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Drug Safety

, Volume 33, Issue 7, pp 539–558 | Cite as

Amiodarone

Review of Pulmonary Effects and Toxicity
  • Spyros A. PapirisEmail author
  • Christina Triantafillidou
  • Likurgos Kolilekas
  • Despoina Markoulaki
  • Effrosyni D. Manali
Review Article

Abstract

Amiodarone, a bi-iodinated benzofuran derivative, is, because of its high effectiveness, one of the most widely used antiarrhythmic agents. However, adverse effects, especially potentially fatal and non-reversible acute and chronic pulmonary toxicity, continue to be observed. This review provides an update of the epidemiology, pathophysiology, clinical presentation, treatment and outcome of amiodarone pulmonary effects and toxicity. Lung adverse effects occur in approximately 5% of treated patients. The development of lung complications appears to be associated with older age, duration of treatment and cumulative dosage, high levels of its desethyl metabolite, history of cardiothoracic surgery and/or use of high oxygen mixtures, use of iodinated contrast media, and probably pre-existing lung disease as well as co-existing respiratory infections. Amiodarone-related adverse pulmonary effects may develop as early as from the first few days of treatment to several years later. The onset of pulmonary toxicity may be either insidious or rapidly progressive. Cough, new chest infiltrates in imaging studies and reduced lung diffusing capacity in the appropriate clinical setting of amiodarone use, after the meticulous exclusion of infection, malignancy and pulmonary oedema, are the cardinal clinical and laboratory elements for diagnosis. Pulmonary involvement falls into two categories of different grades of clinical significance: (i) the ubiquitous ‘lipoid pneumonia’, the so-called ‘amiodarone effect’, which is usually asymptomatic; and (ii) the more appropriately named ‘amiodarone toxicity’, which includes several distinct clinical entities related to the differing patterns of lung inflammatory reaction, such as eosinophilic pneumonia, chronic organizing pneumonia, acute fibrinous organizing pneumonia, nodules or mass-like lesions, nonspecific interstitial pneumonia-like and idiopathic pulmonary fibrosis-like interstitial pneumonia, desqua-mative interstitial pneumonia, acute lung injury/acute respiratory distress syndrome (ARDS) and diffuse alveolar haemorrhage. Pleural/pericardial involvement may be observed. Three different and intertwined mechanisms of lung toxicity have been suggested: (i) a direct toxic effect; (ii) an immunemediated mechanism; and (iii) the angiotensin enzyme system activation. Mortality ranges from 9% for those who develop chronic pneumonia to 50% for those who develop ARDS. Discontinuation of the drug, control of risk factors and, in the more severe cases, corticosteroids may be of therapeutic value. Supportive measures for supervening ARDS in the intensive care setting may become necessary.

Keywords

Amiodarone Idiopathic Pulmonary Fibrosis Pulmonary Toxicity Diffuse Alveolar Haemorrhage Lung Toxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank Mr Spyros Vlachos for assistance with the preparation of the figure section. No sources of funding were used in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Dharmarajan TS, Shah AB, Dharmarajan L. Amiodarone-induced pulmonary toxicity: potentially fatal, recognize early during life! J Am Geriatr Soc 2008 Jul; 56(7): 1363–1Google Scholar
  2. 2.
    Charlier R, Deltour G, Tondeur R. Recherche dans la serie des benzofurannes, VII: etude pharmacologique preliminaire du butyl-2 (diiodo 3’5’-beta-N-diethylaminoethoxy-4′benzoyl)-3 benzofurannes. Arch Int Pharma-codyn Ther 1962; 139: 255–62Google Scholar
  3. 3.
    Charlier R, Delaunois G, Bauthier J. Recherche dans la serie des benzofurannes, XL: propriete anti-arrhythmiques de l’amiodarone. Cardiologia 1969; 54: 83–9PubMedCrossRefGoogle Scholar
  4. 4.
    Nademanee K, Singh BN, Stevenson WG, et al. Amiodarone and post-MI patients. Circulation 1993; 88: 764–8PubMedCrossRefGoogle Scholar
  5. 5.
    Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007; 298(11): 1312–22PubMedCrossRefGoogle Scholar
  6. 6.
    Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4: 1250–9PubMedCrossRefGoogle Scholar
  7. 7.
    Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol 2008 July; 66(1): 82–7PubMedCrossRefGoogle Scholar
  8. 8.
    Rotmensch HH, Liron M, Tupilski M, et al. Possible association of pneumonitis with amiodarone therapy [letter]. Am Heart J 1980; 100: 412–3PubMedCrossRefGoogle Scholar
  9. 9.
    Ikäheimo K, Kettunen R, Mäntyjärvi M. Visual functions and adverse ocular effects in patients with amiodarone medication. Acta Ophthalmol Scand 2002; 80: 59–63PubMedCrossRefGoogle Scholar
  10. 10.
