Non-invasive tests to detect invasive aspergillosis (IA) in immunocompromised patients have the potential to save lives, but their performance varies depending on many factors including the prevalence of IA and patient characteristics of the group in question.
A new Cochrane systematic review (Cruciani et al, 2019) summarises 29 studies using PCR on blood samples. For a single positive test, sensitivity and specificity were both ~80%. For two consecutive positive tests, sensitivity was lower (~60%) but specificity was greatly improved (~95%). The authors conclude that consecutive PCR testing is useful for screening high-risk patients, possibly in combination with serum galactomannan testing, and that with further validation this could become the standard of care.
Indeed, EORTC/MSGERC recently added Aspergillus PCR to the consensus definitions of probable invasive fungal disease (IFD) for research. This definition underpins clinical trials, epidemiology studies and development of new diagnostics. Read the new guidelines (Donnelly et al, 2019) and accompanying commentary (Rogers, 2019).
A new course is now available through Future Learn called 'The Role of Antifungal Stewardship'. Developed as a collaboration between BSAC and MRCM (the reference mycology lab based at the National Aspergillosis Centre), this course is aimed at GPs and other primary care clinicians.
The FDA has granted Breakthrough Therapy status to olorofim (previously F901318), for invasive mould infections including aspergillosis. It is hoped this will help to expedite its approval process.
Video-assisted thoracoscopic surgery for IPA in haematology patients
Up to a third of patients die during surgery for massive haemoptysis, but the criteria for selecting asymptomatic patients for pre-emptive surgery (wedge resection, segmentectomy or lobectomy) remain controversial. A group in China (Ma et al, 2019) recently published a series of 51 haematology patients who received video-assisted thorascopic surgery (VATS), who had been selected on the basis of having a limited lesion that was resistant to antifungals. Mean blood loss was 112.35 ml and mean hospital stay was 7.75 days. No operations were converted to open surgery, and no recurrences or deaths were seen within 30 days. Postoperative complications were seen in 21.6%, most commonly excessive effusions and prolonged air leak (especially for wedge resections).
Effective plasma concentrations of itraconazole and its active metabolite for IPA
Therapeutic drug monitoring is often recommended for itraconazole but may be unavailable - for example, it is not covered by the national health insurance scheme in Japan for pulmonary aspergillosis. A recent study (Nakamura et al, 2019) measured trough plasma concentrations of itraconazole (ITZ) and its active metabolite hydroxyitraconazole (OH-ITZ) by HPLC among 34 patients taking 200 mg/day itraconazole. The variation in total ITZ+OH-ITZ concentrations was striking, ranging from 47 ng/ml to 7750 ng/ml. Concentration was clearly related to efficacy: ITZ levels were 4.8x higher among patients who improved (mean 1254 ng/ml) than those who worsened (mean 260 ng/ml), while OH-ITZ levels were 3.5x higher among patients who improved (mean 1830 ng/ml) than those who worsened (mean 530 ng/ml).
The Aspergillus fumigatus Mismatch Repair MSH2 Homolog Is Important for Virulence and Azole Resistance
Mutations in the cyp51A gene are the major mechanism for acquired azole resistance in Aspergillus, but it can also arise through defects in the DNA mismatch repair (MMR) system that lead to a genomic instability. A recent study (Fernanda dos Reis et al, 2019) looked at 62 environmental and clinical strains of A. fumigatus, of which 12 (18%) had variants in mshA, which initiates MMR. Mortality was lower for an mshA deletion mutant (30-60%) than for wild type (90%) in a mouse model of invasive aspergillosis. However, when the deletion strains were repeatedly (x10) transferred onto fresh solid agar, they began to accumulate mutations that increased virulence, and exposure to a single round of voriconazole exposure led to the appearance of mutants with 200-fold higher resistance to posaconazole than mutants evolved from the wild type strain.
