Autopsy of Drug-induced Lung Injury with Atypical Diffuse Alveolar Disorder due to Amiodarone
Amiodarone is a cardiovascular drug that prevents fatal arrhythmias and severe chronic heart failure. However, it may also cause adverse events, of which lung injury is the most serious ( ). Specifically, the pathological findings of diffuse alveolar damage (DAD) are associated with fatal respiratory failure. We herein report an autopsy case of acute lung injury presumed to have been induced by amiodarone, along with a literature review. 

An 87-year-old man was placed on an implantable cardioverter defibrillator for nonpersistent ventricular tachycardia 12 years previously, and amiodarone 100 mg/day was administered over the previous 5 years. He visited our emergency department presenting with dysarthria and was subsequently diagnosed with hypoglycemia, corrected for blood glucose, and he was therefore hospitalized due to prolonged hypoglycemia. Electrocardiography (ECG) revealed atrial fibrillation with a heart rate of 67 beats/min, findings that were not significantly different from those in the past. The brain natriuretic peptide (BNP) level was 372 pg/mL. There were no respiratory symptoms at admission, but percutaneous oxygen saturation (SpO 2 ) was within 80% (room air). Oxygen was administered at a rate of approximately 2 L/min (via nasal cannula). Chest radiography showed ground-glass opacities in the left upper lung field ( ), chest computed tomography (CT) showed ground-glass opacities in S 3 of the left lung ( ), and a low-grade fever was present. Therefore, pneumonia was suspected and antibacterial treatment with ampicillin-sulbactam was initiated. Hypoglycemia improved on the day after admission, and dysarthria was not observed after the blood glucose level improved. The SpO 2 remained unchanged after admission; however, on the 9th hospital day, the patient's oxygenation deteriorated rapidly. The SpO 2 could not be maintained at 90% despite oxygen administration at 8 L/min (reservoir oxygen mask). The patient was then referred to our department. His medical history included myocardial infarction, non-persistent ventricular tachycardia, hypertension, and diabetes. He was a nonsmoker. The oral medications included aspirin, cilostazol, vildagliptin, glimepiride, atenolol, olmesartan, azelnidipine, and amiodarone. The patient's physical findings were as follows: height, 160 cm; weight, 71 kg; blood pressure, 157/87 mmHg; pulse, 75 beats/min; SpO 2 , 88% (reservoir oxygen mask 10 L/min); and temperature, 36.8°C. Physical examination revealed fine crackles in both lungs. Major laboratory examinations at the time of referral to our department showed the following: white blood cells, 10,900 /μL; hemoglobin, 12.2 g/dL; platelet count, 32.6×10 4 /μL; C-reactive protein, 0.3 mg/dL; Krebs von den Lungen-6, 255 U/mL; pulmonary surfactant protein-D, 281 ng/mL; creatine kinase, 81 IU/L; and BNP, 352 pg/mL. An arterial blood gas analysis revealed poor oxygenation, despite high-flow oxygenation ( ). Chest radiography revealed bilateral lung consolidation ( ). Chest computed tomography (CT) revealed multiple consolidations with air bronchograms in both lungs and increased bilateral pleural effusion. The CT values of the liver and lungs increased to approximately 90 and 80 Hounsfield units, respectively ( ). Bronchoscopy could not be performed due to the patient's poor oxygenation. We differentiated DAD from interstitial pneumonia, severe bacterial infections, and heart failure. Steroid pulse therapy (methylprednisolone 500 mg for three days), meropenem, and diuretics were administered. Drug-induced interstitial pneumonia was suspected. As a result, all oral medications including amiodarone were discontinued. In addition, non-invasive positive-pressure ventilation was initiated to maintain oxygenation. However, oxygenation did not improve, chest radiography findings worsened ( ), and the patient died on the 11th hospital day. No significant bacteria were detected in the blood or sputum cultures. Autopsy revealed significant fibrin precipitation and organization within the alveolar spaces. The distribution was patchy and organizing pneumonia-like findings were predominant, with fibrin precipitation in some areas. Hyaline membrane formation was also observed in some regions. In addition, some lesions contained foamy alveolar macrophages. Although CD8+ lymphocytes were present, the proportions of CD8+ and CD4+ lymphocytes were comparable. There was no evidence of any alveolar hemorrhage ( ). Based on these findings and the disease course, respiratory failure was diagnosed as drug-induced lung injury caused by amiodarone. 

