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Amiodarone-Induced Pulmonary Toxicity Case Study With Syndrome Analysis

Introduction

Amiodarone-induced pulmonary toxicity (AIPT), although rare, is a potentially life-threatening adverse reaction [1]. Recent studies have reported that the incidence of AIPT ranges between 5 and 13% [2–5]. Mortality rates due to AIPT have been reported to range from 10 to 23% [2].

Despite its clinical importance, there remain some unanswered questions regarding AIPT. Studies have reported that the daily amiodarone dose, cumulative dose, duration of therapy, patient age and the presence of pre-existing lung disease are associated with an increased risk of AIPT, although these findings are not universally accepted [6–10]. The pathophysiology of, and precise diagnostic criteria for AIPT are still under investigation, its optimal management has yet to be defined, and monitoring guidelines have not been universally implemented [11].

In 2002, the Australian Adverse Drug Reaction Advisory Committee (ADRAC) reported that although amiodarone is indicated only for severe cardiac arrhythmias, its use had doubled between 1989 and 1994 [12]. Furthermore, the number of amiodarone prescriptions dispensed annually in Australia increased almost fourfold from 1994 to 2003 [13], suggesting that amiodarone use is likely to continue to increase in the future. The increasing use of amiodarone, coupled with the potentially fatal outcome of AIPT, results in an increasing need for targeted monitoring of those patients at highest risk of its development to facilitate its early identification and management, to minimize the associated risk of morbidity and mortality. Conclusive identification of the risk factors for AIPT is thus essential.

This study aimed to confirm, using a large database of AIPT cases reported to ADRAC and the United States Center for Drug Evaluation and Research (CDER), whether daily amiodarone dose, cumulative dose, duration of therapy and the age of the patient were risk factors for AIPT; and to reinforce the clinical relevance of these results by determining whether a cohort of tertiary hospital patients diagnosed with AIPT demonstrated the identified risk factors.

Methods

This study consisted of two phases. Phase I involved identification of cases of adverse reactions to amiodarone, particularly AIPT, reported to ADRAC and the CDER, and a comprehensive review and analysis of these reports to identify and explore the risk factors for AIPT. Phase II comprised a retrospective review of the medical records of patients discharged from Fremantle Hospital and Health Service, Western Australia (FHHS) with a diagnosis of interstitial lung disease (ILD) to isolate cases of AIPT. Data were collected regarding these patients’ risk factors for AIPT to validate the findings from Phase I of the study.

Phase I: review of drug agency reports

Details of all case reports of adverse reactions to amiodarone held by ADRAC as of August 2006 were requested by mail. The earliest case report dated from 1983. Data from the CDER were available from their website (http://www.fda.gov/cder/aers/extract.htm). The data were accessed during the period March–July 2006. At that time, data available from the website were quarterly data files from 2004 to 2005. A total of eight quarters were reviewed.

Data were collected regarding the age of the patient at the time of the reaction, duration of therapy, daily dose and the adverse reactions reported. The cumulative dose was estimated by multiplying the recorded daily dose by the duration of therapy.

AIPT was defined as any of the following possible clinical presentations, as described by the reporter of the reaction: ILD, pulmonary fibrosis, pulmonary infiltrates, pleural effusion, alveolitis fibrosis, pneumonitis, bronchiolitis obliterans organizing pneumonia and cryptogenic organizing pneumonia. Patients with the above pulmonary presentations were classified as ‘AIPT patients’ (henceforth referred to as the ‘AIPT group’), whereas those who were not reported as experiencing the above complications but had demonstrated other amiodarone-related toxicities were considered to be ‘non-AIPT patients’ (i.e. the ‘non-AIPT group’).

Data from both ADRAC and the CDER were analysed using independent samples t-testing and univariate binary logistic regression analysis to compare the AIPT and non-AIPT groups and determine whether the previously identified variables (patient age, duration of amiodarone therapy, daily dose and cumulative dose) were unique risk factors for AIPT. Multiple logistic regression analysis was then conducted on the combined data from both agencies in order to identify the significant risk factors for AIPT within this larger population. The non-AIPT group was used as the comparator group as it was methodologically impossible to isolate a control population of Australian and American patients taking amiodarone without developing any form of amiodarone-related toxicity. P-values < 0.05 were considered statistically significant for all analyses.

