September 2020
Research highlight: biological drugs & ABPA
 
Current mainstays of ABPA treatment include antifungals, anti-inflammatories (e.g. steroids) and asthma drugs. However, many of these cause serious side effects and not all patients respond to them sufficiently. Newer biological drugs (based on monoclonal antibodies, or ‘mAbs’) that target specific parts of the molecular machinery of inflammation have achieved good results for patients with severe asthma, and there is increasing evidence that they could also be useful for treating ABPA/SAFS in asthma and cystic fibrosis patients.
 
Omalizumab (brand name Xolair) is a mAb that neutralises free IgE directly and is approved in the UK as an add-on treatment for moderate/severe persistent asthma. It is an injection under the skin given every 2-4 weeks. It is prescribed by NHS asthma specialists but is normally only offered to patients who have had 4 courses of corticosteroids in the past year, or who are on continuous steroids.
Recently, scientists retrieved data from the Australian Xolair Registry (Wark et al., 2020) and found that Xolair significantly improved symptoms and reduced the number of exacerbations in 11 ABPA patients. Older case reports are summarised nicely by Li et al. (2017).
Mepoluzimab (brand name Nucala) is another mAb that targets the cytokine IL-5, which is one of the inducers of the eosinophilic response. It is approved in the UK for treating patients with severe eosinophilic asthma who aren’t responding to other treatments, but can only be used under expert supervision. As ABPA is also an eosinophilic disorder, a team in the US searched the scientific literature for cases where mepoluzimab had been used. All 8 cases showed improvement within 6 months and had an average improvment in FEV1 of 375 ml, with 4 cases also showing a substantial decrease in IgE levels (Tolebeyan et al., 2020).
 
Dupilumab (brand name Dupixent, targets IL-4/IL-13) was rejected by NICE earlier this year for use within the NHS on the grounds of cost and insufficient evidence (read more about this decision at PharmaPhorum). One recent case report describes a patient with ABPA and severe asthma whose condition was deteriorating despite taking daily oral and inhaled corticosteroids, who had previously not shown a strong response to treatment with itraconazole, benralizumab (anti-IL-5 mAb) or omalizumab. After 4 months of treatment with , her symptoms had almost completely resolved and she no longer took oral steroids (Mümmler et al., 2020). The authors emphasise that a history of failing treatment with some biologicals should not rule out trying others.
  • Read more about biological therapies at Asthma UK 
  • Read detailed information about ABPA diagnosis, subtypes, staging and treatments: Patel et al., 2019
 
News & Notices
 
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Would you like to work at the National Aspergillosis Centre? MFT are looking for a Clinical Fellow and a Specialist Nurse to join the Infectious Diseases team - please see the jobs section below to apply.
 
 
This month's MRC CMM Monthly Myco-talks are on Thurs 29th Oct at 16:00 UK time:
 
Several key conferences have been postponed due to COVID-19:
 
Have you had your annual flu jab? Find out whether you're eligible on the NHS website
 
 
New research from NAC & MRCM
 
No azole-resistant strains of Aspergillus fumigatus found on root vegetables (Van der Torre et al., 2020)
Evidence is currently mixed for a causal link between agricultural (over)use of antifungals and the rise of azole-resistant strains of Aspergillus. Staff at the Mycology Reference Centre Manchester isolated 146 strains of fungi from the soil found on root vegetables from farm shops and private gardens. Around 55% of samples contained Aspergillus fumigatus, but no azole-resistant strains were seen.
-  You can find out more about the MRCM's research on their new website
 
 
Research Articles & Reviews
 
Invasive tracheobronchial aspergillosis in influenza patients (Nyga et al., 2020)
Researchers at a hospital in France reviewed the notes of 35 patients with influenza complicated by invasive aspergillosis, in order to compare those with tracheobronchial Aspergillus lesions (ITBA group, n=10) and those without (non-ITBA group, n=25).  The ITBA group had a higher fungal burden and were more likely to test positive for Aspergillus antigens (galactomannan/beta-D-glucan). Mortality (by 90 days) was dramatically higher in the ITBA group (90%) than the non-ITBA group (44%). Most with ITBA were current smokers, which is interesting because smoking helps Aspergillus stick to the tracheobronchial epithelium (lining) and prevents mucociliary clearance of spores.
 
How good are animal models of invasive aspergillosis? (Walsh et al., 2020)
Many preclinical studies of antifungals and biomarkers are carried out in a line of immunocompromised rabbits that are given invasive pulmonary aspergillosis, in order to help design the best possible clinical trials to test dosages, safety and efficacy. This review describes in detail how this has contributed to new aspergillosis treatments such as combination antifungal (azole+echinocandin) therapy and the development of new drugs including olorofim.
-  You can watch Thomas Walsh's AAAM2020 talk on this subject on the LIFE Worldwide YouTube channel
 
Short courses of voriconazole and risk of IPA relapse (Shin et al., 2020)
Recommendations for the minimum length of treatment with voriconazole range from 6-12 weeks. A group at a Korean hospital found that 16% of IPA patients relapsed within a year, particularly if given voriconazole for less than 9 weeks, and especially if the radiological response to treatment has been poor (<50%) by the time treatment was discontinued.
 
