in the peri-procedural period [60-63]. However, the role of amiodarone in acute periprocedural ARDS is controversial, and a review of amiodarone pulmonary toxicity cites evidence against such an association [62,64-66]. In reports describing surgical patients, ARDS developed within one to four days after extubation [60,61]. In comparison, the report of two patients with fatal ARDS following pulmonary angiography described respiratory deterioration within 30 minutes of the procedure [62]. While some surgical literature suggests that use of amiodarone is safe after lung resection [64,66,67], others have voiced concern about lung toxicity in such circumstances and call for clinical studies to determine the true risks and benefits of peri-operative amiodarone [65]. Diagnosis The diagnosis of ARDS is based on clinical criteria: acute onset of symptoms ( 1 week), bilateral opacities consistent with pulmonary edema on chest computed tomography (CT), absence of cardiac failure or fluid overload, and a moderate to severe impairment of oxygenation. The differential diagnosis of ARDS includes cardiogenic pulmonary edema, diffuse alveolar hemorrhage (see below), acute interstitial pneumonia, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 12/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate acute eosinophilic pneumonia, and cancer. Usually, when ARDS is suspected, bronchoalveolar lavage (BAL) is performed to exclude lung infection, hemorrhage, eosinophilic pneumonia, and malignancy. Once these processes have been excluded, other causes of ARDS, such as sepsis, aspiration, transfusion, and drug toxicity (other than amiodarone), need to be excluded. (See 'Diffuse alveolar hemorrhage' below and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults" and "Basic principles and technique of bronchoalveolar lavage".) Acute fibrinous and organizing pneumonia (AFOP) is a separate process that is in the differential diagnosis of ARDS as it presents similarly. At least one case of AFOP associated with amiodarone has been reported [68]. AFOP has a different histopathologic pattern from ARDS, characterized by the presence of intra-alveolar fibrin (fibrin "balls") and organizing pneumonia, but without the hyaline membranes associated with ARDS. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.) Treatment Management of ARDS associated with amiodarone toxicity should include cessation of amiodarone, implementation of supportive care for the critically ill patient, and use of mechanical ventilation with strategies to minimize supplemental oxygen and also reduce barotrauma and volutrauma. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Ventilator management strategies for adults with acute respiratory distress syndrome".) While systemic glucocorticoids are not part of routine care in ARDS and have not been formally evaluated in ARDS associated with amiodarone, most patients with amiodarone- associated ARDS are treated empirically with systemic glucocorticoids (eg, methylprednisolone 500 to 1000 mg/day intravenously, followed by prednisone 0.5 mg/kg daily) after infection has been excluded [7,69]. This practice is based on the response to glucocorticoids observed in other forms of amiodarone lung toxicity and in a small number of patients with amiodarone-associated ARDS [7,69]. Often, patients will need to be treated empirically for more than one possibility (eg, infection and drug-induced lung toxicity) while studies are pending. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.) In one patient with life-threatening amiodarone lung toxicity manifested by diffuse radiographic opacities and respiratory failure that were unresponsive to glucocorticoids, hemoperfusion with a polymyxin B-immobilized fiber column dramatically improved https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 13/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate oxygenation with concomitant reduction in serum amiodarone and desethylamiodarone levels [70]. Further study is needed to determine the efficacy of this treatment. Patients in whom ARDS develops due to amiodarone have a mortality rate of approximately 50 percent [71]. Prevention Given the apparent association of amiodarone-associated ARDS with surgery or medical procedures, it has been hypothesized that amiodarone may sensitize