title: 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-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.
authors.affiliation: Department of Biosystemic Science and Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Fukuoka, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Kuruma
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hiramatsu
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Shioto
authors.initials: S
authors.lastname: Yasuda
authors.forename: Keita
authors.initials: K
authors.lastname: Odashiro
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000638:Amiodarone / Q000008:administration & dosage / Q000633:toxicity*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000276:immunology
chemical_list: D000889:Anti-Arrhythmia Agents; C508598:IL4 protein, human; D015847:Interleukin-4; D007371:Interferon-gamma; D000638:Amiodarone