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Diffuse Alveolar Damage in a Patient Receiving DronedaroneDronedarone Lung Toxicity FREE TO VIEW

Shobha Stack, MD, PhD; Dan-Vinh Nguyen, MD; Amanda Casto, MD, PhD; Neera Ahuja, MD
Author and Funding Information

From Stanford University (Drs Stack, Casto, Ahuja), Stanford, CA; and the University of California, Davis (Dr Nguyen), Davis, CA.

CORRESPONDENCE TO: Neera Ahuja, MD, Department of Medicine, 300 Pasteur Dr, Room: S102, MC: 5110, Stanford, CA 94305; e-mail: nkahuja@stanford.edu


Data from this study were reported in a poster presentation at the 2014 Society of General Internal Medicine California-Hawaii Regional Meeting, January 31, 2014, Palo Alto, CA.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(4):e131-e133. doi:10.1378/chest.14-1849
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Dronedarone is an amiodarone-like antiarrhythmic with a modified structure. The addition of a methyl sulfonyl group theoretically reduces the toxicity of amiodarone, specifically, adverse thyroid and pulmonary effects. Although animal studies have implicated dronedarone as a cause of lung injury, to date controlled trials in humans have not demonstrated an association. A 68-year-old woman developed a dry cough and worsening respiratory distress after receiving dronedarone for 6 months. Discontinuation of dronedarone therapy and subsequent steroid therapy led to a dramatic improvement of symptoms. Dronedarone may be associated with interstitial lung disease. We believe that patients receiving dronedarone should have their diffusing capacity of lung for carbon monoxide and lung volumes monitored prior to initiation of therapy and frequently thereafter.

Figures in this Article

Dronedarone hydrochloride (Multaq; Sanofi SA) is an oral agent approved by the US Food and Drug Administration in 2009 for the treatment of nonpermanent atrial fibrillation or flutter.1 It was developed to be as effective as its parent compound, amiodarone, but modified with a methyl sulfonyl group to eliminate the risk of pulmonary toxicity. Although animal studies have implicated dronedarone as a cause of lung injury, controlled trials in humans have not demonstrated an association. We describe the first case, to our knowledge, of interstitial lung disease attributed solely to dronedarone.2

A 68-year-old woman with paroxysmal atrial fibrillation, coronary artery disease, Raynaud phenomenon, and gastroesophageal reflux presented with a 5-month history of progressive dry cough and dyspnea. Her symptoms began 1 month after initiation of dronedarone. Her other medications were amlodipine, aspirin, atorvastatin, conjugated estrogens and medroxyprogesterone, ezetimibe, hydrochlorthiazide, ibandronate, lisinopril, metoprolol, omeprazole, and warfarin. She had no exposure to sick contacts, animals, or occupational hazards, but smoked for 1 year in her early 20s.

The patient was afebrile, with a heart rate of 90 beats/min, BP of 157/73 mm Hg, a respiratory rate of 24 breaths/min, and oxygen saturation of 93% while breathing room air. Her examination was notable for diffuse pulmonary rales and rhonchi, jugular venous distension, and sclerodactyly. Laboratory values were remarkable for B-type natriuretic peptide level of 734 pg/mL. Dronedarone was discontinued, and empirical antibiotics and diuretics were started. Within hours of admission, the patient developed hypoxemic respiratory failure and was transferred to the ICU.

A chest CT scan revealed a reticular pattern superimposed on diffuse ground-glass opacification bilaterally (Fig 1). An echocardiogram showed only moderate diastolic dysfunction. Because of worsening hypoxia, on hospital day 3, an open lung biopsy was performed and IV methylprednisolone was initiated. Pathology showed interstitial immature granulation tissue and inflammation composed predominantly of lymphocytes, widened septae lined by reactive cells consisting of predominantly type 2 pneumocytes, and abundant alveolar fibrin deposition—most compatible with an organizing pattern of diffuse alveolar damage (Fig 2).

Figure Jump LinkFigure 1 –  A reticular pattern superimposed on diffuse ground-glass opacification bilaterally.Grahic Jump Location
Figure Jump LinkFigure 2 –  Hematoxylin and eosin stain of lung pathology. A, Image magnified × 400. B, Image magnified × 650. Interstitial immature granulation tissue and inflammation composed predominantly of lymphocytes, widened septae lined by reactive cells consisting of predominantly type 2 pneumocytes, and abundant alveolar fibrin deposition—features most compatible with an organizing pattern of diffuse alveolar damage.Grahic Jump Location

On hospital day 10, mycophenolate mofetil was added for suspected connective tissue disease but subsequently discontinued upon confirmation of negative rheumatologic tests. Antibiotics were also discontinued given negative studies for bacterial, viral, and fungal causes. While on an 18-day course of corticosteroids, the patient experienced dramatic improvement, transitioning from noninvasive positive pressure ventilation to 1 L of oxygen via nasal cannula on the day of discharge.

Amiodarone is known to cause pulmonary toxicity.3,4 Dronedarone differs from amiodarone by the addition of a methyl sulfonyl group, which decreases its lipophilicity and half life. This is postulated to reduce organ toxicity.5 However, it has been implicated in acute liver failure, as well as increased heart failure exacerbations, and cardiovascular and all-cause mortality.6,7

The Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation (DIONYSOS) trial aimed to evaluate the pulmonary toxicity of dronedarone vs amiodarone as one of its secondary end points.8 This study evaluated 504 patients with a median treatment duration of 7 months. Although no pulmonary-specific events were reported in either group, pulmonary events have been reported to occur up to 2 years following the initiation of amiodarone therapy.

