Amiodarone-induced alveolar hemorrhage.

Abstract: Amiodarone is increasingly prescribed for patients with ventricular and supraventricular tachyarrhythmias. Many adverse effects have been reported due to this drug and include injury to the liver, thyroid, cornea, skin, and neuromuscular system. Pulmonary toxicity is one of the more serious side effects of this anti-arrhythmic drug and is potentially fatal. Since the first case of amiodarone-induced pneumonitis was described in the early 1980s, amiodarone pneumonitis has been recognized as a distinctive and not uncommon form of drug-induced lung injury. On the other hand, amiodarone-induced pulmonary toxicity resulting in alveolar hemorrhage is rare. The authors report a patient with amiodarone-induced alveolar hemorrhage and review the literature.

Key Words: amiodarone, pulmonary toxicity, alveolar hemorrhage

**********

In the United States, amiodarone is approved by the Food and Drug Administration for the treatment of life-threatening ventricular dysrhythmias. Recently, its use in the treatment of atrial tachyarrhythmia has increased, making it one of the most commonly prescribed anti-arrhythmic agents. (1) Adverse effects are common and involve many organ systems. Pulmonary toxicity is one of the more serious complications and occurs in 10 to 17% of cases, with fatality occurring in about 10%. (2)

Several forms of pulmonary toxicity have been described with amiodarone, the most common of which is interstitial pneumonitis. (3) Other lung injuries include acute respiratory distress syndrome, organizing pneumonia, bronchiolitis obliterans with organizing pneumonia, and pulmonary nodules. (4,5) Medical databases (Pubmed, Embase, Cochrane) were searched using the terms alveolar hemorrhage, hemoptysis, and amiodarone. Alveolar hemorrhage was determined to be a rare complication of amiodarone with nine biopsy-proven cases described in the English medical literature (Table). (6-9) We report an additional patient with alveolar hemorrhage due to amiodarone and summarize what is known about this drug-induced phenomenon.

Case Report

A 69-year-old man complained of severe, progressive shortness of breath that had started 4 to 5 days earlier. His dyspnea was associated with a nonproductive cough, generalized weakness, and weight loss. He denied fever or chills. His medical history was significant for paroxysmal atrial fibrillation, atherosclerotic coronary artery disease with myocardial infarction, congestive heart failure with an estimated ejection fraction of 30, and ventricular tachycardia for which an implantable defibrillator had been placed. He had never smoked cigarettes and had no known lung disease. He had taken amiodarone 200 mg a day orally, for 8 months. Other medications included aspirin, lansoprazole, levothyroxine, methocarbamol, metoprolol, oxycodone, and risperidone. He did not use over-the-counter medications or herbal remedies. He had not recently undergone any surgical or angiographic interventions.

On examination, he was tachypneic and diaphoretic with an oral temperature of 100.2[degrees]F. His blood pressure was 100/64 mm Hg, heart rate was regular at 60 beats per minute, and respiratory rate was increased to 24 breaths per minute. Crackles were heard in the right lower lung field. Cardiac auscultation documented a Grade II/VI systolic murmur best heard at the apex. This murmur was unchanged in description from one year earlier. No jugular venous distention or hepatojugular reflux was found on examination.

Arterial blood gas analysis was performed with the patient breathing room air. The pH was measured as 7.41, partial pressure of oxygen was 46 mm Hg, and a partial pressure of carbon dioxide was 41 mm Hg. His white blood cell count was 4.7 X [10.sup.3]/mm. His platelet count, prothrombin time, and partial thromboplastin time were normal. Complement levels, serum creatinine, and urinalysis were normal. His brain natriuretic peptide was 82 pg/mL. Cryoglobulins were not present. The chest x-ray demonstrated a predominant right upper lobe infiltrate (Fig. 1). Computed tomography of the patient's chest demonstrated that the infiltrate was bilateral (Fig. 2).

His clinical examination and chest imaging did not support a diagnosis of congestive heart failure. The working diagnosis was an atypical pathogen causing community-acquired pneumonia. Flexible fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy was performed in the hopes of better identifying a pathogen or alternate explanation for his infiltrates. The specimens obtained at bronchoscopy were processed for bacteria, fungi, and mycobacteria, but failed to isolate a microorganism. Viral cultures of the specimens were negative. The transbronchial biopsies, however, documented focal alveolar fibrin deposition with acute hemorrhage and hemosiderin-laden macrophages consistent with alveolar hemorrhage. The BAL also demonstrated high concentrations of hemosiderin-containing macrophages. Antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibody, antinuclear antibody, and rheumatoid factor were negative.

