Amiodarone-induced pulmonary hemorrhage.

Amiodarone is a widely prescribed anti-arrhythmic for atrial and ventricular arrhythmias. The adverse effect profile of amiodarone is diverse, involving the cardiac, thyroid, pulmonary, hepatic, gastrointestinal, ocular, neurologic and dermatological systems. (1) However, the most severe and potentially life threatening of these side effects is the development of pulmonary toxicity.

Amiodarone pulmonary toxicity (APT) is usually manifested by acute pneumonitis and chronic fibrosis. (2) The toxicity can occur early in the treatment course, or several years after initiation of amiodarone. The rate of amiodarone-induced pulmonary toxicity varies from 1.6% with low doses, to 5 to 10% with higher doses (> 400 mg/d). (3)

Two distinct clinical presentations of amiodarone pulmonary toxicity have been described. One usually occurs at doses of 100 mg day, occurring within weeks of therapy, with the abrupt onset of dyspnea, fever, cough and patchy alveolar infiltrates. The other, more common form, seen with higher doses of the medication (400 mg) has an insidious onset and occurs after 2 or more months of therapy with progressive nonproductive cough, dyspnea, weight loss, low-grade fever and interstitial infiltrates. (4) Patients with pre-existing lung disease, radiographic abnormalities, and a history of lung resection (5) or pulmonary angiography are at higher risk. (6) However, pulmonary toxicities secondary to amiodarone may also include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, (7) pulmonary mass or nodules, (8,9) acute respiratory failure secondary to acute respiratory distress syndrome (10) and fatal pulmonary hemorrhage. (11)

Since the clinical spectrum of amiodarone toxicity is so diverse, it is difficult to predict which patients will develop this toxicity. A baseline chest x-ray (CXR) and pulmonary function tests are performed initially, even though pretreatment pulmonary function abnormalities are not predictive for the development of subclinical pulmonary toxicity. (12) Long-term treatment with low-dose amiodarone has been shown to be associated with a substantial decrease in carbon monoxide transfer factor (TLCO) with a dose-response relationship. (13) It may be worthwhile to obtain two or three measurements of pulmonary function, including diffusion capacity, within the first few months of therapy to establish variations in the individual patient, (12) although changes in pulmonary function, including diffusion capacity over time, do not identify patients at risk for development of APT. Repeat lung function testing should be reserved for patients who develop new symptoms or CXR findings. Although follow-up surveillance with CXR at three- to six-month intervals has been recommended, pulmonary toxicity can develop rapidly, and radiographic abnormalities may not precede clinical toxicity. (3) High-resolution computed tomography used in the prone and supine positions has been proposed as a technique for detecting ground glass opacities due to amiodarone pulmonary toxicity. (14)

The accumulation of phospholipids in the lung has been proposed as a mechanism for this lung injury. (15) This has led to the development of several novel serum markers like serum Krebs von den Lungen-6 (KL-6), previously recognized as a marker for the activity of diffuse interstitial lung disease, as a potential marker to diagnose amiodarone-induced lung disease. (9,16,17) Other potential serum markers include surfactant protein SP-D levels, even when KL-6 levels are normal, (18) and serum mucin antigen (CASA). (19)

Therapeutic options are limited once amiodarone-induced pulmonary toxicity has been diagnosed but the disease is reversible, if diagnosed at an early stage. (20)

In this issue of the Journal, Iskandar et al (21) describe a case of amiodarone-induced alveolar hemorrhage presenting without hemoptysis and review the previous reports of this unique entity. Amiodarone-induced alveolar hemorrhage appears to be an unusual drug-induced pulmonary toxicity, which poses a diagnostic challenge, as most cases present without hemoptysis, and the symptoms are nonspecific and mimic other disease processes. A few reports of amiodarone-induced hemoptysis have been described in the literature. (2,10,22) Amiodarone-induced alveolar hemorrhage appears to have a later onset than other, more common forms of pulmonary toxicities. Bronchoalveolar lavage and lung tissue biopsy may be necessary to establish the diagnosis. Iskandar et al propose prompt discontinuation of the drug and initiation of glucocorticosteroid therapy, as it may be fatal.

The judicious use of amiodarone requires balancing the risks and benefits of this medication. Despite rapid advances in the development of modern radiographic tools and novel serum markers, regular clinical evaluation and symptom monitoring remain the cornerstone of diagnosing amiodarone-induced pulmonary toxicity.

References

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15. Martin II, WJ Standing JE. Amiodarone pulmonary toxicity: biochemical evidence for a cellular phospholipidosis in the bronchoalveolar lavage of human subjects. J Pharmacol Exp Ther 1988;244:774-779.

16. Endoh Y, Hanai R, Uto K, et al. KL-6 as a potential new marker for amiodarone-induced pulmonary toxicity. Am J Cardiol 2000;86:229-231.

17. Endoh Y. Hanai R, Uto K, et al. Diagnostic accuracy of KL-6 as a marker of amiodarone-induced pulmonary toxicity. Pacing Clin Electrophysiol 2000;23:2010-2013.

18. Umetani K, Abe M, Kawabata K, et al. SP-D as a marker of amiodarone-induced pulmonary toxicity. Intern Med 2002;41:709-712.

19. Devine PL, Siebert WJ, Morton SL, et al. Serum mucin antigen (CASA) as a marker of amiodarone-induced pulmonary toxicity. Dis Markers 1998;14:169-175.

20. Jessurun GA, Boersma WG, Crijns HJ. Amiodarone-induced pulmonary toxicity: predisposing factors, clinical symptoms and treatment. Drug Saf 1998;18:339-344.

21. Iskandar S, Abi-Saleh B, Keith R, et al. Amiodarone-induced alveolar hemorrhage. South Med J 2006;99:383-387.

22. Vizioli LD, Cho S. Amiodarone-associated hemoptysis. Chest 1994;105:305-306.

We must learn to live together as brothers or perish together as fools.
--Martin Luther King Jr.

Sonal Singh, MD

From the Section of General Internal Medicine, Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC and the MPH Program, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.

Reprint requests to Sonal Singh, MD, Department of Medicine, Wake Forest University, Medical Centre Boulevard, Winston-Salem, NC 27157. Email: [e-mail]

Accepted January 13, 2006.