New research from NAC on prescribing posaconazole and isavuconazole

The National Aspergillosis Centre is at the forefront of understanding the best ways to treat chronic forms of aspergillosis. Two papers published this month add to the body of knowledge about how newer azoles (posaconazole and isavuconazole) can be used in this patient group.   

Attainment of therapeutic posaconazole serum levels during coadministration with rifampicin (Power et al, 2020)

  • Treating patients affected by co-infections of Aspergillus and Mycobacterium is notoriously difficult because of drug interactions: rifamycin antibiotics are known to switch on liver enzymes that lower the amount of itraconazole/voriconazole in the blood. Staff at the Infectious Diseases department of Wythenshawe Hospital (part of MFT) have expertise in treating both conditions and recently published 2 cases of patients with both NTM-PD and CPA, who were treated twice daily with 300 mg delayed-release posaconazole. Both patients tolerated and responded well to the treatment.

Isavuconazole TDM during long-term treatment for CPA (Kosmidis et al, 2020)

  • Isavuconazole is the newest azole antifungal and was approved for invasive aspergillosis, but less is known about possible side effects among CPA patients, who tend to be immunocompetent and receive treatment for many months. Usually 200 mg daily is prescribed, but here they found that a lower dose (100 mg) was less likely to give side effects and gave a satisfactory level of the drug in the blood. Another study by Furfaro et al (2019) found that around 1 in 3 patients on 200 mg daily isavuconazole experienced side effects (mainly gastrointestinal).

Selection of reviews – May 2020

Here’s our choice of review article highlights this month.

Diagnosis of severe respiratory infections in immunocompromised patients. Azoulay et al., 2020

This review focuses on the diagnosis of severe respiratory infections in immunocompromised patients. Special attention is given to newly validated diagnostic tests designed to be used on non-invasive samples or bronchoalveolar lavage fluid and capable of increasing the likelihood of an early etiological diagnosis.

Antifungal Therapy: New and Evolving Therapies. Nivoix et al., 2020

This article gives an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug-drug interactions, and frequent side effects, all of which should inform the choice of agent when managing invasive fungal infections.

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species. Garcia-Rubio et al., 2020

This paper reviews recent data on the composition and synthesis, influence of the components of the cell wall in fungi-host interaction and the role as a target for the next generation of antifungal drugs in yeasts and filamentous fungi (Aspergillus).

Pick of the papers – May 2020

Each month we choose a handful of papers that stood out to us as highlights. Let us know if you think a particular piece of research should feature.

Levels of evidence supporting clinical practice guidelines on invasive aspergillosis. Tejada et al., 2020.

This paper is the first study analysing the quality of evidence supporting invasive aspergillosis guidelines.  In evaluating the level of evidence (LOE) supporting recommendations in clinical practice guidelines (CPGs) of invasive aspergillosis (IA) it reports that among 238 strong recommendations, only 57 (24.0%) were supported by LOE A (multiple randomized controlled trial (RCT) or meta-analysis). When comparing recent CPGs with previous versions, the proportion of recommendations supported by LOE A did not significantly increase over time. The authors conclude that IA is a condition with an urgent unmet clinical need for more high-quality randomized trials.

Impact of high baseline Aspergillus-specific IgG levels on weight and quality-of-life outcomes of patients with chronic pulmonary aspergillosis. Bongomin et al., 2020.

This retrospective study evaluates the impact of quantitative baseline Aspergillus-specific immunoglobulin G (IgG) serum levels on weight changes of patients with chronic pulmonary aspergillosis (CPA) under antifungal treatment. A very high Aspergillus IgG may confer a higher likelihood of weight gain as a key, objective marker of clinical response, if patients can tolerate 12 months of antifungal therapy.

Clinical outcomes of patients with chronic pulmonary aspergillosis managed surgically. Setianingrum et al., 2020.