A review of the patient's medications identified only one medication associated with alveolar hemorrhage. The amiodarone was withdrawn and IV glucocorticosteroids were initiated. After four days of glucocorticosteroid therapy, the patient's oxygen saturation normalized and his symptoms abated. Amiodarone was not restarted. He was discharged on a tapering dose of prednisone over six months and was instructed to continue his other outpatient medications. He has remained free of pulmonary pathology during follow up for one year.

Discussion

Amiodarone is a class III anti-arrhythmic agent that is structurally related to thyroxine. Although initially developed as a new class of anti-anginal vasodilator, its derivative, desethylamiodarone, proved to be a powerful anti-arrhythmic agent with atypical class III Vaughan-Williams properties, provoking substantial clinical interest. Surprisingly, patients with a variety of atrial and ventricular arrhythmias benefit from this agent. Clinical patient groups with myocardial infarction, heart failure, sudden cardiac arrest and postresuscitation syndromes all respond favorably to the medication. (10)

Enthusiasm for this agent, however, has been tempered by its well-recognized side effects, the most common being a dose-related pneumonitis. The prevalence of amiodarone pulmonary toxicity varies from 0.1% in patients who are on a low dosage to 50% in patients who receive higher dosage regimens. On average, amiodarone pulmonary toxicity will develop in 0.1% to 0.5% of patients that take up to 200 mg per day and 5 to 15% of patients that take 500 mg or more per day. (11)

A meta-analysis of amiodarone therapy estimated the risk of amiodarone pulmonary toxicity at 1% per year. (12) Patients with pre-existing lung disease or an abnormal chest x-ray before the commencement of treatment with amiodarone seem to have an increased risk of pulmonary toxicity. (13,14) Likewise, patients who undergo surgery and/or pulmonary angiography while on amiodarone therapy have an increased risk for developing amiodarone-induced pulmonary toxicity. (15)

Two distinct presentations of amiodarone pulmonary toxicity have been described and reflect the dose-response relationship for lung injury. In one third of cases, amiodarone pulmonary toxicity manifests within weeks of beginning therapy. The patient experiences an abrupt onset of dyspnea, fever, and cough. The chest x-ray usually demonstrates patchy alveolar infiltrates. This presentation occurs with doses of amiodarone as low as 100 mg per day. The more common form of amiodarone pulmonary toxicity has an insidious onset and typically manifests after 2 or more months of therapy. This presentation is characterized by the progressive development of nonproductive cough, dyspnea, weight loss, and occasionally, low-grade fever. In this form, pulmonary infiltrates tend to be interstitial, and the associated doses of amiodarone are usually 400 mg/d or more. (16)

Amiodarone-induced alveolar hemorrhage has been described in nine patients (Table). Use of the Naranjo Adverse Drug Reaction probability scale estimates that the association between amiodarone and our patient's alveolar hemorrhage is probable. (17) No probability prediction was made in the other reported cases of amiodarone-induced alveolar hemorrhage. The average age of these patients is 66.8 years. All of the patients except for one were male. This observation probably reflects the fact that males have a higher frequency of arrhythmia, necessitating anti-arrhythmic therapy. Approximately half of the patients had pre-existing lung disease. This suggests that chronic respiratory disease may increase the risk for amiodarone-induced alveolar hemorrhage as has been witnessed with other amiodarone-induced pulmonary disorders. We do not have enough data to determine whether invasive procedures increase the occurrence of amiodarone-induced alveolar hemorrhage.

Alveolar hemorrhage occurred on average 6.5 months after initiation of the drug. The presentation of amiodarone-induced alveolar hemorrhage appears to be later than that typically encountered with other amiodarone pulmonary toxicities and may offer a clue to its diagnosis. The average daily dosage of amiodarone in the small group comprised of biopsy-proven amiodarone-induced alveolar hemorrhage was 570 mg per day. No cases of amiodarone-induced alveolar hemorrhage have been reported in patients taking less than 200 mg per day.