Phase II: retrospective review of medical records

FHHS is a publicly funded tertiary teaching hospital with approximately 500 beds situated in Fremantle, Western Australia. The medical records of all patients discharged between January 2000 and December 2005 with International Classification of Diseases 9 and 10 (ICD-9 and ICD-10) discharge codes consistent with ILD were requested. The codes selected were 508.8 (respiratory conditions due to other specified external agents), J70.2 (acute drug-induced interstitial lung disorders), J70.3 (chronic drug-induced interstitial lung disorders), J70.4 (drug-induced interstitial lung disorders, unspecified) and J84.1 (idiopathic pulmonary fibrosis) in an attempt to detect the maximum number of patients diagnosed with AIPT, or patients with a history of amiodarone use and a diagnosis of idiopathic pulmonary fibrosis which may have been unrecognized AIPT. A retrospective review of these patients’ medical records was undertaken and data collected regarding the previously identified variables. Descriptive statistics were calculated and compared with the findings from the drug agency data to identify apparent trends.

Ethical approval for the study was granted by the Human Research Ethics Committees of Curtin University of Technology, and the South Metropolitan Area Health Service, Western Australia.

Results

Phase I: review of drug agency reports

Of the 1020 cases of amiodarone-induced toxicity reported to ADRAC from 1983 to August 2006, the most commonly reported adverse reaction was thyroid disorders (225; 22%), followed by skin reactions such as photosensitivity (141; 13.8%). As displayed in Figure 1, pulmonary toxicity was the third most common adverse reaction, with 116 (11.4%) cases. Pulmonary fibrosis (55; 47.4%) was the most frequent manifestation of AIPT reported to ADRAC, with pulmonary infiltrates reported in 31 cases (26.7%) and 13 patients identified with ILD (11.2%). Pleural effusion and alveolitis fibrosis were each reported in seven patients (6%).

From January 2004 to December 2005, the CDER received reports of 1196 patients developing adverse reactions related to amiodarone therapy, and of these there were 121 (10.1%) patients with pulmonary toxicity. As seen in Figure 2, the frequency of reported adverse reactions varied from the ADRAC data, with arrhythmias the most commonly reported adverse reaction. Blood disorders and thyroid disorders were second (213; 17.8%) and third (156; 13%), respectively, while AIPT was fourth (121; 10%). Of these 121 AIPT cases, pulmonary toxicity presented most frequently as ILD (38; 31.4%), pulmonary fibrosis (31; 25.6%) and pleural effusion (30; 24.8%).

Table 1 displays the descriptive statistics and the results of the t-test analyses for the ADRAC and CDER datasets. Among the cases reported to ADRAC, statistically significant differences between the AIPT and non-AIPT groups were demonstrated for all variables. Patients with AIPT were older, had a longer duration of therapy and a lower daily amiodarone dose, but a higher cumulative dose than the non-AIPT group. Analysis of the CDER data revealed significant differences between the AIPT and non-AIPT groups only for patient age and the duration of amiodarone therapy, with AIPT patients being older and having a longer duration of therapy.

Age
(years)
73.469.2<0.001*73.470.60.010*
(71.4, 75.5)(68.3, 70.1) (71.4, 75.4)(69.7, 71.4) 
Duration
(days)
498.9204.40.001*654.5326.70.011*
(340.1, 657.6)(164.2, 244.6) (415.5, 893.6)(251.1, 402.2) 
Daily dose
(mg)
302.9357.40.037*445.6451.60.914
(256.4, 349.4)(335.9, 378.9) (340.8, 550.3)(403.7, 499.5) 
Cumulative dose
(g)
150.360.10.008*252.3122.90.093
(87.2, 213.3)(40.3, 80.0) (104.1, 400.5)(86.0, 159.7) 