patients to high concentrations of inspired oxygen or to iodinated contrast media. Some experts advise close monitoring of the pulse oxygen saturation (SpO ) and/or partial pressure of 2 arterial oxygen (PaO ) to minimize supplemental oxygen, although data to support this 2 practice are lacking. While caution should be used when considering patients on amiodarone for surgery, especially in the setting of preoperative pulmonary dysfunction, the concerns about performing surgery on such patients must be weighed against the alternative concern that withdrawal of amiodarone before surgery may delay the operation for several weeks (because amiodarone has a very long half-life) and put the patient at increased risk of malignant dysrhythmias. DIFFUSE ALVEOLAR HEMORRHAGE Diffuse alveolar hemorrhage (DAH) is a rare complication of amiodarone [40,72-75]. It may occur abruptly in the first few days or months (average six months) after initiation of the drug [29,73,74,76-78]. Clinical features The patients commonly present with an acute onset of cough, shortness of breath, fever, and sometimes hemoptysis. Many of the patients have pre- existing chronic lung disease [74]. Laboratory studies often show a decrease in hemoglobin. Imaging studies show bilateral diffuse ground glass opacities and/or consolidation. Diagnosis The diagnosis of DAH due to amiodarone is usually suspected based on the clinical presentation (eg, acute onset, hemoptysis) and imaging studies (diffuse opacities). Confirmation is usually obtained by sequential bronchoalveolar lavages (BALs) in an area of radiographic opacities that reveal progressively more hemorrhagic returns [40]. Hemosiderin-laden macrophages, which may be demonstrated by Prussian blue staining, are also characteristic of DAH. While hemosiderin-laden macrophages can be seen in cardiogenic pulmonary edema, they are typically present in lower numbers than in pulmonary hemorrhage due to amiodarone. A lung biopsy is generally not indicated. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.) https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 14/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Differential diagnosis The differential diagnosis of DAH includes pulmonary edema (cardiogenic and noncardiogenic), systemic lupus, vasculitis, and hemorrhage due to another drug (eg, cocaine, propylthiouracil) or due to therapy with anticoagulants or platelet glycoprotein IIB/IIIA inhibitors. These possibilities can be narrowed by studies, such as a platelet count, coagulation tests, urinalysis, drug screening for cocaine, plasma brain natriuretic peptide (BNP), serologic tests for antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA) and antiglomerular basement membrane antibodies, and an echocardiogram. (See 'Acute respiratory distress syndrome' above and "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.) Treatment As with other forms of amiodarone toxicity, prompt discontinuation of the medication is indicated. Most patients are treated with systemic glucocorticoids following the treatment approach for other causes of DAH, although the value and dosing in this setting are uncertain. A reasonable initial dose of glucocorticoids, is the equivalent of methylprednisolone 500 to 1000 mg intravenously in divided doses, daily for up to five days followed by gradual tapering and then maintenance for weeks to months on an oral preparation. (See "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.) One patient, who required continuation of amiodarone to prevent life-threatening arrhythmias, was successfully treated with glucocorticoids and a reduction in the dose of amiodarone to half of the prior dose [74]. PULMONARY NODULES OR MASS Solitary and multiple pulmonary nodules and masses have been attributed to amiodarone toxicity in a number of case reports and case series [79,80]. Among four such patients who had histopathologic evaluation, one had a single mass with a background of increased reticular markings, while the others had two or more nodules [80]. Increased F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake was noted in two patients. Pathologic examination revealed areas of necrosis within solid inflammation [80]. Surrounding the necrosis were sheets of vacuolated histiocytes and aggregates of neutrophils. Patches of organizing pneumonia were noted peripheral to some nodules. The appearance was somewhat similar to granulomatosis with polyangiitis, but palisading histiocytes, vasculitis, and granulomatous inflammation were not present. The patient with multiple nodules had improvement in symptoms and resolution of the nodules after cessation of amiodarone; the others had excisions of the lesions due to suspicion for malignancy. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 15/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate In a separate report, a solitary pulmonary mass simulating a pulmonary malignancy and associated with additional smaller, peripheral nodules was described as a complication of amiodarone therapy [79]. Increased uptake was noted on FDG-PET scan in support of possible malignancy. However, needle aspirates yielded foamy macrophages and type II cells, and no evidence of malignancy. With cessation of amiodarone and treatment with prednisone, the lung abnormalities resolved over 12 months. Dual energy computed tomography (CT) demonstrated high iodine content in a mass-like lung consolidation of a patient treated with amiodarone, which was confirmed to be due to amiodarone by lung biopsy [81]. PLEURAL DISEASE A few case reports have described exudative pleural effusions associated with amiodarone therapy either isolated or in combination with pneumonitis [82-85]. In at least one case, the patient presented with features of drug-induced lupus [84]. (See "Drug-induced lupus".) Pleuroparenchymal fibroelastosis was described in one patient after five years of amiodarone therapy [86]; no other cause of PPFE was identified. SUMMARY AND RECOMMENDATIONS Amiodarone is associated with several forms of pulmonary toxicity including interstitial pneumonitis (the most common presentation), eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH), pulmonary nodules and masses, and rarely pleural effusions. The incidence of pulmonary toxicity from amiodarone is not precisely known; it is estimated to be 1 to 5 percent, depending on the dose of amiodarone. (See 'Introduction' above and 'Interstitial pneumonitis' above.) Risk factors for amiodarone-induced pulmonary toxicity include a daily dose 400 mg/day, duration of therapy exceeding two months, patient age >60 years, preexisting lung disease, surgery, and pulmonary angiography. Pulmonary toxicity can also occur at lower daily doses. (See 'Risk factors' above.) Permanent discontinuation of amiodarone is the primary therapy for amiodarone pulmonary toxicity. (See 'Treatment' above.) Interstitial pneumonitis Interstitial pneumonitis due to amiodarone toxicity is characterized by the insidious onset of nonproductive cough and/or dyspnea. Fever, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 16/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate pleuritic pain, weight loss, and malaise can also occur. The onset of symptoms is usually 6 to 12 months of amiodarone therapy, but may occur within two months or after several years of treatment. (See 'Clinical manifestations' above.) The chest radiograph typically reveals new focal or diffuse reticular or ground glass opacities. High-resolution computed tomography (HRCT) of the chest and upper abdomen usually shows ground glass and reticular opacities and also increased attenuation in the lungs, liver, and spleen. Pulmonary function tests typically show restriction and a reduced diffusing capacity (DLCO). (See 'Laboratory studies' above.) Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed to exclude alternative diagnoses (eg, infection, hemorrhage, malignancy). Samples should be sent for cell counts, culture, and cytologic evaluation. The presence of "foam" cells (alveolar macrophages full of amiodarone-phospholipid complexes) is a characteristic of, but not pathognomonic for, pulmonary toxicity ( picture 1). (See 'Bronchoalveolar lavage' above and 'Histopathology' above.) A clinical diagnosis of amiodarone-induced interstitial pneumonitis can often be made when the clinical features are consistent; other possibilities (eg, infection, heart failure) have been excluded; and the patient improves with drug cessation and, possibly, a trial of glucocorticoid therapy. Lung biopsy is usually deferred unless the diagnosis remains uncertain after a trial of drug