Surgical resection is one treatment modality for chronic pulmonary aspergillosis (CPA), and sometimes a preoperative presumption of lung cancer turns out to be CPA. This study audits surgical experience with regard to risk factors for relapse, and the value of postoperative monitoring of Aspergillus-immunogolubulin G (IgG) titres. It concludes that surgery in selected patients with CPA can have favourable outcomes. Relapse is common after surgical treatment of CPA but can be minimized with antifungal therapy, emphasizing the importance of an accurate diagnosis prior to surgery.

Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation. Wiesner et al., 2020. 

Wiesner et al. show a secreted fungal protease allergen of humans induces inflammation in mice with hallmarks of allergic asthma. The protease damages junctions of bronchiolar epithelial club cells, which the mechanosensor and gated calcium channel TRPV4 detects. Calcineurin mediates the calcium signaling and cellular alarms initiating lung allergic inflammation.

Aspergillus Endophthalmitis: Clinical Presentations and Factors Determining Outcomes. Dave et al., 2020.

This retrospective, interventional, multicentric case series describes the clinical presentations, management and factors determining outcomes of Aspergillus endophthalmitis, an eye infection. It reports trauma and intraocular surgery as common causes. The common infecting fungi are Fusarium and Aspergillus species for exogenous endophthalmitis, the latter having high ocular morbidity and poor outcome.

Veterinary research

Development of a comprehensive protein microarray for immunoglobulin E profiling in horses with severe asthma. White et al., 2019.

This study reports that protein microarrays can be used for large-scale IgE mapping of allergens associated with the environment of horses. This technology provides a sound platform for specific diagnosis, management, and treatment of severe equine asthma (SEA). SEA is a prevalent, performance-limiting disease associated with increased allergen-specific immunoglobulin E (IgE) against a range of environmental aeroallergens.

Selection of reviews – April 2020

Here’s our choice of review article highlights this month.Treatment of allergic bronchopulmonary aspergillosis: from evidence to practice (Dhooria et al., 2020) This review illustrates the treatment pathway for ABPA in different situations, using a case-based approach. In each case, the options for treatment based on the available evidence from recent clinical trials is presented.

Detecting azole-antifungal resistance in Aspergillus fumigatus by pyrosequencing (van der Torre et al., 2020)Failure to detect azole-resistance dramatically increases the mortality rates of azole-treated patients. Despite drug susceptibility tests not being routinely performed currently, the authors of this review suggest including resistance testing whilst diagnosing Aspergillus disease. It also describes current diagnostic methods and highlights the potential of pyrosequencing to aid in a diagnosis complete with a resistance profile to improve clinical outcomes.

Role of lipid transporters in fungal physiology and pathogenicity (Rizzo et al., 2019)This review focuses on the structural and biological aspects of ATP-driven lipid transporters, comprising P-type ATPases and ATP-binding cassette transporters, (ii) the role of these transporters in fungal physiology and virulence, and (iii) the potential of lipid transporters as targets for the development of novel antifungals. These recent observations indicate that the lipid-trafficking machinery in fungi is a promising target for studies on physiology, pathogenesis and drug development.

Pick of the papers from April 2020

Each moth we choose a handful of papers that stood out to us as highlights. Let us know if you think a particular piece of research should feature!.

Deep cutaneous fungal infections in solid-organ transplant recipients (Galezowski et al., 2020) This retrospective, observational, multicentre study was conducted in France to determine deep cutaneous fungal infections (DCFIs) diagnostic characteristics and outcomes with treatments in adult solid-organ transplant recipients. It describes the diversity and occurrence frequency of DCFIs. Phaeohyphomycoses were the most frequent DCFIs, representing a prevalence of 46%. Aspergillus species represented 8.7%.

Prevalence of fungal infection in nasal polyposis – A cross-sectional study, conducted at a tertiary care hospital in Karachi (Qaisar Sajjad et al., 2020) This cross sectional study, carried out from October 2010 to January 2015 on 221 patients in a tertiary care centre in Karachi was undertaken to determine the prevalence of fungal infections in nasal polyposis. Data was collected, a descriptive analysis was performed and a Computed Tomography (CT) grading was done. On the basis of histopathology, 90 (40.7%) patients were found to have fungal infection.

