Amiodarone-Induced Pulmonary Toxicity With Severe Pulmonary Fibrosis Complicated by Stenotrophomonas maltophilia Pneumonia: A Fatal Case Report and Literature Review

Abstract

Amiodarone is a widely used antiarrhythmic agent, valued for its efficacy and low proarrhythmic risk, but it carries a known potential for serious toxicities, particularly pulmonary toxicity. Amiodarone-induced pulmonary toxicity (APT) remains a life-threatening adverse effect. We report the case of a 75-year-old male with a 30-year history of amiodarone use (200 mg twice daily) who developed progressive respiratory distress consistent with APT. Despite treatment with broad-spectrum antibiotics and corticosteroids, his condition deteriorated. Imaging and clinical findings raised suspicion for APT, which was managed with amiodarone discontinuation and pulse-dose steroid therapy. Subsequently, he developed hospital-acquired Stenotrophomonas maltophilia pneumonia, a multidrug-resistant opportunistic infection. Targeted antibiotics were initiated based on sensitivities, but the patient progressed to respiratory failure and multiorgan dysfunction, ultimately resulting in death. This case highlights the diagnostic and therapeutic challenges of managing APT, particularly in elderly patients on long-term therapy. The absence of standardized pulmonary surveillance and delayed recognition can result in advanced disease at presentation. Superimposed nosocomial infections, especially with resistant organisms such as S. maltophilia, further complicate outcomes. Clinicians must maintain a high index of suspicion for APT in patients presenting with unexplained respiratory symptoms while on amiodarone. This case underscores the importance of appropriate dosing, consistent outpatient monitoring, and prompt evaluation for opportunistic infections in the setting of clinical deterioration.

Introduction

Amiodarone is a commonly prescribed antiarrhythmic medication, highly effective for a range of tachyarrhythmias. Despite adverse effects such as thyroid dysfunction, pulmonary toxicity, hepatic toxicity, corneal deposits, optic neuritis, and peripheral neuropathy, its broad antiarrhythmic efficacy, reduction in arrhythmic mortality, and relatively low proarrhythmic risk have contributed to its widespread use [1-5]. Among these adverse effects, amiodarone-induced pulmonary toxicity (APT) is the most serious and lacks a definitive cure [6,7].

Mechanistic studies have demonstrated that APT involves phospholipid accumulation within type II pneumocytes and macrophages, producing injury patterns that range from organizing pneumonia to chronic interstitial fibrosis. The NLRP3 inflammasome pathway has emerged as a central driver of fibrotic signaling via IL-1β and IL-18 cytokine release [8,9]. Experimental evidence also indicates that amiodarone induces significant oxidative stress and mitochondrial injury in lung tissue [10]. Clinically, APT presents with a spectrum of manifestations, from chronic interstitial pneumonitis to acute respiratory distress syndrome (ARDS). Contemporary reports describe severe acute presentations mimicking ARDS, underscoring the critical importance of rapid recognition and immediate drug cessation, as some cases demonstrate dramatic improvement with corticosteroid therapy following amiodarone discontinuation [11,12]. Therefore, a high degree of clinical suspicion is essential, supported by characteristic radiographic findings and the exclusion of other pulmonary diseases [13].

Diagnosing APT can be particularly challenging in hospitalized or critically ill patients, where it may mimic or obscure conditions such as lung infections or preexisting pulmonary disease. Hospital-acquired infections caused by multidrug-resistant organisms are a major concern in intensive care units, given their increasing prevalence and therapeutic challenges [14]. Stenotrophomonas maltophilia has emerged as a notable nosocomial respiratory pathogen in critically ill patients, with prolonged hospitalization, mechanical ventilation, corticosteroid use, and invasive airway procedures identified as key risk factors for lower respiratory tract infections in vulnerable populations [15].

