Amiodarone, a class III antiarrhythmic agent widely used for the management of supraventricular and ventricular arrhythmias, is known for its broad-spectrum efficacy and distinctive pharmacokinetics. However, its long-term use is often limited by multiple systemic toxicities, among which pulmonary toxicity is one of the most severe and potentially fatal complications [1]. Amiodarone-induced pulmonary toxicity (AIPT) encompasses a spectrum of clinical manifestations ranging from acute pneumonitis to chronic interstitial fibrosis, with pulmonary fibrosis being the most concerning due to its irreversible and progressive nature. The pathogenesis of AIPT is multifactorial, involving direct cytotoxic effects, immunologic hypersensitivity reactions, and accumulation of phospholipids within alveolar macrophages due to the drug’s high iodine and lipid solubility [2]. These pathological mechanisms result in varied radiological and histopathological patterns of lung injury, including organizing pneumonia, nonspecific interstitial pneumonia (NSIP), diffuse alveolar damage, and classical features of usual interstitial pneumonia (UIP) [3]. Early identification of these patterns is critical for minimizing morbidity, especially since discontinuation of amiodarone and initiation of corticosteroids may reverse or at least stabilize pulmonary injury in some patients [4].

Amiodarone remains a cornerstone in the management of atrial and ventricular arrhythmias due to its efficacy in rhythm control and its relatively low proarrhythmic potential compared to other antiarrhythmics [5]. It is particularly favored in patients with left ventricular dysfunction or structural heart disease, where alternative therapies may be contraindicated or less effective. However, its use is frequently curtailed by the risk of systemic toxicity, which affects multiple organ systems including the thyroid, liver, eyes, skin, and most critically, the lungs [6]. Pulmonary toxicity due to amiodarone is one of the most dreaded complications, with reported incidence rates ranging from 1% to 17%, depending on the dosage, duration, and the presence of pre-existing lung disease [7]. The risk increases significantly in patients receiving high cumulative doses (>400 mg/day), elderly individuals, and those undergoing thoracic surgery or oxygen therapy [8]. The pulmonary manifestations are protean and may range from subclinical alveolitis to life-threatening acute respiratory distress syndrome (ARDS). Pulmonary fibrosis, often a chronic and irreversible sequela, represents one of the final common pathways of unresolved inflammation and tissue injury associated with long-term amiodarone exposure [9]. The underlying mechanism of fibrosis in amiodarone-induced lung injury involves a complex interplay of direct toxicity and immune-mediated responses. Amiodarone accumulates in high concentrations in pulmonary tissue due to its lipophilicity and long half-life (up to 100 days), leading to phospholipidosis in type II pneumocytes and alveolar macrophages. This is compounded by oxidative stress, mitochondrial injury, and subsequent fibroblast activation, which together drive collagen deposition and fibrotic remodelling [10]. Clinically, this manifests with insidious dyspnea, dry cough, and exercise intolerance symptoms that may be overlooked or attributed to cardiac disease unless specifically investigated. Radiologically, patients may exhibit a wide range of interstitial abnormalities, including ground-glass opacities, reticular patterns, and honeycombing. High-resolution computed tomography (HRCT) is often the modality of choice for detecting early fibrotic changes and helps in differentiating amiodarone-induced patterns from other interstitial lung diseases (ILDs) [11].

Objective

To assess the clinicopathological patterns of pulmonary fibrosis in patients receiving long-term amiodarone therapy.

A retrospective observational study was conducted on 89 patients who had received amiodarone for more than six months and presented with respiratory symptoms suggestive of pulmonary toxicity. A total of 89 patients were included in the study.

Inclusion Criteria

Patients were eligible if they were 40 years of age or older, had been on amiodarone therapy for more than 6 months, had high-resolution CT scans of the chest available, and had histopathological data from lung biopsy or autopsy. Presence of respiratory symptoms such as chronic cough or progressive dyspnea was also required for inclusion.

Exclusion Criteria

Patients were excluded if they had any pre-existing interstitial lung disease prior to starting amiodarone, a history of autoimmune disease or occupational exposure to fibrogenic dusts, incomplete medical or radiological records, or any active lung infection that could mimic fibrosis on imaging.

Data Collection Procedure

Patient demographics, duration, and dosage of amiodarone use, associated comorbidities, and clinical symptoms were retrieved from hospital records. Radiological findings were assessed by two radiologists blinded to the clinical data, and patterns such as ground-glass opacities, reticulations, honeycombing, and zonal distribution were noted. Histopathological evaluation of lung tissue was performed by two pathologists independently, classifying fibrosis into patterns such as usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage.

Data Analysis

Data were analyzed using SPSS version 11. Quantitative variables such as age and treatment duration were presented as mean and standard deviation. Categorical variables, including fibrosis patterns, imaging features, and presence of symptoms, were reported as frequencies and percentages. A p-value less than 0.05 was considered statistically significant.