Univariate logistic regression analysis was conducted for each potential risk factor. The ADRAC data confirmed age, duration of therapy and cumulative amiodarone dose as significant risk factors for AIPT, but not daily dose. The risk of AIPT in those aged in their 80s was almost fourfold higher than those aged ≤ 60 years [odds ratio (OR) 3.92, 95% confidence interval (CI) 1.73, 8.89]. AIPT risk increased significantly in those who were on amiodarone for >1 month, with the highest risk for those who were on therapy for 6–12 months. Patients in this group were 33.68 (95% CI 7.53, 150.66) times more likely to develop AIPT than those who were on amiodarone for <2 weeks. Compared with those patients who had received <10 g of amiodarone, AIPT risk gradually increased with increasing cumulative dose and reached a plateau in the 101–150 g and >150 g groups (OR 10.29, 95% CI 3.42, 30.92 and 9.50, 95% CI 3.82, 23.67, respectively).

Univariate analysis of the CDER data confirmed only that a longer duration of amiodarone therapy increased the risk of AIPT; however, the magnitude of the increased risk was lower. In patients receiving >6 months’ therapy, AIPT risk was increased approximately sixfold for the CDER cases vs. 30-fold for the ADRAC cases.

The results of the multiple logistic regression analysis of the combined data from ADRAC and CDER are displayed in Table 2. When the data source (i.e. ADRAC vs. CDER) was included in the model for analysis, it failed to influence the risk of AIPT (P = 0.310), which supported the decision to combine the two data sources. Multiple logistic regression confirmed age (P = 0.035) and duration of amiodarone therapy (P < 0.001), but not daily dose or cumulative dose, as significant risk factors for AIPT. The risk of AIPT was increased almost three times in every age group over the age of 60 years compared with those aged ≤ 60 years. As in the univariate analyses of the individual datasets, duration of amiodarone therapy was a significant risk factor for AIPT after >1 month of amiodarone therapy, with the highest risk once again seen in those who had received amiodarone for 6–12 months.

Age (years)≤6010.035
61–702.660.008
(1.29, 5.47)
71–802.580.011
(1.25, 5.32)
≥812.750.035
(1.07, 7.07)
Duration (days)0–141<0.001
15–302.160.312
(0.49, 9.55)
31–1806.81<0.001
(2.47, 18.74)
181–36518.28<0.001
(6.42, 52.04)
366–73011.74<0.001
(3.68, 37.42)

Phase II: retrospective review of medical records

The characteristics of the seven FHHS patients diagnosed with AIPT are displayed in Table 3. These patients were all aged > 60 years, and six of the seven had been on amiodarone for >6 months. They thus met the criteria for being at increased risk of AIPT, as confirmed by multiple logistic regression analysis.

67575200 mg119.2
81111200 mg26.2
75182200 mg40.6
90966200 mg200.2
702443100 mg488.6
821790200 mg for 6 months, then 100 mg203.0
93‘Long term’200 mgUnknown

Discussion

In support of previous reports [6], the current study has demonstrated a wide range of adverse reactions associated with amiodarone therapy. Thyroid disorders were the most frequent adverse reaction reported to ADRAC, whereas in the CDER dataset, arrhythmias were the most frequently reported adverse reaction. One possible explanation for the differences in the adverse reactions reported to the two agencies might be the slightly higher doses of amiodarone recommended in the USA as opposed to Australia [14].

Both univariate logistic regression analysis of the ADRAC data and multiple logistic regression analysis of the combined data confirmed patient age as a significant risk factor for AIPT, with older patients at higher risk of AIPT. This is particularly interesting because, although some authors have claimed that the risk of AIPT is higher in elderly patients [15], other studies have demonstrated that increasing age did not increase the risk of AIPT [1, 16], a finding mirrored by the CDER analysis.

Duration of amiodarone therapy was confirmed as a significant risk factor for AIPT from the univariate logistic regression analysis of both the ADRAC and CDER datasets and multiple logistic regression analysis of the combined data. Risk increased after 1 month and was highest in those who were on amiodarone for 6–12 months. This confirmed the findings of Dusman et al., who claimed that duration of amiodarone therapy was a significant risk factor for AIPT, with the highest risk of developing pulmonary toxicity in the first 12 months after starting on the drug [16].

