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

Abstract

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-γ: 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-γ 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.