    Tsang W, Houlden RL. Amiodarone-induced thyrotoxicosis: a review. Can J Cardiol 2009 Jul; 25(7): 421–4PubMedCrossRefGoogle Scholar
  11. 11.
    Babatin M, Lee SS, Pollak PT. Amiodarone hepato-toxicity: review. Curr Vasc Pharmacol 2008 Jul; 6(3): 228–36PubMedCrossRefGoogle Scholar
  12. 12.
    Dezile G, Roullier A, Arbeille-Brassart B. Interstitial pneumopathy in subjects treated with amiodarone [in French]. Presse Med 1983; 12: 2747–50PubMedGoogle Scholar
  13. 13.
    Yamada Y, Shiga T, Matsuda N, et al. Incidence and predictors of pulmonary toxicity in Japanese patients receiving low-dose amiodarone. Circ J 2007; 71: 1610–6PubMedCrossRefGoogle Scholar
  14. 14.
    Sunderji R, Kanji Z, Gin K. Pulmonary effects of low dose amiodarone: a review of the risks and recommendations for surveillance. Can J Cardiol 2000; 16: 1435–40PubMedGoogle Scholar
  15. 15.
    Singh SN, Fisher SG, Singh BN, et al. Pulmonary effect of amiodarone in patients with heart failure. JACC 1997; 30: 514–7PubMedGoogle Scholar
  16. 16.
    Labombarda F, Ou P, Stos B, et al. Acute amiodarone-induced pulmonary toxicity: an association of risk factors in a child operated by arterial switch operation. Congenit Heart Dis 2008; 3: 365–7PubMedCrossRefGoogle Scholar
  17. 17.
    Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995; 333: 77–82PubMedCrossRefGoogle Scholar
  18. 18.
    Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82: 51–9PubMedCrossRefGoogle Scholar
  19. 19.
    Magro SA, Lawrence EC, Wheeler SH, et al. Amiodarone pulmonary toxicity: prospective evaluation of serial pulmonary function tests. J Am Coll Cardiol 1988; 12: 781–8PubMedCrossRefGoogle Scholar
  20. 20.
    Weinberg BA, Miles WM, Klein LS, et al. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J 1993; 125: 109–20PubMedCrossRefGoogle Scholar
  21. 21.
    Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86: 4–10PubMedCrossRefGoogle Scholar
  22. 22.
    Ott MC, Khoor A, Leventhal JP, et al. Pulmonary toxicity in patients receiving low-dose amiodarone. Chest 2003; 123: 646–51PubMedCrossRefGoogle Scholar
  23. 23.
    Ashrafian H, Davey P. Is amiodarone an underrecognized cause of acute respiratory failure in the ICU? Chest 2001; 120: 275–1Google Scholar
  24. 24.
    Polkey MI, Wilson POG, Rees PJ. Amiodarone pneumonitis: no safe dose. Respir Med 1995; 89: 233–5PubMedCrossRefGoogle Scholar
  25. 25.
    Greenspon AJ, Kidwell GA, Hurley W, et al. Amiodarone-related postoperative adult respiratory distress syndrome. Circulation 1991 Nov; 84 (5 Suppl.): III407–15PubMedGoogle Scholar
  26. 26.
    Van der Zeijden H, Znadstra DF. Amiodarone and the development of ARDS after lung surgery. Chest 1995; 107: 885–6PubMedCrossRefGoogle Scholar
  27. 27.
    Van Mieghem W, Coolen L, Malysse I, et al. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105: 1642–5PubMedCrossRefGoogle Scholar
  28. 28.
    Donaldson L, Grant IS, Naysmith MR, et al. Acute amiodarone-induced lung toxicity. Intensive Care Med 1998 Jun; 24(6): 626–30PubMedCrossRefGoogle Scholar
  29. 29.
    Olshansky B, Sami M, Rubin A, et al. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. NHLBI AFFIRM investigators. Am J Cardiol 2005; 95: 404–5PubMedCrossRefGoogle Scholar
  30. 30.
    Bargout R, Jankov A, Dincer E, et al. Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 2000; 278: L1039–44PubMedGoogle Scholar
  31. 31.
    Uhal BD, Wang R, Laukka J, et al. Inhibition of amiodarone-induced lung fibrosis but not alveolitis by angio-tensin system antagonists. Pharmacol Toxicol 2003; 92: 81–7PubMedCrossRefGoogle Scholar
  32. 32.
    Uhal BD, Zhang H, Abdul-Hafez A, et al. Amiodarone induces angiotensinogen gene expression in lung alveolar epithelial cells through activation protein-1. Basic Clin Pharmacol Toxicol 2007; 100: 59–66PubMedCrossRefGoogle Scholar
  33. 33.
    Nikaido A, Tada T, Nakamura K, et al. Clinical features of the effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity. Int J Cardiol 2010; 140: 328–35PubMedCrossRefGoogle Scholar
  34. 34.