cessation. (See 'Diagnosis and differential diagnosis' above.) In addition to cessation of amiodarone, for the majority of patients with more than mild symptoms of interstitial pneumonitis due to amiodarone, we suggest initiation of systemic glucocorticoid therapy (Grade 2C). The usual dose is the equivalent of oral prednisone 40 to 60 mg/day. Due to the long elimination half-life (approximately 45 days) of amiodarone, pulmonary toxicity may initially progress despite drug discontinuation and may recur upon glucocorticoid withdrawal. (See 'Treatment' above.) For screening, guidelines suggest a baseline and annual chest radiograph and baseline pulmonary function tests for patients on long-term amiodarone therapy. However, serial pulmonary function tests are not helpful in predicting amiodarone toxicity. (See 'Screening' above.) Eosinophilic pneumonia Acute and chronic eosinophilic pneumonia are rarely associated with amiodarone. Chest computed tomography (CT) features include ground glass opacities, diffuse reticular changes, and masses. Peripheral blood eosinophilia may be present. In both acute and chronic eosinophilic pneumonia, the diagnosis is supported by https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 17/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate BAL fluid that often contains >25 percent eosinophils. Other causes of pulmonary eosinophilia (eg, fungal or parasitic infection, pulmonary eosinophilia due to another drug, vasculitis) must be excluded. (See 'Eosinophilic pneumonia' above and "Overview of pulmonary eosinophilia".) Treatment includes cessation of amiodarone and administration of systemic glucocorticoids, following the approaches for acute or chronic eosinophilic pneumonia, depending on the pattern manifested by the individual patient. (See "Idiopathic acute eosinophilic pneumonia", section on 'Treatment' and "Chronic eosinophilic pneumonia", section on 'Treatment'.) Organizing pneumonia Organizing pneumonia (such as that seen in cryptogenic organizing pneumonia) is present in approximately 25 percent of cases of amiodarone pulmonary toxicity. Suggestive features include a subacute or acute onset mimicking an infectious pneumonia, patchy or nodular consolidative opacities on imaging, and no response to antimicrobial therapy. A lung biopsy is needed for diagnosis. Treatment requires cessation of amiodarone; addition of systemic glucocorticoids is based on severity of disease and follows that for cryptogenic organizing pneumonia. (See 'Organizing pneumonia' above and "Cryptogenic organizing pneumonia".) Acute respiratory distress syndrome ARDS is a rare but potentially fatal form of amiodarone pulmonary toxicity that typically occurs shortly after a pulmonary angiogram or surgery. (See 'Acute respiratory distress syndrome' above.) Patients present with rapidly progressive respiratory failure, impaired oxygenation, and diffuse ground glass opacities on radiographic imaging. BAL is performed promptly to exclude infection, hemorrhage, and eosinophilic pneumonia. Other common causes of ARDS (eg, sepsis, aspiration) are also investigated. Management includes amiodarone cessation, supportive care, and mechanical ventilation. In addition, we suggest systemic glucocorticoid therapy (Grade 2C). A reasonable dose (after the exclusion of infection) is methylprednisolone 500 to 1000 mg/day intravenously, followed by prednisone 0.25 to 0.5 mg/kg daily. (See 'Acute respiratory distress syndrome' above.) Diffuse alveolar hemorrhage DAH due to amiodarone has an acute presentation of dyspnea, cough, and sometimes hemoptysis. Imaging shows diffuse or patchy ground glass or consolidative opacities. The diagnosis is usually made by sequential BAL sampling that shows progressively more hemorrhagic effluent; other causes of DAH must be excluded. In addition to cessation of amiodarone, we suggest systemic glucocorticoid https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 18/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate therapy (Grade 2C). A reasonable dose (after the exclusion of infection) is methylprednisolone 500 to 1000 mg/day, intravenously in divided doses for up to five days, followed by gradual tapering. (See 'Diffuse alveolar hemorrhage' above and "The diffuse alveolar hemorrhage syndromes", section on 'Glucocorticoids'.) Pulmonary