Although the ADRAC data suggested a trend towards increased risk in patients who had received cumulative amiodarone doses of 101–150 g, this was not supported by the CDER or combined data. This issue requires further clarification. One previous study has suggested that a similar cumulative dose (of 140–230 g) is clinically significant in inducing lung toxicity [10], whereas another author has reported that a cumulative dose of amiodarone as low as 10 g may result in pneumonitis [17]. Other studies, however, have argued that AIPT is more common in patients with high cumulative doses of amiodarone [2, 6, 8, 16]. These conflicting findings may result from the two hypothesized mechanisms of AIPT exhibiting differential cumulative dose dependencies [1].

The relevance of age and duration of therapy as risk factors was demonstrated in a small cohort of AIPT patients from a Western Australian tertiary hospital. According to the multiple logistic regression analysis, the FHHS patients were all at increased risk of AIPT based on their age, and six of the seven had been receiving amiodarone for >6 months at the time of diagnosis of pulmonary toxicity.

This study was not without its limitations. As discussed previously, an ideal control group was not available for the drug agency data, a common problem with retrospective studies. Retrospective studies may also suffer from poor data quality, and that may have influenced the results. Data collected from the drug agencies was based on voluntary case reports; consequently, information was often missing, especially regarding the indication for, and duration of, amiodarone therapy. The CDER records were at times difficult to manipulate, requiring configuration of the data to determine the daily amiodarone dose and the duration of therapy. Determination of the manifestations of AIPT may have been complicated by the use of different terms to describe the observed toxicity. While some reports may have used the term ‘ILD’ (the Medical Subject Heading) to describe the toxicity experienced, others may have used more specific or interchangeable terms; thus it must be accepted that certain inconsistencies in these data were inevitable.

If the patients at high risk of AIPT could be identified, monitoring of these patients could be performed in an appropriate, timely and cost-effective manner, facilitating the early identification and management of AIPT and thus minimizing the risk of AIPT-related morbidity and mortality. This requires final clarification of the risk factors for AIPT, and while the large dataset of AIPT cases compiled during this study has made some progress in that direction, the best hope of truly confirming these risk factors lies with a future long-term prospective cohort study with an appropriate control group.

In conclusion, amiodarone possesses a significant adverse reaction profile, including potentially life-threatening pulmonary toxicity. AIPT remains a significant potential cause of morbidity and mortality, a fact confirmed in a small local population of ILD patients. Although a variety of factors have been suggested to increase the risk of AIPT, this study has confirmed only patient age and duration of amiodarone therapy as significant risk factors. These risk factors were also exhibited by a small group of hospital AIPT patients. This study has thus allowed identification of those patients at the highest risk of pulmonary toxicity, and therefore those requiring closest monitoring. Further prospective studies are needed to clarify definitively the risk factors for AIPT and the appropriate frequency and intensity of monitoring of ‘at-risk’ patients.

D.K.E. acknowledges the financial support of AusAid in the completion of her MPharm project, which formed the basis of this manuscript.

Amiodarone Induced Pulmonary Toxicity: A Fatal Case Report

Oyku Gulmez1* and Aylin Ozsancak2

1Department of Cardiology, Baskent University Istanbul Medical and Research Center, Turkey

2Department of Pulmonary Medicine, Baskent University Istanbul Medical and Research Center, Turkey

*Corresponding Author:
Oyku Gulmez
Department of Cardiology
Baskent University Istanbul Medical
and Research Center, Turkey
Tel: +90 5352496139
Fax: +902616519858 E-mail:[email protected]

Received date: July 14, 2017; Accepted date: July 24, 2017; Published date: July 31, 2017

Citation: Gulmez O, Ozsancak A (2017) Amiodarone Induced Pulmonary Toxicity:A Fatal Case Report. J Clin Case Rep 7:998. doi: 10.4172/2165-7920.1000998