    Kosseifi SG, Halawa A, Bailey B, et al. Reduction of amiodarone pulmonary toxicity in patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blocker. Ther Adv Respir Dis 2009; 3: 289–94PubMedCrossRefGoogle Scholar
  35. 35.
    Adams PC, Holt DW, Storey GC, et al. Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy. Circulation 1985; 72: 1064–75PubMedCrossRefGoogle Scholar
  36. 36.
    Lapinsky SE, Mullen JB, Balter MS. Rapid pulmonary phospholipid accumulation induced by intravenous amiodarone. Can J Cardiol 1993; 9: 322–24PubMedGoogle Scholar
  37. 37.
    Haffajee CI, Love JC, Canada AT, et al. Clinical pharm-acokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 1983; 67: 1347–55PubMedCrossRefGoogle Scholar
  38. 38.
    Kaushik S, Hussain A, Clarke P, et al. Acute pulmonary toxicity after low-dose amiodarone therapy. Ann Thorac Surg 2001;72: 1760–1PubMedCrossRefGoogle Scholar
  39. 39.
    Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89: 896–8PubMedCrossRefGoogle Scholar
  40. 40.
    Halliwell WH. Cationic amphiphilic drug-induced phos-pholipidosis. Toxicol Pathol 1997; 25(1): 53–60PubMedCrossRefGoogle Scholar
  41. 41.
    Hostetler KY, Reasor MJ, Walker RE, et al. Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats. Biochim Biophys Acta 1986; 875: 400–5PubMedCrossRefGoogle Scholar
  42. 42.
    Anderson N, Borlak J. Drug-induced phospholipidosis. FEBS Lett 2006; 580: 5533–40PubMedCrossRefGoogle Scholar
  43. 43.
    Chung MJ, Lee KS, Franquet T, et al. Metabolic lung disease: imaging and histopathologic findings. Eur J Radiol 2005; (54): 233–45Google Scholar
  44. 44.
    Bedrossian C, Warren C, Ohar J, et al. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry. Ann Dign Pathol 1997; (1): 47–56Google Scholar
  45. 45.
    Kennedy JI, Myers JL, Plumb VJ, et al. Amiodarone pulmonary toxicity: clinical, radiologic, and pathologic correlations. Arch Intern Med 1987; 147: 50–5PubMedCrossRefGoogle Scholar
  46. 46.
    Minchin RF, Ho PC, Boyd MR. Reductive metabolism of nitrofurantoin by rat lung and liver in vitro. Biochem Pharmacol 1986; 35: 575–80PubMedCrossRefGoogle Scholar
  47. 47.
    Fantone JC, Phan SH. Oxygen metabolite detoxifying enzyme levels in bleomycin-induced fibrotic lungs. Free Radic Biol Med 1988; 4: 399–402PubMedCrossRefGoogle Scholar
  48. 48.
    Venkatesan N, Punithavathi V, Chandrakasan G. Curcumin protects bleomycin-induced lung injury in rats. Life Sci 1997; 61: L51–8CrossRefGoogle Scholar
  49. 49.
    Myers JL, Kennedy JI, Plumb VJ. Amiodarone lung: pathologic findings in clinically toxic patients. Hum Pathol 1987 Apr; 18(4): 349–54PubMedCrossRefGoogle Scholar
  50. 50.
    Baritussio A, Marzini S, Agostini M, et al. Amiodarone inhibits lung degradation of SP-A and perturbs the distribution of lysosomal enzymes. Am J Physiol Lung Cell Mol Physiol 2001; 281: L1189–99PubMedGoogle Scholar
  51. 51.
    Reasor MJ, Kacew S. An evaluation of possible mechanisms underlying amiodarone-induced pulmonary toxicity. Proc Soc Exp Biol Med 1996 Sep; 212(4): 297–304PubMedGoogle Scholar
  52. 52.
    Massey TE, Leeder RG, Rafeiro E, et al. Mechanisms in the pathogenesis of amiodarone-induced pulmonary toxicity. Can J Physiol Pharmacol 1995 Dec; 73(12): 1675–85PubMedCrossRefGoogle Scholar
  53. 53.
    Otsuka M, Takahashi H, Shiratori M, et al. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax 2004; 59: 31–8PubMedCrossRefGoogle Scholar
  54. 54.
    Lopez AD, Avasarala S, Grewwal S, et al. Differential role of the Fas/Fas ligant apoptotic pathway in inflammation and lung fibrosis associated with reovirus 1/L induced bronchiolitis obliterans organizing pneumonia and acute respiratory distress syndrome. J Immunol 2009; 183: 8244–57PubMedCrossRefGoogle Scholar
  55. 55.
    Selman M, Pardo A. The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29: S93–7PubMedGoogle Scholar
  56. 56.
