Amiodarone induced acute interstitial pneumonitis

Abstract

Amiodarone has several potentially fatal toxicities, the most important of which is amiodarone pulmonary toxicity (APT). We report a rare case where a patient developed acute interstitial pneumonitis 2 days after starting amiodarone. This report reveals the potential for rapid onset of APT and will help to increase awareness among health care professionals who very often underestimate the incidence of the toxic effects of amiodarone. A simple, cost effective screening tool to detect APT in its early stage is recommended.

BACKGROUND

Amiodarone has several potentially fatal toxicities,¹ the most important of which is pulmonary toxicity that has resulted in clinically manifest disease at rates as high as 10–17% and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Amiodarone pulmonary toxicity (APT) is usually recognised after 2–3 months of treatment, especially in patients taking dosages higher than 400 mg/day.² Presentation may vary from a mild, subacute illness to rapidly progressive and fatal adult respiratory distress syndrome (ARDS).³ No well defined clinical predictors of amiodarone pulmonary toxicity have been reported.

We report a rare case where a patient developed acute interstitial pneumonitis 2 days after starting amiodarone 200 mg/day for the treatment of atrial fibrillation. Failure to diagnose this condition early could have caused significant morbidity.

This case report reveals the potential for rapid onset of APT and will increase the awareness among health care professionals who very often underestimate the incidence of the toxic effects of amiodarone. We recommend a simple, cost effective screening tool to detect APT in its early stage.

CASE PRESENTATION

An 80-year-old Caucasian man with a history of insulin controlled diabetes and diet controlled hypertension had a fall and was brought to the emergency room. An asymptomatic small laceration in his liver was detected on abdominal computed tomography (CT), which was treated conservatively in the intensive care unit (ICU) by monitoring his vital signs, which were quite stable. During the 2 day course of treatment in the ICU, he developed atrial fibrillation. His chest x ray was normal (fig 1). He has not had prior cardiac or lung disease. After 2 days in hospital he was discharged home on amiodarone and was not on warfarin because of his liver laceration. Two days later, the patient presented with sudden onset of mild difficulty in breathing, cough and vague diffuse chest pain which was non-specific in character. He has no drug allergies and denies tobacco, alcohol and illicit drug abuse. He is retired and lives with his family. There was no significant family history. On examination his blood pressure was 126/49 mm Hg, respiratory rate 24 per min, afebrile, pulse 84 per min and irregular in rhythm, soft grade 2 ejection systolic murmur over the aortic area with radiation to carotids, clear chest, soft abdomen with active bowel sounds. All cranial nerves were intact and no focal neurological deficit noted. His extremities were warm and distal vasculature intact.

Figure 1.

Normal chest x ray.

INVESTIGATIONS

His laboratory results, which include complete blood count, basic metabolic profile, troponin and B-type natriuretic peptide, were unremarkable except for mild leucocytosis. No growth was found on blood and sputum cultures. Electrocardiogram showed atrial fibrillation with right bundle branch block. Chest radiograph (fig 2) and chest CT scan demonstrated bilateral diffuse pulmonary infiltrate suggestive of either pulmonary oedema or pneumonia or acute interstitial pneumonitis. Cardiac cause of pulmonary oedema was ruled out. Acute interstitial pneumonitis was the primary differential diagnosis and lesser consideration was given to pneumonia and non-cardiogenic pulmonary oedema. A pulmonary consultation was obtained and bronchoscopy was planned to rule out other possible causes of this sudden onset of bilateral pulmonary infiltrates. Bronchoalveolar lavage (BAL) findings included foam cells and neutrophilic alveolitis. Lung biopsy revealed extensive interstitial fibroblast proliferation within an oedematous appearing stroma; alveolar septa were dramatically thickened and lined by hyperplastic type II pneumocytes that were often cytologically atypical, suggestive of diffuse alveolar damage.

Figure 2.

Bilateral diffuse pulmonary infiltrate suggestive of acute interstitial pneumonitis.

TREATMENT

The patient was intubated, amiodarone was stopped, and intravenous methylprednisolone was started followed by a tapering dose of oral prednisolone.

OUTCOME AND FOLLOW-UP

After 6 days of treatment, bilateral interstitial infiltrates on chest x ray was resolving, and the patient was able to maintain oxygen saturation without any oxygen therapy following extubation.

DISCUSSION

Two mechanisms for APT have been proposed.⁴ The first is a direct toxic reaction in which cell injury results from release of toxic oxygen free radicals and/or due to accumulation of cellular phospholipids secondary to inhibition of lysosomal phospholipases by the drug. Phospholipidosis (foamy cells, foamy macrophages) should be used as markers of treatment but not as evidence of toxicity. The second is an indirect immunologic reaction suggested by CD8 T cell lymphocytosis and positive IgG immunofluorescence in the lung. Onset of APT may be rapid, occurring within weeks, or more commonly insidious occurring after several months of therapy. Risk factors for APT include a daily dose >400 mg/day, duration of treatment exceeding 2 months, old age, pre-existing lung disease, thoracic or non-thoracic surgery, and pulmonary angiography. In our patient, old age is a risk factor for development of APT. Symptoms and signs of APT include fever, non-productive cough, pleuritic chest pain, dyspnoea, diffuse rales, and a pleural rub. These findings mimic an infectious pneumonitis.⁵ In patients receiving amiodarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest x ray, and pulmonary function tests (with diffusion capacity) should be considered. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. If a diagnosis of amiodarone induced interstitial/alveolar pneumonitis is made, amiodarone is discontinued.

If amiodarone cannot be withdrawn in those rare and exceptional circumstances where it is the only or optimal therapy available for a patient, lowering the dosage and administering concurrent low dose steroids may be effective. Although specific steroid regimens often are not reported, prednisone 40–60 mg per day with tapering over 2–6 months can be used for severe cases and for those with less severe disease in whom withdrawal of amiodarone is not desirable. Supportive therapy to manage respiratory distress should be started if necessary. The prognosis for patients with APT is generally good, as pulmonary toxicity is often reversible.⁶ Fatalities secondary to pulmonary toxicity have occurred in approximately 10% of cases. However, in patients with life threatening arrhythmias, discontinuation of amiodarone due to suspected drug induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death due to arrhythmia. Therefore, every effort should be made to rule out other causes of respiratory impairment (that is, congestive heart failure with Swan–Ganz catheterisation if necessary, respiratory infection, pulmonary embolism, malignancy, etc) before discontinuing amiodarone in these patients.

LEARNING POINTS

• This case report increases the awareness of amiodarone pulmonary toxicity (APT).

• It also recommends judicious use of amiodarone, when other effective alternative treatment strategies are not available, or when other effective antiarrhythmics could not be tolerated or have not responded, because of its life threatening side effects and the substantial management difficulties associated with its use.

• A simple and important screening method for APT involves patient self reporting of pulmonary symptoms such as non-productive cough, dyspnoea, and pleuritic chest pain. Patients should be educated and instructed to report development of such symptoms promptly, as this is often the earliest indication of APT.

• In addition, baseline chest radiography and pulmonary function testing with diffusion capacity, and repeat chest films every 3 months, are suggested for monitoring. However, if APT presents rapidly as in our patient, the value of serial chest radiograph monitoring is questionable.