We report the case of a 75-year-old male on chronic amiodarone therapy who developed severe pulmonary toxicity, subsequently complicated by hospital-acquired S. maltophilia pneumonia. This case highlights the challenges of managing concurrent drug-induced lung injury and opportunistic infection, emphasizing the importance of vigilant outpatient monitoring in patients receiving amiodarone. Furthermore, in severe cases of APT, even pulse-dose steroid therapy may fail to achieve improvement, underscoring the need for future controlled trials to establish standardized treatment guidelines.

Case presentation

A 75-year-old male with a past medical history of hypertension, coronary artery disease, atrial fibrillation, hyperthyroidism, and diabetes mellitus presented with shortness of breath and a nonproductive cough, ongoing for several months and worsening over the past week. He denied fever, weight loss, appetite loss, or peripheral edema. The patient had a history of chronic amiodarone use (200 mg twice daily for 30 years). He previously worked in copper mines but reported no known exposure to asbestos, silica dust, or household pets.

The patient was initially admitted to an outside hospital, where he received a one-week course of meropenem, linezolid, and methylprednisolone for pneumonia and a suspected COPD exacerbation. He was subsequently transferred to our facility for evaluation of nonresolving pneumonia.

Upon arrival, the patient was in respiratory distress, requiring high-flow nasal cannula (HFNC) at 40 L/min with FiO₂ 90%, but remained hemodynamically stable. Initial laboratory evaluation revealed leukocytosis, elevated erythrocyte sedimentation rate and CRP, and normal procalcitonin (Table 1). Chest X-ray (CXR) demonstrated a mixed reticular and consolidative pattern throughout both lungs (Figure 1). High-resolution CT revealed diffuse bilateral consolidation and interstitial thickening, scattered ground-glass opacities, and honeycombing (Figure 2). CT angiography of the chest, performed at the outside hospital, ruled out pulmonary embolism. Transthoracic echocardiography demonstrated preserved left ventricular systolic function. The right ventricle was dilated with reduced systolic function, and the tricuspid annular plane systolic excursion measured 1.3 cm (Figure 3).

Table 1. Laboratory findings on admission and during ICU stay.

Ab, antibody; Ag, antigen; BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate; HCO₃, bicarbonate; Hgb, hemoglobin; T4 free, free thyroxine; TSH, thyroid-stimulating hormone

Laboratory test	Reference range	Day 1 (admission)	Day 6	Day 7 (intubated)	Day 11	Day 16 (deceased)
WBC (10³/mm³)	4.5-11	17	24.9	31.9	25.3	21.6
Hgb (g/dL)	12-16	9.7	10.4	9.7	8.2	8.1
HCO₃ (mmol/L)	21-31	35	26	29	26	28
BUN (mg/dL)	6-25	47	35	61	120	93
Creatinine (mg/dL)	0.3-1.3	1.3	0.7	1.8	3.5	2.1
CRP (mg/dL)	0.1-1.0	7.5	6.27	-	10.27	9.45
ESR (mm/hr)	0-9	26	19	33	77	24
Procalcitonin (ng/mL)	≤0.50	0.08	11.97	8.65	1.72	-
T4 free (ng/dL)	0.6-2.0	2.69	1.86	-	1.68	-
TSH (µIU/mL)	0.4-5.0	<0.010	<0.010	-	<0.010	-
Thyroid peroxidase Ab (IU/mL)	0-34	>600	-	-	-	-
Thyroglobulin Ab (IU/mL)	0-0.9	2162.7	-	-	-	-

Figure 1. PA view CXR on admission.

CXR on admission demonstrating a mixed reticular and consolidative pattern throughout both lungs (black arrow), more pronounced in the right hemithorax.

CXR, chest X-ray

Figure 2. High-resolution CT of the chest demonstrating advanced fibrotic interstitial lung disease.

(a) Axial section at the mid-lower thorax (atrial level) showing advanced fibrotic changes with diffuse opacities (black arrow) and interstitial thickening, more pronounced on the right. (b) Axial section at the mid-thorax demonstrating similar findings with right-sided predominance. (c) Coronal section at the level of the tracheal bifurcation showing diffuse fibrotic changes, opacities (black arrow), ground-glass opacities, and honeycombing (brown arrow), more prominent on the right. (d) Coronal section anterior to the trachea demonstrating similar advanced fibrotic changes, opacities (black arrow), and honeycombing (brown arrow), predominantly on the right.