    Kuruma T, Maruyama T, Hiramatsu S, et al. Relationship between amiodarone-induced subclinical lung toxicity and Th1/Th2 balance. Int J Cardiol 2009 May 15; 134(2): 224–30PubMedCrossRefGoogle Scholar
  57. 57.
    Reinhart PG, Gairola CG. Amiodarone-induced pulmonary toxicity in Fischer rats: release of tumor necrosis factor alpha and transforming growth factor beta by pulmonary alveolar macrophages. J Toxicol Environ Health 1997; 52: 353–65PubMedGoogle Scholar
  58. 58.
    Argyriou M, Hountis P, Antonopoulos N, et al. Acute fatal post-CABG low dose amiodarone lung toxicity. Asian Cardiovasc Thorac Ann 2007 Dec; 15(6): e66–8PubMedGoogle Scholar
  59. 59.
    Skroubis G, Galiatsou E, Metafratzi Z, et al. Amiodarone-induced acute lung toxicity in an ICU setting. Acta An-aesthesiol Scand 2005 Apr; 49(4): 569–71CrossRefGoogle Scholar
  60. 60.
    Charles PE, Doise JM, Quenot JP, et al. Amiodarone-related acute respiratory distress syndrome following sudden withdrawal of steroids. Respiration 2006; 73: 248–9PubMedGoogle Scholar
  61. 61.
    Wood DL, Osborn MJ, Rooke J, et al. Amiodarone pulmonary toxicity: report of two cases associated with rapidly progressive fatal respiratory distress syndrome after pulmonary angiography. Mayo Clin Proc 1985; 60: 601–3PubMedCrossRefGoogle Scholar
  62. 62.
    Behnia M. Association of alveolar hemorrhage with amiodarone: role of bronchoscopy. Tanaffos 2008; 7(2): 75–8Google Scholar
  63. 63.
    Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol 1999; 84: 37–45CrossRefGoogle Scholar
  64. 64.
    Camus P, Martin WJ, Rosenow EC. Amiodarone pulmonary toxicity. Clin Chest Med 2004; 25(1): 65–75PubMedCrossRefGoogle Scholar
  65. 65.
    Fraire AE, Guntupalli KK, Greenberg SD, et al. Amiodarone pulmonary toxicity: a multidisciplinary review of current status. South Med J 1993; 86(1): 67–77PubMedCrossRefGoogle Scholar
  66. 66.
    Thiyagarajan T, Mahajan V, Katragadda S, et al. Amiodarone induced acute interstitial pneumonitis. BMJ Case Reports. Epub 2009 Mar 6Google Scholar
  67. 67.
    Goldstein I, Topilsky M, Segev D, et al. Very early onset of acute amiodarone pulmonary toxicity presenting with hemoptysis. Chest 1997 May; 111(5): 1446–7PubMedCrossRefGoogle Scholar
  68. 68.
    Iskandar SB, Abi-Salem B, Keith RL, et al. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99: 383–7PubMedCrossRefGoogle Scholar
  69. 69.
    Papiris SA, Manali ED, Kalomenidis I, et al. Bench-to-bedside review: pulmonary-renal syndromes — an update for the intensivist. Crit Care 2007; 11(3): 213PubMedCrossRefGoogle Scholar
  70. 70.
    Gutierez R, del Pozo J, Carrión C, et al. Vasculitis associated with amiodarone treatment [letter]. Ann Pharmacother 1994; 28(4): 537Google Scholar
  71. 71.
    Scharf C, Oechslin EN, Salomon F, et al. Clinical picture: amiodarone-induced pulmonary mass and cutaneous vasculitis. Lancet 2001; 358(9298): 2045PubMedCrossRefGoogle Scholar
  72. 72.
    Dootson G, Byatt C. Amiodarone-induced vasculitis and a review of the cutaneous side-effects of amiodarone. Clin Exp Dermatol 1994; 19: 422–4PubMedCrossRefGoogle Scholar
  73. 73.
    Stafford L. Hypersensitivity reaction to amiodarone in a patient with a previous reaction to an iodinated radiocontrast agent. Ann Pharmacother 2007 Jul; 41(7): 1310–4PubMedCrossRefGoogle Scholar
  74. 74.
    Junge B, Popp W, Ruehm S, et al. Fire eater’s risk: lipoid pneumonia following aspiration of a liquid hydrocarbon mixture. Pneumologie 2002; 56(9): 547–9PubMedCrossRefGoogle Scholar
  75. 75.
    Spickard III A, Hirschmann JV. Exogenous lipoid pneumonia. Arch Intern Med 1994; 154: 686–92PubMedCrossRefGoogle Scholar
  76. 76.
    Katzenstein A-LA. Katzenstein and Askin’s surgical pathology of nonneoplastic lung disease: major problems in pathology. 4th ed. Philadelphia (PA): WB Saunders, 2006Google Scholar
  77. 77.
    Barta Z, Szabo GG, Bruckner G, et al. Endogenous lipoid pneumonia associated with undifferentiated connective tissue disease (UCTD). Med Sci Monit 2001; 7: 134–6PubMedGoogle Scholar
  78. 78.