Functional characterization of clinical isolates of the opportunistic fungal pathogen Aspergillus nidulans (Bastos et al., 2020) Aspergillus nidulans has mainly been studied in the context of chronic granulomatous disease (CGD), with characterisation of clinical isolates obtained from non-CGD patients remaining elusive. This study reports a detailed biological characterisation of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, nonclinical FGSC A4 strain. Differences in metabolic responses, growth rates and other strain-specific virulence traits and pathogenicity are described.

Diversity of secondary metabolism in Aspergillus nidulans clinical isolates (Drott et al., 2020) Despite its importance, there is little information about the natural diversity of secondary metabolism (SM) in A. nidulans. This paper describes six novel clusters that contribute to the considerable variation in both biosynthetic gene clusters content and SM production within A. nidulans. The authors emphasize that A. nidulans may also be a strong model to use within-species diversity to elucidate regulatory cross talk, fungal ecology, and drug discovery systems.

Exposure to mold proteases stimulates mucin production in airway epithelial cells through Ras/Raf1/ERK signal pathway. (Wu et al., 2020). This paper seeks to understand the underlying molecular mechanisms of airway obstruction and immune hyper-responsiveness caused by mucus overproduction in A.fumigatus induced lung diseases. It identifies and describes a novel downstream signal pathways that mediate A.fumigatus induced mucin production in airway epithelial cells. The discovery of this novel pathway contributes to the understanding of the pathogenesis of fungal sensitisation in allergic diseases such as fungal asthma.

Knowledge into invasive fungal diseases during COVID-19 continues to develop

Influenza can be complicated by invasive aspergillosis, as first described in 1952. About 35% of critically ill patients with COVID-19 are treated with corticosteroids and we know from meta-analyses that these patients have nearly double the mortality, lower ICU stay and more secondary infections, probably including aspergillosis (Rodrigo et al., 2015 and Ni et al., 2019). This link with corticosteroids is likely with COVID-19. Aspergillus antigen testing of respiratory fluids should be routine for these very ill patients.

Research into COVID-19 is taking place at an incredible pace but there is still much we don’t know. One key unknown is the frequency and impact of co-infections. Gangneux et al. highlights the fact that invasive fungal infections are still rarely reported and may be underdiagnosed. It reports what is not known and what should be done.

Studies are starting to emerge reporting fungal co-infection rates. Koehler et al. published this week that clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection. They noted that five of 19 critically ill patients (26%) developed COVID-19 associated invasive pulmonary aspergillosis.  A pre-published report from Alanio et al. found putative IPA in almost one third of successive critically ill COVID-19 patients (not yet peer-reviewed). A further early release article describes a fatal case of invasive pulmonary aspergillosis in an immunocompetent patient in France who had severe coronavirus disease–associated pneumonia (Blaize et al., 2020).

As further research is undertaken we will collate it and make it available on the LIFE Worldwide website. The page will be updated as more information becomes available.

A new systematic review and a 91-case series shed light on Aspergillus endophthalmitis

While less common than bacterial eye infections, fungal infections can lead to worse outcomes, especially if diagnosis and treatment are delayed.

Corneal ulcers (keratitis) are a significant public health problem in low-resource settings where many people work in industries (e.g. farming, forestry) with a high risk of traumatic onculation of fungi into the eye, and patients may present later in the course of infection due to poverty. Prajna et al (2017) shared their experiences of carrying out clinical research at Aravind Eye Hospital (India) with these challenges.

Many systemic formulations of antifungals have limited penetration into the eyes. Some antifungals can be administered intravitreally, but amphotericin B can cause retinal toxicity at higher doses (Payne et al, 2010). Voriconazole is less toxic but requires more frequent injection(every 24 hours) than amphotericin B (every 48 hours).