nodules and masses Solitary and multiple pulmonary nodules and masses due to amiodarone toxicity can mimic pulmonary malignancy in radiographic appearance and F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake. A pathologic diagnosis is needed to exclude malignancy. (See 'Pulmonary nodules or mass' above.) Pleural effusion Exudative pleural effusions are a rare manifestation of amiodarone toxicity; they may be isolated or occur in association with interstitial pneumonitis. (See 'Pleural disease' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ruzieh M, Moroi MK, Aboujamous NM, et al. Meta-Analysis Comparing the Relative Risk of Adverse Events for Amiodarone Versus Placebo. Am J Cardiol 2019; 124:1889. 2. Mason JW. Amiodarone. N Engl J Med 1987; 316:455. 3. Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest 1988; 93:1067. 4. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol 2011; 108:705. 5. Papiris SA, Triantafillidou C, Kolilekas L, et al. Amiodarone: review of pulmonary effects and toxicity. Drug Saf 2010; 33:539. 6. Schwaiblmair M, Berghaus T, Haeckel T, et al. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect? Clin Res Cardiol 2010; 99:693. 7. Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Interstitial Lung D isease, 5th, Schwartz MI, King TE Jr (Eds), People's Medical Publishing House, Shelton, CT 20 11. p.637. 8. Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part 2). Chest 1988; 93:1242. 9. Seki S, Itagaki S, Kobayashi M, et al. Amiodarone increases the accumulation of DEA in a https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 19/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate human alveolar epithelium-derived cell line. Biol Pharm Bull 2008; 31:1449. 10. Yano T, Itoh Y, Yamada M, et al. Combined treatment with L-carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells. Apoptosis 2008; 13:543. 11. Lee KY, Oh S, Choi YJ, et al. Activation of autophagy rescues amiodarone-induced apoptosis of lung epithelial cells and pulmonary toxicity in rats. Toxicol Sci 2013; 136:193. 12. Mahavadi P, Knudsen L, Venkatesan S, et al. Regulation of macroautophagy in amiodarone- induced pulmonary fibrosis. J Pathol Clin Res 2015; 1:252. 13. Nikaido A, Tada T, Nakamura K, et al. Clinical features of and effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity. Int J Cardiol 2010; 140:328. 14. Kosseifi SG, Halawa A, Bailey B, et al. Reduction of amiodarone pulmonary toxicity in patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ther Adv Respir Dis 2009; 3:289. 15. Akoun GM, Gauthier-Rahman S, Milleron BJ, et al. Amiodarone-induced hypersensitivity pneumonitis. Evidence of an immunological cell-mediated mechanism. Chest 1984; 85:133. 16. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol 2008; 66:82. 17. Range FT, Hilker E, Breithardt G, et al. Amiodarone-induced pulmonary toxicity a fatal case report and literature review. Cardiovasc Drugs Ther 2013; 27:247. 18. Ott MC, Khoor A, Leventhal JP, et al. Pulmonary toxicity in patients receiving low-dose amiodarone. Chest 2003; 123:646. 19. Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89:896. 20. Pfeil MN, Vollenweider P, Fitting JW. Fatal pulmonary toxicity after a short course of amiodarone therapy. Clinical Geriatrics 2012; 20:34. 21. Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51. 22. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 23. 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. 24. Singh SN, Fisher SG, Deedwania PC, et al. Pulmonary effect of amiodarone in patients with heart failure. The Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF- https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 20/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate STAT) Investigators (Veterans Affairs Cooperative Study No. 320). J Am Coll Cardiol 1997; 30:514. 25. Olshansky B, Sami M, Rubin A, et al. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95:404. 26. 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. 27. Kohno N, Yokoyama A, Kondo K. KL-6 as a serum marker for amiodarone-induced pulmonary toxicity. Intern Med 2000; 39:1004. 28. Bernal Morell E, Hern ndez Madrid A, Mar n Mar n I, et al. [Multiple pulmonary nodules and amiodarone. KL-6 as a new diagnostic tool]. Rev Esp Cardiol 2005; 58:447. 