Amiodarone pulmonary toxicity

Clin Chest Med 25 (2004) 65 – 75

Amiodarone pulmonary toxicity Philippe Camus, MDa,*, William J. Martin II, MDb, Edward C. Rosenow III, MD, MSc a

Department of Pulmonary Medicine and Critical Care, Centre Hospitalier et Universite´ de Bourgogne, F-2100 Dijon, France b College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cinccinnati, OH 45267, USA c Mayo School of Medical Education, Rochester, MN 55905, USA

Amiodarone (Am) is an antiarrhythmic benzofuran drug with an imposing adverse effect profile, that involves the liver, thyroid, cornea, skin, and neuromuscular system, which often limits its use. Am pneumonitis was described first in the early 1980s [1], as the drug was becoming increasingly popular in the United States for the treatment of ventricular dysrhythmias. Although Am was used in Europe for many years before that time, no case of Am pulmonary toxicity (APT) had been reported. Although it was speculated that the higher dosages of Am that were used in the United States were responsible for the development of Am pneumonitis, retrospective analysis showed that cases had been observed in Europe but were missed [2]. Am pneumonitis is one of the leading reasons for discontinuation of the drug [3]. APT (also called ‘‘amiodarone pneumonitis’’ or ‘‘amiodarone lung’’) is a common and distinctive form of drug-induced lung injury. Am pneumonitis develops after a few months or up to several years into treatment. The cumulative prevalence ranges between 1% and 15% of the treated population [4 – 8]. On average, APT is diagnosed approximately 2 months after the onset of clinical symptoms; this leaves ample room for earlier diagnosis. Although the disease typically is asymmetrical on imaging, the patterns of Am pneumonitis are varied and it is easy to be misled. In the absence of biopsy, diagnosis is by exclusion. Wide variations in clinical practice

* Corresponding author. E-mail address: [email protected] (P. Camus).

exist regarding the follow-up and management of patients who are receiving Am on a continuing basis [9]. In addition to the specific risks that are associated with Am withdrawal, the main problems in patients who are suspected of having APT is to distinguish it from interstitial pulmonary edema or from other less frequent pulmonary diseases and to decide whether a lung biopsy is required for diagnosis. The amount of literature on APT peaked in 1983 – 1984 with several hundred cases reported cumulatively and declined thereafter. Since the mid 1990s, however, publications have increased which suggests that APT is a current problem in clinical practice.

Pharmacokinetics of amiodarone The distinctive chemical structure and pharmacokinetics of Am impact on the clinical, imaging, and pathologic features of APT, as well as on its outcome. Am and its quantitatively-relevant metabolite, desethyl-amiodarone (DEAm), are cationic amphiphilics, which accumulate in tissues, including the lung. In addition to sequestering into the lung, Am and DEAm infiltrate into the liver, skin (particularly the discolored skin of patients who receive Am on a continual basis [10]), thyroid, and eye. These tissues are common sites for adverse effects of the drug; because Am localizes in those tissues, sequestration of the drug and metabolite is regarded as a major determinant of toxicity. Am and DEAm are toxic to lung cells at therapeutic serum concentrations [11,12]; this is probably magnified by the 100-fold and 500-fold concentration ratio of Am and DEAm in lung tissue, as

