Publications
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Hughes DA, Cuthbertson L, Price H, et al., 2021, PSEUDOMONAS AERUGINOSA IMPAIRS GROWTH OF ASPERGILLUS FROM CF AIRWAY SAMPLES, Publisher: BMJ PUBLISHING GROUP, Pages: A159-A159, ISSN: 0040-6376
Murray A, Cass L, Ito K, et al., 2020, PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections, JOURNAL OF FUNGI, Vol: 6
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- Citations: 13
Williams TJ, Harvey S, Armstrong-James D, 2020, Immunotherapeutic approaches for fungal infections, CURRENT OPINION IN MICROBIOLOGY, Vol: 58, Pages: 130-137, ISSN: 1369-5274
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- Citations: 10
Pagani N, Armstrong-James D, Reed A, 2020, Successful salvage therapy for fungal bronchial anastomotic infection after-lung transplantation with an inhaled triazole anti-fungal PC945, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 39, Pages: 1505-1506, ISSN: 1053-2498
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- Citations: 8
Nuh A, Ramadan N, Schelenz S, et al., 2020, Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of <i>Aspergillus species</i> against four commonly used antifungals, MEDICAL MYCOLOGY, Vol: 58, Pages: 1085-1090, ISSN: 1369-3786
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- Citations: 7
Armstrong-James D, Youngs J, Bicanic T, et al., 2020, Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA), European Respiratory Journal, Vol: 56, Pages: 1-10, ISSN: 0903-1936
Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities [1]. Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [2]. Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy [3]. However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) [6]. From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail [2] and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region [7]. More recently, retrospective case series from Belgium [8], France [9], The Netherlands [10] and Germany [11] have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.
Hughes D, Cuthbertson L, Price H, et al., 2020, <i>PSEUDOMONAS AERUGINOSA</i> IMPAIRS GROWTH OF <i>ASPERGILLUS</i> FROM CF AIRWAY SAMPLES, Publisher: WILEY, Pages: S153-S153, ISSN: 8755-6863
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- Citations: 1
Nwankwo L, Armstrong-James D, Shah A, 2020, Use of Isavuconazole MIC to guide dosing in the management of Aspergillosis in patients with pulmonary disease, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Vakili M, Aliyali M, Mortezaee V, et al., 2020, Relationship between spirometry results and colonisation of <i>Aspergillus</i> species in allergic asthma, CLINICAL RESPIRATORY JOURNAL, Vol: 14, Pages: 748-757, ISSN: 1752-6981
Currie AJ, Main ET, Wilson HM, et al., 2020, CFTR Modulators Dampen<i>Aspergillus</i>-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes, FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, Vol: 10, ISSN: 2235-2988
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- Citations: 10
Chua F, Armstrong-James D, Desai SR, et al., 2020, The role of CT in case ascertainment and management of COVID-19 pneumonia in the UK: insights from high-incidence regions, The Lancet Respiratory Medicine, Vol: 8, Pages: 438-440, ISSN: 2213-2600
Armstrong-James D, Koh M, Ostermann M, et al., 2020, Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B, BMJ CASE REPORTS, Vol: 13
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- Citations: 7
Cushen B, Stead R, Malley S, et al., 2019, DEVELOPMENT OF A DEDICATED PROTOCOL FOR SCREENING FOR OCCULT PARASITIC INFECTION PRIOR TO INITIATION OF ANTI-IL5 THERAPY IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A36-A36, ISSN: 0040-6376
Rudramurthy SM, Colley T, Abdolrasouli A, et al., 2019, In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 2943-2949, ISSN: 0305-7453
ObjectivesManagement 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.MethodsA 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)].ResultsSeventy-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.ConclusionsPC945 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.
Budden KF, Shukla SD, Rehman SF, et al., 2019, Functional effects of the microbiota in chronic respiratory disease, Lancet Respiratory Medicine, Vol: 7, Pages: 907-920, ISSN: 2213-2600
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.
Hughes D, Rowley J, Elborn J, et al., 2019, SPYING ON INTER-SPECIES WARFARE: COMPLEX INTERACTIONS BETWEEN <i>PSEUDOMONAS</i> AND <i>ASPERGILLUS</i>, Publisher: WILEY, Pages: S306-S306, ISSN: 8755-6863
Eades CP, Armstrong-James DPH, 2019, Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics, Medical Mycology, Vol: 57, Pages: S307-S317, ISSN: 1369-3786
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.
