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 pneumonitis /pneu·mo·ni·tis/ (noo?mo-ni´tis) inflammation of the lung; see also pneumonia.
hypersensitivity 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 alveolar /al·ve·o·lar/ (al-ve´o-lar) [L. alveolaris ] pertaining to an alveolus.
Relating to an alveolus. 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 tachyarrhythmia /tachy·ar·rhyth·mia/ (tak?e-ah-rith´me-ah) any disturbance of the heart rhythm in which the heart rate is abnormally increased.
n. 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 acute respiratory distress syndrome
See adult respiratory distress syndrome. , organizing pneumonia, bronchiolitis obliterans with organizing pneumonia, and pulmonary nodules Nodules
A small mass of tissue in the form of a protuberance or a knot that is solid and can be detected by touch.
Mentioned in: Leprosy . (4,5) Medical databases (Pubmed, Embase, Cochrane) were searched using the terms alveolar hemorrhage, hemoptysis Hemoptysis Definition
Hemoptysis is the coughing up of blood or bloody sputum from the lungs or airway. It may be either self-limiting or recurrent. Massive hemoptysis is defined as 200-600 mL of blood coughed up within a period of 24 hours or less. , 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.
A 69-year-old man complained of severe, progressive shortness of breath Shortness of Breath Definition
Shortness of breath, or dyspnea, is a feeling of difficult or labored breathing that is out of proportion to the patient's level of physical activity. that had started 4 to 5 days earlier. His dyspnea was associated with a nonproductive non·pro·duc·tive
1. Not yielding or producing: nonproductive land.
2. Not engaged in the direct production of goods: nonproductive personnel.
n. cough, generalized weakness, and weight loss. He denied fever or chills. His medical history was significant for paroxysmal paroxysmal (per´ksiz´ml),
adj recurring in paroxysms. atrial fibrillation, atherosclerotic coronary artery disease coronary artery disease, condition that results when the coronary arteries are narrowed or occluded, most commonly by atherosclerotic deposits of fibrous and fatty tissue. with myocardial infarction, congestive heart failure congestive heart failure, inability of the heart to expel sufficient blood to keep pace with the metabolic demands of the body. In the healthy individual the heart can tolerate large increases of workload for a considerable length of time. 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 metoprolol /met·o·pro·lol/ (met?ah-pro´lol) a cardioselective ß used in the form of the succinate and tartrate salts in the treatment of hypertension, chronic angina pectoris, and myocardial infarction. , oxycodone oxycodone /oxy·co·done/ (-ko´don) an opioid analgesic derived from morphine; used in the form of the hydrochloride and terephthalate salts.
n. , 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 diaphoretic /di·a·pho·ret·ic/ (-fo-ret´ik)
1. pertaining to, characterized by, or promoting sweating.
2. an agent that promotes sweating.
adj. 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 beats per minute Cardiac pacing The unit of measure for the frequency of heart depolarizations or contractions each minute–or pulse rate , and respiratory rate was increased to 24 breaths per minute. Crackles were heard in the right lower lung field. Cardiac auscultation auscultation
Procedure for detecting certain defects or conditions by listening for normal and abnormal heart, breath, bowel, fetal, and other sounds in the body. The invention of the stethoscope in 1819 improved and expanded this practice, still very useful despite the documented a Grade II/VI systolic murmur best heard at the apex. This murmur was unchanged in description from one year earlier. No jugular jugular /jug·u·lar/ (jug´u-lar)
2. pertaining to a jugular vein.
3. a jugular vein.
adj. venous distention dis·ten·tion or dis·ten·sion
The act of distending or the state of being distended.
n a state of dilation. or hepatojugular reflux was found on examination.
Arterial blood gas arterial blood gas Critical care Analysis of arterial blood for O2, CO2, bicarbonate content, and pH, which reflects the functional effectiveness of lung function and to monitor respiratory therapy Ref range pO2 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 white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. was 4.7 X [10.sup.3]/mm. His platelet count, prothrombin time, and partial thromboplastin time Partial Thromboplastin Time Definition
The partial thromboplastin time (PTT) test is a blood test that is done to investigate bleeding disorders and to monitor patients taking an anticlotting drug (heparin). were normal. Complement levels, serum creatinine, and urinalysis were normal. His brain natriuretic peptide Brain natriuretic peptide (also known as B-type natriuretic peptide or "GC-B") is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of myocytes (heart muscles cells) in the ventricles. 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 (1) (Basic Assembly Language) The assembly language for the IBM 370/3000/4000 mainframe series.
(2) (Branch And Link) An instruction used to transfer control to another part of the program.
