12th Annual Fungal Update
3rd & 4th February 2017, St Bartholomew’s Hospital, London
Dr Samir Agrawal, Chair of the Organising Committee, welcomed participants to the 12th Annual Fungal Update in the Great Hall at St Bartholomew’s Hospital, London. Building on the success of recent years, the meeting brought clinicians and researchers together with leading specialists from Europe and the United States to review the latest evidence on fungal infections. The programme tackled many of today’s key challenges, including global resistance patterns, the emergence of new species, the immune response and management guidelines.
Antifungal resistance – a global and national perspective
The challenge posed by an increase in pathogenic fungi is not limited to immunocompromised patients, or even to humankind, as Professor Matthew Fisher (London, UK) made clear in his presentation on global patterns of resistance. He pointed out that fungal diseases are increasing among animals and plants and their spread around the planet is facilitated by human activity. As we rise to meet this challenge we use antifungal drugs on a massive scale and, as a result, resistance to frontline therapies is increasing. Emerging global genomic data will help us better understand the true biodiversity of pathogenic fungi and develop new scientific and societal strategies to combat the growing threat. Resistance to azole antifungal agents is now a global problem.
Dr Jacques Meis (Nijmegen, Netherlands) noted that resistant Aspergillus spp were rare only fifteen years ago but the reliance on azole fungicides for crop protection has led to the emergence of mutations such as TR34/L98H in cyp51A, the target gene for azoles in Aspergillus fumigatus; this is now known to cause broad azole resistance in many countries. Low or variable susceptibility to voriconazole and itraconazole associated with the TR46/Y121F/T289A mutation in A. fumigatus is also increasingly common. In Dutch hospitals the prevalence of azole resistant A. fumigatus isolates recovered from clinical samples varied between 0.8% and 9.4%.1
Dr Meis concluded that antifungal resistance should form part of the One Health approach in Europe and screening for susceptibility to antifungal agents should become routine so that suitable management guidelines can be introduced.
Attention then shifted to Candida spp as the potential threat posed by C. auris was reviewed by Dr Tom Chiller (Atlanta, United States) and Dr Silke Schelenz (London, UK). Dr Chiller brought insights from the US Centers for Disease Control and Prevention when he said this organism, first identified in Japan in 2009, has now been reported on five continents. C. auris, in contrast to other Candida spp, frequently has multiple drug resistance and is readily transmitted in healthcare settings where it can result in outbreaks which are very difficult to contain. Whole genome sequencing analysis suggests that within regions, spread of C. auris is highly clonal, however diverse clonal populations are emerging independently in different parts of the world.
Dr Schelenz described the first outbreak of C. auris infection in Europe. During 2015 and 2016, C. auris was identified in 50 patients in one London hospital trust. In most cases, the organism colonised only skin or mucosa but 22 patients needed treatment with an antifungal agent for invasive infection (including nine episodes of candidaemia). Control measures which were implemented included: isolation of cases and contacts; personal protective clothing for staff; screening of patients; decontamination of skin with chlorhexidine and disinfection of the local environment. This outbreak demonstrates the importance of suspecting C. auris when a resistant non-albicans Candida spp is isolated.
The English Surveillance Programme for Antimicrobial Use and Resistance (ESPAUR) has set up a subgroup to monitor the use of antifungal agents and resistance patterns. Dr Berit Muller- Pebody (London, UK) and Dr Elizabeth Johnson (Bristol, UK) summarised ESPAUR’s 2016 report which, for the first time, included data on antifungal resistance. Aspergillosis, largely due to A. fumigatus, was the most common invasive mould infection in the UK. Of the isolates tested in 2015, 5% were resistant to any azole – up from 1% in 2011 to 2013. The report notes that few hospital trusts in England have a dedicated antifungal stewardship programme.
One of the obstacles to the cost effective use of antifungal agents is difficulty in obtaining a rapid and accurate diagnosis, so that patients receive unnecessary treatment initiated on the basis of aspecific signs and symptoms.