    Nicholson AG, Wells AU, Hooper J, et al. Successful treatment of endogenous lipoid pneumonia due to Niemann-Pick type b disease with whole-lung lavage. Am J Respir Crit Care Med 2002; 165: 128–31PubMedGoogle Scholar
  79. 79.
    Chiang IC, Lin YT, Liu GC, et al. Exogenous lipoid pneumonia: serial chest plain roentgenography and high-resolution computerized tomography findings. Kaoh-siung J Med Sci 2003; 19(12): 593–8CrossRefGoogle Scholar
  80. 80.
    Baron SE, Haramati LB, Rivera VT. Radiological and clinical findings in acute and chronic exogenous lipoid pneumonia. J Thorac Imaging 2003; 18(4): 217–24PubMedCrossRefGoogle Scholar
  81. 81.
    Rossi SE, Erasmus JJ, Volpacchio M, et al. “Crazy-paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics 2003; 23(6): 1509–19PubMedCrossRefGoogle Scholar
  82. 82.
    Carrilon Y, Tixier E, Revel D, et al. MR diagnosis of lipoid pneumonia. J Comput Assist Tomogr 1988; 12: 876–7CrossRefGoogle Scholar
  83. 83.
    Papiris SA, Maniati MA, Manoussakis MN, et al. Ortho-deoxia in amiodarone-induced acute reversible pulmonary damage. Chest 1994 Mar; 105(3): 965–6PubMedCrossRefGoogle Scholar
  84. 84.
    Martin II WJ, Rosenow III EC. Amiodarone pulmonary toxicity: recognition and pathogenesis. Part I. Chest 1988; 93: 1067–75PubMedCrossRefGoogle Scholar
  85. 85.
    Polverosi R, Zanellato E, Doroldi C. Thoracic radiography and high resolution computerized tomography in the diagnosis of pulmonary disorders caused by amiodarone. Radiol Med 1996; 92: 58–62PubMedGoogle Scholar
  86. 86.
    Cottin V, Cordier JF. Eosinophilic pneumonias. Allergy 2005; 60: 841–57PubMedCrossRefGoogle Scholar
  87. 87.
    Milbrandt EB, Byron W, Davis B. Progressive infiltrates and eosinophilia with multiple possible causes. Chest 2000; 118: 230–4PubMedCrossRefGoogle Scholar
  88. 88.
    Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71: 301–26PubMedCrossRefGoogle Scholar
  89. 89.
    Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest 1992; 102: 105–12CrossRefGoogle Scholar
  90. 90.
    Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med 2001; 161: 158–64PubMedCrossRefGoogle Scholar
  91. 91.
    Oymak FS, Dermirbas HM, Mavili E, et al. Brochiolitis obliterans organizing pneumonia: clinical and roentgen-ological features in 26 patients. Respiration 2005; 72: 254–62PubMedCrossRefGoogle Scholar
  92. 92.
    Malhorta A, Muse VV, Mark EJ. Case records of the Massachusetts General Hospital: weekly clinico-pathological exercises. Case 12–2008. An 82-year old man with dyspnea and pulmonary abnormalities. N Engl J Med 2003; 348: 1574–85CrossRefGoogle Scholar
  93. 93.
    Antón Aranda E, Alkiza Basanñz R, Laplaza Jiménez Y. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone treatment. Neth J Med 1998; 53: 109–12PubMedCrossRefGoogle Scholar
  94. 94.
    Jessurum GA, Hoogenberg K, Crinjs HJ. Bronchiolitis obliterans organizing pneumonia during low dose amiodarone therapy. Clin Cardiol 1997; 20: 300–2CrossRefGoogle Scholar
  95. 95.
    Epler GR. Drug-induced bronchiolitis obliterans organizing pneumonia. Clin Chest Med 2004; 25: 89–94PubMedCrossRefGoogle Scholar
  96. 96.
    Valle JM, Alvarez D, Antúnez J, et al. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology. Eur Respir J 1995; 8: 470–1PubMedCrossRefGoogle Scholar
  97. 97.
    Camus P, Lombard JN, Perrichon M, et al. Bronchiolitis obliterans organizing pneumonia in patients taking ace-butolol or amiodarone. Thorax 1989; 44: 711–5PubMedCrossRefGoogle Scholar
  98. 98.
    Conte SC, Pagan V, Murer B. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: clinical, radiological and histological pattern. Monaldi Arch Chest Dis 1997; 52: 24–6PubMedGoogle Scholar
  99. 99.
    Oren S, Turkot S, Golzman B, et al. Amiodarone induced bronchiolitis obliterans organizing pneumonia. Respir Med 1996; 90: 167–9PubMedCrossRefGoogle Scholar
  100. 100.