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compared with serum [13 – 15]. Plasma levels of Am generally do not predict the occurrence of APT; however, higher DEAm plasma levels were found in patients who had APT compared with unaffected patients [16]. Am and DEAm localize in cell lysosomes and block the turnover of endogenous phospholipids [17,18]. This biochemical feature explains the common finding of increased numbers of foamy lipid-laden macrophages that contain whorled lamellar membranous inclusions in the bronchoalveolar lavage (BAL) or in lung tissue of patients who have taken Am for long periods. Myelinic figures are indicative of Am-induced effect, regardless of the presence of overt pulmonary toxicity. Conversely, Am pneumonitis is considered unlikely if foam cells are not present in the BAL [19]. The presence of excessive numbers of foam cells in lung tissue is a histologic characteristic of APT, as opposed to other drug-induced lung diseases [19]. Two iodines are present for each molecule of Am or DEAm; this is believed to account for the common finding of increased attenuation of the pulmonary infiltrates on imaging of patients who have APT [20,21]. Occasionally, increased density of the liver and spleen is present as well [22]; this may help to establish the diagnosis of APT. Clearance of Am and DEAm from tissues is slow. Autopsy studies showed that significant amounts of both compounds can persist in lung 1 year after cessation of treatment [23]. Accordingly, withdrawal of Am as the sole intervention may not translate into demonstrable improvement in symptoms or on imaging [24,25]. Similarly, if patients who have Am pneumonitis are placed on a drug holiday and corticosteroid drugs, withdrawing the latter drugs too early (eg, after 2 – 3 months) exposed to a sort of ‘‘recurrence’’ of Am pneumonitis that was quelled by steroids [26].

Epidemiology and risk factors There is some link between indexes of exposure to Am (a composite of daily dosage and duration of treatment) and the likelihood of developing APT [27 – 29]. Thus, Am should be titrated to the lowest possible effective dosage [30]. Am pneumonitis is more frequent in men and is unusual in patients who are younger than 40 [31]. Rare reports described its occurrence in children or adolescents [32]. The risk of developing APT increases with age, and, on average, with daily dosage of the drug [33]. Having an abnormal chest radiograph or poor pulmonary reserve before the

commencement of treatment with Am may increase the risk of developing APT, but this is not a universal finding [33,34]. A widely-held concept is that patients who are taking low-dose Am (eg, 200 mg/ day) are unlikely to develop APT. As experience has grown, several sources indicated that APT also can occur in patients who are exposed to low doses of the drug, although the prevalence is lower [35,36]. The prevalence of Am pneumonitis varies from 0.1% in patients who are on a low dosage to 50% in patients who receive elevated dosage regimens (eg, 1200 mg/day). On the average, APT will develop in 5% to 15% of patients who take 500 mg/day or more [37] and 0.1% to 0.5% who take up to 200 mg/day. In one patient, Am pneumonitis developed after the dosage of Am was doubled [38]. High-loading doses may increase the risk of early APT [39]. Although low dosage regimens have decreased the prevalence of APT, the clinical impression is that the severity of the disease has not been altered substantially. Exposure of patients who have been taking Am long term to elevated concentrations of oxygen (O2) may trigger the onset of APT. APT also is synergized by mechanical ventilation in conjunction with high inspired concentrations of O2; this is believed to account for the high prevalence of diffuse alveolar damage (DAD) and the adult respiratory distress syndrome (ARDS) picture following cardiac or pulmonary surgery [40 – 42]. In one patient, unilateral pulmonary opacities that were believed to reflect APT developed after a brief period of intraoperative single-lung mechanical ventilation with 100% O2 [43]. In two Am-treated patients, fatal ARDS followed the parenteral injection of iodinated contrast media [44]. Although no further cases have been reported, caution is advised before administering contrast media in patients who are taking Am. Patients who undergo pneumonectomy for lung cancer are at particular risk because they combine frequent needs for Am in the treatment of postoperative arrhythmias, poor ventilatory reserve because of recent lung resection, and, often, a background of chronic obstructive pulmonary disease (COPD) or pulmonary emphysema [41].

Clinical imaging patterns of amiodarone pulmonary toxicity Am pneumonitis can develop at any time from a few days after an initial loading dose of Am [33,39,45] to more that a decade into treatment. Most cases, however, develop at some point during the first 1 or 1.5 years of treatment. Time to onset of pneu-

