Woman, 78, With Dyspnea, Dry Cough, and Fatigue

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

Continue reading for discussion... 

DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

Continue reading for the conclusion...

CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. 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(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

Continue reading for discussion... 

DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

Continue reading for the conclusion...

CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. 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(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

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DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

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CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. 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(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.