The study included 89 patients with a mean age of 67.4 ± 8.9 years, and the majority were male (65.2%). A significant portion had a history of smoking (43.8%) and pre-existing cardiac disease (80.9%). The average duration of amiodarone use was 14.2 ± 5.6 months, with a mean daily dose of 305.6 ± 50.7 mg. Common comorbidities included hypertension (53.9%) and diabetes mellitus (40.4%). The baseline oxygen saturation (SpO₂) averaged 95.3 ± 1.8%.

Table 1: Demographic and Baseline Characteristics of Patients (n = 89)

The radiological evaluation of patients treated with amiodarone revealed that the most common pulmonary fibrosis pattern was Usual Interstitial Pneumonia (UIP), identified in 33 patients (37.1%). This was followed by Nonspecific Interstitial Pneumonia (NSIP) in 28 patients (31.5%) and Organizing Pneumonia (OP) in 14 patients (15.7%). Less common findings included Diffuse Alveolar Damage (DAD) in 7 patients (7.9%), Desquamative Interstitial Pneumonia (DIP) in 4 patients (4.5%), and Constrictive Bronchiolitis (CB) in 3 patients (3.3%).

Table 2: Radiological Patterns of Pulmonary Fibrosis in Patients Treated with Amiodarone (n = 89)

The most commonly reported clinical symptom among patients with amiodarone-induced pulmonary fibrosis was dyspnea, observed in 68 patients (76.4%). This was followed by a nonproductive cough in 54 patients (60.7%) and fatigue in 41 patients (46.1%). Chest discomfort was reported in 29 patients (32.6%), while less frequent symptoms included fever in 17 patients (19.1%) and weight loss in 10 patients (11.2%).

Table 3: Common Clinical Symptoms in Amiodarone-Induced Pulmonary Fibrosis (n = 89)

Pulmonary function testing (PFT) revealed that the most prevalent abnormality among patients was a restrictive ventilatory pattern, found in 51 individuals (57.3%). Additionally, 42 patients (47.2%) demonstrated a reduced diffusing capacity for carbon monoxide (DLCO), indicating impaired gas exchange. A smaller proportion of patients exhibited a mixed obstructive/restrictive pattern (15.7%), while 23 patients (25.8%) had normal PFT results.

Table 4: Pulmonary Function Test Abnormalities (n = 89)

This study evaluated pulmonary fibrosis patterns in patients undergoing long-term amiodarone therapy and identified the most prevalent clinical, radiological, and histopathological changes associated with its use. Amiodarone-induced pulmonary toxicity (APT) remains one of the most serious adverse effects of this antiarrhythmic agent, particularly due to its high lipophilicity and prolonged half-life, which allow accumulation in pulmonary tissues. The demographic distribution of our study revealed a predominance of elderly males, consistent with previous reports suggesting increased susceptibility in older age groups due to reduced pulmonary reserve and polypharmacy [12]. Most patients had a background of cardiovascular disease, reflecting the typical patient population receiving amiodarone therapy. Smoking history was present in a significant proportion of patients, which may have acted as an independent risk factor for fibrotic changes or as a compounding contributor [13].

Radiologically, high-resolution CT scans revealed that the most common patterns included diffuse interstitial infiltrates and ground-glass opacities, followed by reticular changes and honeycombing. These findings align with prior studies indicating that amiodarone-induced pulmonary fibrosis can mimic idiopathic interstitial pneumonias, especially nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) patterns [14]. Notably, a subset of patients in our cohort exhibited features of organizing pneumonia (OP), which further underscores the heterogeneity of APT manifestations. Histologically, the biopsy findings were also variable but commonly featured intra-alveolar foamy macrophages, fibrosis, and chronic inflammatory infiltrates [25]. These findings support the postulated pathophysiological mechanism of direct cytotoxicity, phospholipid accumulation, and immune-mediated injury. The presence of eosinophils and lymphocytes in several cases suggested a hypersensitivity-type reaction, which has been described in other APT case series [16]. Our study also highlighted the importance of the cumulative dose and duration of amiodarone use. Although pulmonary toxicity has been reported at doses as low as 200 mg/day, most patients with fibrosis had been on higher daily doses (>300 mg) for over a year [17]. These findings emphasize the need for regular monitoring and re-evaluation of the risk-benefit ratio in patients maintained on long-term therapy. One of the striking observations was the decline in baseline oxygen saturation and spirometric parameters (e.g., reduced FVC and DLCO) in patients with radiological fibrosis, suggesting functional impairment associated with structural changes. Timely identification of APT and prompt withdrawal of the drug can reverse or stabilize pulmonary function in some cases, but fibrosis, once established, is often irreversible.a

It is concluded that long-term use of amiodarone is significantly associated with the development of diverse pulmonary fibrosis patterns, with diffuse interstitial infiltrates and ground-glass opacities being the most prevalent radiological findings. Histopathological evaluation frequently reveals chronic inflammatory changes, fibrosis, and intra-alveolar foamy macrophages, which align with known mechanisms of amiodarone-induced pulmonary toxicity. The study emphasizes the importance of early recognition, regular respiratory monitoring, and timely discontinuation of the drug to prevent irreversible pulmonary damage.

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