Publications by authors named "Darius Armstrong-James"

66 Publications

Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study.

J Cyst Fibros 2021 May 3. Epub 2021 May 3.

National Heart & Lung Institute, Imperial College London, UK; Royal Brompton and Harefield Hospitals, London, UK.

Background: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection.

Methods: Patients on the UK CF Registry in 2016 were grouped into: absent (Pa-), intermittent (Pai) or chronic Pa (Pac), each with Asp positive (Asp+) or negative (Asp-). Primary outcome was best percentage predicted FEV (ppFEV) that year. Secondary outcomes were intravenous (IV) antibiotic courses, growth (height, weight, BMI) and additional disease complications. Associations between outcomes and infection-status were assessed using regression models adjusting for significant confounders (age, sex, Phe508del homozygosity and CF-related diabetes (CFRD)).

Results: 9,270 patients were included (median age 19 [IQR 9-30] years, 54% male, 50% Phe508del/F508del). 4,142 patients (45%) isolated Pa, 1,460 (16%) Asp. Pa-/Asp+ subjects had an adjusted ppFEV that was 5.9% lower than Pa-/Asp- (p < 0.0001). In patients with Pai or Pac, there was no additional impact of Asp on ppFEV. However, there was a higher probability that Pac/Asp+ patients had required IV antibiotics than Pac/Asp- group (OR 1.23 [1.03-1.48]). Low BMI, ABPA, CF-liver disease and CFRD were all more frequent with Asp alone than Pa-/Asp-, though not more common in Pac/Asp+ than Pac/Asp-.

Conclusions: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.
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http://dx.doi.org/10.1016/j.jcf.2021.04.007DOI Listing
May 2021

Fungal-Induced Programmed Cell Death.

J Fungi (Basel) 2021 Mar 20;7(3). Epub 2021 Mar 20.

Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, UK.

Fungal infections are a cause of morbidity in humans, and despite the availability of a range of antifungal treatments, the mortality rate remains unacceptably high. Although our knowledge of the interactions between pathogenic fungi and the host continues to grow, further research is still required to fully understand the mechanism underpinning fungal pathogenicity, which may provide new insights for the treatment of fungal disease. There is great interest regarding how microbes induce programmed cell death and what this means in terms of the immune response and resolution of infection as well as microbe-specific mechanisms that influence cell death pathways to aid in their survival and continued infection. Here, we discuss how programmed cell death is induced by fungi that commonly cause opportunistic infections, including , , and , the role of programmed cell death in fungal immunity, and how fungi manipulate these pathways.
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http://dx.doi.org/10.3390/jof7030231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003624PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency.

Thorax 2021 Feb 25. Epub 2021 Feb 25.

Immunology, Imperial College London, London, UK.

Bronchiectasis is a well-recognised complication of primary antibody deficiency (PAD) syndromes. Previous data suggest that mortality in common variable immune deficiency (CVID) is not associated with isolated bronchiectasis. A retrospective analysis of patients with CVID and specific antibody deficiency in two tertiary referral centres with lung disease was conducted. Severity of bronchiectasis at presentation was associated with mortality. Lower FEV, colonisation with and a diagnosis of COPD were also associated with mortality. Bronchiectasis is an important driver of mortality in patients with PAD syndromes.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215585DOI Listing
February 2021

A retrospective multicenter analysis of candidaemia among COVID-19 patients during the first UK pandemic wave.

J Infect 2021 Feb 18. Epub 2021 Feb 18.

Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London SW10 9NH, UK; North West London Pathology, Fulham Palace Road, London W6 8RF, UK; Imperial College London, Department of Infectious Diseases, Flowers Building, Armstrong Road, London SW7 2AZ, UK.

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http://dx.doi.org/10.1016/j.jinf.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890346PMC
February 2021

PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections.

J Fungi (Basel) 2020 Dec 17;6(4). Epub 2020 Dec 17.