Most of the patients with amiodarone-induced alveolar hemorrhage have an acute onset of cough, shortness of breath, and fever, and the abrupt worsening of dyspnea generally prompts medical investigation. It has not been established if subclinical alveolar hemorrhage due to amiodarone occurs. Importantly, hemoptysis is not a predominant feature of amiodarone-induced alveolar hemorrhage. It has been documented in only one of the 10 patients reported with biopsy-proven amiodarone-induced alveolar hemorrhage.

Due to the nonspecific symptoms, all of the patients with amiodarone-induced alveolar hemorrhage were initially misdiagnosed. Moreover, chest x-rays offer little advantage in separating other forms of pulmonary toxicity from amiodarone-induced alveolar hemorrhage. (16) Although a consideration of amiodarone-induced alveolar hemorrhage may be prompted by the acute presentation of symptoms after a prolonged use of the agent, a firm diagnosis of amiodarone-induced alveolar hemorrhage may require tissue sampling.

Recovery of BAL that contains hemosiderin-laden macrophages in high concentrations is the strongest suggestion of alveolar hemorrhage. Staining techniques demonstrate intra-cytoplasmic fragments of red blood cells in the alveolar macrophages. Concurrent biopsies of parenchymal tissue help eliminate other lung disease. Other characteristic changes of amiodarone exposure that may be present include macrophages with foamy, vacuolated cytoplasm. (18)

Because hemosiderin-laden macrophages are not specific for amiodarone-induced alveolar hemorrhage, the clinician must carefully consider the clinical situation. Low concentrations of hemosiderin-laden macrophages can be found in the respiratory secretions of patients who experience pulmonary edema. As amiodarone pulmonary toxicity can occur superimposed upon significant left ventricular dysfunction, all efforts should be made to ensure that the patient's baseline fluid status has remained unchanged. Clinical examination and measurement of the serum brain natriuretic peptide may be helpful in this regard. Some researchers have suggested quantitative scoring systems for hemosiderin-laden macrophages in an attempt to distinguish pulmonary edema from true alveolar hemorrhage. (19) It is expected that low concentrations would be present in pulmonary edema while higher concentrations would be present in alveolar hemorrhage. The logic is presumably correct, but utilization of quantitative scoring systems is not routine in most laboratories.

[FIGURE 1 OMITTED]

Another important consideration that may limit our ability to diagnosis amiodarone-induced alveolar hemorrhage is the use of oral anticoagulants, an especially common occurrence in the subgroup of patients with atrial fibrillation. In addition to the normal variability in the INR associated with diet and absorption, there is a well-described pharmacokinetic interplay between warfarin and amiodarone that can persist for a long time after the withdrawal of one or both drugs. (20) The degree of warfarin adjustment required to maintain adequate anticoagulation and avoid significant bleeding depends on both the dose of amiodarone as well as the duration of amiodarone therapy. Difficulty addressing this important drug interaction would be expected to lead to alveolar hemorrhage more often than amiodarone-induced alveolar injury and must be addressed before the latter diagnosis can be made with confidence.

Most forms of pulmonary toxicity result in pulmonary fibrosis that typically leads to a restrictive pattern of lung disease on pulmonary function testing. This is accompanied by a decreased carbon monoxide diffusing capacity (DLCO) as an early finding. (16) Although yet to be documented, it is likely that amiodarone-induced alveolar hemorrhage should also result in a restrictive ventilatory defect. The DLCO, however, would be expected to be increased due to the accumulation of hemoglobin molecules within the respiratory units. Pulmonary function testing may, therefore, offer a clue to the diagnosis. Unfortunately, pulmonary edema can cause both a restrictive ventilatory defect and an elevated DLCO.

Two mechanisms for amiodarone-induced pulmonary toxicity have been proposed. First is a direct toxic reaction in which cell injury occurs due to accumulation of cellular phospholipids resulting from the inhibition of lysosomal phospho-lipases by the drug. The second proposed mechanism is an indirect immunologic mechanism mediated through CD8 T-cell lymphocytosis, (5,21) It is not known whether these mechanisms are responsible for amiodarone-induced alveolar hemorrhage or if there is another, yet to be described, pathophysiologic phenomenon. Since alveolar hemorrhage is an unusual complication of treatment with amiodarone, an independent form of alveolar capillary vasculitis may be operative. (22)

[FIGURE 2 OMITTED]