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 (ATHENA) trial, composed of 4,628 patients with a mean follow-up period of 21 months, compared dronedarone to placebo.9 There was no significant difference in pulmonary-related adverse events. Yet, the rate of premature discontinuation of dronedarone was 30.2%, potentially limiting demonstrable increases in adverse effects.

In an animal study, rabbit alveolar macrophages were exposed to amiodarone and its analogs, including dronedarone.10 Interestingly, dronedarone was found to have greater toxicity toward alveolar macrophages than amiodarone.

Three cases of dronedarone-induced lung toxicity have been reported. Symptoms developed within 12 days to 9 months after therapy, with one resulting death.11,12 Chest CT scans revealed bilateral diffuse parenchymal opacification and biopsy specimens indicated organizing pneumonia. However, in contrast to this patient, these patients were exposed to amiodarone prior to dronedarone.

Although there was high suspicion for connective tissue disease, serologies for systemic sclerosis, mixed connective tissue disease, Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematous, vasculitides, and inflammatory myopathies were negative. Aside from the lung disease, the patient exhibited no other signs of drug toxicity. By exclusion, the symmetric timing between drug administration and symptoms, and her significant response to steroids lead us to believe the patient’s interstitial lung disease was secondary to dronedarone toxicity.

There are currently no recommendations regarding the use of dronedarone and pulmonary function monitoring. We recommend measuring diffusing capacity of lung for carbon monoxide and lung volumes prior to initiation of therapy and frequently thereafter. Moreover, dronedarone should be promptly discontinued if pulmonary function declines.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Prescribing information for dronedarone. Sanofi SA website. http://products.sanofi.us/multaq/multaq.html. Accessed September 18, 2013.
 
Stack S, Nguyen DV, Casto A, Ahuja N. It started with a cough: diffuse alveolar damage in a patient receiving dronedarone. Poster presented at: Society of General Internal Medicine California-Hawaii Regional Meeting; January 31, 2014; Palo Alto, CA.
 
Bhadra K, Suratt BT. Drug-induced lung diseases: a state-of-the-art review. J Respir Dis. 2009;30(1):1-17.
 
Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity. Recognition and pathogenesis (part I). Chest. 1988;93(5):1067-1075. [CrossRef] [PubMed]
 
Schweizer PA, Becker R, Katus HA, Thomas D. Dronedarone: current evidence for its safety and efficacy in the management of atrial fibrillation. Drug Des Devel Ther. 2011;5:27-39. [PubMed]
 
FDA Drug Safety Communication. Severe liver injury associated with the use of dronedarone (marketed as Multaq). US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. Published January 14, 2011. Accessed September 18, 2013.
 
Chatterjee S, Ghosh J, Lichstein E, Aikat S, Mukherjee D. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol. 2012;110(4):607-613. [CrossRef] [PubMed]
 
Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21(6):597-605. [CrossRef] [PubMed]
 
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):668-678. [CrossRef] [PubMed]
 
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-L447. [CrossRef] [PubMed]
 
Hernandez Voth AR, Catalán JS, Benavides Mañas PD, et al. A 73-year-old man with interstitial lung disease due to dronedarone. Am J Respir Crit Care Med. 2012;186(2):201-202. [CrossRef] [PubMed]
 
Siu CW, Wong MP, Ho CM, et al. Fatal lung toxic effects related to dronedarone use. Arch Intern Med. 2012;172(6):516-517. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A reticular pattern superimposed on diffuse ground-glass opacification bilaterally.Grahic Jump Location
Figure Jump LinkFigure 2 –  Hematoxylin and eosin stain of lung pathology. A, Image magnified × 400. B, Image magnified × 650. Interstitial immature granulation tissue and inflammation composed predominantly of lymphocytes, widened septae lined by reactive cells consisting of predominantly type 2 pneumocytes, and abundant alveolar fibrin deposition—features most compatible with an organizing pattern of diffuse alveolar damage.Grahic Jump Location

Tables

References

Prescribing information for dronedarone. Sanofi SA website. http://products.sanofi.us/multaq/multaq.html. Accessed September 18, 2013.
 
Stack S, Nguyen DV, Casto A, Ahuja N. It started with a cough: diffuse alveolar damage in a patient receiving dronedarone. Poster presented at: Society of General Internal Medicine California-Hawaii Regional Meeting; January 31, 2014; Palo Alto, CA.
 
Bhadra K, Suratt BT. Drug-induced lung diseases: a state-of-the-art review. J Respir Dis. 2009;30(1):1-17.
 
Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity. Recognition and pathogenesis (part I). Chest. 1988;93(5):1067-1075. [CrossRef] [PubMed]
 
Schweizer PA, Becker R, Katus HA, Thomas D. Dronedarone: current evidence for its safety and efficacy in the management of atrial fibrillation. Drug Des Devel Ther. 2011;5:27-39. [PubMed]
 
FDA Drug Safety Communication. Severe liver injury associated with the use of dronedarone (marketed as Multaq). US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. Published January 14, 2011. Accessed September 18, 2013.
 
Chatterjee S, Ghosh J, Lichstein E, Aikat S, Mukherjee D. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol. 2012;110(4):607-613. [CrossRef] [PubMed]
 
Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21(6):597-605. [CrossRef] [PubMed]
 
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):668-678. [CrossRef] [PubMed]
 
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-L447. [CrossRef] [PubMed]
 
Hernandez Voth AR, Catalán JS, Benavides Mañas PD, et al. A 73-year-old man with interstitial lung disease due to dronedarone. Am J Respir Crit Care Med. 2012;186(2):201-202. [CrossRef] [PubMed]
 
Siu CW, Wong MP, Ho CM, et al. Fatal lung toxic effects related to dronedarone use. Arch Intern Med. 2012;172(6):516-517. [CrossRef] [PubMed]
 
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