Pulmocide Ltd., Office Suite 3.01, 44 Southampton Buildings, London WC2A 1AP, UK.

Disease due to pulmonary infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus spp. and spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug-drug interactions.
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http://dx.doi.org/10.3390/jof6040373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765807PMC
December 2020

Immunotherapeutic approaches for fungal infections.

Curr Opin Microbiol 2020 12 2;58:130-137. Epub 2020 Nov 2.

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, United Kingdom. Electronic address:

Despite the availability of antifungal treatments, fungal infections are still causing morbidity all around the globe with unacceptably high mortality rates. A major driver for the rising incidence of serious fungal infections is due to a substantial increase in immunocompromised individuals with autoimmune diseases, cancers and transplants. Because of growing resistance in fungus to frontline triazole antifungals and the association of fungal disease with the immunocompromised host, adjunctive host-directed therapy is seen as a promising choice to improve patient outcomes. Immunotherapeutic treatments being explored as adjunct therapies to existing antifungal treatments include cytokine therapy, monoclonal antibodies and cellular immunotherapy. In this review, we give a brief overview of potential immunotherapies and recent developments in the field, which are needed to tackle the growing problem of fungal diseases.
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http://dx.doi.org/10.1016/j.mib.2020.09.007DOI Listing
December 2020

Successful salvage therapy for fungal bronchial anastomotic infection after -lung transplantation with an inhaled triazole anti-fungal PC945.

J Heart Lung Transplant 2020 12 29;39(12):1505-1506. Epub 2020 Sep 29.

Royal Brompton and Harefield NHS Foundation Trust, Respiratory and Transplant Medicine, Harefield Hospital, Harefield, United Kingdom.

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http://dx.doi.org/10.1016/j.healun.2020.09.015DOI Listing
December 2020

CFTR Modulators Dampen -Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes.

Front Cell Infect Microbiol 2020 24;10:372. Epub 2020 Jul 24.

Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom.

Excessive inflammation by phagocytes during infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce colonization , however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen -induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction ( < 0.05) in -induced ROS. For CF PBMC, -induced ROS was significantly reduced when pre-treated with ivacaftor alone ( < 0.01) or in combination with lumacaftor ( < 0.01), with a comparable significant reduction in control subject PBMC ( < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat -induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action.
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http://dx.doi.org/10.3389/fcimb.2020.00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393064PMC
July 2020

Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B.

BMJ Case Rep 2020 May 12;13(5). Epub 2020 May 12.

Department of Nephrology, Queen Elizabeth Hospital Birmingham, Birmingham, UK

Critically ill patients are at risk of developing both acute kidney injury (AKI) and invasive fungal infections (IFIs). Prompt and efficient treatment of the IFI is essential for the survival of the patient. This article examines three distinct clinical situations where liposomal amphotericin B, a broad-spectrum antifungal agent, was successfully used in the setting of AKI. The first was infection in a 63-year-old man with bleeding oesophageal varices related to advanced liver disease. The second was gastrointestinal mucormycosis in a 74-year-old man who developed a small bowel obstruction following an autologous stem cell transplant for mantle cell lymphoma. The third was a infection in a 32-year-old woman on immunosuppression for a bilateral lung transplant for cystic fibrosis. In all three cases, liposomal amphotericin B was required for urgent management of the patient's IFI. We discuss the rationale for treatment with a potentially nephrotoxic agent in this setting.
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http://dx.doi.org/10.1136/bcr-2019-233072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228453PMC
May 2020

Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of Aspergillus species against four commonly used antifungals.

Med Mycol 2020 Nov;58(8):1085-1090

Department of Microbiology, Laboratory Medicine, Royal Brompton and Harefield NHS foundation trust, London.