Management of amiodarone-induced pulmonary toxicities involves discontinuation of the drug and treating the patient with glucocorticosteroids. Prednisone at 40 to 60 mg per day with a tapering dose over 2 to 6 months has been suggested as an appropriate regimen. (16) If the patient's pulmonary toxicity is not life threatening and amiodarone cannot be withdrawn because it is the only or is the optimal therapy for a patient, lowering the dosage of amiodarone as much as possible and administering concurrent low-dose steroids may be a meaningful alternative. (16,23) Due to the small numbers of patients with documented amiodarone-induced alveolar hemorrhage, the optimal therapy is not known, but a treatment regimen similar to other forms of pulmonary toxicities has been recommended. Each of the patients with biopsy-proven amiodarone-induced alveolar hemorrhage was treated with glucocorticosteroids.

The prognosis of patients with amiodarone-induced pulmonary toxicities is generally good since the injuries are typically reversible. Death due to pulmonary toxicity is 5 to 10% when patients were on amiodarone dosages of more than 400 mg/d. (16) However, in patients who develop acute respiratory failure due to amiodarone pulmonary toxicity and require mechanical ventilation, mortality rises to 50 to 100%. (21) In the subgroup of patients reported with alveolar hemorrhage, only half of the patients with amiodarone-induced alveolar hemorrhage have survived. None of the fatalities were respiratory in nature. Three individuals died as a result of arrhythmias and two suffered sudden coronary death.

Conclusion

Alveolar hemorrhage appears to be an unusual drug-induced pulmonary toxicity associated with amiodarone. The symptoms of amiodarone-induced alveolar hemorrhage are nonspecific and mimic other disease processes such as congestive heart failure, pneumonia, and the more common pulmonary toxicities associated with amiodarone. Further complicating the clinical picture is the unexpected observation that hemoptysis is an unusual occurrence in amiodarone-induced alveolar hemorrhage. Lack of this herald sign may lead to cases of amiodarone-induced alveolar hemorrhage going unrecognized and the risk of this pulmonary toxicity being underestimated. (24) Amiodarone-induced alveolar hemorrhage appears to have a later onset than other, more common forms of pulmonary toxicities and coupled with an abrupt onset or worsening of dyspnea may offer a clue to the diagnosis. Bronchoalveolar lavage and lung tissue biopsy may be necessary to establish the diagnosis. While experience in the treatment of this disorder is limited, discontinuation of the drug and glucocorticosteroid therapy is recommended.

References

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

2. Brinker A, Johnston M. Acute pulmonary injury in association with amiodarone, Chest 2004;125:1591-1592.

3. 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;350:1417-1424.

4. Magro SA, Lawrence EC, Wheeler SH, et al. Amiodarone pulmonary toxicity: prospective evaluation of serial pulmonary function tests. J Am Coll Cardiol 1988;12:781-788.

5. Kudenchuk PJ, Pierson DJ, Greene HL, et al. Prospective evaluation of amiodarone pulmonary toxicity. Chest 1984;86:541-548.

6. 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;87:7-13.

7. Iskander S, Raible DG, Brozena SC, et al. Acute alveolar hemorrhage and orthodeoxia induced by intravenous amiodarone. Catheter Cardiovasc Interv 1999;47:61-63.

8. Goldstein I, Topilsky M, Segev D, et al. Very early onset of acute amiodarone pulmonary toxicity presenting with hemoptysis. Chest 1997;111:1446-1447.

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

10. Camus P, Martin II, WJ Rosenow EC III. Amiodarone pulmonary toxicity. Clin Chest Med 2004;25:65-75.

11. Zitnik RJ. Drug-induced lung disease: anti-arrhythmic agents. J Respir Dis 1996;17:254-270.

12. Valle JM, Alvarez D, Antunez J, et al. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology. Eur Respir J 1995;8:470-471.

13. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest 1998;93:425-427.

14. Naccarelli GV, Wolbrette DL, Patel HM, et al. Amiodarone: clinical trials. Curr Opin Cardiol 2000;15:64-72.

15. Morady F, Sauve MJ, Malone P, et al. Long-term efficacy and toxicity of high-dose amiodarone therapy for ventricular tachycardia or ventricular fibrillation. Am J Cardiol 1983;52:975-979.

16. Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity: recognition and pathogenesis. Chest 1988;93:1067-1075.

17. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

18. Costabel U, Uzaslan E, Guzman J. Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med 2004;25:25-35.

19. Grebski E, Hess T, Hold G, et al. Diagnostic value of hemosiderin-containing macrophages in bronchoalveolar lavage. Chest 1992;102:1794-1799.

20. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002;121:19-23.

21. Fraire AE, Guntupalli KK, Greenberg SD, et al. Amiodarone pulmonary toxicity: a multi-disciplinary review of current status. South Med J 1993;86:67-77.

22. Gutierrez R, Del Pozo, J Carrion C, et al. Vasculitis associated with amiodarone treatment. Ann Pharmacother 1994;28:537.

23. Zaher C, Hamer A, Peter T, et al. Low dose steroid therapy for prophylaxis of amiodarone-induced pulmonary infiltrates. N Engl J Med 1983;308:779.

24. Singh BN. Amiodarone: the expanding anti-arrhythmic role and how to follow a patient on chronic therapy. Clin Cardiol 1997;20:608-618.

Said B. Iskandar, MD, Bernard Abi-Saleh, MD, Rob L. Keith, MD, Ryland P. Byrd, Jr, MD, and Thomas M. Roy, MD

From the Veterans Affairs Medical Center, Mountain Home, TN, and the Division of Pulmonary Diseases and Critical Care Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Dr. Ryland P. Byrd, Jr., Veterans Affairs Medical Center 111-B, Division of Pulmonary Medicine and Critical Care, PO Box 4000, Mountain Home, TN 37684. Email: [e-mail]

Accepted January 13, 2006.

RELATED ARTICLE: Key Points

* Amiodarone is a commonly prescribed anti-arrhythmic agent.

* Amiodarone pulmonary toxicity is not uncommon and manifests itself in several forms, particularly pneumonitis.

* Amiodarone-induced alveolar hemorrhage is a rarely reported, but important, adverse drug reaction.

Table. Demographics of patients with alveolar hemorrhage

                                     Duration of
                            Chronic  amiodarone   Daily
Patient no.  Age            lung     therapy      dosage
(reference)  (yrs)  Gender  disease  (days)       (mg)

 1 (6)       76     Male    No       350          1,200
 2 (6)       70     Male    Yes      198            500
 3 (6)       70     Male    Yes      274            400
 4 (6)       37     Male    Yes       91          1,100
 5 (6)       63     Male    No       236            600
 6 (6)       74     Female  No       465            700
 7 (7)       59     Male    NA        25            400
 8 (8)       70     Male    Yes       15            200
 9 (9)       80     Male    NA        60            400
10           69     Male    No       240            200

Patient no.                              Initial clinical
(reference)  Symptoms            CXR     diagnosis

 1 (6)       Cough, SOA, fever   IO      APT
 2 (6)       SOA, fever          IO      Pneumonitis
 3 (6)       Cough, SOA, fever   IO      Pneumonitis
 4 (6)       Cough, SOA, fever   IO      Pneumonitis
 5 (6)       Cough, fever        AO      ARDS
 6 (6)       Cough               IO      CHF
 7 (7)       Dyspnea, platypnea  IO      CHF
 8 (8)       Hemoptysis, cough,  PI      Pneumonia
               SOA, fever
 9 (9)       Cough, SOA, fever   IO, AO  Pneumonia
10           Cough, SOA, fever   IO, AO  Pneumonia, CHF

Patient no.
(refrence)   Biopsy          Treatment  Outcome

 1 (6)       Open lung       Steroids   Died -- arrhythmia
 2 (6)       Necropsy        Steroids   Died -- arrhythmia
 3 (6)       Open lung       Steroids   Died -- arrhythmia
 4 (6)       Open lung       Steroids   Died -- sudden coronary death
 5 (6)       Open lung       Steroids   Died -- sudden coronary death
 6 (6)       Transbronchial  Steroids   Alive
 7 (7)       Open lung       Steroids   Alive
 8 (8)       Transbronchial  Steroids   Alive
 9 (9)       Open lung       Steroids   Alive
10           Transbronchial  Steroids   Alive

NA, not available; SOA, shortness of air; IO, interstitial infiltrate;
AO, alveolar infiltrate; PI, pulmonary infiltrate; APT, acute pulmonary
toxicity; CXR, chest radiograph; ARDS, acute respiratory distress
syndrome; CHF, congestive heart failure.