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monitis tends to be shorter in patients who take elevated dosages of Am [46]. In a few patients, APT developed up to 3 months after cessation of treatment [47]; this may reflect the extended storage of Am in lung. Signs and symptoms of APT are not specific. Establishing the diagnosis of APT may be easier when other adverse effects of the drug are present, which is infrequent. No other adverse effects of Am has demonstrated a significant association with APT at the time of diagnosis of the latter. Progressive dyspnea often is present for several weeks or months before the time of diagnosis; this symptom can be exaggerated if an Am-induced hyperthyroid state is present in association. Malaise, nonproductive cough, and pleuritic chest pain also can be present. There is no single biologic abnormality or concatenation of biologic findings that are specific for the diagnosis of APT. An increased erythrocyte sedimentation rate (ESR) often is present at the time of diagnosis and can precede the clinical onset of APT. An increase in ESR also is present in some patients who have left ventricular failure, however [8]. Leukocytosis is a common finding as is an increase in circulating lactate dehydrogenase (LDH) levels; the latter finding can precede the onset of APT [48]. Increased circulating levels of KL-6, a human MUC1 mucin, was described in patients who had APT [49], but the sensitivity and specificity of this test remain unclear [50]. An increased serum level of surfactant-associated protein D was reported on in two patients who had APT [50]. The role of serum brain natriuretic peptide (BNP) in distinguishing APT from left ventricular failure remains imprecise [8], because patients may present with APT superimposed on a background of decompensated left ventricular dysfunction. Adverse effects of Am in liver or thyroid may be present in association with the pulmonary toxicity; appropriate tests are required to detect nonpulmonary complications of Am. Rarely, does Am induce the drug lupus, with elevated serum antinuclear autoantibodies (ANA). Am pulmonary toxicity is a disease of the alveolar space or interstitial compartment. It is therefore characterized by alveolar, interstitial, or mixed alveolar-interstitial shadows on imaging. In contrast to other drug-induced lung diseases, APT commonly manifests with an asymmetrical pattern of lung involvement. When considering the diagnosis of APT, left ventricular dysfunction, infectious pneumonia, pulmonary infarction, eosinophilic pneumonia, organizing pneumonia, exogenous lipoid pneumonia, broncho-

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alveolar carcinoma or lymphoma should be considered as competing diagnoses. Patients who have heart disease also can develop adverse effects of drugs other than Am (eg, aspirin, b-blocking drugs, angiotensin-converting enzyme inhibitors, anticoagulants, 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors [statins], hydrochlorothiazide, flecainide, tocainide) [51], although these are less frequent than APT. Diuresis usually distinguishes Am pneumonitis from interstitial pulmonary edema [33]; however, if there is only partial clearing of pulmonary infiltrates after diuresis, continued consideration of Am-induced lung condition is warranted. Am pulmonary toxicity is not a single clinical entity; several patterns are cataloged [52]. The most common pattern of APT is a subacute infiltrative lung illness [53 – 57] with patchy or diffuse infiltrates that involve the lung bilaterally. Alveolar, groundglass, or mottling opacities with high attenuation on CT usually indicate a more acute presentation [58]. The opacities of APT may be localized in the lung bases or be diffuse [59]. Unexplainably, there is an impression that the right lung (mainly the right upper lobe) is involved more frequently than the left [8,25]. Alveolar shadowing and moderate volume loss of the right upper lobe in a patient who takes Am are suggestive of APT. Patients who have basilar disease tend to have denser shadowing [60]. Kerley B lines, reticular opacities, alveolar shadows, and volume loss are seen on plain chest film; a nodular pattern is unusual [60]. Although the chest radiograph indicates that the disease is unilateral, the high-resolution CT (HRCT) often indicates bilateral disease [57]. Images that are seen on CT include scattered or localized haze with or without recognizable segmental distribution, inter- or intralobular septal thickening, or diffuse, patchy, small-sized alveolar shadows with a random distribution. In a study of 20 patients who had mild APT [61], all patients had ground-glass opacities. Areas of consolidation were found in four patients and intralobular reticulations were noted in five patients. A subpleural distribution of the opacities was more common (n = 18) than a central distribution (n = 2). High density in the area of APT was present in eight patients [61]. In more advanced disease, increased attenuation seems a more consistent feature of APT [20]. The impression is that all patients who have APT have distinct patterns of involvement on imaging. An exudative pleural effusion occasionally is present in association with the pulmonary disease [62] or occurs in isolation (see later discussion).