Amiodarone is an antiarrhythmic drug belonging to group III of the Vaughan-Williams classification system and it is used for ventricular tachyarrhythmias and chronic atrial fibrillation. It has a strong antiarrhythmic effect, but on the other hand, it is known to be associated with various extracardiac adverse events such as lung injury, thyroid dysfunction, visual impairment, liver damage, and skin symptoms. Lung injury is the most significant of such events, with a frequency of 1-17%, and the mortality rate of interstitial pneumonia is 9.1-22%, which is considerably high ( ). Lung injury can occur at any time after amiodarone is administered, but it is particularly high when >400 mg/day is administered for >2 months or when a low dose (usually 200 mg/day) is administered for >2 years ( ). Yamada et al. reported that the risk of lung injury increased with the age at which amiodarone treatment was initiated and the amount of amiodarone maintained ( ). In this case, amiodarone was administered at a low dose of 100 mg/day; however, the administration began at of 83 years of age, and the administration period was 5 years, thus suggesting that the risk of lung injury was extremely high. Currently, there are no clear diagnostic criteria for lung injury caused by amiodarone, and ruling out such a diagnosis is the main focus. Differential diagnoses include infectious diseases, collagen diseases, congestive heart failure, and pulmonary infarction ( ). In the present case, there were no serological findings suggestive of collagen disease. An autopsy revealed no significant congestion or pulmonary infarction. Moreover, no significant bacteria were detected in these cultures. It was therefore difficult to determine whether the patient responded to antibacterial treatment during the course of the disease and the possibility of infection was low. Direct lung injury, in which amiodarone inhibits lysosomal phospholipase A and accumulates phospholipids in alveolar macrophages, and an indirect immune response involving CD8 lymphocytes have been suggested as the mechanism of amiodarone-induced lung injury ( ). Direct lung injury is known to be involved in chronic lung injury, whereas an indirect immune response has been reported to be involved in acute lung injury ( ). Imaging findings include diffuse or localized interstitial opacities, alveolar opacities, or a combination of these. The sites of the lesions are asymmetric and bilateral in many cases ( ). In our case, the lung injury was characterized by bilateral asymmetry and consolidation. In addition, amiodarone tends to accumulate in the lysosomes and mitochondria of the hepatocytes. Due to the fact that it contains iodine in its structure, the liver CT value increases after long-term administration ( ). In lung lesions, amiodarone-containing iodine and its metabolites increase the CT value because of their distribution in macrophages and alveolar type II cells. A prolongation of its half-life in the lungs is also related ( ). In addition, interstitial pneumonia accompanied by foamy alveolar macrophages is the most characteristic histopathological finding of amiodarone-induced lung injury ( ). In this case, histopathological imaging revealed interstitial pneumonia with DAD and foamy alveolar macrophages. Drug-induced lung injury due to amiodarone was suspected because of the history of long-term amiodarone use, an increase in the liver and lung CT values, the presence of foamy alveolar macrophages on histopathology, and the exclusion of any other causes. Notably, our patient did not experience dyspnea despite presenting with hypoxemia at the time of admission. The subjective sensation of dyspnea is caused by the sensitivity of the respiratory center of the brain to increases in carbon dioxide levels and decreases in oxygen levels. The respiratory center can become insensitive due to aging or chronic diseases such as diabetes ( ). Our patient was elderly and taking several antidiabetic medications. These factors may have decreased the likelihood of dyspnea, which is a subjective symptom. Our patient also presented with hypoglycemia and dysarthria at admission. After hospitalization, hypoglycemia was considered to have been due to the prolonged effect of antidiabetic drugs, and dysarthria was considered to be a symptom of hypoglycemia. In this case, histopathological imaging revealed DAD; however, fibrin deposition in the alveolar space was conspicuous. Based on its time course, DAD is classified into exudative, organizing, and fibrotic stages ( ). Typical lesions in autopsied lung tissues of patients with DAD are diffuse, and their morphological stages tend to be closely similar. These findings indicate that the injuries occur simultaneously within the lungs and that the lesions change simultaneously over time ( ). In this case, hyaline membrane formation (an exudative stage finding) and organization (a characteristic of the organizing stage) were observed, thus suggesting that the patient transitioned from the exudative stage to the organizing stage. However, fibrin deposition was patchy and it differed from the diffuse changes characteristic of DAD. Beasley et al. reported that acute fibrinous and organizing pneumonia (AFOP) is a histological pattern of acute lung injury with a clinical course similar to that of acute interstitial pneumonia and it is considered to be a subtype of DAD ( ). AFOP is characterized by organized lesions with intense intra-alveolar fibrin depositions. Amiodarone-induced lung injury has also been reported to exhibit the pathological features of AFOP. However, we found only two previously reported cases ( , ), and foamy alveolar macrophages were not observed on histopathological examinations in either case. The present case also showed relatively few foamy alveolar macrophages. This suggests that the recognition of foamy alveolar macrophages may be difficult, and this is a characteristic finding in cases of AFOP pathology due to amiodarone-induced lung injury. Although it is sometimes possible to demonstrate foamy alveolar macrophages in the bronchoalveolar lavage fluid, bronchoscopy could not be performed in this case because of the patient's poor respiratory condition. Fibrin deposition in the alveolar spaces, the main feature of AFOP, can be observed if two conditions are met: namely, a biopsy is performed immediately after symptoms appear, and in severe inflammatory conditions ( ). In this case, the two conditions were met based on the patient's clinical course. Caution is required when fibrin deposition is pathologically observed in the alveolar spaces due to amiodarone-induced lung injury as a rapid deterioration of respiratory failure may occur, similar to that observed in this case. As a limitation of this case, we could not completely exclude heart failure or medications other than amiodarone as the cause of respiratory failure. In conclusion, we herein described an autopsy case of drug-induced lung injury with atypical diffuse alveolar disorder caused by amiodarone. Our case showed that amiodarone-induced lung injury can exhibit pathological features similar to those of AFOP, and that such cases are likely to be exacerbated by acute respiratory injury. 

