7th Advances Against Aspergillosis: Basic, diagnostic, clinical and therapeutic studies

The genus Aspergillus is comprised of over 260 different species, whose relevance to humans ranges from harmless saprophyte to opportunistic pathogen. Some species are used in industrial fermentation, others produce toxins that are carcinogenic, and about 20–30 of the species are known to cause disease in humans or animals. As advances in medical therapy over the last 30 years have resulted in a marked increase in the numbers of immunocompromised patients, aspergillosis has become a significant cause of morbidity and mortality. Interestingly, while Aspergillus spp. are largely opportunistic pathogens in humans, they are primary pathogens for a number of animal species. The increased prevalence of aspergillosis has fostered increased interest in these fungi and as a result, fundamental and clinical research on these organisms has grown exponentially. The growth in studies on the aspergilli and their increased importance in clinical medicine led to the establishment of the biennial Advances Against Aspergillosis meeting. The papers in this issue of Medical Mycology represent a cross-section of the work presented by the invited speakers from the most recent meeting held March 3–5, 2016 in Manchester, UK. This successful meeting brought together clinicians, research scientists, and patients drew 354 attendees from 39 countries with submission of 132 abstracts. Additional details of the meeting and the programs from the previous meetings can be viewed at http://www.advancesagainstaserpgillosis.org; additional slides, abstracts, and video summations of sessions done by the session chairs can be viewed at http://aspergillus.org.uk. In this issue, Professor Latge presents a summary of our understanding of the importance and composition of the cell wall of conidia and hyphae.1 Conidia, as the likely infectious propagule, do not have the same cell wall structure and composition as the hyphal wall, and our understanding of the immune consequences of these differences remains incomplete. Further insights into the molecular mechanisms underlying virulence are presented by Bultman et al. in a discussion of the role of A. fumigatus transcription factors in the regulation of virulence.2 Although not all of the transcription factors have been defined in Aspergillus, these studies provide the basis of continued work to define mechanisms of virulence and pathogenicity. The use of CRISPR-Cas9 as a molecular tool is discussed by Professor Krappmann, who utilizes mutagenesis to identify and study virulence-associated genes in A. fumigatus.3 This study also emphasizes the importance of applying new tools to the study of fungi. The host response is critical to the host-pathogen interaction and successful eradication of fungal pathogens. Because the innate response often begins with a phagocytic event, the mechanisms underlying endosomal sensing of fungi are presented by Bercusson et al.4 A better understanding of these events will also allow us to understand how the organism may evade phagocytosis and killing. Takazono and Sheppard present an overview of the range of non-invasive Aspergillus airway infections in patients with chronic lung disease and the advances and limitations of animal models of colonization and allergic airway response for experimental studies of these increasingly common diseases.5 The diagnosis of aspergillosis remains one of the greatest challenges facing clinicians. Culture from a sterile site remains the “Gold Standard” for diagnosis of infection, but isolation of Aspergillus from non-sterile samples, such as sputum or bronchoalveolar lavage, does not distinguish between colonization and infection. Antigen detection methods such as galactomannan or β-glucan are useful, but suffer from both sensitivity and specificity limitations. More recently, the usefulness of the detection of specific antibodies has been revisited. Richardson and Paige present an overview of the role of antibodies in the diagnosis of aspergillosis and the utility of this technique in distinguishing colonization from infection.6 Molecular methods of diagnosis using PCR have received a great deal of study over the last 20 years. Alanio and Bretange examine the use of multiplex PCR as a possible diagnostic test, and conclude that although the methodology is quite attractive, one must be cautious in the interpretation of the results.7 Both of these papers highlight that while diagnostics for Aspergillus have improved, the development of a highly sensitive and specific test for the diagnosis of Aspergillus infection remains an important unmet clinical need. As noted above, the clinical importance of aspergillosis continues to rise world-wide, and the spectrum of disease caused by these fungi continues to expand. Difficulties in the management of chronic pulmonary aspergillosis is the topic of the paper by Kosmidis and Muldoon who present three specific cases highlighting approaches to the management of hemoptysis, co-infection with nontuberculous Mycobacteria and drug resistance.8 These cases should provide guidance to clinicians with similar cases. Bronchiectasis is a common underlying condition in a range of Aspergillus-associated syndromes. De Soyza and Aliberti discuss different aspects of pathogenesis and management of bronchiectasis associated with Aspergillus infections.9 Dragonetti et al. review changes in the outcomes of invasive aspergillus infection.10 The authors note that with the advent of better antifungal therapies the mortality due to invasive aspergillosis during induction chemotherapy of acute myeloid leukemia has declined in recent years, with the advent of better therapies. However, they also note that mortality remains high in patients with relapsed or refractory disease. Agarwal et al. pose the question of whether allergic diseases such as ABPA or rhinosinusitis are manifestations of the same condition, and conclude that the lack of sufficient clinical information causes these diseases to remain life-long problems.11 Lastly, Paspuneti et al. discuss how lung transplant patients are affected by aspergillosis, relating the high incidence of pulmonary aspergillosis in these patients to hypoxia of the airways, and how the excess of iron also contributes as a risk factor for the acquisition of infection.12 Clinical studies such as these continue to identify risk factors for acquisition of infection and highlight the need for experimental studies to better understand the fungal and host factors underlying the pathogenesis of these conditions. One of the most attractive approaches for the management of infectious diseases is prevention though vaccination. Professor Levitz13 addresses the question of whether vaccines for the prevention of aspergillosis might be useful and whether resources should be devoted to more work in this area. To date, no licensed vaccine is clinically available even though a significant amount of work has been devoted to the difficulties of development and use of a vaccine against aspergillosis. Conventional antifungal therapy is critical to the treatment of patients with Aspergillus infections. Chen et al. use a case of Aspergillus ventriculitis to emphasize the importance of pharmacokinetic and immunological factors in the treatment of these infections.14 In addition, they propose useful guidelines and suggestions for treatment of this unusual disease manifestation of aspergillosis. Looking to the future, the development of new antifungal drugs has slowed dramatically in the last few years, yet resistance, toxicity and limitations of the efficacy of currently available antifungals emphasizes the need for continued drug development. Osherov and Kontoyiannis15 examine the progress made in the discovery and development of novel small molecules as antifungals and the progress on repurposing available drugs and novel formulations of the older agents for the treatment of aspergillosis. We trust that these papers will provide the reader with up-to-date and useful information on the topics presented. Although significant challenges remain in improving aspergillosis outcomes, we are confident that both translational and basic research progress will lead to significant improvements in therapeutic outcomes. We wish to thank the authors for their contributions to this issue of Medical Mycology and we also thank the reviewers for their time and thoughtful critiques of these papers. R.A.C, D.C.S, and K.V.C. were members of the scientific planning committee of the 7th Advances Against Aspergillosis that was held in Manchester, UK March 2–5, 2016.

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