95 results found
Rhodes J, 2022, Population genomics confirms acquisition of drug resistant Aspergillus fumigatus infection by humans from the environment, Nature Microbiology, ISSN: 2058-5276
Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus from across the United Kingdom and Ireland (comprising 153 clinical isolates from 143 patients, and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (‘A’ and ‘B’) with little interclade recombination and the majority of environmental azole resistance found within Clade A. Secondly, we show occurrences where azole resistant isolates of near identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, whilst other regions under selection have no defined function. Lastly, pangenome analysis identified genes linked to azole resistance and novel resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.
Nuh A, Ramadan N, Shah A, et al., 2022, Sputum galactomannan has utility in the diagnosis of chronic pulmonary aspergillosis, Journal of Fungi, Vol: 8, Pages: 1-10, ISSN: 2309-608X
Diagnosis of pulmonary aspergillosis (PA), a fungal disease caused by Aspergillus species, is challenging since symptoms are unspecific. The galactomannan (antigen secreted by Aspergillus species) test in bronchoalveolar lavage (BAL) fluid is a valuable diagnostic adjunct test in the diagnosis of PA. However, BAL collection is invasive and may not be suitable to severely ill patients. Sputum is non-invasive, easily collected, and lung specific and may be an alternative to BAL. The aim of this research was to retrospectively evaluate the utility of sputum galactomannan in the diagnosis of pulmonary aspergillosis in patients with chronic respiratory diseases and to estimate the sputum galactomannan cut-off value. We collected data from patients with clinical suspicion of pulmonary aspergillosis who had sputum galactomannan, culture, and Aspergillus IgG tests performed within four weeks. Sputum galactomannan was validated against the clinical diagnosis of aspergillosis, Aspergillus culture, and Aspergillus IgG tests. In total, 218 patients met inclusion criteria. Overall, sputum GM showed satisfactory agreement with clinical diagnosis of aspergillosis, Aspergillus culture, and Aspergillus IgG. When a receiver operating characteristic curve was constructed using Aspergillus culture/IgG and clinical diagnosis, the same cut-off (CO) of 0.71 (AUC: 0.83; CI: 0.69–0.86, p < 0.001) was determined. Against clinical diagnosis, sputum GM gave sensitivity and specificity of 70% and 71%, respectively. Sensitivity of 77% and specificity of 78% were found when sputum GM was evaluated against Aspergillus culture/IgG. In conclusion, this study showed that sputum galactomannan antigen testing has utility in the diagnosis of chronic forms of pulmonary aspergillosis and further prospective validation is indicated.
Nuh A, Ramadan N, Schelenz S, et al., 2022, Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of Aspergillus species against four commonly used antifungals (vol 81, myaa020, 2018), MEDICAL MYCOLOGY, Vol: 60, ISSN: 1369-3786
Hughes DA, Archangelidi O, Coates M, et al., 2022, Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 129-135, ISSN: 1569-1993
Thompson GR, Le T, Chindamporn A, et al., 2021, Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology, LANCET INFECTIOUS DISEASES, Vol: 21, Pages: E364-E374, ISSN: 1473-3099
Periselneris J, Schelenz S, Loebinger M, et al., 2021, Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency, THORAX, Vol: 76, Pages: 1036-1039, ISSN: 0040-6376
Armstrong-James D, 2021, Future Directions for Clinical Respiratory Fungal Research., Mycopathologia, Vol: 186, Pages: 685-696
There has been a growing appreciation of the importance of respiratory fungal diseases in recent years, with better understanding of their prevalence as well as their global distribution. In step with the greater awareness of these complex infections, we are currently poised to make major advances in the characterization and treatment of these fungal diseases, which in itself is largely a consequence of post-genomic technologies which have enabled rational drug development and a path towards personalized medicines. These advances are set against a backdrop of globalization and anthropogenic change, which have impacted the world-wide distribution of fungi and antifungal resistance, as well as our built environment. The current revolution in immunomodulatory therapies has led to a rapidly evolving population at-risk for respiratory fungal disease. Whilst challenges are considerable, perhaps the tools we now have to manage these infections are up to this challenge. There has been a welcome acceleration of the antifungal pipeline in recent years, with a number of new drug classes in clinical or pre-clinical development, as well as new focus on inhaled antifungal drug delivery. The "post-genomic" revolution has opened up metagenomic diagnostic approaches spanning host immunogenetics to the fungal mycobiome that have allowed better characterization of respiratory fungal disease endotypes. When these advances are considered together the key challenge is clear: to develop a personalized medicine framework to enable a rational therapeutic approach.
Shah A, Armstrong-James D, Chotirmall SH, 2021, Respiratory mycoses: a call to action to recognize, educate and invest., Mycopathologia, Vol: 186, Pages: 569-573, ISSN: 0301-486X
Arastehfar A, Carvalho A, Houbraken J, et al., 2021, Aspergillus fumigatus and aspergillosis: From basics to clinics, STUDIES IN MYCOLOGY, ISSN: 0166-0616
Di Paolo M, Hewitt L, Nwankwo E, et al., 2021, A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis (vol 12, dlab086, 2021), JAC-ANTIMICROBIAL RESISTANCE, Vol: 3
Di Paolo M, Hewitt L, Nwankwo E, et al., 2021, Erratum to: A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis., JAC Antimicrob Resist, Vol: 3
[This corrects the article DOI: 10.1093/jacamr/dlab026.].
Denny S, Abdolrasouli A, Elamin T, et al., 2021, A retrospective multicenter analysis of candidaemia among COVID-19 patients during the first UK pandemic wave, Journal of Infection, Vol: 82, Pages: 276-316, ISSN: 0163-4453
Williams TJ, Gonzales-Huerta LE, Armstrong-James D, 2021, Fungal-induced programmed cell death, Journal of Fungi, Vol: 7, Pages: 1-15, ISSN: 2309-608X
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 Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, the role of programmed cell death in fungal immunity, and how fungi manipulate these pathways.
Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627
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 bona fide 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.
Arkell P, Mahboobani S, Wilson R, et al., 2021, Bronchoalveolar lavage fluid IMMY Sona Aspergillus lateral-flow assay for the diagnosis of invasive pulmonary aspergillosis: a prospective, real life evaluation, MEDICAL MYCOLOGY, Vol: 59, Pages: 404-408, ISSN: 1369-3786
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
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
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
Nuh A, Ramadan N, Schelenz S, et al., 2020, Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of Aspergillus species against four commonly used antifungals, MEDICAL MYCOLOGY, Vol: 58, Pages: 1085-1090, ISSN: 1369-3786
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 . 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) . 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 . 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) . 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  and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region . More recently, retrospective case series from Belgium , France , The Netherlands  and Germany  have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.
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
Currie AJ, Main ET, Wilson HM, et al., 2020, CFTR Modulators DampenAspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes, FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, Vol: 10, ISSN: 2235-2988
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
Vakili M, Aliyali M, Mortezaee V, et al., 2020, Relationship between spirometry results and colonisation of Aspergillus species in allergic asthma, CLINICAL RESPIRATORY JOURNAL, Vol: 14, Pages: 748-757, ISSN: 1752-6981
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.
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, Aspergillus colonization and antifungal immunity in cystic fibrosis patients, MEDICAL MYCOLOGY, Vol: 57, Pages: S118-S126, ISSN: 1369-3786
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