Association between Mycobacterial Genotypes and Disease Progression in Mycobacterium avium Pulmonary Infection

Toshiaki Kikuchi ^1*, Akira Watanabe ², Kazunori Gomi ¹, Tomohiro Sakakibara ¹, Kei Nishimori ³, Hisayoshi Daito ⁴, Shigeru Fujimura ², Ryushi Tazawa ⁵, Akira Inoue ¹, Masahito Ebina ⁴, Yutaka Tokue ⁶, Mitsuo Kaku ⁴ and Toshihiro Nukiwa ⁴

¹ Tohoku University Hospital, Japan
² Institute of Development, Aging and Cancer, Tohoku University, Japan
³ National Institute of Animal Health, Japan
⁴ Tohoku University Graduate School of Medicine, Japan
⁵ Niigata University Medical and Dental Hospital, Japan
⁶ Gunma University Hospital, Japan

^* To whom correspondence should be addressed. E-mail: kikuchi{at}idac.tohoku.ac.jp.

Accepted 5 June 2009

Abstract

Background: Nontuberculous mycobacterial (NTM) lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established.

Methods: We evaluated variable numbers of tandem repeats (VNTR) in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M. avium isolates that were cultured from respiratory specimens obtained from 2005-2007. Specifically, we assessed the association between VNTR profiles and disease progression.

Results: Among the 37 subjects who provided positive respiratory cultures for M. avium during the 2005-2006 period, 15 subjects were treated within 10 months following a microbiological diagnosis of progressive M. avium lung disease. Nine subjects underwent long-term follow-up (> 24 months) without treatment for stable M. avium lung disease. Based on a neighbor-joining cluster analysis used to classify M. avium-positive subjects according to VNTR profile, we found that subjects with progressive versus stable lung disease grouped together in distinct clusters. Further analysis using logistic regression modeling showed that disease progression was significantly associated with the genetic distance of the M. avium isolate from an appropriately selected reference (age-adjusted odds ratio, 1.95; 95% confidence interval, 1.16-3.30; P = 0.01 for the most significant model). A best-fit model could be used to predict the progression of M. avium lung disease in the combined 2005-2006 and 2007 subjects (P = 0.003).

Conclusion: Progressive lung disease due to M. avium infection is associated with specific VNTR genotypes of M. avium.