Copyright: © 2017 Gulmez O, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Amiodarone Induced Pulmonary Toxicity (AIPT) is a rare but one of the most serious adverse event that can be potentially life threatening. The incidence of AIPT is 2% to 10% and mortality rate ranges from 10% to 50% in patients who develop Acute Respiratory Distress Syndrome (ARDS). Age, preexisting lung disease, cumulative dose, thoracic surgery and pulmonary angiography are the risk factors associated with AIPT. Although there is no pathognomonic clinical, laboratory, radiographic or histological findings the diagnosis depends on clinical suspicion and exclusion of other possibilities of pulmonary disease. We present a case of 77-year-old man who presented with symptoms of pneumonia and diagnosed as AIPT by the elimination method for specific and non-specific pulmonary infection. Despite discontinuation of amiodarone and systemic therapy with corticosteroids the patient continued worsen. Pre-existing lung disease, the rapid onset of the clinical picture and the extent of lung injury on CT were the poor prognostic factors for our patient.

Keywords

Amiodarone; Pulmonary toxicity; Thoracic surgery

Introduction

Amiodarone is an iodinated benzofuran derivate Class III antiarrhythmic drug that is used for effective management and prevention of life-threating ventricular arrhythmias and atrial fibrillation [1,2]. Unfortunately, due to its lipophilic properties, it has a large distribution volume and a wide range of adverse events including pulmonary toxicity, hepatotoxicity, cardiotoxicity, thyroid dysfunction and corneal microdeposits. Of these, amiodaron-induced pulmonary toxicity (AIPT) is a rare but the most important complication of amiodaron due to its non-reversible and fatal potential. The incidence of AIPT is 2% to 10% and mortality rate ranges from 10% to 50% in patients who develop acute respiratory distress syndrome (ARDS) [3]. Although AIPT has no pathognomonic clinical, laboratory, radiographic or histological findings the diagnosis depends on clinical suspicion and exclusion of other possibilities of pulmonary disease [3,4]. Risk factors for AIPT include age, duration and intensity of therapy (cumulative dose), preexisting lung disease, thoracic surgery and pulmonary angiography [3,5]. We describe a case of fatal pulmonary toxicity in a 77-year-old man with known coronary artery disease and preexisting lung disease who presented with progressive dyspnea, cough, weakness and chest imaging and laboratory findings revealed suspicion of pneumonia.

