Amiodarone, a derivative ofbenzo-furan, has been in wide use since 1967 as an antianginal and antiarrhythmic drug, and its multiple side effects are well known. However and unexpectedly, it is only since 1980 that several dozen cases of lung disease associated with the use of this drug have been reported.
We present here a case of pneumonitis which developed after nine years of treatment with amiodarone. Several biologic findings favor an immunologic origin of the disease (hypersensitivity due to amiodarone).
Case Report
An 81-year-old man complained of loss of weight, fatigue, and effort dyspnea for a few months. In 1954, at age 52, he had had a myocardial infarction. In 1974, at 72, angina and arteritis of the legs were diagnosed and he was treated, irregularly and intermittently, with dipyridamole and pentoxifylline. For the last nine years he had been taking amiodarone regularly (200 to 400 mg per day, cumulative dose 985 g).
Clinical findings were negative except for a few crepitations at the base of the right lung; his general condition was good and temperature normal. The chest x-ray film showed small opacities of the interstitial type disseminated over both lungs, especially at the periphery. The x-ray film in 1972 had been normal. Tests of respiratory function pointed to a purely restrictive syndrome (vital capacity reduced to 83 percent predicted) with a Pa02 of 11.2 kFa (84 mm Hg), a slightly increased alveolo-arterial gradient of 3.1 kPa (23 mm Hg) and hypoxia of effort of 9.2 kFa (69 mm Hg); static recoil pressures at 90 and 60 percent of total lung capacity are increased respectively at 18.82 and 2.88 cm H,0 (normal values: 7.75 and 2.74). Results of bronchofiberoscopy were normal. Corneal deposits, detected four years earlier, were seen again with the slit lamp. Sputum and serologic tests for the presence of bacterial, viral or mycotic infection were negative. Tuberculin skin test was negative. Polyclonal hyperglobulinemia was found by electrophoresis and immunoelectrophoresis. Immunoglobulin G levels (radial immunodiffusion) were increased to 21.94 g/L (normal values: 9.50-16.70). Complement and total IgE titers were normal. No auto-antibodies to lung were found by immunofluorescence (negative at titer 1/5).
Ibe patients HLA phenotype was as follows: All, B5; A-, B13. The levels of the angiotensin-converting enzyme in serum and alveolar lavage fluid were normal. The total and differential blood counts were normal, with 7,800 white blood cells, of which 34 percent were lymphocytes (2,652 lymphocytes/pil). Among these, there were 44 percent T helper (1,166/jjlI) and 14 percent T suppressor (371/) lymphocytes with a ratio T helper/T suppressor lymphocytes of 3.18. Bronchoscopy was performed with a flexible fiber-optic instrument (Olympus BF-B3) and bronchoalveolar lavage was performed according to the usual technique using 0.9 percent saline solution until 100 ml were recovered; the alveolar lavage fluid cell count was 150.103 cells/ml, with 31 percent lymphocytes, 62.5 percent macrophages, and 6.5 percent polymorphs. Helper T lymphocytes were 24 percent and suppressors 48 percent in lavage fluid with an inverted ratio of 0.50.
An intradermal test with 0.10 ml of a solution of 5 mg/ml of amiodarone in benzyl alcohol provoked an erythema of 13 mm with induration at six hours, whereas an erythema of only 6 mm was obtained in two other patients treated with amiodarone, but without pneumonitis. The patients' basophil degranulation test was positive (78 percent) in the presence of400 ng/ml amiodarone. The lymphoblastic transformation test in the presence of 1 M-g/ml of amiodarone was positive in peripheral blood lymphocytes, with a stimulation index of 3.5.
The migration of peripheral blood leukocytes in the presence of 1 jig/ml of amiodarone was inhibited by 45 percent with the capillary tube technique of Soborg and Bendixen. The migration of peripheral blood leukocytes from agarose micro-droplets in the presence of different concentrations (8 logs) of amiodarone was studied with a photoelectric procedure. The percentage migration inhibition was calculated for each antigen concentration as compared to the migration of the same cells in medium without amiodarone. Migration inhibition of 15, 50 and 20 percent was observed at amiodarone concentrations of 0.01 jig, 0.1 (ig and 1 M-g/ml respectively (Fig 1). The leukocyte migration inhibition test with the photoelectric procedure was negative in two other patients under treatment with amiodarone for two years but without pneumopathy.
Discussion
This pulmonary side effect of amiodarone therapy is beginning to become known, but its mechanism is not clear. Fibrosis is generally found on pathologic examination of the lungs,' for which a toxic mechanism has been suggested by some authors. The long half-life (28 days) of amiodarone and its structural similarity to certain antidepressive drugs known to cause “toxic” cellular changes are in favor of this hypothesis.
However, in some cases at least, a hypersensitivity mechanism cannot be excluded for the following reasons. It is well known that fibrosis may be the final stage of an allergic granulomatosis after a relatively long period of contact with the offending antigen (nine years in our patient). Moreover, deposits of the third fragment of complement have been observed in this type of pneumonitis. Furthermore, in our patient, lymphocytosis and inversion of the helper/suppressor ratio in alveolar lavage fluid are good indications of hypersensitivity pneumonitis and have already been described in other drug pneumopathies of this type, as well as in extrinsic allergic alveolitis due to inhaled antigens. The positive late skin reaction and positive lymphoblastic transformation test, and the presence of the lymphokine leukocyte inhibitory factor (LIF) may be suggestive of the presence of cell-mediated hypersensitivity, while the positive basophil degranulation test would suggest concomitant sub-clinical hypersensitivity of the immediate type.
For the clinician, the early diagnosis of amiodarone lung implies the immediate cessation of treatment with the drug and the prescription of corticosteroids for some weeks, which generally leads to cure of the drug-induced pneumonitis. If this lung complication is not diagnosed early enough, death may occur, of which there are a dozen examples in the literature. Half appear to be directly related to the drug.
Pulmonary complications, therefore, should be watched for when long-term treatment with amiodarone is prescribed, with surveillance of these patients at regular intervals.
Figure 1. The inhibition of the migration of peripheral blood leukocytes in presence of different concentrations of amiodarone. The migration of peripheral blood leukocytes from 1 μ agarose microdroplets was studied with a photoelectric procedure. Percentage of inhibition was calculated as compared to the migration of the same cells in normal medium without amiodarone. Eight logs of concentrations of amiodarone are shown. Concentrations of log 1 (10 ill/ml), or more, are toxic for peripheral blood leukocytes.
No comments:
Post a Comment