29. Dean PJ, Groshart KD, Porterfield JG, et al. Amiodarone-associated pulmonary toxicity. A clinical and pathologic study of eleven cases. Am J Clin Pathol 1987; 87:7. 30. Standertskj ld-Nordenstam CG, Wandtke JC, Hood WB Jr, et al. Amiodarone pulmonary toxicity. Chest radiography and CT in asymptomatic patients. Chest 1985; 88:143. 31. Oyama N, Oyama N, Yokoshiki H, et al. Detection of amiodarone-induced pulmonary toxicity in supine and prone positions: high-resolution computed tomography study. Circ J 2005; 69:466. 32. Taylor AC, Verma N, Slater R, Mohammed TL. Bad for Breathing: A Pictorial of Drug-Induced Pulmonary Disease. Curr Probl Diagn Radiol 2016; 45:429. 33. Kuhlman JE, Teigen C, Ren H, et al. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177:121. 34. Hudzik B, Polonski L. Amiodarone-induced pulmonary toxicity. CMAJ 2012; 184:E819. 35. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16:43. 36. Xaubet A, Roca J, Rodriguez-Roisin R, et al. Bronchoalveolar lavage cellular analysis and gallium lung scan in the assessment of patients with amiodarone-induced pneumonitis. Respiration 1987; 52:272. 37. Ohar JA, Jackson F, Dettenmeier PA, et al. Bronchoalveolar lavage cell count and differential are not reliable indicators of amiodarone-induced pneumonitis. Chest 1992; 102:999. 38. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis. Bronchoalveolar lavage findings in 15 patients and review of the literature. Chest 1992; 102:1005. 39. Akoun GM, Cadranel JL, Blanchette G, et al. Bronchoalveolar lavage cell data in amiodarone- associated pneumonitis. Evaluation in 22 patients. Chest 1991; 99:1177. 40. Iskandar SB, Abi-Saleh B, Keith RL, et al. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99:383. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 21/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate 41. Bedrossian CW, Warren CJ, Ohar J, Bhan R. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry. Ann Diagn Pathol 1997; 1:47. 42. Larsen BT, Vaszar LT, Colby TV, Tazelaar HD. Lymphoid hyperplasia and eosinophilic pneumonia as histologic manifestations of amiodarone-induced lung toxicity. Am J Surg Pathol 2012; 36:509. 43. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4:1250. 44. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007; 298:1312. 45. Mason JW. Prediction of amiodarone-induced pulmonary toxicity. Am J Med 1989; 86:2. 46. 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. 47. Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45:1303. 48. Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147:e131. 49. Hern ndez Voth AR, Catal n JS, Benavides Ma as PD, et al. A 73-year-old man with interstitial lung disease due to dronedarone. Am J Respir Crit Care Med 2012; 186:201. 50. Thornton D, Avery S, Edey AJ, Medford AR. Organising pneumonia due to dronedarone. J R Coll Physicians Edinb 2015; 45:213. 51. De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11:1023. 52. Grabczak EM, Zielonka TM, Wiwa a J, et al. Amiodarone induced pneumonitis and hyperthyroidism: case report. Pol Arch Med Wewn 2008; 118:524. 53. Sato S, Watanabe K, Ishida T, et al. [Amiodarone-induced pneumonitis associated with marked eosinophilia in BALF]. Nihon Naika Gakkai Zasshi 2006; 95:356. 54. LeVee A, Trieu M, Bhattacharyya S, Sandhu G. Eosinophilic pneumonia: A rare manifestation of amiodarone toxicity diagnosed using traditional bronchoscopy. Respir Med Case Rep 2019; 27:100856. 55. Valle JM, Alvarez D, Ant nez J, Vald s L. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology. Eur Respir J 1995; 8:470. 56. Kozlova N, Lanier GM, Kleinman G, Epelbaum O. Acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation. Respir https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 22/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Med Case Rep 2021; 34:101532. 57. Zizzo G, Caruso S, Ricchiuti E, et al. Amiodarone-induced organizing pneumonia mimicking COVID-19: a case report. Eur J Med Res 2021; 26:62. 58. Zitnik, RJ. Drug-induced lung disease: Antiarrhythmic agents. J Respir Dis 1996; 17:254. 59. Schindler K, Schima W, Kaliman JF. Cryptogenic organizing pneumonia due to amiodarone: long-term follow-up after corticosteroid treatment. Wien Klin Wochenschr 2010; 122:511. 60. Van Mieghem W, Coolen L, Malysse I, et al. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105:1642. 