    Rakita L, Sobol SM, Mostow N, et al. Amiodarone pulmonary toxicity. Am Heart J 1983; 106 (4 Pt 2): 906–16PubMedCrossRefGoogle Scholar
  101. 101.
    American Thoracic Society/European Respiratory Society. International multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002; 165: 277–304Google Scholar
  102. 102.
    Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2): 43–8PubMedGoogle Scholar
  103. 103.
    Lim KK, Radford DJ. Amiodarone pneumonitis diagnosed by gallium-67 scintigraphy. Heart Lung Circ 2002; 11: 59–62PubMedCrossRefGoogle Scholar
  104. 104.
    Beasly MB, Franks TJ, Galvin JK, et al. Acute fibrinous organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002; 126: 1064–70Google Scholar
  105. 105.
    Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ 2007; 176(10): 1411–3PubMedCrossRefGoogle Scholar
  106. 106.
    Ruangchira-Urai R, Colby TV, Klein J, et al. Nodular amiodarone lung disease. Am J Surg Pathol 2008; 32: 1654–60PubMedCrossRefGoogle Scholar
  107. 107.
    Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest 1988; 93: 425–7PubMedCrossRefGoogle Scholar
  108. 108.
    Inampudi P, Gross BH, Tankanow LB. Lung masses in a 70 year old man. Chest 2005; 127: 1433–6PubMedCrossRefGoogle Scholar
  109. 109.
    Schechter CJ, O’Neill G, Schweppe I, et al. Asymptomatic cavitary pneumonitis due to amiodarone pulmonary toxicity. Tex Heart Inst J 1985; 12: 371–5PubMedGoogle Scholar
  110. 110.
    Rodriguez Garcia JL, Garcia Nieto JC, Ballesta F, et al. Pulmonary mass and multiple lung nodules mimicking a lung neoplasm as amiodarone induced pulmonary toxicity. Eur J Intern Med 2001; 12: 372–6PubMedCrossRefGoogle Scholar
  111. 111.
    Sheikhzadeh A, Schäfer U, Schnabel A. Drug-induced lupus erythematosus by amiodarone. Arch Intern Med 2002 Apr 8; 162(7): 834–6PubMedCrossRefGoogle Scholar
  112. 112.
    Gonzalez-Rothi RJ, Hannan SE, Hood CI, et al. Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions. Chest 1987; 92: 179–82PubMedCrossRefGoogle Scholar
  113. 113.
    Carmichael LC, Newman JH. Lymphocytic pleural exu-date in a patient receiving amiodarone. Br J Clin Pract 1996; 50(4): 228–30PubMedGoogle Scholar
  114. 114.
    Morelock SY, Sahn SA. Drugs and the pleura. Chest 1999; 116: 212–21PubMedCrossRefGoogle Scholar
  115. 115.
    Stein B, Zaatari GS, Pine JR. Amiodarone pulmonary toxicity: clinical, cytologic and ultrastructural findings. Acta Cytol 1987; 31(3): 357–61PubMedGoogle Scholar
  116. 116.
    Akoun G, Gauthier-Rahman S, Milleron BJ. Amiodarone-induced hypersensitivity pneumonitis: evidence of an immunological cell-mediated mechanism. Chest 1984; 85: 133–5PubMedCrossRefGoogle Scholar
  117. 117.
    Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol 2001; 11(9): 1697–703PubMedCrossRefGoogle Scholar
  118. 118.
    Clarke B, Ward DE, Honey M. Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy. Int J Cardiol 1985; 8: 81–8PubMedCrossRefGoogle Scholar
  119. 119.
    Susano R, Caminal L, Ramos D, et al. Amiodarone induced lupus. Letter Ann Rheum Dis 1999; 58: 655–6CrossRefGoogle Scholar
  120. 120.
    Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356: 935–41PubMedCrossRefGoogle Scholar
  121. 121.
    Endoh Y, Hanai R, Uto K, et al. Diagnostic accuracy of KL-6 as a marker of amiodarone-induced pulmonary toxicity. Pace 2000; 23: 2010–3PubMedGoogle Scholar
  122. 122.
    Bandoh S, Fujita J, Ohtsuki Y, et al. Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis. Ann Rheum Dis 2000; 59(4): 257–62PubMedCrossRefGoogle Scholar
  123. 123.
    Kobayashi J, Kitamura S. Serum KL-6 for the evaluation of active pneumonitis in pulmonary sarcoidosis. Chest 1996; 109: 1276–82PubMedCrossRefGoogle Scholar
  124. 124.
    Standertskjöld-Nordenstam CG, Wandtke JC, Hood WB, et al. Amiodarone pulmonary toxicity: chest radiography and CT in asymptomatic patients. Chest 1985; 88: 143–5PubMedCrossRefGoogle Scholar
  125. 125.
    Rossi SE, Erasmus JJ, McAdams HP, et al. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics 2000; 20: 1245–59PubMedGoogle Scholar
  126. 126.
