A 67-year-old man presents to the emergency department (ED) with severe, progressive shortness of breath that started 4-5 days prior to presentation. He also reports an associated cough that produces blood-tinged sputum, as well as generalized weakness, lack of appetite, and weight loss. The patient has no fever or chills and denies any chest pain, orthopnea, and swelling of the lower extremities. He has no history of recent travel or immobilization for long periods of time, has not had any sick contacts or toxic exposures, and has not been in any high-risk environments for tuberculosis (eg, incarceration, shelters). His past medical history is significant only for cardiac disease, including paroxysmal atrial fibrillation, coronary artery disease leading to a myocardial infarction, and congestive heart failure (with an estimated ejection fraction of 35%). An automatic implanted cardiac defibrillator (AICD) has been placed for frequent episodes of ventricular tachycardia. There is no history of cigarette use. His medications include amiodarone, metoprolol, and simvastatin.
On physical examination, the patient appears ill, with diaphoresis and moderately labored respirations at a rate of 26 breaths/min. His blood pressure is 110/74 mm Hg, with a regular heart rate of 62 beats/min. The patient’s oral temperature is elevated, at 100.4°F (38°C), and his oxygen saturation rate while breathing room air is 86%. Crackles are auscultated in the right upper lung field. No murmurs or rubs are noted on the cardiac examination; however, a faint third heart sound (S3) is noted. No jugular venous distention, hepatojugular reflux, or peripheral edema is present, and there is no evidence of cervical, axillary, or inguinal adenopathy. The distal pulses are equal and 2+.
An arterial blood gas analysis on room air reveals a pH of 7.42, a partial O2 pressure of 44 mm Hg, and a partial CO2 pressure of 41 mm Hg. Laboratory investigations, including a complete blood count, coagulation profile, serum electrolyte panel, and renal function tests (including creatinine level), are unremarkable. A brain natriuretic peptide assay is measured at 80 pg/mL. An urgently performed transthoracic echocardiogram shows a decreased ejection fraction and normal valvular function (unchanged from studies prior to this presentation). The chest radiograph reveals a right upper lobe infiltrate (see Image 1). A follow-up computed tomography (CT) scan of the patient’s chest shows evidence of a more extensive pulmonary process than can be appreciated on his chest radiograph, with diffuse bilateral infiltrates (Image 2).
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What is the diagnosis?
HINT
This condition resulted from a medication with known potential pulmonary toxicity.
Authors:
Said B. Iskandar, MD,
Fellow in the Cardiology Division,
Quillen College of Medicine,
East Tennessee State University,
Johnson City, Tenn.
Ryland P. Byrd, Jr, MD,
Chief of Pulmonary Medicine,
Medical Director of Respiratory Therapy,
Quillen Mountain Home Veterans
Affairs Medical Center,
Professor, Department of Internal Medicine,
Division of Pulmonary Diseases
and Critical Care Medicine,
James H. Quillen College of Medicine,
East Tennessee State University
Thomas M. Roy, MD,
Chief of the Division of Pulmonary Diseases
and Critical Care Medicine
and Professor of Medicine Department
of Internal Medicine,
James H. Quillen College of Medicine,
East Tennessee State University
eMedicine Editors:
Erik D. Schraga, MD,
Department of Emergency Medicine,
Kaiser Permanente,
Santa Clara Medical Center, Calif
Rick G. Kulkarni, MD,
Assistant Professor,
Yale School of Medicine,
Section of Emergency Medicine,
Department of Surgery,
Attending Physician,
Medical Director,
Department of Emergency Services,
Yale-New Haven Hospital, Conn
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ANSWER
DAH is a progressive condition associated with a high morbidity and mortality and characterized by pulmonary hemorrhage that originates in the pulmonary microcirculation. Although the associated alveolar hemorrhage may be focal, the hemorrhage, as suggested by the condition’s name, more commonly involves multiple areas in a diffuse pattern. Prompt diagnosis and aggressive therapy are required, as the condition can be a life-threatening medical emergency. DAH must be clinically distinguished from other localized abnormalities, such as bronchitis, bronchiectasis, infection, and malignancies that may also cause bleeding from the bronchial circulation. In these other conditions, brisk bleeding from the bronchial circulation can flood the alveoli, thereby mimicking the clinical and radiographic appearance of DAH.1 DAH may be caused by many conditions that result in damage to the alveolar microcirculation (see Table 1). Although some specific laboratory investigations, such as serum antineutrophil cytoplasmic antibodies (ANCA) and anti–glomerular basement membrane antibodies, may be helpful in diagnosing DAH, definitively establishing the diagnosis requires a bronchoscopy to directly observe the alveolar hemorrhage and obtain lavage samples. The practice of transbronchial biopsy during bronchoscopy may help to rule out other clinical conditions. Surgical biopsy is only indicated if the diagnosis remains unclear despite a bronchoscopy.