Periselneris J, Nwankwo L, Schelenz S, et al., 2019, Posaconazole for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis., Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1701-1703, ISSN: 0305-7453
OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) can accelerate lung function decline in patients with cystic fibrosis (CF). Antifungal medication can be used in addition to systemic corticosteroid treatment. PATIENTS AND METHODS: We evaluated Aspergillus-specific IgE and the use of therapeutic drug monitoring of triazoles in a retrospective analysis of 32 patients. RESULTS: There was a significant reduction in Aspergillus IgE with posaconazole but not with other triazoles (P = 0.026). Aspergillus IgE levels were inversely correlated with the therapeutic drug level of posaconazole. CONCLUSIONS: These data suggest that posaconazole is better than comparator azoles at decreasing serological response to Aspergillus and that this response was better with therapeutic levels of posaconazole.
Warris A, Bercusson A, Armstrong-James D, 2019, <i>Aspergillus</i> colonization and antifungal immunity in cystic fibrosis patients, MEDICAL MYCOLOGY, Vol: 57, Pages: S118-S126, ISSN: 1369-3786
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- Citations: 23
Yu L-S, Rodriguez-Manzano J, Malpartida-Cardenas K, et al., 2019, Rapid and sensitive detection of azole-resistant Aspergillus fumigatus by tandem-repeat loop-mediated isothermal amplification, Journal of Molecular Diagnostics, Vol: 21, Pages: 286-295, ISSN: 1525-1578
Invasive human fungal infections caused by multi-azole resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multi-azole 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 multi-azole 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.
Zusag M, Angheleanu R, Norhan H, et al., 2018, WEAKLY SUPERVISED DEEP LEARNING ON CT SCANS PREDICTS SURVIVAL FROM CHRONIC PULMONARY ASPERGILLOSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A110-A111, ISSN: 0040-6376
Chua F, George P, Devaraj A, et al., 2018, PLEURO-PARENCHYMAL FIBROELASTOSIS: TRACTION BRONCHIECTASIS AND EXTENT OF PLATYTHORAX ON COMPUTED TOMOGRAPHY ARE DETERMINANTS OF DISEASE PROGRESSION AND MORTALITY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A46-A47, ISSN: 0040-6376
Abdolrasouli A, Scourfield A, Rhodes J, et al., 2018, High prevalence of triazole resistance in clinical Aspergillus fumigatus isolates in a specialist cardiothoracic centre, International Journal of Antimicrobial Agents, Vol: 52, Pages: 637-642, ISSN: 0924-8579
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. TR34/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 TR34/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.
Santiago V, Rezvani K, Sekine T, et al., 2018, Human NK cells develop an exhaustion phenotype during polar degranulation at the aspergillus fumigatus hyphal synapse, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
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 A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus 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 A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.
Nwankwo L, Periselneris J, Cheong J, et al., 2018, Impact of an antifungal stewardship programme in a tertiary respiratory medicine setting: a prospective real-world study, Antimicrobial Agents and Chemotherapy, Vol: 62, ISSN: 0066-4804
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 healthcare 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 eighteen 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 (p=0.005) by £130,000 per month. There was also a significant reduction in antifungal use measured as Defined Daily Dose/100 bed days (p=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 (p=0.086) and a significant increase in therapeutic levels of posaconazole (p<0.0001).This study shows that an effective antifungal stewardship programme can significantly reduce expenditure in a specialist respiratory service.
Abdolrasouli A, Petrou MA, Park H, et al., 2018, Surveillance for azole-resistant Aspergillus fumigatus in a centralized diagnostic mycology service, London, United Kingdom, 1998-2017, Frontiers in Microbiology, Vol: 9, ISSN: 1664-302X
Background/Objectives: Aspergillus fumigatus 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.Methods: A large number (n = 1469) of clinical A. fumigatus 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.Results: 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 A. fumigatus in our laboratory. Among five isolates collected from 2015 to 2017 and available for molecular testing, three harbored TR34/L98H alteration in the cyp51A gene that are associated with the acquisition of resistance in the non-patient environment.Conclusion: These data show that historically low prevalence of azole resistance may be increasing, warranting further surveillance of susceptible patients.
Di Paolo M, Dave K, Vijayasingam A, et al., 2018, Azoles therapeutic drug monitoring and fungal antimicrobial resistance in adults with Cystic Fibrosis, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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George P, Armstrong-James D, Devaraj A, et al., 2018, Traction bronchiectasis and platythorax on computed tomography are determinants of progression and mortality in pleuroparenchymal fibroelastosis, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Hughes D, Archangelidi O, Armstrong-James D, et al., 2018, CLINICAL CHARACTERISTICS OF PSEUDOMONAS AERUGINOSA AND ASPERGILLUS SPECIES CO-INFECTED CYSTIC FIBROSIS PATIENTS IN THE UK, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: 278-279, ISSN: 8755-6863
Abdolrasouli A, Bercusson AC, Rhodes JL, et al., 2018, Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis, Mycoses, Vol: 61, Pages: 665-673, ISSN: 0933-7407
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 six 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 three out of four cases. Antifungal therapy was initiated in two patients, to which only one exhibited a clinical response. Three out of six patients died within three 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 colonization 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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