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Pleural thickening is a common finding, especially if the pulmonary opacities of APT are localized in the periphery of the lung. Am pulmonary toxicity only produces attenuated changes on imaging in patients who have emphysema, whereas the impact on gas exchange is substantial. The pattern of a single mass or multiple, subpleural masses with increased attenuation on HRCT is seen in 6% to 12% of patients who have APT [60,63]. The masses generally abut the pleura, which can be thickened en face, and cause pleuritic chest pain or a friction rub. The masses can localize anywhere in the subpleural region of the lung and simulate pulmonary infarction, pneumonia, organizing pneumonia, peripheral carcinoma, or lymphoma [64]. Am-induced pulmonary fibrosis is a severe and uncommon pattern of Am pulmonary toxicity, with an estimated frequency of 0.1% [65]. Am fibrosis develops in 5% to 7% of patients following an episode of classic Am pneumonitis [60] or as a de novo phenomenon. Criteria for the diagnosis of Am-induced fibrosis include a normal chest radiograph before institution of treatment with Am; onset of fibrosis during or shortly after termination of treatment with Am; more rapid progression with time as compared with idiopathic pulmonary fibrosis; absence of other causes for the fibrosis; and sometimes, the idea of previous APT with incomplete resolution. In Am fibrosis, there are dense, bibasilar, reticular opacities, with coarse crackles at auscultation of the chest, significant hypoxemia, and weight loss. On HRCT, there are coarse, interstitial reticular and perilobular opacities and traction bronchiectases that predominate at the lung bases. Honeycombing is unusual at the time of diagnosis. Am-induced fibrosis is irreversible, response to corticosteroids is limited or of short duration, and the disease adversely impacts life expectancy. Whether a history of past exposure to Am is a risk factor for ‘‘idiopathic’’ pulmonary fibrosis later in life is unclear [66]. Sometimes, migratory or fixed flocculent alveolar opacities in the patient who is taking Am correspond to the histologic pattern of organizing pneumonia [67 – 69]. The clinical and imaging features of organizing pneumonia that is associated with Am are indistinguishable from those of the idiopathic form of the disease [67]. On histology, excessive numbers of foam cells on a background of endoluminal fibrosis and interstitial inflammation help relate the condition to exposure to the drug. Over the course of this complication, the infiltrates can migrate, even though the patient is placed on corticosteroids [67], until treatment with Am is stopped. Because Am persists in lung for extended periods

of time, prolonged use of corticosteroids is required to avoid relapse of the opacities of organizing pneumonia or reinitiation of therapy with corticosteroids is indicated. Am pulmonary toxicity can present in the form of pulmonary nodules. The radiographic appearance includes multiple, shaggy nodules that sometimes are surrounded by a halo that corresponds to attenuated Am pneumonitis peripherally [70] or large masses that sometimes exhibit a central area of decreased density on CT. Histology is similar to classic APT [70]. ARDS in patients who were treated with Am occurs almost exclusively following thoracic (cardiac or pulmonary) surgery [41,71,72]. The syndrome also has been reported in up to 10% of patients after automatic defibrillator implantation [73]. The clinical picture is of rapidly progressive respiratory failure in the context of diffuse alveolar opacities, which requires mechanical ventilation and responds poorly to treatment with corticosteroid drugs. The fatality rate is approximately 50% [74]. Patients who undergo an open lung biopsy procedure to establish the diagnosis of APT often deteriorate postprocedure [25]. This is an important consideration when contemplating surgical biopsy to diagnose one of the Am-associated lung conditions. ARDS can develop in patients who have Am-induced fibrosis as a terminal event. Subclinical APT has been evidenced in patients on chronic Am therapy and a normal chest radiograph, after HRCT, indicates ground-glass density, small alveolar opacities [63], or increased septal lines [75]. The abnormalities correspond histologically to aggregates of mural or alveolar foam cells or to alveolitis [19,75]. In addition, increased inflammatory cells in the BAL and positive gallium scans were reported in asymptomatic patients who were exposed chronically to Am [76]. Subclinical APT is reversible upon cessation of the drug. The significance of subclinical toxicity, in terms of possible progression to overt APT, is unclear. Alveolar hemorrhage is an unusual complication of treatments with Am [77,78]. It must be differentiated from hemorrhagic pulmonary edema and the adverse effects of oral anticoagulants [51].