Genetic testing and voriconazole (Villatoro et al., 2020)
A hospital in Spain will soon be starting a trial (VORIGENIPHARM, 2019-000376-41) to test whether haematology patients at risk of invasive Aspergillus infections could benefit from genetic testing early on in their cancer treatment, to predict how their body would react to taking voriconazole. Their study protocol describes testing a set of 180 mutations (SNPs) in genes such as CYP2C19, which control blood concentrations of voriconazole.
 
Genetic susceptibility to fungal infection in children (Ochoa et al., 2020)
Children who suffer from serious fungal infections but have no obvious risk factors may have an underlying genetic immunodeficiency. This review summarises the major genetic variants and their mechanisms. Of particular note are STAT3, CARD9 and various genes causing chronicgranulomatous disease, which are all associated with aspergillosis.
 
 
Case of the month
 
The Target Sign in MRI scans of Cerebral Aspergillosis (Finelli, 2020)
 
A 71-year-old man was admitted to hospital with pneumonia and fever that got progressively worse over 2 weeks, despite treatment with antibiotics. One blood culture grew Candida tropicalis and a Fungitell (beta-D-glucan) test was positive (>500), but other fungal tests were negative, so he was given IV micafungin.
 
However, he continued to deteriorate and ultimately died of a perforated caecum (intestine) caused by the ifnection. Cultures and microscopy of tissue samples taken from his lungs, brain and heart at the post-mortem showed disseminated Aspergillus infection as well as Candida pneumonia. The patient had a very low lymphocyte count (~80 cells/mm3) that would have made him vulnerable to infections, but the underlying reason for this was not clear.
 
This case highlights the difficulty of diagnosing invasive aspergillosis in patients who may have nonspecific symptoms and negative cultures, particularly when other coinfections are present.
 
CT scans of his head appeared normal, but an MRI scan showed many lesions throughout the brain, some of which reached 2-3 cm and were evolving into abscesses. In radiological terminology, each lesion appeared on both the ADC and T2W series as a 'target' (bullseye) with several layers:
  • Hypertinense (bright) necrotic centre
  • Hypointense (dark) inner ring of dense hyphae
  • Hyperintense (bright) outer ring of granulation tissue
The authors recommend this as a useful sign to help distinguish Aspergillus lesions from other conditions such as cancer metastases. Toxoplasmosis and lymphoma produce similar lesions but the number/location of lesions and the patient's clinical context can help to discern which is present.
 
 
  Patients and carers
 
Maybe you or a loved one has just received a diagnosis of aspergillosis and you’re not sure where to start. Or maybe you need to share information about your condition with your doctor, carer, housing association or benefits assessor. Our patients and carers website can provide you with everything you need to know about aspergillosis. 
 
This month we have talked a lot about the considerations for people who are classified as highly vulnerable to COVID-19 severe symptoms as they are being asked to stop shielding now that many countries are slowly lifting the lockdown..
 
Further information on this, and other COVID-19 information is available on aspergillosis.org
Other meetings and support
We host a weekly video phone call (Software: Zoom) with around 4-8 patients and a member of National Aspergillosis Centre (NAC) staff twice each week. You can use a computer or mobile device to join the video at Aspergillosis Community Support. This meeting runs from 10:00-11:00 BST every Tuesday & Thursday and is also presented in our private Facebook group (see below).
There is an additional meeting on the first Friday of every month which normally takes place at NAC but for the period of time when we are unable to hold face-to-face meetings we are meeting on Zoom, using the same registration details.To receive a text reminder when each monthly meeting is approaching send us your mobile phone number (NB this doesn't operate in the US) to admin@aspergillus.org.uk
 
 
  • Our Aspergillosis Support Facebook Group has over 2300 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 for 'aspergillosis' in Facebook.
 
 
Jobs
Clinical networks
Conferences
 
- Wythenshawe Hospital (MFT), UK
- Deadline 30th Oct
 
- Wythenshawe Hospital (MFT), UK
- Deadline 18th Oct
 
- Radboud UMC, Netherlands
- Deadline 20th Oct
 
- University of Exeter, UK
- Deadline 23rd Nov
 
More and more conferences are switching to exclusively online presentation as COVID-19 continues to restrict travel and social contact throughout the world.
 
Most recently the 38TH ANNUAL MEETING OF THE EUROPEAN SOCIETY FOR PAEDIATRIC INFECTIOUS DISEASES has been set for the 26 - 29th October 2020 as a virtual meeting
 
See more groups and societies
 
     
Fungal Infection Trust, PO Box 482, Macclesfield, Cheshire SK10 9AR
 
 
 
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