BAL - Basic Assembly Language ) and transbronchial biopsy was performed in the hopes of better identifying a pathogen or alternate explanation for his infiltrates. The specimens obtained at bronchoscopy Bronchoscopy Definition
Bronchoscopy is a procedure in which a cylindrical fiberoptic scope is inserted into the airways. This scope contains a viewing device that allows the visual examination of the lower airways. were processed for bacteria, fungi, and mycobacteria mycobacteria
members of the genus Mycobacterium.
see opportunist (atypical) mycobacteria (below).
see opportunist (atypical) mycobacteria (below). , but failed to isolate a microorganism microorganism /mi·cro·or·gan·ism/ (-or´gah-nizm) a microscopic organism; those of medical interest include bacteria, fungi, and protozoa. . Viral cultures of the specimens were negative. The transbronchial biopsies, however, documented focal alveolar fibrin fibrin: see blood clotting. deposition with acute hemorrhage and hemosiderin-laden macrophages Macrophages
White blood cells whose job is to destroy invading microorganisms. Listeria monocytogenes avoids being killed and can multiply within the macrophage. 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 prednisone (prĕd`nĭsōn): see corticosteroid drug. 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.
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 vasodilator /vaso·di·la·tor/ (-di-la´ter)
1. causing dilatation of blood vessels.
2. a nerve or agent that does this.
n. , 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 adverse drug reaction,
n a detrimental outcome from a drug. Two types of ADRs exist: Type 1 results from dosage mismatch and Type 2 from rare conditions often as a consequence of a small dose. See also risk or sensitive type. 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 arrhythmia (ārĭth`mēə), disturbance in the rate or rhythm of the heartbeat. Various arrhythmias can be symptoms of serious heart disorders; however, they are usually of no medical significance except in the presence of , 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 subclinical /sub·clin·i·cal/ (sub-klin´i-k'l) without clinical manifestations.
Not manifesting characteristic clinical symptoms. Used of a disease or condition. 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 nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. 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 Red blood cells
Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.
Mentioned in: Bone Marrow Transplantation
red blood cells in the alveolar macrophages. Concurrent biopsies of parenchymal pa·ren·chy·ma
1. Anatomy The tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
2. tissue help eliminate other lung disease. Other characteristic changes of amiodarone exposure that may be present include macrophages with foamy foam·y
adj. foam·i·er, foam·i·est
1. Of, consisting of, or resembling foam.
2. Covered with foam.
foam , vacuolated vacuolated /vac·u·o·lat·ed/ (vak´u-o-lat?ed) containing vacuoles.
vac·u·o·lat·ed or vac·u·o·late
Containing vacuoles or a vacuole.
containing vacuoles. 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 su·per·im·pose
tr.v. su·per·im·posed, su·per·im·pos·ing, su·per·im·pos·es
1. To lay or place (something) on or over something else.
2. 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 pre·sum·a·ble
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster. 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 Anticoagulants
Drugs that suppress, delay, or prevent blood clots. Anticoagulants are used to treat embolisms.
Mentioned in: Embolism, Heart Valve Replacement , an especially common occurrence in the subgroup of patients with atrial fibrillation. In addition to the normal variability in the INR INR
In currencies, this is the abbreviation for the Indian Rupee.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. associated with diet and absorption, there is a well-described pharmacokinetic interplay between warfarin warfarin (wôr`fərĭn), anticoagulant used to treat blood clots. In large doses it causes bleeding. Warfarin, mixed with bait, is used in rodent control.
Anticoagulant drug, marketed as Coumadin. 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 DLco
diffusing capacity of the lung for carbon monoxide. ) 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 lysosomal
pertaining to or emanating from lysosomes.
enzymes located in the lysosomes.
lysosomal phospholipidosis phospho-lipases by the drug. The second proposed mechanism is an indirect immunologic mechanism mediated through CD8 T-cell lymphocytosis lymphocytosis /lym·pho·cy·to·sis/ (-si-to´sis) an excess of normal lymphocytes in the blood or an effusion.
n. , (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 Vasculitis Definition
Vasculitis refers to a varied group of disorders which all share a common underlying problem of inflammation of a blood vessel or blood vessels. The inflammation may affect any size blood vessel, anywhere in the body. 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.
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.
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irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" trials. Lancet 1997;350:1417-1424.
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see etiology. . Eur Respir J 1995;8:470-471.
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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 East Tennessee State University (ETSU) is an accredited American university, founded October 21911 and located in Johnson City, Tennessee. It is part of the Tennessee Board of Regents system of colleges and universities. , 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: Ryland.Byrd@med.va.gov
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.