The aim of this study was to evaluate a colorimetric method, MIRONAUT-AM, for determining susceptibility testing of anidulafungin, amphotericin, voriconazole, and itraconazole by comparing the minimum inhibitory (effective) concentrations (MICs/MECs) obtained by this method to those generated by the reference Clinical Laboratory Standard Institute (CLSI) broth microdilution method. In sum, 78 clinical isolates of Aspergillus species, nine of them non-wild type (non-WT) with itraconazole MIC ranging from 2 mg/l to >16 mg/l, were tested against above antifungals. A. fumigatus ATCC 204305 was used as a reference strain, and test was performed in accordance with slightly modified yeast susceptibility testing instruction of the manufacture; conidia suspension inoculum and alamarBlue concentration were optimized. These same isolates were referred to Bristol Mycology reference laboratory and tested by CLSI method. The MICs and MECs generated by the two methods were compared using concordance analysis. MIRONAUT-AM showed significant concordance (P < .0001) with CLSI method, and overall agreement was high (≥90%). In addition, MIRONAUT-AM produced echinocandin MECs results within 18-24 hours incubation time and correctly detected all non-WT isolates except one isolate. This colorimetric method is very promising and appears to be a suitable alternative susceptibility testing method to labor intensive broth microdilution reference method for Aspergillus species.
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http://dx.doi.org/10.1093/mmy/myaa020DOI Listing
November 2020

Relationship between spirometry results and colonisation of Aspergillus species in allergic asthma.

Clin Respir J 2020 Mar 26. Epub 2020 Mar 26.

Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Introduction And Objectives: Exposure to fungi in patients with asthma leads to the release of various fungal antigens, which can increase the severity of asthma. Regarding this, the present study was conducted to evaluate the relationship between the colonisation of Aspergillus species and spirometry results in allergic asthma.

Materials And Methods: Two hundred sixteen patients with mild to severe asthma and 30 healthy controls were included. All participants underwent pulmonary function tests. Furthermore, sputum samples were collected from each subject. Each sputum sample was subjected to direct microscopic examination and fungal culture. All cultured Aspergillus colonies were identified at species level by molecular methods. Finally, all available data from sputum culture and spirometry test were analysed.

Results: Out of 216 sputum samples, 145 (67.1%) were positive for fungal growth. Furthermore, out of 264 grown fungal colonies, 137 (51.9%) were Aspergillus species. Among the Aspergillus isolates, A. flavus (29.2%) was the most prevalent species, followed by A. fumigatus (27.7%). The mean forced expiratory volume in one second (FEV1) in the mild, moderate and severe asthmatic patients with a positive sputum culture for fungi were obtained as 90.0 ± 11.1, 71.1 ± 15.9 and 54.9 ± 16.4, respectively. In general, Aspergillus species colonisation had no statistically significant effect on spirometry results of study patients.

Conclusion: Our results showed that there is no difference in the FEV1 and forced vital capacity between Aspergillus positive and negative patients in any asthma severity group.
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http://dx.doi.org/10.1111/crj.13192DOI Listing
March 2020

In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris.

J Antimicrob Chemother 2019 10;74(10):2943-2949

Medical Microbiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Objectives: Management of Candida auris infection is difficult as this yeast exhibits resistance to different classes of antifungals, necessitating the development of new antifungals. The aim of this study was to investigate the susceptibility of C. auris to a novel antifungal triazole, PC945, optimized for topical delivery.

Methods: A collection of 50 clinical isolates was obtained from a tertiary care hospital in North India. Nine isolates from the UK, 10 from a CDC panel (USA) and 3 from the CBS-KNAW culture collection (Japanese and South Korean isolates) were also obtained. MICs (azole endpoint) of PC945 and other triazoles were determined in accordance with CLSI M27 (third edition). Quality control strains were included [Candida parapsilosis (ATCC 22019) and Candida krusei (ATCC 6258)].

