Amiodarone Lung Toxicity Research Articles

A CRAZY CAUSE OF CRAZY PAVING: AN UNUSUAL CASE OF AMIODARONE INDUCED LUNG TOXICITY

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Amiodarone induced pulmonary toxicity is a well described entity that can present with an array of histopathologic and radiologic findings. The exact incidence of amiodarone pulmonary toxicity is estimated to between 1-10% of patients [1]. Radiologic findings vary and can include ground glass opacities, interlobular septal thickening, pulmonary nodules, reticulation, fibrosis and honeycombing [2]. Isolated unilateral findings of amiodarone pulmonary toxicity, as described in the case below, is far less common and not well described. CASE PRESENTATION: A 78 year old man with non-ischemic cardiomyopathy and atrial fibrillation on amiodarone, presented with dyspnea on exertion and a non-productive cough. He was afebrile and hemodynamically stable but was hypoxemic with an oxygen saturation of 80% on ambient air. His chest X-ray at the time showed diffuse reticular opacifications on the right side. A follow up CT of the chest showed extensive interlobular septal thickening and ground glass opacities in a “Crazy Paving” pattern on the right side only. On physical examination, the patient had bilateral lower extremity pitting edema and an elevated NT-ProBnp of 6660. Given constellation of clinical and radiologic findings, there was suspicion for cardiogenic pulmonary edema and the patient was treated with diuresis. Despite maintenance of negative fluid balance, the patient had increasing oxygen requirements and did not improve clinically. His radiologic findings had persisted as well, and a decision was made to pursue a surgical lung biopsy. Pathology of the biopsy showed acute organizing process as well as lipid laden or “foamy” macrophages. A diagnosis of unilateral amiodarone lung toxicity was made. The patient was started on glucocorticoids, amiodarone was discontinued and the patients clinical status improved. DISCUSSION: This case highlights a unique presentation of amiodarone induced pulmonary toxicity in that the findings on CT were quite significant but only found unilaterally. The pathology findings, in particular the foamy macrophages, are consistent with the diagnosis of pulmonary toxicity from amiodarone 3. This highlights the importance of recognizing amiodarone induced lung toxicity as prompt cessation of the drug and if indicated steroid therapy can result in significant clinical improvement CONCLUSIONS: Although less common, unilateral amiodarone pulmonary toxicity can occur. If the clinical timeline, symptoms, and radiologic features are otherwise consistent, consideration should be given to amiodarone induced pulmonary toxicity even with unilateral findings. Reference #1: Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108(5):705-710. https://doi.org/10.1016/j.amjcard.2011.04.024 Reference #2: Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48. https://doi.org/10.1155/2009/282540 Reference #3: Schwaiblmair M, Berghaus T, Haeckel T, Wagner T, von Scheidt W. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect? Clin Res Cardiol Off J Ger Card Soc. 2010;99(11):693-700. https://doi.org/10.1007/s00392-010-0181-3 DISCLOSURES: No relevant relationships by Erica Altschul, source=Web Response No relevant relationships by Nader Ishak Gabra, source=Web Response No relevant relationships by Oki Ishikawa, source=Web Response No relevant relationships by Omar Mahmoud, source=Web Response No relevant relationships by Bushra Mina, source=Web Response No relevant relationships by Maly Oron, source=Web Response No relevant relationships by Varun Shah, source=Web Response

The appropriate time for stem cell transplantation in albino rat with amiodarone induced lung fibrosis: histological and immunohistochemical study

