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

Mechanism of 5-flucytosine resistance in Aspergillus fumigatus

The drug 5-flucytosine is licensed for treatment of fungal diseases but is rarely used to treat Aspergillus infection. This is due to limited activity observed against A. fumigatus in vitro. However, when the pH is reduced to 5.0, 5-flucytosine shows increased activity in vitro.

A recent study reveals the mechanism for this increase in activity. Authors report that a gene (fcyB) that encodes purine-cytosine permease orthologous to known 5-flucytosine importers is downregulated at pH 7.0, and therefore may be responsible for the low activity of 5-flucytosine against Aspergillus spp. at this pH.

The researchers also described two transcriptional regulators that are responsible for repression of the fcyB gene and therefore mediate 5-flucytosine resistance – the CCAAT binding complex and the pH regulatory protein PacC.

The authors suggest that 5-flucytosine activity against Aspergillus spp. could be enhanced through manipulation of factors that repress fcyB expression. 
News
 
Following its advisory meeting in April 2018, the World Health Organisation (WHO) has issued its first listing of Essential Diagnostics. The list is split into laboratory tests and specific tests for key infections. It is also split into sections relating to testing in primary care settings versus hospital laboratory settings. 
 
With respect to fungal diseases and mycology, several key tests are included: microscopy, blood culture, other cultures and cryptococcal antigen test. These provide a good start for a mycology service.
 
The WHO will issue a call for proposals each year to incorporate additional tests. They will base such applications on need and on the evidence supporting the clinical value of each test. 

Dr Rachel Orritt leaves the NAC
 
Rachel has worked in the Science and Medical Communications team at the National Aspergillosis Centre, producing newsletters, blog articles and other communications for researchers, clinicians and patients. She has also managed the Microfungi.net online course, seeing it through the release of its fourth and final module. 
 
Rachel is leaving the NAC to take up a position at the National Institue for Health and Care Excellence in Manchester. We wish her the best in her future endeavors. 

 
An enthusiastic, enquiring clinician is sought for a 1 year clinical post with the Infectious Diseases team at the Wythenshawe Hospital, Manchester University Foundation Trust. The multidisciplinary Infectious Diseases team is attached to the National Aspergillosis Centre, a world-leading centre for the management and research on fungal infections. We are seeking an ST2+ level physician with experience in different medical specialties and an interest in Infectious Diseases. The successful applicant will contribute to the outpatient care of those with suspected or proven infectious diseases including TB, chronic pulmonary aspergillosis, ABPA and SAFS and those needing long term IV antibiotic therapy as well as to the inpatient care of patients under the care of the Infectious Diseases team, and undertake audit, teaching and research. Salary funding is guaranteed for 1 year, and may be extended.
Articles
 
New research sought to characterise risk factors for invasive fungal infections in paediatric liver transplant recipients during the early (3 months) post-transplantation period. Researchers used data collected retrospectively at a transplantation centre between 2004-2014. Analysis using a stepwise logistic regression model was used to formulate a predictive model, in spite of the small sample size (81 liver transplant recipients).
 
Risk factors for invasive fungal infections included multiple blood transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two factors to define high-risk patients – those receiving a liver transplant from a living donor, and duration of IV antibiotic treatment. Further research is needed to confirm the risk factors identified in this study.
 
 
Additional therapy is sometimes required for adults who, despite maintenance treatment, have uncontrolled persistent asthma. The authors of a recent study aimed to assess the efficacy of azithromycin, a macrolide antibiotic, as an add-on therapy. They used a randomised, double-blind trial to compare patients treated with azithromycin (500mg, 3 times per day for 48 weeks) with those receiving placebo.
 
The researchers found that azithromycin reduced asthma exacerbations compared to placebo. Patients in the treatment group had an average of 1.07 severe or moderate exacerbations per year, compared to patients in the placebo group who has 1.86. However, diarrhoea was significantly more common in the treatment group. 
 
 
A study reviewed 85 samples from 38 immunocompromised patients. Patients were administered with voriconazole and/or corticosteroid medication orally or intravenously. Corticosteroid treatment was classed as ‘concurrent’ if administered within 3 days of voriconazole administration.

Patients received an average of 59.2 mg of corticosteroid daily. Voriconazole concentrations were inversely correlated with corticosteroid dose (r-.26) and voriconazole concentration was significantly lower in corticosteroid users compared with those who did not receive corticosteroid medication (p=.013).
 
The authors of the study speculate that voriconazole might be metabolized by an enzyme induced by corticosteroid treatment. Thus clinicians might be best advised to carefully consider voriconazole metabolism prior to concurrent treatment with corticosteroids. 
Reviews

This review focusses on fungal disease epidemiology - in particular invasive candidiasis and invasive aspergillosis. The authors note that progress has been made in preventing, treating and managing invasive fungal disease in children, highlighting the decreasing incidence of paediatric invasive candidiasis as an example.
 
The authors discuss the incidence of invasive fungal disease in children and how these are affected by geography, population and time. They note that epidemiological study is key to directing preventative, diagnostic and therapeutic resources to the populations that need them most.
 
The major groups of children at risk of invasive fungal disease are children with a hematologic malignancy or a primary or secondary immunodeficiency, those receiving solid organ or hematopoietic stem cell transplantation, and premature neonates. The review focusses heavily on invasive candidiasis and invasive aspergillosis as the two most common invasive fungal diseases affecting children and neonates. 
Veterinary

This case study followed the treatment of a four year old Bennet’s wallaby (Macropus rufogriseus) for destructive mycotic rhinosinusitis. The authors describe the wallaby’s presentation with chronic left-sided facial swelling and nasal discharge. Diagnosis was supported with computed tomography, endoscopy, biopsy, mycologic culture and panfungal polymerase chain reaction.
 
The infection was treated with a long-term injectable antibiotic, oral antifungal therapy, and multiple intranasal infusions of voriconazole suspended in a reverse thermodynamic pluronic gel. This is the first documented case of mycotic rhinosinusitis in a macropod. 
 
Attention!
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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.
 
PLEASE NOTE that the next Patients' meeting (scheduled 1st June 2018) has been cancelled due to lack of room availability.
 
For more details see the Patients' Community Newsletter

Online Meetings

If you would like to listen or chat with fellow patients and a NAC staff member we are running a successful online meeting every week! We are a chatty group of 8 - 12 most weeks. If you have a computer or smartphone you will be able to join in using Zoom - download of this software is free and easy. Just click on https://zoom.us/j/243782379. This 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