Key Teaching Points
•
Because of tissue-specific drug accumulation properties, recognizing the association
between flecainide and drug-induced acute lung injury is important. Early withdrawal
of the offending agent is critical to clinical recovery.
•
Flecainide-associated lung injury remains a diagnosis of exclusion. Infectious processes
and cardiogenic pulmonary edema must be ruled out. A radiographic pattern of bilateral
or unilateral opacities with a ground-glass pattern has been described in previous
cases of pneumonitis as well as in our patient. The diagnosis must be made rapidly
given the potentially severe consequences of misdiagnosis.
•
The proposed mechanism of injury in flecainide drug toxicity is a cell-mediated immunologic
reaction. Corticosteroids are the treatment of choice, and response to them plays
a key role in the diagnostic process.
Introduction
Atrial fibrillation (AF) is the most commonly encountered sustained tachyarrhythmia.
Flecainide is a class IC antiarrhythmic drug used frequently for treatment of supraventricular
tachyarrhythmias.
1
Common cardiac and noncardiac side effects of flecainide are well described and recognized
in clinical practice. Subacute flecainide lung toxicity has been described in a small
number of case reports2, 3, 4 but is not commonly recognized or well understood. Here
we report a case of acute drug-induced pneumonitis after flecainide administration
and discuss key points in the recognition and management of this rare but potentially
serious clinical scenario.
Case report
A 70-year-old woman with a past medical history of rheumatic mitral stenosis, status
post percutaneous transseptal mitral valvotomy in 2012, hypertension, persistent AF,
and amiodarone-induced hepatotoxicity was referred to the electrophysiology clinic
for evaluation and management of symptomatic AF. She was subsequently scheduled for
pulmonary vein isolation (PVI) ablation.
The patient’s presenting rhythm on the day of her procedure was AF. She had stopped
taking amiodarone 6 weeks before ablation. Amiodarone was the only antiarrhythmic
medication the patient had taken in the past. She underwent radiofrequency PVI with
successful acute isolation of all 4 of her pulmonary veins with evidence of exit and
entrance block. She was discharged the next morning on warfarin for anticoagulation
and off any antiarrhythmic medications. The patient presented 2 days after her ablation
procedure with symptomatic AF. She was admitted to the hospital and successfully cardioverted
to sinus rhythm with a single 360-J shock. After cardioversion, she was started on
flecainide 100 mg every 12 hours. Approximately 5 hours later the patient developed
fever of 38.7°C, chills, and dry cough. In addition, her oxygen requirements increased
from 2 L of oxygen via nasal cannula to high-flow nasal cannula. Laboratory findings
showed leukocytosis of 12,000. Blood cultures were collected, and a respiratory pathogen
panel was performed. Portable chest radiograph performed at that time showed increased
interstitial markings (Figure 1) compared to baseline chest radiograph (Figure 1A).
The patient was given a 20-mg intravenous dose of furosemide. Her symptoms of fever,
chills, and cough slowly improved during the rest of the day.
Figure 1
A: Baseline portable chest radiograph on the day of pulmonary vein isolation ablation.
B: Portable chest radiograph a few hours after the onset of symptoms on hospital day 1.
Three hours after receiving her second 100-mg dose of flecainide, fever recurred with
shortness of breath. The patient’s oxygen requirements increased from high-flow nasal
cannula to bilevel positive airway pressure support within a few hours. Laboratory
findings showed increased leukocytosis to 16,000. With worsening clinical picture,
computed tomographic scan of the chest was performed and showed diffuse ground-glass
opacities bilaterally, predominantly in the upper lobes (Figure 2). In addition, the
lower lobes showed multifocal areas of consolidation in a perilobular distribution.
The airways within these changes seemed to demonstrate at least mild traction bronchiectasis
and bronchiolectasis. The findings of computed tomographic scan were interpreted as
compatible with changes of acute lung injury, that is, a combination of changes of
likely scattered noncardiogenic edema and organizing pneumonia pattern. The patient
remained on bilevel positive airway pressure support. Bedside echocardiography showed
left ventricular ejection fraction of 65%–70% and no evidence of mitral valve stenosis.