Pulmonary function testing Patients who receive Am often have a background of exposure to tobacco, emphysema, or heart failure, which can impact of pulmonary functions. For that reason, it was suggested to repeat three or four determinations of pulmonary function in the first months

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of treatment with Am [33]; this will serve as a baseline to which further changes can be compared. The earliest abnormality in APT is a consistent decrease in the diffusing capacity for carbon monoxide (CO) [33]. Chronic left heart failure does not alter this test significantly [8,79]. Using the diffusion capacity for CO as a surrogate marker of APT, Magro et al [33] determined that the best sensitivity and specificity corresponded to a decrease of 15+% and 30%, respectively [33]. Patients who develop APT demonstrate a precipitous decrease in this measurement. An isolated decrease of the diffusing capacity for CO does not indicate clinically-recognizable disease necessarily, because overt Am pneumonitis will develop in only one third of such patients [33]. In practice, a reduction of the diffusing capacity should not prompt discontinuation of the drug, unless there is clinical or imaging evidence of pneumonitis [80]. Conversely, a stable diffusing capacity is considered to indicate the lack of clinically-meaningful APT [81]. An isolated measurement of the diffusing capacity should be interpreted with caution in patients who have a background of pulmonary emphysema. In one patient who had emphysema, Am pneumonitis was associated with near-normalization of the obstructive pattern [82].

Bronchoalveolar lavage The contribution of BAL to the diagnosis of Amrelated lung disease is controversial. An increase in the numbers of CD8+ lymphocytes used to be considered of diagnostic value. Other studies, however, indicated that a wide range of abnormalities can be found in the BAL in Am pneumonitis, including a normal distribution or an increase in neutrophils or lymphocytes or lymphocytes and neutrophils [81,83,84]. The time to onset of the pneumonitis tends to be shorter in patients who have lymphocytosis in the BAL. Eosinophilia as an isolated finding in BAL is unusual. The presence of foam cells with lamellar inclusions on microscopic or electron microscopic examination of BAL of patients who are exposed chronically to Am is a routine finding and does not indicate drug toxicity [19]. In the absence of foam cells, however, the diagnosis of classic APT is considered unlikely. There are no consistent data on the BAL pattern of patients who have Am-induced ARDS or fibrosis. Hemosiderin-laden macrophages were described in the BAL in a few patients who had Am pneumonitis [83].

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Histopathologic evaluation A lung biopsy specimen of significant size is required to establish confidently the diagnosis of APT; however, it is not indicated in every patient. The histopathologic appearances of Am pneumonitis and of subpleural masses include septal thickening, interstitial edema, nonspecific inflammation and fibrosis, as well as the presence of lipids within interstitial and endothelial cells and lying free in alveolar spaces [5,8,25,81,85]. Free foamy intraalveolar macrophages also are seen, and, if present in huge numbers, support the diagnosis of APT. They may be so numerous that they mimic the pattern of desquamative interstitial pneumonia [86]. Other findings include organizing pneumonia [67], acute organizing and fibrinous pneumonia [69], and hyperplasia of type II cells. The latter finding correlates with the presence of interstitial fibrosis [19]. Active or resolving DAD and hyaline membranes represent ARDS [73]. The histopathologic features of Aminduced fibrosis are those of severe interstitial fibrosis, with thickened alveolar septa, type II cell hyperplasia/dysplasia, and the accumulation of foamy alveolar macrophages [30]. Alveolar foam cells are seen, depending on the time from biopsy to discontinuation of the drug. In patients in whom the Am was withdrawn several months before the time of biopsy, Am fibrosis may resemble nonspecific interstitial pneumonia-fibrotic subtype.

