48 results found
Lewington-Gower E, Chan L, Shah A, 2021, Review of current and future therapeutics in ABPA, THERAPEUTIC ADVANCES IN CHRONIC DISEASE, Vol: 12, ISSN: 2040-6223
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
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.].
Nwankwo L, McLaren K, Donovan J, et al., 2021, Utilisation of remote capillary blood testing in an outpatient clinic setting to improve shared decision making and patient and clinician experience: a validation and pilot study, BMJ Open Quality, Vol: 10, Pages: 1-11, ISSN: 2399-6641
Background In a tertiary respiratory centre, large cohorts of patients are managed in an outpatient setting and require blood tests to monitor disease activity and organ toxicity. This requires either visits to tertiary centres for phlebotomy and physician review or utilisation of primary care services.Objectives This study aims to validate remote capillary blood testing in an outpatient setting and analyse impact on clinical pathways.Methods A single-centre prospective cross-sectional validation and parallel observational study was performed. Remote finger prick capillary blood testing was validated compared with local standard venesection using comparative statistical analysis: paired t-test, correlation and Bland-Altman. Capillary was considered interchangeable with venous samples if all three criteria were met: non-significant paired t-test (ie, p>0.05), Pearson’s correlation coefficient (r)>0.8% and 95% of tests within 10% difference through Bland-Altman (limits of agreement). In parallel, current clinical pathways including phlebotomy practice were analysed over 4 weeks to review test predictability. A subsequent pilot cohort study analysed potential impact of remote capillary blood sampling on shared decision making. A final implementation phase ensued to embed the service into clinical pathways within the institution.Results 117 paired capillary and venous blood samples were prospectively analysed. Interchangeability with venous blood was seen with glycated haemoglobin (%), total protein and C reactive protein. Further tests, although not interchangeable, are likely useful to enable longitudinal remote monitoring (eg, liver function and total IgE). 65% of outpatient clinic blood tests were predictable with 16% of patients requiring further follow-up. Patient and clinician-reported improvement in shared decision making given contemporaneous blood test results was observed.Conclusions Remote capillary blood sampling can be used accurately fo
Prendecki M, Clarke C, Edwards H, et al., 2021, Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression., Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967
OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.
Aldossary S, Shah A, 2021, Healthcare Utilization and Impact of Antifungal Stewardships Within Respiratory Care Settings: A Systematic Literature Review, MYCOPATHOLOGIA, Vol: 186, Pages: 673-684, ISSN: 0301-486X
Rademacher J, Dettmer S, Fuge J, et al., 2021, The Primary Ciliary Dyskinesia Computed Tomography Score in Adults with Bronchiectasis: A Derivation und Validation Study, RESPIRATION, Vol: 100, Pages: 499-509, ISSN: 0025-7931
Nunes A, Desai SR, Semple T, et al., 2021, 3D Pathological signs detection and scoring on CPA CT lung scans, Pages: 82-85, ISSN: 1945-7928
Chronic Pulmonary Aspergillosis (CPA) is a complex type of fungal infection caused by the Aspergillus fungus that mostly affects people with pre-existing lung lesions or weakened immune systems. Pleural thicknening, fungal balls and cavities visualized on CT scans are used to score the extent and gravity of CPA, in a qualitative manner. This work focuses on the use of deep-learning to improve current standards in localising and scoring CPA signs for longitudinal follow-up. We propose an original framework fully implemented in 3D, combining imaging and time series encoding, to provide activation maps, CPA severity scores and 5-years mortality prediction.
Angelini E, Shah A, 2021, Using artificial intelligence in fungal lung disease: CPA CT imaging as an example, Mycopathologia, Vol: 186, Pages: 733-737, ISSN: 0301-486X
This positioning paper aims to discuss current challenges and opportunities for artificial intelligence (AI) in fungal lung disease, with a focus on chronic pulmonary aspergillosis and some supporting proof-of-concept results using lung imaging. Given the high uncertainty in fungal infection diagnosis and analyzing treatment response, AI could potentially have an impactful role; however, developing imaging-based machine learning raises several specific challenges. We discuss recommendations to engage the medical community in essential first steps towards fungal infection AI with gathering dedicated imaging registries, linking with non-imaging data and harmonizing image-finding annotations.
