Azole-resistant Aspergillus fumigatus and related species in Japan

Azole-resistant Aspergillus, particularly azole-resistant Aspergillus fumigatus (ARAf), is an increasingly consequential problem in Japan because triazoles remain central to aspergillosis management and chronic pulmonary aspergillosis (CPA) often requires prolonged oral therapy. CPA provides a within-host evolutionary niche in which persistent fungal burden and long-term azole exposure select resistant subpopulations, contributing to non-response, relapse, and progressive lung destruction. This review synthesizes Japan-specific clinical and environmental epidemiology, resistance mechanisms, and diagnostic considerations. Clinical studies show heterogeneous, isolate-based detection frequencies influenced by cohort design, testing strategy, and referral patterns. Prospective regional surveillance identified resistance in 7/55 A. fumigatus isolates, and a CPA cohort showed an overall isolate-based rate of 8.3%; the higher rate during azole-treatment failure (46.2%) represents a high-yield clinical subgroup, not population prevalence. Although CPA is the clearest Japanese model for patient-route selection, IPA-specific data remain scarce and are needed because environmentally acquired resistance may compromise initial empirical therapy. Referral-center data suggest increasing tandem-repeat (TR) mechanisms, including TR₃₄/L98H and TR₄₆/Y121F/T289A. Environmental investigations indicate intermittent TR detection in outdoor air and highlight horticultural commodities, especially flower bulbs, as reservoirs and exposure sources. Japanese mechanisms span cyp51A point mutations, TR-promoter variants, and non-cyp51A pathways (e.g., hmg1 and hapE), supporting a polygenic framework that may be missed by TR-focused PCR alone. Interpretation is further complicated by limited routine susceptibility testing, cryptic Fumigati species, and section Nigri isolates with reduced azole susceptibility. We propose structured multicenter collection, referral pathways, species-level identification, and environmental surveillance to guide management.