Results: Seventy-four percent of isolates tested showed reduced susceptibility to fluconazole (≥64 mg/L). PC945 (geometric mean MIC = 0.058 mg/L) was 7.4-fold and 1.5-fold more potent than voriconazole and posaconazole, respectively (both P < 0.01). PC945 MIC values correlated with those of voriconazole or posaconazole, and only three isolates were found to be cross-resistant between PC945 and other azoles. ERG11 sequence analysis revealed several mutations, but no correlation could be established with the MIC of PC945. Tentative epidemiological cut-off values (ECOFFs) evaluated by CLSI's ECOFF Finder (at 99%) with 24 h reading of MICs were 1, 4 and 1 mg/L for PC945, voriconazole and posaconazole, respectively. MIC values for quality control strains of all triazoles were in the normal ranges.

Conclusions: PC945 was found to be a more potent inhibitor than posaconazole, voriconazole and fluconazole of C. auris isolates collected globally, warranting further laboratory and clinical evaluations.
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http://dx.doi.org/10.1093/jac/dkz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753477PMC
October 2019

Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics.

Med Mycol 2019 Jun;57(Supplement_3):S307-S317

National Heart and Lung Institute, Imperial College London, UK.

The use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors.
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http://dx.doi.org/10.1093/mmy/myy136DOI Listing
June 2019

Functional effects of the microbiota in chronic respiratory disease.

Lancet Respir Med 2019 10 8;7(10):907-920. Epub 2019 Apr 8.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, NSW, Australia; Centre for Inflammation, Centenary Institute, and University of Technology Sydney, NSW, Australia. Electronic address:

The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.
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http://dx.doi.org/10.1016/S2213-2600(18)30510-1DOI Listing
October 2019

Aspergillus colonization and antifungal immunity in cystic fibrosis patients.

Med Mycol 2019 Apr;57(Supplement_2):S118-S126

National Heart and Lung Institute, Imperial College London, United Kingdom.

Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and chronic airway inflammation is the major determinant of survival with a median age at death of 29 years. Approximately 60% of CF patients are infected with Aspergillus fumigatus, a ubiquitous environmental fungus, and its presence has been associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. Yet time of acquisition of this fungus and determinants of CF-related Aspergillus disease severity and progression are not known. CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal function. Research delineating the role of CFTR-deficient phagocytes in Aspergillus persistence and infection in the CF lung, has only recently received attention. In this concise review we aim to present the current understanding with respect to when people with CF acquire infection with A. fumigatus and antifungal immune responses by CF immune cells.
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http://dx.doi.org/10.1093/mmy/myy074DOI Listing
April 2019

Rapid and Sensitive Detection of Azole-Resistant Aspergillus fumigatus by Tandem Repeat Loop-Mediated Isothermal Amplification.

J Mol Diagn 2019 03 4;21(2):286-295. Epub 2018 Dec 4.

Centre for Bio-Inspired Technology, Institute of Biomedical Engineering, Department of Electrical and Electronic Engineering.

Invasive fungal infections caused by multiazole-resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multiazole-resistant A. fumigatus are, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings. Here, we developed a LAMP assay to detect a 34 bp tandem repeat, named TR34-LAMP. TR34 is a high-prevalence allele that, in conjunction with the L98H single-nucleotide polymorphism, is associated with the occurrence of multiazole resistance in A. fumigatus in the environment and in patients. This process was validated with both synthetic double-stranded DNA and genomic DNA prepared from azole-resistant isolates of A. fumigatus. Use of our assay resulted in rapid and specific identification of the TR34 allele with high sensitivity, detecting down to 10 genomic copies per reaction within 25 minutes. Fluorescent and colorimetric detections were used for the analysis of 11 clinical isolates as cross validation. These results show that the TR34-LAMP assay has the potential to accelerate the screening of clinical and environmental A. fumigatus to provide a rapid and accurate diagnosis of azole resistance, which current methods struggle to achieve.
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http://dx.doi.org/10.1016/j.jmoldx.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419584PMC
March 2019

Human NK Cells Develop an Exhaustion Phenotype During Polar Degranulation at the Hyphal Synapse.

Front Immunol 2018 22;9:2344. Epub 2018 Oct 22.