Figure 3. Transthoracic echocardiographic views demonstrating RV dilatation and impaired systolic function with preserved LV function.

(a) Apical four-chamber view showing a normal LV chamber with a slightly dilated RV. (b) Parasternal long-axis view demonstrating a normal LVOT (diameter 2.5 cm). (c) Color tissue Doppler echocardiogram showing reduced right ventricular systolic function with a TAPSE of 1.3 cm.

LV, left ventricle; LVOT, left ventricular outflow tract; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion

The patient was evaluated for both infectious and noninfectious causes of unresolved pneumonia. Treatment with meropenem (1 g every eight hours) and linezolid (600 mg every 12 hours) was continued, with the addition of azithromycin (500 mg daily); linezolid was later discontinued after cultures were negative for methicillin-resistant Staphylococcus aureus. Given the high clinical suspicion for APT, amiodarone was discontinued, and pulse-dose corticosteroid therapy was initiated with intravenous methylprednisolone 250 mg every six hours for three days, followed by methylprednisolone 60 mg IV daily with a gradual taper. Atrial fibrillation remained well controlled on the patient’s home dose of carvedilol (6.25 mg twice daily), which was later discontinued due to bradycardia and hypotension. Bronchoscopy could not be performed because of the patient’s high oxygen requirements. Extensive infectious and autoimmune workups were negative (Table 2). Despite ongoing therapy, the patient could not be weaned off HFNC, experiencing intermittent desaturation even with minimal activity.

Table 2. Comprehensive infectious and autoimmune workup in this case of unresolved pneumonia showing negative findings.

ANA, antinuclear antibody; c-ANCA, cytoplasmic anti-neutrophil cytoplasmic antibody; CMV, cytomegalovirus; MPO, myeloperoxidase; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibody

Test	Result	Reference range
Influenza and SARS-CoV-2 screen	Negative	Negative
Serum Fungitel beta-D-glucan	<31.25	0.00-60.00
Serum cryptococcal antibody	Negative	<1:20 titer
Serum histoplasma antibody	Negative	<1:1 titer
CMV IgM	Negative	0.00-0.60
CMV IgG	Negative	0.00-30.00
Urine Streptococcus pneumoniae antigen	Negative	Negative
Urine Legionella antigen	Negative	Negative
Blastomyces antibody	Negative	<1:1 titer
Respiratory pathogen panel	Negative	Negative
Serum Coccidioides IgM	0.1	<1.0
Serum Coccidioides IgG	0.4	<1.0
Serum Aspergillus antigen	0.05	0.00-0.49
HIV screen	Negative	Negative
ANA screen	Negative	Negative
p-ANCA	Negative	<1:20 titer
c-ANCA	Negative	<1:20 titer
MPO antibody	<0.2	0.0-0.9
Intrinsic factor blocking antibody	1	0.0-1.1

The patient had long-standing hyperthyroidism managed with methimazole (10 mg daily). Thyroid ultrasound demonstrated an enlarged, heterogeneous gland (Figure 4). Thyroid peroxidase and thyroglobulin antibodies were elevated (Table 1), suggesting type I amiodarone-induced thyrotoxicosis. This condition may have significantly worsened respiratory function and overall prognosis, particularly in critically ill or high-risk patients, as observed in our case.

Figure 4. Thyroid ultrasound showing heterogeneous echotexture (white arrows) throughout the right thyroid lobe parenchyma.

The thyroid is enlarged, with generalized parenchymal heterogeneity, suggestive of diffuse thyroid disease. The right thyroid lobe measures 6.9 × 3.7 cm (yellow dotted lines).