    Siniakowicz RM, Narula D, Suster B, et al. Diagnosis of amiodarone pulmonary toxicity with high-resolution computerized tomographic scan. J Cardiovasc Electro-physiol 2001; 12: 431–6CrossRefGoogle Scholar
  127. 127.
    Kuhlman JE, Teigen C, Ren H, et al. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177: 121–5PubMedGoogle Scholar
  128. 128.
    Mason JW. Amiodarone pulmonary toxicity and Professor Hounsfield. J Cardiovasc Electrophysiol 2001; 12: 437–8PubMedCrossRefGoogle Scholar
  129. 129.
    Nicholson AA, Hayward C. The value of computed tomography in the diagnosis of amiodarone-induced pulmonary toxicity. Clin Radiol 1989; 40: 564–7PubMedCrossRefGoogle Scholar
  130. 130.
    Marchiori E, Franquet T, Gasparetto TD, et al. Consolidation with diffuse or focal high attenuation: computed tomography findings. J Thorac Imaging 2008; 23: 298–304PubMedCrossRefGoogle Scholar
  131. 131.
    Hoteit MA, Sanchez W. A bright liver. Clin Gastroenterol Hepatol 2008; 6: xxiiPubMedCrossRefGoogle Scholar
  132. 132.
    Nicholson AA, Caplin JL, Steventon DM. Measurement of tissue-bond amiodarone and its metabolites by computed tomography. Clin Radiol 1994; 49: 14–8PubMedCrossRefGoogle Scholar
  133. 133.
    Markos J, Veronese ME, Nicholson MR, et al. Value of hepatic computerized tomographing scanning during amiodarone therapy. Am J Cardiol 1985; 56: 89–92PubMedCrossRefGoogle Scholar
  134. 134.
    Van-Rooij WJ, Vandermeer SC, Van Royen EA, et al. Pulmonary gallium-67 uptake in amiodarone pneumonitis. J Nucl Med 1984; 25: 211–3PubMedGoogle Scholar
  135. 135.
    Moinuddin M, Rockett J. Gallium scintigraphy in the detection of amiodarone lung toxicity. AJR Am J Roent-genol 1986; 147(3): 607–9Google Scholar
  136. 136.
    Zhu YY, Botvinick E, Dae M, et al. Gallium lung scintigraphy in amiodarone pulmonary toxicity. Chest 1988; 93: 1126–31PubMedCrossRefGoogle Scholar
  137. 137.
    Foresti V, Carini L, Lovagnini-Scher CA, et al. Amiodarone lung toxicity: role of pulmonary function tests. Int J Clin Pharmacol Res 1987; 7(5): 373–80PubMedGoogle Scholar
  138. 138.
    Costabel U, Guzman J, Bonella F, et al. Bronchoalveolar lavage in other interstitial lung diseases. Semin Respir Crit Care Med 2007; 28: 514–24PubMedCrossRefGoogle Scholar
  139. 139.
    Israël-Biet D, Venet A, Caubarrère I, et al. Bronchoalveolar lavage in amiodarone pneumonitis: cellular abnormalities and their relevance to pathogenesis. Chest 1987; 91: 214–21PubMedCrossRefGoogle Scholar
  140. 140.
    Karpel JP, Ligenza C, Aldrich T, et al. Amiodarone-induced interstitial lung disease: evidence for sensitized T lymphocytes [abstract]. Am Rev Respir Dis 1988; 137: S347Google Scholar
  141. 141.
    Akoun G, Milleron BJ, Badaro DM, et al. Pleural T-lymphocyte subsets in amiodarone-associated pleuro-pneumonitis. Chest 1989; 95: 506–7CrossRefGoogle Scholar
  142. 142.
    Wilson BP, Jaworski AJ, Donner ME, et al. Amiodarone induced pulmonary toxicity in the rat. Lung 1989; 167: 301–11PubMedCrossRefGoogle Scholar
  143. 143.
    Nagata N, Suematsu R, Yoshii C, et al. Characterization of amiodarone pneumonitis as related to inflammatory cells and surfactant apoprotein. Chest 1997; 112: 1068–74PubMedCrossRefGoogle Scholar
  144. 144.
    Mermolja M, Rott T, Debeljak A. Cytology of bronch-oalveolar lavage in some rare pulmonary disorders: pulmonary alveolar proteinosis and amiodarone pulmonary toxicity. Cytopathology 1994; 5: 9–16PubMedCrossRefGoogle Scholar
  145. 145.
    Xaubet A, Roca J, Rodriguez-Roisin R, et al. Bronch-oalveolar lavage cellular analysis and gallium lung scan in the assessment of patients with amiodarone-induced pneumonitis. Respiration 1987; 52: 272–80PubMedCrossRefGoogle Scholar
  146. 146.
    Pozzi E, Sada E, Luisetti M, et al. Interstitial pneumopathy and low-dose amiodarone. Eur J Respir Dis 1984; 65: 620–2PubMedGoogle Scholar
  147. 147.