Work-up in patients who are suspected of having amiodarone pulmonary toxicity In addition to taking drug history, patients should undergo detailed imaging, pulmonary function testing, BAL, and diuresis as a first step in evaluation. Results of these tests may establish a presumptive diagnosis of APT, especially if pretherapy imaging and pulmonary function tests, including the diffusing capacity, were normal. If there is sufficient confidence in the diagnosis of APT, Am should be discontinued (under cardiologic guidance) and the patient should be observed until improvement in symptoms and imaging is noted. The general consensus is that corticosteroid drugs should be given to patients who show substantial involvement on imaging or hypoxemia in the attempt to accelerate recovery and possibly to minimize the likelihood of lung fibrosis. If improvement fails to be detected after 1 to 2 months, diagnoses other than APT should be considered. Lung biopsy should be considered when an accurate diagnosis is required early, for instance, in

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patients in whom Am cannot be withheld without risks or if the diagnosis of pulmonary opacities is required before heart surgery is contemplated. Biopsy also is indicated in patients who do not improve by 1 to 2 months after drug discontinuation and initiation of corticosteroids. Pulmonary functions may be too compromised to allow for a lung biopsy in patients who are taking Am and develop ARDS. The respective merits of lung biopsy, as opposed to a more conservative approach in the evaluation of patients who have possible APT, has not been evaluated systematically [8].

Outcome Clinical improvement and clearing of pulmonary opacities typically require 1 to 3 months [25]. Discontinuation of Am as the sole therapeutic measure may be sufficient, if disease extent is limited; however, unless corticosteroid drugs are added, discontinuation of Am rarely is followed by convincing improvement in patients who have more advanced disease [13]. Despite the lack of controlled studies, clinical evidence has accumulated that supports the beneficial effects of corticosteroid treatment: (1) early mortality was observed in patients in whom corticosteroids were not used [24,87] or were used too late [33]; (2) in some patients, Am withdrawal was not followed by detectable improvement or the patients deteriorated unless corticosteroids were applied eventually [88]; (3) early corticosteroid withdrawal was associated with recurrence; in some patients, the disease went out of control and a catastrophic course ensued [26]. Radiological follow-up shows complete clearing in about 85% of patients; residual opacities persist in the remainder of patients [61]. In a few patients, pulmonary fibrosis develops. Improvement of imaging and pulmonary function generally lags behind clinical improvement [89]. A persistent decrease in diffusing capacity for CO is observed commonly in the long term, despite clearing of the pulmonary opacities, because of the combined effect of APT and emphysema in variable proportions among patients. Prevention of arrhythmia recurrences should be organized in conjunction with the cardiologist and may rely on other antiarrhythmic agents or insertion of an automatic defibrillator. In a few patients who had arrhythmia and APT, drug dosage was decreased (eg, halved) and corticosteroids were given, with satisfactory control of both conditions [90].

Corticosteroids need to be administered for extended periods of time, otherwise, recurrences may develop during corticosteroid tapering; recurrences have been described up to 8 months after Am withdrawal. The pattern of recurrence may be more severe than the initial episode of Am pneumonitis and uncontrollable respiratory failure or death may ensue [91]. Although no controlled studies are available to endorse corticosteroids’ efficacy, they are advocated with five lines of suggestions: (1) a sufficient initial dosage should be given (eg, 0.75 to 1 mg/kg prednisolone or equivalent); (2) initial dosage should be maintained until definite clinical and radiographic response is obtained, otherwise increased doses should be considered; (3) corticosteroid tapering should be slow and prudent; (4) a reasonable estimate of duration of treatment is 6 months, more often 1 year; and (5) patients should be monitored carefully after discontinuation of corticosteroids for possible recurrence of the disease. Patients who demonstrate a recurrence or those who have Am-induced fibrosis may require long-term corticosteroids and need to be monitored for the development of corticosteroid adverse effects, including opportunistic infections. In a fraction of patients, irreversible sequelae will persist [84] or the disease will progress [45]. Mortality in Am pneumonitis is substantial and ranges between 21% and 33% of patients who are admitted to the hospital [6,13,46,84]. The prognosis is worse when Am pneumonitis occurs on a background of COPD [80]. Unwitting continuation of treatment with Am after diagnosis of APT leads to an increase in disease extent or severity. Resumption of Am after a period of drug holiday, if indicated for the control of refractory or life-threatening arrhythmia, is followed by the recurrence of clinical symptoms [92,93] and radiographic abnormalities in about two-thirds of patients within shorter periods of time. Monitoring the diffusing capacity may enable the earlier detection of recurrence; 67-gallium scanning may be used as a confirmatory test, if needed [92].

