Fungal Infection Trust Aspergillus Newsletter Feb 2018
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Highlights of this month...

Consensus Statement on Research Priorities for Chronic Pulmonary Aspergillosis

- Kindly contributed by Dr Helmut Salzer
 
In March 2017, the Chronic Pulmonary Aspergillosis Network (CPAnet) was established to promote clinically oriented research in the field of CPA driven by a self-organized multinational research collaboration. Relevant research topics and questions were discussed by a panel of experts and systematically ranked according to their clinical importance in terms of costs and feasibility. Four key research priorities were identified that could be addressed without significant funding at the beginning (Godet et al. JAC 2017).
 
1. Establish a multinational web-based registry gathered comprehensive data on a large CPA study population. The online registry has been ready to use since Autumn 2017, facilitating a multisite study that reflects real-world clinical practice (open for participation; hsalzer@fz-borstel.de or danila.seidel@uk-koeln.de).
 
2. Validate different diagnostic tests in large and well-defined patient cohorts are needed and will be one of the key research priorities of CPAnet.
 
3. Establish a culture collection, which will be linked to other CPAnet studies and help to generate more information on the epidemiology and antifungal susceptibility profile of Aspergillus strains isolated from CPA patients.
 
4. Establish a consensus on a treatment outcome definition  to evaluate the treatment response in clinical trials on CPA by prospectively defined endpoints. 
 
 
News
8th Advances Against Aspergillosis

The 8th Advances Against Aspergillosis conference was held in Lisbon, Portugal this month. The meeting set the stage for the world’s leading aspergillosis academics, researchers and clinicians to discuss all aspects of Aspergillus research.
 
 
Speakers were selected on the basis of research that actively advances the field, and the presenting delegates represented a truly international group, with new talent and perspectives on aspergillosis. Slides from some of the major presentations are available to view hereTopics included optimizing antifungal therapy, the immune response, future therapies, Aspergillus in the host, airways and disease, diagnostic lab challenges, patient management, resistance, mechanisms, mucormycosis, and aspergillosis risk.

There was also a unique opportunity for delegates to discuss clinical development topics for invasive, chronic and allergic aspergillosis with representatives from the FDA and PMDA.
 
 
The world’s first online Fungal Microscopy course was developed by experts in The University of Manchester and collaborators worldwide and was first launched in 2016.
 
The first three modules are aimed at helping doctors, clinical scientists and laboratory technologists across the world to detect different fungi by direct microscopy and  to identify the top 10 most common fungal infections histologically.
 
The final module will be released shortly, and is designed to equip learners with advanced skills in microscopy to identify rare fungal pathogens.
Articles
 
The treatment and prognosis of fungal rhinosinusitis (FRS) is influenced by the  species that cause the disease. A recently published study demonstrates how a new immunohistochemistry method distinguishes between 2 agents of FRS – Aspergillus spp. and Mucorales fungi.
 
The study compared nasal tissue specimens from patients with FRS and esophageal cancer patients. The differences between immunohistochemical assay using interferon-gamma (IFNy) antibody and using PBS was also compared, using the FRS patient samples.
 
The researchers found that staining of IFNy was positive for 92.6% of Aspergillus-associated specimens, but only 4.2% of Mucorales-associated specimens. Further, immunohistochemical staining of cell cultures was 100% positive for Aspergillus species, compared to 0% Mucorales. These results suggest that IFNy antibody immunohistochemical staining could be a useful supplementary technique for FRS diagnosis. 
 

An investigation of Aspergillus flavus resistance to voriconazole used isolates collected in a chest hospital in New Delhi, India. The authors screened 120 A. flavus isolates from respiratory and sino-nasal specimens for azole resistance. They found that 2.5% (3/120) of the isolates had voriconazole minimum inhibitory concentrations that were above the threshold of 1μg/ml, indicating resistance.
 
The resistant isolates showed polymorphisms in azole target genes (cyp51A, cyp51B, cyp51C). In one non-wildtype isolate, four novel substitutions (S196F, A324P, N423D, V465M) were found in the cyp51C gene. This non-wildtype isolate also showed over-expression of cyp51A, B and C genes and the transporter genes MDR1, MDR2, atrF and mfs1. The other two isolates did not show upregulation of any of the analysed target genes.
 
