Drug Induced Interstitial Lung Disease.pptx Amiodarone

1. Drug Induced Interstitial
Lung Disease

2. Amiodarone Induced Pulmonary
Toxicity

3. Amiodarone
• iodinated benzofuran derivative
• metabolized in the liver by cytochrome P450 3A4
• class III antiarrhythmic agent

4. Effects
• Interstitial pneumonitis (most common)
• Organizing pneumonia
• Acute respiratory distress syndrome (ARDS)
• Diffuse alveolar hemorrhage (DAH)
• Pulmonary nodules and solitary masses
• Pleural effusion (rare)

5. Other effects
• Photosensitivity
• Blue-gray discoloration of the skin
• Thyroid dysfunction
• Corneal deposits
• Abnormal liver function tests
• Bone marrow suppression

6. INTERSTITIAL PNEUMONITIS

7. INTERSTITIAL PNEUMONITIS
• Usually presents after two or more months of therapy (esp on
patients taking 400 mg per day)
• Incidence unknown (1 to 5 percent)

8. Pathogenesis
• Two major hypotheses: a direct toxic injury to lung cells and an
indirect immunologic reaction
• Long half-life and a high tissue affinity for the lung.
• active metabolite of amiodarone, monodesethylamiodarone (DEA), exhibits
cytotoxic activity and tends to accumulate in the lungs even more than
amiodarone
• Drug-phospholipid complexes accumulate in lung cells and interfere
with normal cellular metabolic pathways, which ultimately leads to
direct cell injury and death

9. Pathogenesis
• phospholipid bilayer which in turn disrupts cellular and organelle
membrane function
• Toxic oxygen species resulting in tissue injury
• Lymphocytic infiltration, often with "intraalveolar buds" (organizing
pneumonia-like reaction)
• •CD8 T-cell lymphocytosis
• •Positive IgG immunofluorescence in the lung

10. Risk factors
• High cumulative dose
• Doses ≥400 mg/day (5 to 15%)
• Increased patient age
• ?Preexisting lung disease

11. • 573 patients treated with amiodarone for recurrent ventricular (456 patients) or
supraventricular (117 patients) tachyarrhythmias. Amiodarone pulmonary toxicity
was diagnosed in 33 of the 573 patients (5.8%), based on symptoms and new
chest radiographic abnormalities (32 of 33 patients) and supported by abnormal
pulmonary biopsy (13 of 14 patients), low pulmonary diffusion capacity (DLCO)
(nine of 13 patients), and/or abnormal gallium lung scan (11 of 16 patients).
Toxicity occurred between 6 days and 60 months of treatment for a cumulative
risk of 9.1%, with the highest incidence occurring during the first 12 months (18
of 33 patients).
• Older patients developed it more frequently (62.7 +/- 1.7 versus 57.4 +/- 0.5
years, p = 0.018), with no cases diagnosed in patients who started therapy at less
than 40 years of age. Gender, underlying heart disease, arrhythmia, and
pretreatment chest radiographic, spirometric, or lung volume abnormalities did
not predict development of amiodarone pulmonary toxicity, whereas
pretreatment DLCO was lower in the group developing it (76.0 +/- 5.5% versus
90.4 +/- 1.4%, p = 0.01)
Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51.

12. High cumulative dose
• There was no significant difference
between the group with and the group
without amiodarone pulmonary toxicity
with respect to the actual length of the
loading period (mean, 35±12; range, 6-56
days versus mean, 36+16; range, 3-83
days,p=0.47) and the mean daily loading
dose (838±40 versus 848+11 mg,p=0.79).
• During the maintenance period, however,
the patients who developed toxicity
received a significantly higher mean daily
dose of amiodarone when compared
with the group without toxicity (515+25
versus 409±6 mg,p<0.001).
Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51.

13. Clinical manifestations
• Insidious onset
• Onset of symptoms : 6 to 12 months
• Nonproductive cough and/or dyspnea (50 to 75%)
• Fever (33 to 50%)
• Pleuritic pain
• Weight loss
• Malaise

14. Clinical manifestations
• PE: Bilateral inspiratory crackles
• Pulmonary function tests: restrictive pattern with reduced FVC and
TLC and reduced DLCO
• Laboratory
• Amiodarone levels are not predictive or diagnostic of pulmonary
toxicity

15. Serum KL-6
• Measurement of serum concentrations of KL-6, a mucin-like high
molecular weight glycoprotein secreted by proliferating type II
pneumocytes, is a sensitive marker of disease activity in various
interstitial lung diseases.