Case Report

A 77-year-old man was admitted to the hospital with progressive dyspnea, cough and weakness for 1-week duration. He had a medical history of coronary artery disease since 2011 diagnosed by coronary angiography, hypertension, diabetes mellitus, sick sinus syndrome with a definite pacemaker insertion 4 months ago. The patient underwent left upper segmentectomy for giant cell carcinoma 5 years ago (T1AN0M0) and had chemotherapy and radiotherapy. He was maintained on amiodarone 400 mg/daily for the past 2 months due to recurrent episodes of symptomatic atrial fibrillation. His physical examination revealed blood pressure of 120/80 mmHg, heart rate of 70 beats/min, respiratory rate of 16 breaths/min, temperature of 37.2°C and oxygen saturation of 80% on room air. Bilateral crackles were heard on examination. At the time of admission, laboratory examination revealed white blood cell count of 9280 bin/uL, 70.1% neutrophils and 6.2% eosinophils and elevated C-reactive protein: 142.3 mg/L. Other laboratory workup showed creatinine level of 0.9 mg/dL, brain natriuretic peptide 259.1 pg/mL, thyroid stimulating hormone 0.29 μIU/mL, aspartate aminotransferase 41 U/L, alanine aminotransferase 37 U/L, and electrolyte concentrations within normal limits with no elevation of cardiac enzymes. D-dimer under oxygen level was also within normal limits. Blood gas analysis supply of 5 L/min showed hypoxemia without CO2 retention. Urinalysis was unremarkable. Electrocardiography showed sinus rhythm with no ischemic changes. Echocardiographic examination showed normal size and function of left and right ventricle with a left ventricular ejection fraction of 55%. There was also no significant valvular disease. Chest X-ray showed bilateral pulmonary interstitial infiltration (Figure 1). Chest computed tomography demonstrated a diffuse bipulmonary ground glass confluent opacities, and areas of consolidation at the bases resembling ARDS (Figure 2). Pulmonary embolism was excluded. Blood cultures were drawn and empiric broad-spectrum antibiotic therapy was initiated. Bronco dilatator therapy was also added to patient’s home medications (clopidogrel, apixaban, amlodipine, metoprolol, amiodarone). On day 4, cultures of blood, sputum, and urine were still negative. Procalcitonin was negative. Despite medical therapy on day 5, patient continued to complain of dyspnea and required noninvasive ventilatory support. On day 6, pulmonary infection was excluded, and based on clinical, laboratory, radiological and microbiological findings, clinical diagnosis of AIPT was made. Amiodarone was discontinued and pulse high dose steroid therapy was administrated. On day 7, mechanical ventilation was instituted. On day 8, bronchoscopy with Bronchoalveolar Lavage (BAL) was performed after clinical stabilization. BAL revealed intense blood elements, sparse alveolar macrophages and lymphocytes (71.9% neutrophiles, 12.7% lymphocytes, 7.7% eosinophils). No bacteria or fungi were also identified via microscopic examination or culture of lavage fluid. In addition, screening for pathogenic viruses including influenza strain H1N1, influenza A, influenza B, Corona virus OC43- 229E-NL63-HKU1, parainfluenza 1-2-3-4, rhinovirus, enterovirus, adenovirus, respiratory syncytial virus A, B, human matepneumo virus and bocavirus were negative. Additionally, tests for antiviral antibodies (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, cytomegola virus) were negative. Moreover, serological (Legionnella, Chlamydophia pneumonia, Mycoplasma pneumonia, Bordetella pertusis) and immunological tests (Ig A, Ig G, and Ig M) were normal. Galactomannan level was within normal levels. He improved symptomatically and radiographically within 4 days. On day 15, he was extubated but he was still requiring 5 L to 8 L intranasal oxygen. On day 18, he again presented progressive dyspnea with high oxygen requirements and again intubated. However, the patient died after 12 hours in respiratory failure.

Discussion

In this case we report a fatal case of amiodarone pulmonary toxicity. Initial treatment included antibiotics because pneumonia was suspected. The AIPT diagnosis was made based on clinical risk factors for AIPT and sterile culture results at a median of 6 days post-admission. Risk factors of our patient were age, pre-existing lung disease and a daily dose of 400 mg amiodarone. Unfortunately, our patient did not benefit from discontinuation of amiodarone, and steroid therapy and continued worsen. Pre-existing lung disease, the rapid onset of the clinical picture and the extent of lung injury on CT were the poor prognostic factors for our patient.

Despite various adverse events, amiodarone is a highly effective antiarrhythmic agent that is used for both ventricular and supraventricular arrthymias. For supraventricular arrthymias maintenance doses are limited to 200 mg/d to 400 mg/d [6,7]. AIPT was first reported in 1980 [8]. Although the incidence of AIPT is declined due to learning curve in maintenance doses (reduced doses) and diagnosing AIPT, it is reported to be 5% to 10% [9].

The mechanism of AIPT is incompletely understood but direct toxic effects of the accumulated metabolite of the drug in the pulmonary tissue, T-cell which are predominately CD8 positive mediated immunologic reactions in genetically predisposed patients and the activation of angiotensin enzyme system are the possible mechanisms of AIPT. The high volume of drug distribution close to 5000 liters, extensive tissue binding and long elimination half-life of approximately 30 days to 108 days may explain the toxic effects of the drug seen at any time during treatment, and even months after discontinuation of therapy [3]. Toxicity can present either in acutely in the form of fever, pleuritic chest pain, and cough or sub acutely with chronic non-productive cough, progressive dyspnea, low-grade fever, malaise, weight loss and hypoxia [3]. Moreover, there is no threshold to avoid toxicity from amiodarone [3].