    Nalos PC, Kass RM, Gang ES, et al. Life-threatening postoperative pulmonary complications in patients with previous amiodarone pulmonary toxicity undergoing cardiothoracic operations. J Thorac Cardiovasc Surg 1987; 93: 904–12PubMedGoogle Scholar
  148. 148.
    Darey P. Is amiodarone an underrecognized cause of acute respiratory failure in the ICU? Chest 2001; 120: 275–82CrossRefGoogle Scholar
  149. 149.
    Rosenbaum MB, Chiale PA, Halpern MS, et al. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976; 38: 934–44PubMedCrossRefGoogle Scholar
  150. 150.
    Homoud MK. Review: amiodarone reduces risk for sudden death but not all-cause mortality in cardiomyopathy. ACP Journal Club. Ann Intern Med 2009; 151: JC4–13PubMedGoogle Scholar
  151. 151.
    Esinger W, Schleiffer T, Leinberger H, et al. Steroid-refractory amiodarone-induced pulmonary fibrosis: clinical features and morphology after an amiodarone-free interval of 3 months. Dtsch Med Wochenschr 1988; 113: 1638–41PubMedCrossRefGoogle Scholar
  152. 152.
    Parra O, Ruiz J, Ojanguren I, et al. Amiodarone toxicity: recurrence of interstitial pneumonitis after withdrawal of the drug. Eur Respir J 1989; 2: 905–7PubMedGoogle Scholar
  153. 153.
    Chendrasekhar A, Barke RA, Druck P. Recurrent amiodarone pulmonary toxicity. South Med J 1996; 89: 85–6PubMedCrossRefGoogle Scholar
  154. 154.
    Zaher C, Hamer A, Peter T, et al. Low-dose steroid therapy for prophylaxis of amiodarone-induced pulmonary infiltrates [letter]. N Engl J Med 1983; 308: 779PubMedCrossRefGoogle Scholar
  155. 155.
    Cox G, Johnson J, Kinnear WJ, et al. Amiodarone and the lung: wide variations in clinical practice. Respir Med 2000; 94: 1130–1PubMedCrossRefGoogle Scholar
  156. 156.
    Card JW, Racz WJ, Brien JF. Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction. J Pharmacol Exp Ther 2003; 304(1): 277–83PubMedCrossRefGoogle Scholar
  157. 157.
    Card JW, Leeder RG, Racz WJ, et al. Effects of dietary vitamin E supplementation on pulmonary morphology and collagen deposition in amiodarone- and vehicle-treated hamsters. Toxicology 1999; 133: 75–84PubMedCrossRefGoogle Scholar
  158. 158.
    Darmanata JI, Van Zandwijk N, Düren DR, et al. Amiodarone pneumonitis: three further cases with a review of published reports. Thorax 1984; 39: 57–64PubMedCrossRefGoogle Scholar
  159. 159.
    Riley SA, William SE, Cooke NJ. Alveolitis after treatment with amiodarone. BMJ 1982; 284: 161–2PubMedCrossRefGoogle Scholar
  160. 160.
    Nicolet-Chatelain G, Prevost MC, Escamilla R, et al. Amiodarone induced pulmonary toxicity: immuno-allergologic tests and bronchoalveolar lavage phospho-lipid content. Chest 1991; 99: 363–9PubMedCrossRefGoogle Scholar
  161. 161.
    Hughes M, Binning A. Intravenous amiodarone in intensive care: time for reappraisal? Intensive Care Med 2000; 26: 1730–Google Scholar
  162. 162.
    Ohar JA, Jackson Jr F, Redd RM, et al. Usefulness of serial pulmonary function testing as an indicator of amiodarone toxicity. Am J Cardiol 1989; 64: 1322–6PubMedCrossRefGoogle Scholar
  163. 163.
    Marchlinski FE, Gansler TS, Waxman HL, et al. Amiodarone pulmonary toxicity. Ann Intern Med 1982; 97(6): 839–45PubMedGoogle Scholar
  164. 164.
    Kudenchuk PJ, Pierson DJ, Greene HL, et al. Prospective evaluation of amiodarone pulmonary toxicity. Chest 1984; 86: 541–8PubMedCrossRefGoogle Scholar
  165. 165.
    Poll LW, May P, Koch JA, et al. HRCT findings of amiodarone pulmonary toxicity: clinical and radiologic regression. J Cardiovasc Pharmacol Ther 2001; 6: 307–11PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Spyros A. Papiris
    • 1
    Email author
  • Christina Triantafillidou
    • 1
  • Likurgos Kolilekas
    • 1
  • Despoina Markoulaki
    • 1
  • Effrosyni D. Manali
    • 1
  1. 1.2nd Pulmonary Department, ‘Attikon’ University HospitalNational and Kapodistrian University of Athens, Athens Medical SchoolHaidariGreece

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