Faculty of Medicine, Imperial College London, National Heart and Lung Institute, London, United Kingdom.

Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of . We show that the interaction between NK cells and induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of . These observations suggest that -mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.
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http://dx.doi.org/10.3389/fimmu.2018.02344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204393PMC
October 2019

Surveillance for Azole-Resistant in a Centralized Diagnostic Mycology Service, London, United Kingdom, 1998-2017.

Front Microbiol 2018 20;9:2234. Epub 2018 Sep 20.

Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

is the leading cause of invasive aspergillosis. Treatment is hindered by the emergence of resistance to triazole antimycotic agents. Here, we present the prevalence of triazole resistance among clinical isolates at a major centralized medical mycology laboratory in London, United Kingdom, in the period 1998-2017. A large number ( = 1469) of clinical isolates from unselected clinical specimens were identified and their susceptibility against three triazoles, amphotericin B and three echinocandin agents was carried out. All isolates were identified phenotypically and antifungal susceptibility testing was carried out by using a standard broth microdilution method. Retrospective surveillance (1998-2011) shows 5/1151 (0.43%) isolates were resistant to at least one of the clinically used triazole antifungal agents. Prospective surveillance (2015-2017) shows 7/356 (2.2%) isolates were resistant to at least one triazole antifungals demonstrating an increase in incidence of triazole-resistant in our laboratory. Among five isolates collected from 2015 to 2017 and available for molecular testing, three harbored TR/L98H alteration in the gene that are associated with the acquisition of resistance in the non-patient environment. These data show that historically low prevalence of azole resistance may be increasing, warranting further surveillance of susceptible patients.
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http://dx.doi.org/10.3389/fmicb.2018.02234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158360PMC
September 2018

High prevalence of triazole resistance in clinical Aspergillus fumigatus isolates in a specialist cardiothoracic centre.

Int J Antimicrob Agents 2018 Nov 10;52(5):637-642. Epub 2018 Aug 10.

Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College London, UK; Department of Microbiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Objectives: To evaluate the prevalence of triazole-resistant Aspergillus fumigatus and common molecular cyp51A polymorphisms amongst clinical isolates in a specialised cardiothoracic centre in London, UK.

Methods: All A. fumigatus isolates were prospectively analysed from April 2014 to March 2016. Isolates were screened with a four-well VIPcheck™ plate to assess triazole susceptibility. Resistance was confirmed with a standard microbroth dilution method according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Triazole-resistant A. fumigatus isolates were subjected to a mixed-format real time polymerase chain reaction (RT-PCR) assay (AsperGenius) to detect common cyp51A alterations.

Results: We identified 167 clinical A. fumigatus isolates from 135 patients. Resistance to at least one azole antifungal drug was confirmed in 22/167 (13.2%) of isolates from 18/135 (13.3%) patients, including 12/74 (16.2%) patients with cystic fibrosis (CF). The highest detection rate of azole-resistant A. fumigatus was among the 11- to 20-y age group. All triazole-resistant isolates (n = 22) were resistant to itraconazole, 18 showed cross-resistance to posaconazole and 10 displayed reduced susceptibility to voriconazole. No pan-azole-resistant A. fumigatus was identified. TR/L98H was identified in 6/22 (27.3%) of azole-resistant isolates and detectable in 5/12 (42%) patients with CF.

Conclusions: In our specialist cardiothoracic centre, the prevalence of triazole-resistant A. fumigatus is alarmingly high (13.2%). The majority of azole-resistant isolates were from patients with CF. We found a higher prevalence of the environmentally driven mutation TR/L98H in our A. fumigatus isolates than in published UK data from other specialist respiratory centres, which may reflect differing patient populations managed at these institutions.
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http://dx.doi.org/10.1016/j.ijantimicag.2018.08.004DOI Listing
November 2018

Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during phagocytosis.

Blood 2018 11 18;132(18):1985-1988. Epub 2018 Jul 18.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1182/blood-2017-12-823393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450054PMC
November 2018

A Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine Setting.