The risk factors for AIPT are age, duration and intensity of amiodarone therapy, pre-existing lung disease, pulmonary angiography, cardiothoracic surgery and high concentrations of oxygen. It is shown that there is positive correlation between age and AIPT. AIPT increases 3-fold for every 10 years of age in patients aged >60 years compared to those aged <60 years. Patients receiving a daily dose greater than 400 mg/day are at higher risk compared to those receiving 200 mg/ day [10,11]. Moreover, a study among Japanese patients demonstrated that the incidence of AIPT increased from 4.2% to 7.8% and 10.6% with 1.3 years and 5 years use of amiodarone respectively, with a mean maintenance dose of 141 mg daily. Additionaly, AIPT is positively correlated with a cumulative dose of 140 g to 230 g [12]. In several studies pre-existing pulmonary disease was associated with higher risk of AIPT and AIPT occurred in 50% surgical survivors, and in 27% pneumonectomy patients [13-15].

Clinical symptoms, signs, laboratory and radiographic findings of AIPT are nonspecific and there is no clinical, physiological, biological or radiological gold standard to diagnose AIPT. The clinical presentations of AIPT include chronic non-specific interstitial pneumonitis, chronic eosinophilic pneumonia, organizing pneumonia, idiopathic pulmonary fibrosis, desquamate interstitial pneumonia, solitary pulmonary mass, diffuse alveolar hemorrhage and ARDS. Pleural effusion which is usually unilateral and at the right side, or bilateral, can be seen during amiodarone treatment mostly after 6 months of therapy. Pleural effusion can also be seen as early as 2 months and as late as 6 years after treatment [16-18]. Moreover, AIPT may mimic other diseases like congestive heart failure and pulmonary embolism. Due to its nonspecific nature and no definite diagnostic criteria, AIPT is a diagnosis of exclusion of other possible diseases.

Several studies, except one showed that amiodarone is a safe antiarrhythmic agent after lung resection [19-21]. Only one study by Mieghe et al. showed increased risk of ARDS, especially in pneumonectomy patients. However, in a recent study by Teerakanok et al. the incidence of amiodarone induced postoperative (mostly after cardiothoracic surgery) ARDS was reported to be 15% [22]. The possible mechanisms are high oxygen administration, lung damage of intubation/ventilation, the systemic inflammatory response induced by surgery. As one of the mechanism of AIPT is the production of toxic oxygen radicals which can cause direct cellular injury, patients with pre-existing lung disease and lung insult from surgery may be prone to amiodarone toxicity. Nevertheless, patients in whom ARDS develops in the context of pulmonary toxicity related to amiodarone show a fatal course despite therapies.

The primary treatment of AIPT is the suspicion of AIPT after exclusion of other possible pulmonary diseases. Discontinuation of amiodarone is the cornerstone of the treatment. However, due to its accumulation in lung tissue and long elimination half-life time pulmonary toxicity may progress despite drug discontinuation. Systemic corticosteroids (40 mg to 60 mg prednisolone per day) are recommended for earlier recovery and decreased parenchymal fibrosis, for at least 4 months to 12 months to avoid relapse [3,23]. Slow improvement as long as three to six months can be noted. Permanent pulmonary fibrosis and death can be seen in case of delayed treatment or refractory cases. Mortality rate is 10% in patients who presented with AIPT, but may be as high as 20% to 30% in patients who require hospital admission, and 50% in patients who develop ARDS [3].

Conclusion

Amiodarone toxicity which may occur even with small doses and short treatment duration should be taken into consideration, especially in elderly patients with underlying lung disease who presents with shortness of breath. Early recognition of AIPT is critical to prevent or minimize its potentially pulmonary effects. Amiodarone-induced lung diseases usually have good prognosis when treated and diagnosed early. However, patients who develop ARDS or pulmonary fibrosis have worse prognosis. Patients education about signs and symptoms and regular clinical follow-up are essential for timely diagnosis and the treatment.

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Figure 1: Chest radiograph on admission revealing bilateral infiltrates.

Figure 2: Computed tomographic slices showing patches of ground glass opacity.

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