The symptoms and presentation in this case were suspected to be from drug-induced DAH. Many drugs have been associated with drug-induced DAH (see Table 2),1,2 including amiodarone, which is known to cause pulmonary toxicity. Amiodarone-induced pulmonary toxicity usually manifests as acute pneumonitis, also known as amiodarone pneumonitis (in up to 5-15% of patients), or as chronic fibrosis; rarely, it can also result in DAH, such as in this case.3-7 The condition can pose a diagnostic challenge, as most cases may present without hemoptysis and with nonspecific symptoms. A few other case reports of amiodarone-induced DAH with hemoptysis have been described in the literature. BAL and lung tissue biopsy may be necessary to establish the diagnosis. As an aside, other lung injuries associated with amiodarone include acute respiratory distress syndrome, organizing pneumonia, bronchiolitis obliterans with organizing pneumonia, and pulmonary nodules.8,9
The management of drug-induced DAH includes discontinuation of the offending medication and possible treatment with glucocorticoids in severe cases; most patients with severe DAH remain steroid unresponsive. In this patient, the amiodarone was discontinued and glucocorticoid therapy was begun. After 4 days of steroid therapy, the patient’s oxygen saturation rate while breathing room air was noted to improve, and there was significant improvement in his symptoms. The patient was discharged to home on a tapering dose of prednisone over 6 months. His outpatient medications were continued, with the exception of amiodarone, and he was noted to be free of complications or recrudescence at the follow-up examination.
Table 1. Etiology of diffuse alveolar hemorrhage.1
Coagulation disorders Disseminated intravascular coagulation
Idiopathic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Idiopathic Idiopathic pulmonary hemosiderosis
Immunologic Acute lung allograft rejection
Connective tissue disease
Goodpasture syndrome
Immune complex–associated glomerulonephritis
Primary antiphospholipid antibody syndrome
Vasculitides Bechet syndrome
Henoch-Schonlein purpura
Microscopic polyangiitis
Mixed cryoglobulinemia
Pauci-immune glomerulonephritis
Wegener granulomatosis
Other Diffuse alveolar damage (acute respiratory distress syndrome)
Lymphangiomyomatosis
Mitral stenosis
Pulmonary capillary hemangiomatosis
Pulmonary veno-occlusive disease
Tuberous sclerosis
Toxic exposure Isocyanates
Trimellitic anhydride
Table 2. Drugs associated with alveolar hemorrhage.1,2 Abciximab Nitrofurantoin
Acetylsalicylic acid Penicillamine
Amiodarone Phenytoin
Azathioprine Propylthiouracil
Carbamazepine Quinidine
Clomiphene Recombinant tissue plasminogen activator
Clopidogrel Retinoic acid
Cyclosporine Rituximab
Cytarabine Rofecoxib
Dimethylsulfoxide Sirolimus
Fludarabine Streptokinase
Glibenclamide Tirofiban
Heparin Tumor necrosis factor-alpha
Hydralazine Urokinase
Methotrexate Valproic acid
Mitomycin C Warfarin
Moxalactam
References:
Collard HR, Schwartz MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004 Sep; 25(3):583-92. [MEDLINE: 15331194]
Foucher P, Camus P. The drug-induced lung diseases. Available at: www.pneumotox.com. Accessed: February 28, 2007.
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. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997 Nov 15;350(9089):1417-24 [MEDLINE: 9371164] .
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 Jan; 87(1):7-13. [MEDLINE: 3799544]
Iskander S, Raible DG, Brozena SC, Gaitanaru DM, Ayala G, Iskandrian AE. Acute alveolar hemorrhage and orthodeoxia induced by intravenous amiodarone. Catheter Cardiovasc Interv 1999 May; 47(1):61-3. [MEDLINE: 10385163]
Goldstein I, Topilsky M, Segev D, Isakov A, Heller I. Very early onset of acute amiodarone pulmonary toxicity presenting with hemoptysis. Chest 1997 May; 111(5):1446-7. [MEDLINE: 9149610]
Vizioli LD, Cho S. Amiodarone-associated hemoptysis. Chest 1994 Jan; 105(1):305-6. [MEDLINE: 8275760]
Magro SA, Lawrence EC, Wheeler SH, Krafchek J, Lin HT, Wyndham CR. Amiodarone pulmonary toxicity: prospective evaluation of serial pulmonary function tests. J Am Coll Cardiol 1988 Sep; 12(3):781-8. [MEDLINE: 3403839]
Kudenchuk PJ, Pierson DJ, Greene HL, Graham EL, Sears GK, Trobaugh GB. Prospective evaluation of amiodarone pulmonary toxicity. Chest 1984 Oct; 86(4):541-8. [MEDLINE: 6478892]
Camus P, Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Clin Chest Med 2004 Mar; 25(1): 65-75. [MEDLINE: 15062598]