Background: The fibrosing form of lung injury had bad progressive course and lethal outcome.Aim of the work: This study throws light on the possible protective and/or therapeutic consequence of mesenchymal stem cell therapy in lung fibrosis induced by amiodarone in albino rat. In addition to study the possible recovery of damaged lung after amiodarone withdrawal. Material & Methods: Forty five adult male albino rats were divided into five equal groups. Group I (control); group II (amiodarone) received amiodarone 30 mg/kg orally for 6 days /week for 6 weeks, group III (withdrawal); group IV (early stem cell) mesenchymal stem cell was administrated after 1st dose of amiodarone therapy ; group VI (late stem cell) mesenchymal stem cell was administrated immediately after amiodarone suspension . Lung samples were processed and examined using histological and immunohistochemical techniques and the obtained data was subjected to statistical analysis.Results: Amiodarone treated group displayed obstructed bronchioles, collapsed alveoli, inflammatory cell infiltration ,thickened interalveolar septa and pulmonary vessels wall. Increased collagen fibers deposition between alveoli and around blood vessels in addition to highly expressed caspase-3. Group III (withdrawal) recorded only mild improvement. Group IV (early stem cell therapy ) showed advanced improvement of pulmonary alveolar architecture, on other side group V (late stem cell therapy)revealed moderate improvement of lung injury.Conclusion: The majority of amiodarone lung toxicity manifestations and lung fibrosis were regressed by bone marrow derived mesenchymal stem cell (BMSCs) therapy and the best result obtained when stem cell initiated early in the development of pathogenesis.

Amiodarone pulmonary toxicity: a report on two cases

Amiodarone is an iodine-containing antiarrhythmic drug commonly used for the treatment of ventricular and supraventricular arrhythmias. Amiodarone toxicity has several clinical presentations and affects multiple organs. One well-known serious side effect of amiodarone is pulmonary toxicity which can be acute, sub-acute, or chronic. Amiodarone pulmonary toxicity may present a diagnostic dilemma, particularly when clinical suspicion of pulmonary infection is high. Here we report two cases of amiodarone lung toxicity that were diagnosed in an early stage and improved after the discontinuation of amiodarone.

Acute Amiodarone Pulmonary Toxicity Following Lung Resection

Amiodarone is one of the most frequently prescribed antiarrhythmic agents. Despite its widespread use, it is associated with systemic side effects. Pulmonary toxicity, the most severe adverse effect of amiodarone, has usually been described in the context of chronic amiodarone use. We report a case of an 80-year-old male presenting acutely following right upper lung lobe resection for stage 1b adenocarcinoma. He developed atrial fibrillation on postoperative day four and received 12.5 g of amiodarone within a 12 day period. On presentation, he had new bilateral lung opacities and a 35% absolute decline in the predicted diffusion capacity for carbon monoxide. Pulmonary embolism was ruled out on chest computed tomography. Amiodarone was discontinued and prednisone was initiated. Despite initial improvement, he suffered from multiple hypoxemic episodes until his death in the fourth month. In a subset of patients undergoing thoracic surgery who are intubated and require high levels of oxygen, the risk of amiodarone lung toxicity increases and patients may present acutely.

Relationship between amiodarone-induced subclinical lung toxicity and Th1/Th2 balance

Background Although amiodarone is a potent antiarrhythmic agent, its clinical use is limited by serious lung toxicity. This study investigated the mechanisms of amiodarone-induced lung toxicity from an immunological perspective. Because interferon gamma (IFN-γ: Th1 cytokine) inhibits pulmonary fibroblast proliferation whereas interleukin-4 (IL-4: Th2 cytokine) augments fibroblast growth and collagen production, we hypothesized that amiodarone lung toxicity is related to Th1/Th2 balance. Methods Twenty-six consecutive Japanese patients with ventricular arrhythmias treated with amiodarone were enrolled in this study and were divided into two groups. Group A contained patients demonstrating amiodarone lung toxicity diagnosed by chest X-ray, KL-6 or D LCO ( n = 6), whereas group B included patients treated without any adverse effects ( n = 20). Th1/Th2 balance was investigated by the ratio of IFN-γ and IL-4 produced by activated peripheral CD4 + T cells. Results Clinical baseline characteristics prior to oral amiodarone did not show any differences between group A and group B except for D LCO (82.0 ± 5.2% vs. 90.8 ± 9.0%, p = 0.032) and Th1/Th2 balance (7.98 ± 1.68 vs. 13.34 ± 5.10, p = 0.020). This balance was not altered three months after withdrawal of amiodarone in group A and under continued treatment in group B, suggesting patient-specific rather than amiodarone-induced. After starting amiodarone, serum concentration of desethylamiodarone was greater in group A than in group B ( p = 0.009) and was inversely proportional to Th1/Th2 ratio ( p = 0.013). Multilogistic regression analysis indicated that Th1/Th2 balance was the most powerful indicator of amiodarone lung toxicity ( p = 0.046, odds ratio of 0.424). Conclusions Although large cohort is required, the present study indicates that Th1/Th2 balance may influence amiodarone metabolism and may be a powerful indicator of amiodarone-induced subclinical lung toxicity at least in Japanese.