Other respiratory adverse effects of amiodarone Pleural effusion An exudative pleural effusion develops in up to one third of patients who have Am pneumonitis [20], although it is considered unusual [8]. The effusion is often unilateral, of moderate volume, and can cause chest pain.

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The development of lone pleural effusion during treatments with Am is unusual. On imaging, a freeflowing effusion is present that often is accompanied by pleural thickening. Bilateral exudates developed in one patient who was placed on high-dose Am (1600 mg/day, decreased to 1200 mg) and subsided after drug withdrawal [94]. In another patient, a large bilateral serosanguineous effusion preceded the onset of Am pneumonitis [95]. Generally, the pleural fluid in Am-induced pleural effusion is an exudate, with a protein concentration that ranges from 2.8 g/dL to 5.5 g/dL [96], and a lymphocyte [97] or lymphocyte and neutrophil predominance [94]. In one patient who had bilateral effusions, the right and left pleural fluid had the same characteristics [94]. Foam cells that resembled those found in the BAL fluid were found on cytologic examination of the pleural fluid in one patient [95]. On histology, thickening and foamy macrophages can be found in pleural tissue [94]. Pericardial effusion was present in some patients as an associated feature [62,98]. Patients generally improved upon discontinuing Am. An important differential diagnosis is left ventricular failure, which also can produce an exudate [99]. A transudate typically suggests left ventricular failure [8]. Pleural thickening Imaging studies commonly indicate smoothedged pleural thickening in patients who have APT [63,100], especially those with large infiltrates or a mass that abuts the pleura. In one study, pleural thickening was present in 13 of 20 patients [61]. The thickening usually predominates in the area where the pulmonary infiltrates are densest. Clinically, patients may complain of pleuritic chest pain and a friction rub may be heard. Upon drug discontinuation, improvement in pleural thickening tends to parallel that of the pulmonary infiltrates. Some degree of pleural thickening may, however, persist after resolution of the pulmonary opacities. Rarely, Am causes the lupus syndrome with pleural or pleuropericardial effusions, endocarditis, and positive ANA [101,102]. The clinical manifestations and autoantibodies disappeared upon drug discontinuation.

Prevention and early detection of amiodarone pulmonary toxicity Given the frequency and potential severity of Am pneumonitis, early detection is desirable; however,

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no consensus exists in that area. Earlier diagnosis of APT may simplify management and improve prognosis, but this is unproved. Patients who should benefit from Am should be carefully selected; a golow attitude regarding Am dosage is warranted, where possible. Pulmonary evaluation, including plain chest radiograph, and pulmonary function, including diffusion capacity for CO are recommended when Am is started. This serves as a background to which changes can be compared. Systematic serial pulmonary function testing in patients who receive conventional dosages of Am is probably unrewarding, because the disease is uncommon in this subset of patients [103]. Nevertheless, education of the patient about amiodarone’s adverse effects and watchful waiting are required. Until further clarification, follow-up of lung functions and imaging should be directed to patients who are at greater risk of developing APT, such as those with poor lung function, pulmonary emphysema, or previous pneumonectomy. Although the optimal frequency of follow-up has not been determined, most cases of APT develop during the first 2 years of treatment and disease onset usually is slow. Pulmonary function tests and imaging may be performed every 3 to 6 months, depending on physician, patient, and perceived risk. An isolated decrease of the diffusing capacity for CO is not indicative of clinically-recognizable disease and should not prompt discontinuation of the drug unless there is clinical or imaging evidence of pneumonitis [80]. If monitoring shows a stable diffusing capacity, clinically meaningful APT is unlikely [81].

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