16. CXR- Amiodarone pulmonary toxicity

17. CXR- Amiodarone pulmonary toxicity

18. HRCT- Amiodarone pulmonary toxicity

19. HRCT- Amiodarone pulmonary toxicity

20. Bronchoalveolar lavage
• Lymphocytosis
• Neutrophilia
• Eosinophilia
• Normal BAL cellular counts
• “Foam" cells (alveolar macrophages full of amiodarone)

21. Foam Cells

22. Treatment
• Stopping amiodarone and avoid restarting medication
• Glucocorticoid therapy (e.g. Prednisone 40 to 60 mg per day) even for
mild symptoms or any evidence of respiratory impairment
• Relapse need slow tapper
• Prognosis: generally favorable

23. EOSINOPHILIC PNEUMONIA

24. EOSINOPHILIC PNEUMONIA
• Presents less than 1 month
• Fever
• Nonproductive cough
• Dyspnea
• Peripheral eosinophilia
• BAL >25% eosinophil and abundant foamy macrophages
• The differential diagnosis of eosinophilic pneumonia includes fungal and
parasitic infection, vasculitis, and eosinophilic pneumonia induced by other
drugs

25. Acute eosinophilic pneumonia on radiography
and CT

26. ORGANIZING PNEUMONIA

27. ORGANIZING PNEUMONIA
• Occurs in approximately 25 percent of cases of amiodarone
pulmonary toxicity
• Excessive proliferation of granulation tissue, consisting of loose
collagen-embedded fibroblasts and myofibroblasts, and involving
alveolar ducts and alveoli, with or without bronchiolar intraluminal
polyps

28. Clinical Presentation
• Acute onset: few weeks to months
• Symptoms: nonproductive cough, pleuritic chest pain, fever, and
dyspnea
• PE: reveals crackles, which may be focal, pleural rub
• Diagnosis of OP is often suspected after a lack of response to
antibiotics administered for suspected bacterial pneumonia

29. CT FINDINGS

30. Histopathology

31. ACUTE RESPIRATORY DISTRESS
SYNDROME

32. ARDS
• Rare but potentially fatal
• Characterized by diffuse alveolar damage with hyaline membranes

33. Amiodarone-associated ARDS
Presentation:
• Reported in patients who have undergone surgery or pulmonary
angiography
• The diagnosis of ARDS is based on clinical criteria: acute onset of
symptoms (≤1 week), bilateral opacities consistent with pulmonary
edema on chest computed tomography (CT), absence of cardiac
failure or fluid overload, and a moderate to severe impairment of
oxygenation

34. Amiodarone-associated ARDS
Management:
• Cessation of amiodarone
• Supportive care for the critically ill patient, and use of mechanical
ventilation with strategies to minimize supplemental oxygen and also
reduce barotrauma and volutrauma
• Systemic glucocorticoids (eg, methylprednisolone 1 to 2 g/day
intravenously, followed by prednisone 1 mg/kg daily) after infection
has been excluded

35. DIFFUSE ALVEOLAR
HEMORRHAGE

36. DIFFUSE ALVEOLAR HEMORRHAGE
• Rare complication
• Occur abruptly in the first few
days or months (average six
months)
• Presentation: cough, shortness
of breath, fever, and
hemoptysis

37. DIFFUSE ALVEOLAR HEMORRHAGE
• Diagnosis is usually made by sequential BAL sampling that shows
progressively more hemorrhagic effluent; other causes of DAH must
be excluded.
Treatment:
• Cessation of amiodarone
• Systemic glucocorticoid therapy (Grade 2C). A reasonable dose (after
the exclusion of infection) is methylprednisolone 0.5 to 2 g/day,
intravenously in divided doses for up to five days, followed by gradual
tapering.

38. Conclusion
• Amiodarone is associated with several forms of pulmonary toxicity
including interstitial pneumonitis (the most common presentation),
eosinophilic pneumonia, organizing pneumonia, acute respiratory
distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH),
pulmonary nodules and masses, and rarely pleural effusions.
• The incidence of pulmonary toxicity is estimated to be 1 to 5 %
• Permanent discontinuation of amiodarone amiodarone is the primary
therapy for amiodarone pulmonary toxicity.