On hospital day 7, the patient’s pulmonary condition worsened, culminating in a hypoxia-driven cardiac arrest. He was intubated and started on vasopressor support. Subsequently, he developed atrial fibrillation with rapid ventricular response, which was managed with intravenous metoprolol pushes (5 mg as needed), achieving adequate rate control. Follow-up CXR demonstrated worsening bilateral infiltrates (Figure 5). Procalcitonin levels were rising, raising suspicion of opportunistic bacterial infection (Table 1). Respiratory cultures grew S. maltophilia, which was not covered by the current antibiotic regimen. Therapy was transitioned to levofloxacin (IV 750 mg every 48 hours, renally dosed), minocycline (oral 100 mg twice daily), and ceftazidime (IV 1000 mg daily), to which the isolate was subsequently confirmed to be susceptible. The antimicrobial susceptibility profile of S. maltophilia isolated from respiratory culture is shown in Table 3. First-line therapy with trimethoprim-sulfamethoxazole was deferred due to concerns of renal toxicity.

Table 3. Antimicrobial susceptibility profile of Stenotrophomonas maltophilia isolated from respiratory culture.

The table demonstrates that S. maltophilia is susceptible to ceftazidime, levofloxacin, and trimethoprim/sulfamethoxazole.

MIC, minimum inhibitory concentration; S, susceptible

Drug	MIC (µg/mL)	Interpretation
Ceftazidime	≤1	S
Levofloxacin	1	S
Trimethoprim/sulfamethoxazole	≤0.5/9.5	S

Figure 5. CXR showing progressive worsening of airspace opacities from admission to day 7 (post-intubation).

(a) CXR on admission demonstrating a mixed reticular and consolidative pattern throughout both lungs (black arrow), more pronounced in the right hemithorax. (b) Repeat CXR on day 7, after intubation, showing diffusely worsened bilateral pulmonary infiltrates, with significant progression of airspace disease in the left upper lobe (white arrow).

CXR, chest X-ray

Despite aggressive interventions, the patient remained in respiratory failure on mechanical ventilation with multiorgan dysfunction. Extracorporeal membrane oxygenation was not available at our institution. On hospital day 15, following a comprehensive goals-of-care discussion with the family, care was transitioned to comfort-focused measures, and the patient ultimately passed away. The family acknowledged that the outcome was inevitable despite all aggressive medical interventions.

Discussion

Low-dose amiodarone is considered effective for maintaining sinus rhythm but is not used as a first-line agent due to its adverse effects and drug interactions. In patients with heart failure with reduced ejection fraction, amiodarone is preferred, as most other first-line agents, such as flecainide, propafenone, and dronedarone, are contraindicated [1,16]. According to the 2023 AHA/ACC guidelines, APT occurs in 1-2% of patients and is fatal in approximately 10% of cases [1]. A retrospective study reported an incidence of 1.9%, while a large meta-analysis reported 2.9% [17,18]. Although a baseline chest radiograph is recommended prior to initiating amiodarone, no specific surveillance interval for pulmonary toxicity monitoring has been established. Nevertheless, a chest radiograph or CT scan should be obtained if patients develop new or unexplained cough or dyspnea during therapy [1,19]. Pharmacovigilance data from nearly 5,000 reported pulmonary adverse events demonstrate a broad time-to-onset distribution, with median onset ranging from 126 to 227 days, supporting the need for long-term clinical surveillance even after drug cessation due to amiodarone’s prolonged tissue half-life [20].

In our case, initial broad-spectrum antibiotic therapy failed to yield clinical improvement, highlighting the diagnostic and therapeutic challenges of APT. Symptoms are often insidious, and imaging findings overlap with other pulmonary conditions, causing APT to mimic both infectious and noninfectious processes, which can delay diagnosis and management [21]. The pathophysiology of APT involves phospholipid accumulation in type II pneumocytes and macrophages, leading to cellular dysfunction and diverse histologic patterns, including diffuse alveolar damage, interstitial pneumonitis, and organizing pneumonia [8]. Experimental evidence also implicates oxidative stress as a key mediator; animal studies have demonstrated increased lipid peroxidation and decreased antioxidant enzyme activity following amiodarone exposure, with antioxidant interventions showing protective effects against drug-induced alveolar damage [10,22]. Although rare, this adverse reaction can be devastating, as seen in our patient.

