25 years of improvement in mortality in invasive aspergillosis in haematology patients: will it be sustained or is it under threat?

Invasive aspergillosis (IA) crude mortality has shown a sustained reduction over the past decades, demonstrated in randomized controlled clinical trials of new antifungal agents and across large population surveys. New diagnostic tools and integrated management approaches have driven faster, more targeted initiation of appropriate antifungal therapy. In parallel, improvements in the identification of periods at highest risk for IA and in practices for management of the underlying disease processes predisposing to immunosuppression, including immunomodulatory therapies, have progressed. Given the highly complex and interconnected relationship between the underlying disease and its treatment and the predisposition to IA that the underlying disease creates, it is difficult to separate out which mortality improvements could be attributable to improved management of IA and which to better management of the underlying disease. The reductions in IA mortality have been sustained despite increases in the number of older, more vulnerable patients with more severe underlying disease undergoing treatment for acute haematological disorders and haematopoietic cell transplantation. This gradual and subtle move to a higher risk, more co-morbid patient population may have obscured any impact from the management developments other than antifungal therapy over this period, including better fungal diagnosis and supportive care. The overwhelming single factor contributing to a reduction in IA mortality over the past years appears to have been the routine adoption of mould-active antifungals, azoles in particular. Any impact of consensus definitions used to classify disease, improvements in diagnostic tools and earlier targeted strategies, remains difficult to measure based on available data. However, recently, the use of mould-active azoles has become threatened by the emergence of azole resistance in Aspergillus fumigatus, the frequent co-occurrence of Aspergillus species and Mucorales species, and difficult to handle drug-drug interactions, thereby fuelling an ongoing search for novel antifungal agents.