Biological Control for Aflatoxin Mitigation in Farmers’ Fields in Nigeria
Aspergillus contamination of crops such as maize and peanuts can bring aflatoxins into the human food chain, leading to chronic poor health or even life-threatening liver disease and cancer, as well as economic losses. One preharvest control method used in the US for many years involves displacing the harmful mould with one or more non-toxin-producing strains. In 2014, a biocontrol product called Aflasafe was registered in Nigeria, which contains a mixture of 4 atoxigenic strains of Aspergillus flavus. A decade-long study (Bandyopadhyay et al, 2019) found that it reduced aflatoxin content by >80% compared to untreated maize, and that >95% of treated maize contained <20ppb aflatoxin.
Is This Zebra Really a Zebra? The Challenge of Diagnosing Rare Fungal Infections in Veterinary Pathology
Many disease-causing fungi are tricky to reliably distinguish from contamination, especially at non-sterile sites in outdoor animals. For molecular techniques like PCR, it is critical to use the right database in order to reduce false positive results, but care must be taken in interpreting results when an unusual fungus is suggested (Lockhart & Gary, 2019).
Prophylaxis of mould infections
Haematology patients and transplant recipients are at particularly high risk of invasive fungal infections but those receiving fluconazole prophylaxis are not protected against Aspergillus, which is intrinsically resistant. A recent review summarised the evidence for the use of different azole antifungals (Moreno-García et al, 2019). While more expensive, posaconazole is more effective at preventing invasive aspergillosis and has excellent pharmacokinetic properties, resulting in greater exposure at the site of infection. Data is currently lacking for isavuconazole.
Inhaled Amphotericin B as Aspergillosis Prophylaxis in Hematologic Disease
IDSA clinical guidelines recommend antifungal prophylaxis for patients with prolonged (>7 days) neutropaenia, generally with a triazole or echinocandin. A new systematic review (Duckwall et al, 2019) presents evidence from 6 trials for the use of nebulised amphotericin B (AmB), with relative risk reduction of IA ranging from 40-60%. The main side effects were bad taste, cough and nausea. They conclude that 12.5 mg inhaled AmB twice weekly is a suitable regimen for prophylaxis where azoles are contraindicated, or in areas where azole resistance is high.
Patients and carers
December’s patient meeting's was a break from the norm. We had a Christmas quiz! Devised by Graham, it was a fun filled hour of science trivia and NAC conundrums. This year's winner wished to remain anonymous but recieved this fantastic trophy and an extra mince pie! The meeting is available to watch so make sure you catch up!
There will be no patient meeting in January but we'll return on February 7th 2020 with a guest speaker from the University of Oxford.
Professor Kyle Pattinson is a Senior Clinical Research Fellow and Associate Professor in the Nuffield Department of Clinical Neurosciences at the University of Oxford. He will be talking about 'Breathing with your Brain', which was the topic of a public engagement event at the Royal Society Summer Science Exhibition. Professor Kyle's exhibit helped visitors to understand the how the brain controls our feelings of being out of breath. We're looking forward to welcoming him to NAC.
Join us for this fascinating talk in the Altounyan Suite, North West Lung Centre, Manchester at 12.30pm BST on February 7th, 2020. If you can't make it in person you are welcome to watch on Facebook. We broadcast live (this is limited to UK patients only) and post the recording so you can watch it in your own time. (Facebook Broadcast)
Other meetings and support
We host a weekly video phone call with around 4-8 patients and a member of NAC staff each week. You can use a computer or mobile device to join the video but you need to register in advance. This meeting runs from 10:00-11:00 BST every Thursday.
To receive a text reminder when each meeting is approaching send us your mobile phone number (NB this doesn't operate in the US) to firstname.lastname@example.org.
Join our Facebook Groups
- Our Aspergillosis Support Facebook Group has over 2000 members and is a safe place to meet and talk to other people with aspergillosis. We have a public group and a private group.
- 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'
3-7 February, 2020
10-14 February 2020
Utrecht, The Netherlands
17-20 February, 2020
27-29 February, 2020
||See more groups and societies
Fungal Infection Trust, PO Box 482, Macclesfield, Cheshire SK10 9AR