Relationship between amiodarone-induced subclinical lung toxicity and Th1/Th2 balance.

Background: Although amiodarone is a potent antiarrhythmic agent, its clinical use is limited by serious lung toxicity. This study investigated the mechanisms of amiodarone-induced lung toxicity from an immunological perspective. Because interferon gamma (IFN-gamma: Th1 cytokine) inhibits pulmonary fibroblast proliferation whereas interleukin-4 (IL-4: Th2 cytokine) augments fibroblast growth and collagen production, we hypothesized that amiodarone lung toxicity is related to Th1/Th2 balance.

Methods: Twenty-six consecutive Japanese patients with ventricular arrhythmias treated with amiodarone were enrolled in this study and were divided into two groups. Group A contained patients demonstrating amiodarone lung toxicity diagnosed by chest X-ray, KL-6 or D(LCO) (n=6), whereas group B included patients treated without any adverse effects (n=20). Th1/Th2 balance was investigated by the ratio of IFN-gamma and IL-4 produced by activated peripheral CD4(+) T cells.

Results: Clinical baseline characteristics prior to oral amiodarone did not show any differences between group A and group B except for D(LCO) (82.0+/-5.2% vs. 90.8+/-9.0%, p=0.032) and Th1/Th2 balance (7.98+/-1.68 vs. 13.34+/-5.10, p=0.020). This balance was not altered three months after withdrawal of amiodarone in group A and under continued treatment in group B, suggesting patient-specific rather than amiodarone-induced. After starting amiodarone, serum concentration of desethylamiodarone was greater in group A than in group B (p=0.009) and was inversely proportional to Th1/Th2 ratio (p=0.013). Multilogistic regression analysis indicated that Th1/Th2 balance was the most powerful indicator of amiodarone lung toxicity (p=0.046, odds ratio of 0.424).

Conclusions: Although large cohort is required, the present study indicates that Th1/Th2 balance may influence amiodarone metabolism and may be a powerful indicator of amiodarone-induced subclinical lung toxicity at least in Japanese.