Acute Fatal Post-CABG Low Dose Amiodarone Lung Toxicity

Amiodarone is one of the commonly used anti-arrhythmic agents with well-recognized chronic pulmonary toxicity. We present our experience of a patient with a fatal outcome after coronary artery bypass grafting and a short course of amiodarone treatment with a low total cumulative dose for the treatment of postoperative atrial fibrillation. Necropsy revealed diffuse pulmonary damage due to acute amiodarone lung toxicity.

Amiodarone lung toxicity in a cardiac transplant candidate initially diagnosed by fine‐needle aspiration: Cytologic, histologic, and electronmicroscopic findings

A cardiac transplant candidate with ischemic cardiomyopathy developed bilateral small parenchymal opacities in lower lobes of the lung. A fine-needle aspiration (FNA) was performed that revealed changes characteristic of amiodarone toxicity. Subsequently performed lung biopsies and electron microscopic studies confirmed the initial FNA diagnosis. The patient has been successfully transplanted with marked improvement in his clinical findings. This is the first case of amiodarone lung toxicity where the diagnosis was initially suggested based on the FNA findings. We also describe the clinical, cytological, histological, and electron microscopic (EM) findings of amiodarone-related pulmonary toxicity and provide a review of the literature.

Use of technetium-99m HMPAO scintigraphy for the detection of amiodarone lung toxicity in a rabbit model.

Amiodarone (AD) is a very effective anti-arrhythmic drug, but its use is often associated with serious pulmonary complications such as pneumonitis and interstitial pulmonary disease. The aim of this study was to investigate the relationship between the amount of amiodarone intake (and the related development of lung toxicity) and the lung uptake of technetium-99m labelled D,L-hexamethylpropylene amine oxime (HMPAO). Eighteen white female New Zealand rabbits were divided into three groups and fed AD by gavage at doses of 10 (group A), 50 (group B) or 150 (group C) mg/kg daily. 99mTc-HMPAO scintigraphy was performed at baseline and after 1, 2, 3 and 4 weeks of drug intake. Anterior images of 1 min duration were acquired at 30 min after the injection of 37 MBq 99mTc-HMPAO. Regions of interest (ROIs) were drawn on the lungs (L) and the upper limb (B) as the background. L/B ratios were calculated using the mean counts. In groups A and B histopathological evaluation of the lungs of all rabbits was performed at the end of the 4 weeks of AD intake, while in group C it was performed at 2 weeks because of increased mortality. At baseline, mean L/B ratios for groups A, B and C were 2.8 +/- 0.3, 2.8 +/- 0.3 and 2.8 +/- 0.4, respectively. After 3 weeks of AD intake, L/B ratios increased to 4.1 +/- 0.6 and 4.8 +/- 0.6 in groups A and B, respectively. The L/B ratio was 3.6 +/- 0.2 after 1 week of AD intake in group C. The correlation coefficients between the lung uptake of 99mTc-HMPAO and AD doses for groups A, B and C were r = 0.51 (P = 0.037), r = 0.74 (P = 0.0002) and r = 0.96 (P = 0.0001), respectively. Histopathological findings related to AD lung toxicity, such as interstitial pneumonitis and foamy alveolar macrophages, were observed more frequently in groups B and C than in group A. According to our findings, 99mTc-HMPAO lung uptake is correlated with AD dose. 99mTc-HMPAO lung imaging can demonstrate AD-induced lung injury.