Dr Ronan McMullan (Belfast, UK) outlined a study that offers progress towards a speedier diagnosis of Candida infection in critical care patients. The three-year study involving 35 intensive care units will determine the accuracy and model the cost effectiveness of commercially available tests using antigen or polymerase chain reaction technology. An algorithm based on these tests will then be evaluated in a randomised trial in patients with suspected Candida infection.
Immune response and pathogenic fungi
Cryptococcus neoformans accounts for one million infections globally each year, of which 60% are fatal. Dr Liz Ballou (Aber deen, UK) explained that one mechanism by which this yeast proliferates and evades the immune response is the development of the Titan cell. Titans are so big that they avoid phagocytosis; they are associated with increased eosinophilia and increased dissemination into the brain. They can bud daughter cells with drug sensitivity profiles that differ from their parent cells and may contribute to drug-resistant lineages. How the yeast transforms into a Titan cell is unknown but it is hoped that clarification of the mechanisms underlying this process will reveal new therapeutic targets. Most Aspergillus spp do not cause human disease; why A. fumigatus is the exception is not entirely clear. Dr Elaine Bignell (Manchester, UK) summarised the in vitro and in vivo research that has revealed how fungal cytotoxicity occurs via multiple mechanisms, suggesting that the interactions between A. fumigatus and lung epithelium may be key to developing new treatments. Professor Tom Rogers (Dublin, Ireland) said the conversion of Aspergillus spp from coloniser to pathogen is facilitated by immunomodulation by respiratory pathogens such as influenza virus and Pseudomonas aeruginosa. The interaction between Ps. aeruginosa and A. fumigatus is complex and includes increased airway injury due to increased elastase production by bacterial cells.
Imaging and guidelines update
Computed tomography pulmonary angiography (CTPA) is the gold standard for diagnosing pulmonary embolism but, said Professor Russell Lewis (Bologna, Italy), it is now proving useful in diagnosing invasive mould disease in the lung. The Bologna centre uses CTPA routinely to assess febrile neutropenic patients in whom CT has identified nodular lesions. In the first 100 patients imaged, CTPA was 100% sensitive (41/41) for detection of proven or probable fungal disease and was positive in 49% (25/51) of patients with possible mould disease. There was one false positive. No patient with an established alternative diagnosis had a positive scan. Importantly for clinical management a negative CTPA scan supported clinical decisions to withhold antifungal treatment.
Dr Jörg Janne Vehreschild, (Cologne, Germany) compared and contrasted the recommendations of updates to guidelines on the management of invasive fungal infections from the European Conference on Infections in Leukaemia (ECIL-62) and the Infectious Diseases Society of America (IDSA3,4) with older recommendations from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Although sharing a similar evidence base, these guidelines differ in their national focus and methodology. In terms of quality, ESCMID guidelines are notable for strongly linking their recommendations to the evidence whereas ECIL-6 is clearest in its guidance on the indications for specific drugs. Coverage of the main treatment areas is similar (Table 1).
The guidelines broadly agree on the best approaches for the diagnosis and prophylaxis of aspergillosis, though they rate the strength of evidence differently. This reflects the level of scientific debate and the different weightings applied when interpreting clinical trials, Dr Vehreschild noted. All recommend isavuconazole as first line therapy for aspergillosis, with ECIL-6 rating the evidence most strongly, and there is close agreement on other treatment options (Table 2).
In the management of candidaemia, the ESCMID 2012 guidance is the only one to detail diagnostic measures but there is close agreement on treatment options, with the more recent ECIL-6 and IDSA able to reflect newer evidence in their ratings. In conclusion, Dr Vehreschild said the guidelines are generally consistent but offer little advice on treatment duration, response assessment and treatment failure – all areas where evidence is lacking.
1 Verweij PE, van de Sande-Bruisma N, Kema GH et al. Azole resistance in Aspergillus fumigatus in the Netherlands – increase due to environmental fungicides? Ned Tijdschr Geneeskd. 2012; 156(25): A4458
2 Tissot F, Agrawal, S, Pagano L et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2016 Dec 23 doi: 10.3324/haematol.2016.152900. [Epub ahead of print]
3 Patterson TF, Thompson GR, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63: e1- e60. doi:10.1093/cid/ciw326
4 Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62: e1- 50. doi: 10.1093/cid/civ933