Risk factors for APT include cumulative dose, advanced age, and prolonged therapy duration, all present in our case [17,23]. A daily dose of 200 mg is typically adequate for most patients but may require individualized adjustment [24]. The absence of a well-defined safety margin and poor correlation between serum levels and toxicity contribute to delayed recognition of pulmonary toxicity. Diagnosis is usually based on clinical suspicion, imaging features, and exclusion of other pulmonary causes. Histological confirmation through biopsy can be obtained, but it is often high-risk in hypoxic patients, as was the case here. Bronchoscopy with bronchoalveolar lavage is commonly performed to exclude infection and may reveal foamy macrophages, although these findings are supportive rather than diagnostic of APT [11,25,26]. Pulmonary function tests typically show a restrictive pattern with reduced diffusion capacity [13,24,27].

Following diagnosis, management of APT involves amiodarone discontinuation and corticosteroids (initial dosing of 0.75-1.0 mg/kg/day of oral prednisolone) tapered over several weeks to months [1,21,28]. Although controlled trial data are lacking, case reports consistently document clinical and radiographic improvement with high-dose corticosteroid therapy [11,29-31]. In some instances of rapidly progressive disease, pulse-dose therapy with methylprednisolone (1,000 mg/day) has been reported to be effective [12,32-34].

Despite appropriate discontinuation of amiodarone and corticosteroid therapy, our patient acutely decompensated due to superimposed multidrug-resistant S. maltophilia. S. maltophilia is an emerging nosocomial pathogen with increasing prevalence and antimicrobial resistance. Although often considered less virulent than other hospital-acquired bacteria, it can be devastating in high-risk patients, particularly those with underlying pulmonary disease, prolonged hospitalization, mechanical ventilation, or prior broad-spectrum antibiotic use, all of which were present in our patient [35-37]. Recent retrospective studies report mortality rates of 13.7% among all hospitalized patients and up to 49.7% in critically ill ICU patients [38,39]. In immunocompromised individuals, especially those with hematologic malignancies, S. maltophilia can cause fulminant hemorrhagic pneumonia with rapid progression and exceptionally high case-fatality rates [40].

In our case, initial antibiotic therapy broadly covered most pathogens but did not target S. maltophilia, an organism intrinsically resistant to many antibiotics due to mechanisms such as beta-lactamase production and efflux pumps [35]. The 2024 Clinical and Laboratory Standards Institute (34th edition) reports established breakpoints for six agents against S. maltophilia: cefiderocol, chloramphenicol, levofloxacin, minocycline, ticarcillin-clavulanate, and trimethoprim-sulfamethoxazole [35]. Recent multicenter studies suggest that while monotherapy with trimethoprim-sulfamethoxazole remains effective in many cases, combination therapy may provide a survival benefit in immunocompromised patients and those with high illness severity scores [41]. Although APT and S. maltophilia infection are distinct processes, underlying lung injury from APT and high-dose steroid therapy may predispose to opportunistic infection.

Conclusions

This fatal case underscores the critical importance of ensuring appropriate amiodarone dosing, with ongoing efforts to identify the lowest effective maintenance dose. Structured follow-up is essential for early detection of APT. Although amiodarone remains widely used, standardized monitoring and surveillance protocols are imperative. Corticosteroids are frequently employed, and case reports suggest benefit, but the absence of randomized controlled trials limits the development of standardized treatment protocols. In severe APT, even pulse-dose steroids may fail to achieve improvement, highlighting the urgent need for well-designed trials to guide evidence-based management. Additionally, this case emphasizes the importance of considering superimposed infections in patients with suspected APT who deteriorate despite appropriate initial management. Early recognition and targeted antimicrobial therapy, based on local resistance patterns and culture data, are crucial; however, outcomes may still be poor in severe cases.