The inferior vena cava was noted to be small and looked collapsed, suggestive of low
central venous pressures. Serum brain natriuretic peptide levels were only mildly
elevated at 186 pg/mL (normal 0–100 pg/mL). Flecainide was immediately discontinued.
Consultation with the pulmonology service indicated a diagnosis of acute hypoxemic
respiratory failure due to evolving diffuse airspace filling process. At the time,
the differential diagnosis of the patient’s presentation was believed to be hospital-acquired
pneumonia, postcardioversion pulmonary edema, cardiogenic pulmonary edema, flecainide
pneumonitis, or delayed amiodarone toxicity.
Figure 2
Computed tomographic scan of the chest on hospital day 2.
Given the patient’s rapid clinical deterioration and suspicion of drug-induced pneumonitis,
the decision was made to start the patient on empiric intravenous methylprednisolone
therapy (1 mg/kg/day). Infectious workup (influenza A, legionella, sputum culture,
gram stain) was negative, and empiric intravenous antibiotics were stopped within
24 hours. The patient remained afebrile after cessation of flecainide, and her respiratory
status and oxygen requirement improved over the next 4 days. She was transitioned
from IV methylprednisolone to oral prednisone 72 hours after initiation of steroids.
While in the hospital, she underwent another direct current cardioversion for symptomatic
AF without complication.
The patient was discharged on hospital day 6 with home oxygen (with the intention
to wean off as an outpatient), metoprolol 25 mg orally every 12 hours for rate control,
warfarin for chronic anticoagulation, and tapering course of oral prednisone. She
was seen at follow-up 2 months later and no longer requires supplemental oxygen. Follow-up
chest radiograph at 3 months showed significant visualized improvement (Figure 3).
Figure 3
Portable chest radiograph 3 months after index hospitalization.
Discussion
Only five cases of flecainide-induced lung injury have been reported in the literature.
In each case, symptom onset seemed to be subacute in nature, and the disease courses
were such that radiographic lung injury patterns developed over weeks to months after
increasing cumulative dose exposure. Histologic findings in those reports were consistent
with diffuse infiltrative lung disease with lymphocytic alveolitis.2, 3, 4 In our
case, the patient’s symptoms and radiographic findings developed acutely (within 24
hours of initial drug administration), and clinical deterioration was rapid. Radiographic
findings in this case were consistent with those described previously. As in the previous
case reports, the diagnosis was made after exclusion of other causes of sudden hypoxic
respiratory failure. Cardiogenic pulmonary edema was eliminated based on the absence
of elevated filling pressures and failure to improve clinically with effective diuresis.
Clinical improvement and resolution of fever (despite early cessation of antibiotic
therapy) occurred after withdrawal of flecainide and initiation of corticosteroid
therapy, a scenario consistent with acute drug-induced lung injury rather than an
infectious etiology.
Drug-induced lung injury is believed to be a cell-mediated immunologic reaction. This
mechanism involves phagocytosis of antigen by an antigen-presenting cell macrophage,
monocyte, or dendritic cell and presenting it to T cells.
4
Flecainide in particular has high affinity for concentrating in lung tissue.
5
It is interesting to speculate whether chronic accumulation of amiodarone (well known
to cause different types of pulmonary toxicity) could have influenced the severity
of or accelerated this immune process after flecainide exposure in our patient.
Conclusion
Our report describes the first acute presentation of flecainide-induced lung injury.
Although drug-induced lung injury from flecainide is rare, clinical recognition of
this phenomenon is important because prolonged flecainide exposure may lead to severe
or potentially fatal pulmonary compromise. Cessation of the offending agent and rapid
exclusion of other etiologies such as cardiogenic edema and infection are pivotal
in choosing optimal treatment.