The results suggest that multiple target genes and mechanisms contribute to azole resistance in A. flavus
 

Guidelines have traditionally recommended glucocorticoids for first-line treatment of ABPA, but an RCT conducted in India (N=131) suggests itraconazole is nearly as effective as prednisolone, but with lower rates of Cushingoid side effects.
 
Dr Agarwal and colleagues conducted an open-label randomised controlled trial comparing oral itraconazole (n=68) against prednisolone (n=63) as a first-line treatment in acute ABPA. All patients (100%) taking prednisolone achieved a treatment response, while 88% of patients on itraconazole did so; there were no obvious characteristics in common between itraconazole non-responders.
 
Itraconazole was not associated with many of the Cushingoid side effects that glucocorticoids are notorious for, but elevated liver enzymes were seen in more itraconazole patients (15%) than prednisolone patients (0%).
 
Overall, these results suggest that itraconazole makes a good alternative for patients who cannot tolerate glucocorticoids (e.g. those with uncontrolled diabetes, obesity or osteoporosis), but treatment should be monitored as around 12% of patients will not respond.
Reviews

Voriconazole can be limited by its adverse effects, which can include neurotoxicity, hepatotoxicity and renal disruption. This prompted Xing and colleagues from The First Affiliated Hospital of Xi’an Jiaotong, China to compare the adverse effects of this drug to other antifungals in a meta-analysis. The authors evaluated randomised controlled trials that provided information about toxicity of various antifungals.
 
They found that voriconazole was less well tolerated than other antifungals, and associated with higher probability of neurotoxicity (2-fold), visual toxicity (6-fold) and hepatotoxicity (1.6-fold) compared to the other drugs investigated. However, its pooled risk of nephrotoxicity was roughly half that of the other agents. This analysis should help clinicians decide between voriconazole and other therapeutic agents for invasive fungal infections. 
Veterinary

Raptors are susceptible to Aspergillus fumigatus infection, which can result in life-threatening respiratory disease. Gyrfalcons (Falco rusticolus) are thought to be more frequently affected than other raptor species. However, epidemiological research in this area is lacking.
 
Researchers from Justus Liebig University Giessen and Ghent University set out to investigate aspergillosis in otherwise healthy gyr-hybrid falcons through experimental inoculation with A. fumigatus. The 8-week-old chicks received a single tracheal inoculation, and were monitored over 28 days. Clinical signs correlated with the dose received, and fungal lesions were found in 10 out of the 18 inoculated falcons, but not in any of the control birds.
 
This study is the first to show that aspergillosis manifests in falcons following a single exposure, providing vital information for the husbandry of these birds. The results might also help to set threshold values for fungal conidia in ambient air, and provide further information as to the clinical signs and diagnostic indicators for aspergillosis in falcons.
 
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Patients & Carers
Patient Meetings

The Aspergillus community/patient group meeting normally meets on the first Friday of each month at the Altounyan Suite, North West Lung Centre, Manchester at 1.30pm BST/GMT. If you can't make it in person, you are welcome to listen in to our Facebook Broadcast

If you want a text reminder when each meeting is approaching (UK only) then send us an email at admin@aspergillus.org.uk with your mobile phone number.
 
N.B. The next patients' meeting will be held in Portugal at the AAA conference on the 1st February - visit the AAA website to learn more and book.
 
For more details see the Patients' Community Newsletter

Skype Meetings

If you would like to listen or chat with fellow patients and a NAC staff member we are running a successful Skype meeting every week! We are a chatty group of 8 - 12 most weeks but we can accommodate up to 24. If you have a computer or smartphone you will be able to join in - just click on https://join.skype.com/nbubWMUM8teC and you will be asked to register, then taken to the group. The Skype meeting is at 11am GMT every Thursday
 
We have recently started running a USA/Worldwide Skype group at 5pm GMT every Thursday, which can be accessed using this link: https://join.skype.com/ffp8FM6UysGf 
 
Join our Facebook Groups
 
Our Aspergillosis Support Facebook Group has over 1000 members and is a safe place to meet and talk to other people with aspergillosis.
 
We also have a Facebook group for carers, friends and family of someone who is affected by the disease - join here
 
To find our regional and international groups, search the following terms within Facebook: 'aspergillosis'; 'aspergillus'; 'ABPA'
Fungal Infection Trust, PO Box 482, Macclesfield, Cheshire SK10 9AR