Fungal endophthalmitis is the infection of the interior parts of the eye (i.e. aqueous or vitreous humour), most commonly by Candida or Aspergillus. Two recent papers give insight into Aspergillus endophthalmitis.

 Dr Leopoldo Spadea and Dr Maria Giannico recently published a systematic review of the available diagnostic and management strategies for treating Aspergillus endophthalmitis. While there is a lack of serological tests, vitreous culture is often positive. Culture should be performed before starting antifungal treatment. Ultrasound examination is mandatory when the fundus cannot be explored by retinography.

Antifungals should be administered for at least a month, either systemically, intravitreally or in combination. Amphotericin B can cause retinal toxicity (especially at higher doses). Systemic voriconazole has relatively good penetration into the ocular compartment. Vitrectomy is often required, and enucleation may even be needed. Steroids should be used with caution as they can cause worsening of the infection.

Dr Vivek Dave and colleagues in India presented a large series of 91 immunocompetent patients with Aspergillus endophthalmitis. The most common causes were trauma (46%), surgery (42%) and endogenous (11%). 51 patients received amphotericin B only, 33 received voriconazole only, and 7 received both. They found that early vitrectomy was superior to vitreous tap alone, but outcomes were often poor. Corneal involvement and presence of fungal hyphae on microscopy were associated with worse outcomes.

Invasive aspergillosis in COVID-19 patients

Invasive pulmonary aspergillosis is a well-known complication of severe influenza, but it is not yet clear whether it could be a major co-infection in COVID-19 cases. Anecdotal reports from clinicians suggest that it is happening, but published data are currently sparse.

As well as having overlapping clinical symptoms (fever, cough), there are several practical barriers to laboratory testing. Collecting a respiratory sample by bronchoscopy generates aerosolised droplets of SARS-CoV-2 and requires full PPE, and in certain cases recovery of Aspergillus by culture may represent colonisation of the airways rather than a true infection.

However, rapid bedside (point of care) tests that measure galactomannan antigen in serum or BAL are available from OLM Diagnostics and IMMY, which give a result in around 30 minutes (read more).

CLINICIANS: If you find any publications or cases of COVID-19 with aspergillosis you can email us or join the conversation on Twitter. You can find out more about diagnosing Aspergillus on the LIFE laboratory diagnostics page or watch video protocols on their YouTube channel.

PATIENTS/CARERS: If you are looking for guidance or support for patients and carers with aspergillosis (e.g. CPA or ABPA) who are concerned about COVID-19, please visit the Aspergillosis Patients & Carers website or direct them towards the Facebook Aspergillosis Support group.

Aspergillus ustus and Invasive Aspergillosis

Invasive aspergillosis (IA) is an infection of severely immunocompromised that has a high mortality rate, especially if not quickly diagnosed, and diagnosis tends to be very difficult in this group of patients. Most infections are caused by Aspergillus fumigatus but there are some important exceptions and understanding those exceptions better is the key to improving mortality.Glamedakis et. al. (2020) have carried out a multicentre retrospective study which included Regional Mycology Centre Manchester but also multiple centres across Europe. The group found 72 cases of A. ustus IA. Of these

  • 80% had undergone either a haematopoietic or solid organ transplant and importantly 92% of cases were not neutropenic when IA was diagnosed whereas IA caused by A. fumigatus seems far more dependant on neutropenia (Muhlemann 2005).
  • The cases seemed to involve more sites of infection compared with A. fumigatus with 46% affecting sites such as skin, brain
  • Mortality is high and the authors comment that this may be due to the lack of optimisation of antifungal therapy for infections caused by this species of Aspergillus.

Recognising the rare infections caused by this species rather than A fumigatus is clearly important to optimise survival rates and that isn’t going to be easy in the limited time available to treat IA. We urgently need to optimise therapy tailored to this species of the pathogen.

Aspergillus ustus

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