18):1811-1813PubMedArticle
2.
Hohnloser SH, Crijns HJ, van Eickels M,  et al; ATHENA Investigators.  Effect of dronedarone on cardiovascular events in atrial fibrillation.  N Engl J Med. 2009;360(7):668-678PubMedArticle
3.
Quaglino D, Ha HR, Duner E,  et al.  Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.  Am J Physiol Lung Cell Mol Physiol. 2004;287(2):L438-L447PubMedArticle
4.
Malhotra A, Muse VV, Mark EJ. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities.  N Engl J Med. 2003;348(16):1574-1585PubMedArticle
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