61. Baumann H, Fichtenkamm P, Schneider T, et al. Rapid onset of amiodarone induced pulmonary toxicity after lung lobe resection - A case report and review of recent literature. Ann Med Surg (Lond) 2017; 21:53. 62. Wood DL, Osborn MJ, Rooke J, Holmes DR Jr. Amiodarone pulmonary toxicity: report of two cases associated with rapidly progressive fatal adult respiratory distress syndrome after pulmonary angiography. Mayo Clin Proc 1985; 60:601. 63. Teerakanok J, Tantrachoti P, Chariyawong P, Nugent K. Acute Amiodarone Pulmonary Toxicity After Surgical Procedures. Am J Med Sci 2016; 352:646. 64. Kolokotroni SM, Toufektzian L, Harling L, Bill A. In patients undergoing lung resection is it safe to administer amiodarone either as prophylaxis or treatment of atrial fibrillation? Interact Cardiovasc Thorac Surg 2017; 24:783. 65. Spartalis M, Tzatzaki E, Schizas D, Spartalis E. eComment. Amiodarone-induced pulmonary toxicity in patients with atrial fibrillation undergoing lung resection. Interact Cardiovasc Thorac Surg 2017; 24:788. 66. Feduska ET, Thoma BN, Torjman MC, Goldhammer JE. Acute Amiodarone Pulmonary Toxicity. J Cardiothorac Vasc Anesth 2021; 35:1485. 67. Riber LP, Christensen TD, Pilegaard HK. Amiodarone is a cost-neutral way of preventing atrial fibrillation after surgery for lung cancer. Eur J Cardiothorac Surg 2014; 45:120. 68. Beasley MB, Franks TJ, Galvin JR, et al. Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002; 126:1064. 69. Kumar S, Bangalore S, Kumari R, et al. Amiodarone-induced acute respiratory distress syndrome masquerading as acute heart failure. J Emerg Med 2012; 43:e311. 70. Sato N, Kojima K, Horio Y, et al. Successful treatment of severe amiodarone pulmonary toxicity with polymyxin B-immobilized fiber column direct hemoperfusion. Chest 2013; 143:1146. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 23/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate 71. Myers JL, Kennedy JI, Plumb VJ. Amiodarone lung: pathologic findings in clinically toxic patients. Hum Pathol 1987; 18:349. 72. Vizioli LD, Cho S. Amiodarone-associated hemoptysis. Chest 1994; 105:305. 73. Borders CW 3rd, Bennett S, Mount C, Claassen SL. A rare case of acute diffuse alveolar hemorrhage following initiation of amiodarone: a case report. Mil Med 2012; 177:118. 74. Tanawuttiwat T, Harindhanavudhi T, Hanif S, Sahloul MZ. Amiodarone-induced alveolar haemorrhage: a rare complication of a common medication. Heart Lung Circ 2010; 19:435. 75. Blasco LM. Trepopnea due to amiodarone-induced diffuse alveolar hemorrhage. Respir Care 2013; 58:e11. 76. Iskander S, Raible DG, Brozena SC, et al. Acute alveolar hemorrhage and orthodeoxia induced by intravenous amiodarone. Catheter Cardiovasc Interv 1999; 47:61. 77. Saeed J, Waqas QA, Khan UI, Abdullah HMA. Amiodarone-induced diffuse alveolar haemorrhage: a rare but potentially life-threatening complication of a commonly prescribed medication. BMJ Case Rep 2019; 12. 78. Busch CD, Heiberger CJ, Mehta TI, Yim D. Amiodarone-induced Hemoptysis: A Rare Presentation of Amiodarone-induced Pulmonary Toxicity Occurs at a Low Dose. Cureus 2019; 11:e5289. 79. Azzam I, Tov N, Elias N, Naschitz JE. Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: the continuing diagnostic challenge. Postgrad Med J 2006; 82:73. 80. Ruangchira-Urai R, Colby TV, Klein J, et al. Nodular amiodarone lung disease. Am J Surg Pathol 2008; 32:1654. 81. Soker T, Yang M, Gilkeson RC, Ansari-Gilani K. Application of dual energy CT in the diagnosis of amiodarone lung toxicity as a cause of lung mass. Clin Imaging 2021; 70:46. 82. Gonzalez-Rothi RJ, Hannan SE, Hood CI, Franzini DA. Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions. Chest 1987; 92:179. 83. Uong V, Nugent K, Alalawi R, Raj R. Amiodarone-induced loculated pleural effusion: case report and review of the literature. Pharmacotherapy 2010; 30:218. 84. Sheikhzadeh A, Sch fer U, Schnabel A. Drug-induced lupus erythematosus by amiodarone. Arch Intern Med 2002; 162:834. 85. Hawatmeh A, Thawabi M, Jmeian A, et al. Amiodarone-induced loculated pleural effusion without pulmonary parenchymal involvement: A case report and literature review. J Nat Sci Biol Med 2017; 8:130. 86. Oliveira M, Melo N, Mota PC, et al. Pleuroparenchymal Fibroelastosis as Another Potential Lung Toxicity Pattern Induced by Amiodarone. Arch Bronconeumol (Engl Ed) 2020; 56:55. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 24/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Topic 4364 Version 22.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 25/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate GRAPHICS Amiodarone pulmonary toxicity Chest radiographs from a patient treated with amiodarone demonstrate left upper lobe consolidation (A) and six months later right upper lobe consolidation with residual scar in left upper lobe (B). Courtesy of Paul Stark, MD. Graphic 50428 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 26/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone pulmonary toxicity Computed tomographic scan obtained without intravenous contrast material reveals a high-attenuation right upper lobe consolidation (upper panel). Images from the upper abdomen (lower panel) demonstrate increased attenuation of the liver parenchyma. The attenuation of this lesion is the result of iodine deposition from chronic amiodarone therapy. Courtesy of Paul Stark, MD. Graphic 58121 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 27/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate BAL in amiodarone pulmonary toxicity Bronchoalveolar lavage (BAL) cytopreparation smear with normal differential and marked foamy appearance of alveolar macrophages. Courtesy of Talmadge E King Jr, MD. Graphic 53653 Version 2.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 28/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone toxicity Electron micrograph shows an alveolar macrophage with intracytoplasmic lamellar bodies typical of amiodarone toxicity. These phospholipid inclusions account for the foamy appearance of histiocytes and epithelial cells in patients taking amiodarone and can be identified even in patients who lack radiographic or clinical evidence of lung disease. Courtesy of Je rey L Myers, MD. Graphic 64923 Version 2.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 29/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone toxicity Amiodarone lung biopsy photomicrograph shows diffuse alveolar damage in a patient with amiodarone toxicity. Alveolar spaces contain histiocytes with finely vacuolated cytoplasm (arrow). Chronic interstitial pneumonia with fibrosis and organizing pneumonia have also been described in patients with amiodarone toxicity. Courtesy of Je rey L Myers, MD. Graphic 78032 Version 3.0 Normal lung High-power photomicrograph shows alveoli containing capillaries within a narrow interstitium. The alveoli are lined with thin, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 30/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate elongated type I pneumocytes (arrow) and smaller numbers of cuboidal type II pneumocytes (dashed arrow). Courtesy of Steven E Weinberger, MD. Graphic 80140 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 31/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Contributor Disclosures Edward D Chan, MD No relevant financial relationship(s) with ineligible companies to disclose. Talmadge E King, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kevin R Flaherty, MD, MS Grant/Research/Clinical Trial Support: Boehringer Ingelheim [IPF]. Consultant/Advisory Boards: Arrowhead [Interstitial lung disease]; AstraZeneca [Interstitial lung disease]; Bellerophon [Interstitial lung disease]; CSL Behring [Interstitial lung disease]; Daewong Pharmaceuticals [Interstitial lung disease]; DevPro [Interstitial lung disease]; Dispersol [Interstitial lung disease]; Fibrogen [Interstitial lung disease]; Horizon [Interstitial lung disease]; Immunmet [Interstitial lung disease]; Insilco [Interstitial lung disease]; Lupin [Interstitial lung disease]; NeRRe Therapeutics [Interstitial lung disease]; Pliant [Interstitial lung disease]; Polarean [Interstitial lung disease]; PureHealth [Interstitial lung disease]; PureTech [Interstitial lung disease]; Respivant [Interstitial lung disease]; Roche/Genentech [Interstitial lung disease]; Shionogi [Interstitial lung disease]; Sun Pharmaceuticals [Interstitial lung disease]; Trevi Pharmaceuticals [Interstitial lung disease]; United Therapeutics [Interstitial lung disease]; Vicore [Interstitial lung disease]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 32/32