Clinical Aspects of Amiodarone Pulmonary Toxicity

Amiodarone pulmonary toxicity is a major clinical problem limiting the utility of this powerful therapeutic agent. The clinical manifestations of amiodarone lung toxicity are protean, but the most common presentation is that of an indolent illness characterized by dyspnea and often associated with cough and/or fever. Diffuse radiographic abnormalities are common, but localized infiltrates can be seen as well. The typical physiologic changes are the development of diffusing impairment and a restrictive ventilatory defect. In the absence of a 15% decline in DLCO from the pretreatment value, significant amiodarone toxicity appears to be unlikely. The diagnosis is made by the careful exclusion of other causes for the observed illness and the finding of clinical, radiographic, physiologic, and pathologic abnormalities compatible with amiodarone toxicity. Although the pathologic findings of amiodarone lung can be distinctive, the histologic demonstration of foam cells and ultrastructural lamellar inclusions alone does not distinguish toxic from nontoxic patients receiving amiodarone. If reasonable alternative antiarrhythmic therapy is available, amiodarone should be withdrawn. If the severity of illness warrants, a trial of corticosteroid therapy is reasonable. Some patients can be maintained on continued therapy despite toxicity, if the drug is deemed to be absolutely essential and clinical deterioration does not continue. The prognosis of patients who develop amiodarone pulmonary toxicity seems to be poor, but may be largely determined by the underlying cardiac disease.

Pulmonary complications of amiodarone toxicity

A MIODARONE HYDROCHLORIDE, a benzofurone derivative, has been used since 1969 for the control of cardiac arrhythmias in the United States. It appears to be uniquely effective for some patients with refractory ventricular arrhythmias. Although serum levels in the range of 1.0 to 2.5 pg/mL have been considered therapeutic,’ amiodarone concentrations in tissues such as fat, skin, and lung may be many times greater. A variety of side effects have been noted following use of this drug, including corneal microdeposits, alteration of thyroid function, dermatitis, pseudocyanotic skin discoloration, hepatic dysfunction, proximal muscle weakness, and peripheral neuropathy. Pulmonary complications were not appreciated until 1980, when the first report of suspected pulmonary toxicity appeared.2 Since then there have been a number of articles describing pulmonary toxicity due to this agent in Europe and the United States. The magnitude of the problem of pulmonary toxicity is difficult to determine. The literature is primarily one of case reports and the criteria used to make the clinical diagnosis of amiodarone pulmonary toxicity are imprecise and inconstant. There is no hallmark of this complication short of pulmonary histology, and lung biopsy has not been performed routinely. Patients receiving amiodarone commonly have a history of clinical conditions, including congestive heart failure, which may be difficult to distinguish from amiodarone lung toxicity. Furthermore, alterations in pulmonary function may occur in some amiodarone treated patients without other clinical manifestations of pulmonary toxicity. All of these factors make it difficult to estimate the incidence of clinically significant amiodarone pulmonary toxicity. Key features that should be used in defining this entity in future studies include: (1) biopsy evidence of alveolitis, (2) diffuse pulmonary infiltrates or infiltrates involving the upper lung zones, (?) dyspnea and cough, (4) exclusion of other conditions likely to produce the clinical picture including congestive heart failure, infection, and collagen vascular disease, and (5) improvement after stopping or decreasing the dose of amiodarone. With these provisos in mind, the best estimate of the incidence of clinically significant amiodarone pulmonary toxicity in the United States is 5% to 15%.3-‘2 It should be noted, however, that autopsy studies suggest this condition may be underdiagnosed.

Gallium scintigraphy in the detection of amiodarone lung toxicity.

Fourteen gallium scans were obtained in 11 patients suspected of having amiodarone lung toxicity on the basis of clinical findings, pulmonary function tests, and chest radiographs. All 11 patients had abnormal scans. Gallium accumulates in various inflammatory and neoplastic lesions, but despite this nonspecificity, the findings suggest gallium scintigraphy is a useful procedure to detect amiodarone lung toxicity when used in the appropriate clinical setting.