Antimicrob Agents Chemother 2018 10 24;62(10). Epub 2018 Sep 24.

Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, United Kingdom.

There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to health care systems. An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice-monthly multidisciplinary team meetings, and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team. During the first 18 months of implementation, the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated, followed by asthma and interstitial lung disease. There was a significant sustained reduction in monthly antifungal expenditure ( = 0.005) by £130,000 per month. There was also a significant reduction in antifungal use, measured as the defined daily dose/100 bed days ( = 0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole ( = 0.086) and a significant increase in therapeutic levels of posaconazole ( < 0.0001). This study shows that an effective antifungal stewardship program can significantly reduce expenditure in a specialist respiratory service.
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http://dx.doi.org/10.1128/AAC.00402-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153826PMC
October 2018

Author Correction: Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris.

Emerg Microbes Infect 2018 05 31;7(1):104. Epub 2018 May 31.

National Heart and Lung Institute, Imperial College London, London, SW3 6LR, UK.

Correction to: Emerging Microbes & Infections (2018) 7,43 https://doi.org/10.1038/s41426-018-0045-x ; published online 29 March 2018.
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http://dx.doi.org/10.1038/s41426-018-0098-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981204PMC
May 2018

Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis.

Mycoses 2018 Sep 20;61(9):665-673. Epub 2018 Jun 20.

Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College London, London, UK.

Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from 6 patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in 3 out of 4 cases. Antifungal therapy was initiated in 2 patients, to which only one exhibited a clinical response. Three out of 6 patients died within 3 years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonisation by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression.
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http://dx.doi.org/10.1111/myc.12789DOI Listing
September 2018

Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris.

Emerg Microbes Infect 2018 Mar 29;7(1):43. Epub 2018 Mar 29.

National Heart and Lung Institute, Imperial College London, London, SW3 6LR, UK.

Candida auris was first described in 2009, and it has since caused nosocomial outbreaks, invasive infections, and fungaemia across at least 19 countries on five continents. An outbreak of C. auris occurred in a specialized cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak in the UK, involving a total of 72 patients. To understand the genetic epidemiology of C. auris infection both within this hospital and within a global context, we sequenced the outbreak isolate genomes using Oxford Nanopore Technologies and Illumina platforms to detect antifungal resistance alleles and reannotate the C. auris genome. Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin; the outbreak showed similar genetic diversity to that of the entire clade, and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1. These mutations add to a growing body of research on multiple antifungal drug targets in this organism. Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission and implement outbreak control measures.
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http://dx.doi.org/10.1038/s41426-018-0045-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874254PMC
March 2018

Improvement in Exophiala dermatitidis airway persistence and respiratory decline in response to interferon-gamma therapy in a patient with cystic fibrosis.

J Cyst Fibros 2018 05 15;17(3):e32-e34. Epub 2018 Feb 15.

National Heart and Lung Institute, Imperial College London, UK; Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/j.jcf.2018.02.002DOI Listing
May 2018

and Efficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, on Aspergillus fumigatus Infection.

Antimicrob Agents Chemother 2018 05 26;62(5). Epub 2018 Apr 26.

Pulmocide Ltd., London, United Kingdom.

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against were tested in a range of and studies. PC1244 demonstrated potent antifungal activities against clinical isolates ( = 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 μg/ml), especially , , , , , , , and PC1244 also proved to be quickly absorbed into both hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole. , once-daily intranasal administration of PC1244 (3.2 to 80 μg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of infection in the lungs of humans.
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http://dx.doi.org/10.1128/AAC.01941-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923123PMC
May 2018

Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM-CSF- and M-CSF-derived Macrophages.

Am J Respir Cell Mol Biol 2018 02;58(2):271-273

1 Airway Disease, National Heart and Lung Institute Imperial College London London, United Kingdom and.

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http://dx.doi.org/10.1165/rcmb.2017-0351LEDOI Listing
February 2018