Pinto AL, Rai RK, Brown JC, et al., 2021, Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium
<jats:title>Abstract</jats:title><jats:p>Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein containing envelope.</jats:p>
Bercusson A, Jarvis G, Shah A, 2021, CF fungal disease in the age of CFTR modulators, Mycopathologia, Vol: 186, Pages: 1-10, ISSN: 0301-486X
Fungi are increasingly recognised to have a significant role in the progression of lung disease in Cystic fibrosis with Aspergillus fumigatus the most common fungus isolated during respiratory sampling. The emergence of novel CFTR modulators has, however, significantly changed the outlook of disease progression in CF. In this review we discuss what impact novel CFTR modulators will have on fungal lung disease and its management in CF. We discuss how CFTR modulators affect antifungal innate immunity and consider the impact of Ivacaftor on fungal disease in individuals with gating mutations. We further review the increasing complication of drug–drug interactions with concurrent use of azole antifungal medication and highlight key unknowns that require addressing to fully understand the impact of CFTR modulators on fungal disease.
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, JAC-ANTIMICROBIAL RESISTANCE, Vol: 3
Turner SEG, Loosemore M, Shah A, et al., 2021, Salivary IgA as a potential biomarker in the evaluation of respiratory tract infection risk in athletes, Journal of Allergy and Clinical Immunology: In Practice, Vol: 9, Pages: 151-159, ISSN: 2213-2198
In recent years, there has been attention focused on the value of salivary IgA (sIgA) as a potential biomarker for the identification of athletes who may be at increased risk of developing respiratory tract infection (RTI). The utility of sIgA, in this context, is based on biological plausibility and several observational studies revealing an apparent association between sIgA and RTI susceptibility. The overall published evidence evaluating the value of sIgA in this context is however conflicting, and there is currently a lack of clear guidance as to whether this marker has a place in the health surveillance and care of athletes. In this review, we critically appraise the literature assessing the potential for sIgA to be used in this context, evaluating it against 4 key biomarker characteristics, including its (1) practicality, (2) reproducibility, (3) specificity/sensitivity, and (4) potential clinical impact and relevance. This process reveals that although there is an apparent association between respiratory illness and sIgA in many studies, with some promising results, overall there remains a paucity of evidence supporting its overall value in this context. Key deficiencies in the metrics employed to endorse a valid biomarker are apparent, including a lack of reproducibility and low specificity and sensitivity in the detection of RTI susceptibility. The review outlines these issues and makes future recommendations.
Wilson MG, Hull JH, Rogers J, et al., 2020, Cardiorespiratory considerations for return-to-play in elite athletes after COVID-19 infection: a practical guide for sport and exercise medicine physicians, BRITISH JOURNAL OF SPORTS MEDICINE, Vol: 54, Pages: 1157-1161, ISSN: 0306-3674
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.
Connell D, Shah A, 2020, The contribution of Aspergillus fumigatus to COPD exacerbations: a "sensitive" topic, European Respiratory Journal, Vol: 56, ISSN: 0903-1936
Vijayasingam A, Frost E, Wilkins J, et al., 2020, Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis, Thorax, Vol: 75, Pages: 632-639, ISSN: 0040-6376
INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.
Osborne W, Fernandes M, Brooks S, et al., 2020, Pulsed echinocandin therapy in azole intolerant or multiresistant chronic pulmonary aspergillosis: A retrospective review at a UK tertiary centre, CLINICAL RESPIRATORY JOURNAL, Vol: 14, Pages: 571-577, ISSN: 1752-6981
Hull JH, Schwellnus MP, Pyne DB, et al., 2020, COVID-19 vaccination in athletes: ready, set, go . . ., LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 455-456, ISSN: 2213-2600
Angelini E, Dahan S, Shah A, 2019, Unravelling machine learning: insights in respiratory medicine., European Respiratory Journal, Vol: 54, Pages: 1-4, ISSN: 0903-1936
Waters VJ, Kidd TJ, Canton R, et al., 2019, Reconciling Antimicrobial Susceptibility Testing and Clinical Response in Antimicrobial Treatment of Chronic Cystic Fibrosis Lung Infections, CLINICAL INFECTIOUS DISEASES, Vol: 69, Pages: 1812-1816, ISSN: 1058-4838
Vijayasingam A, Frost E, Wilkins J, et al., 2019, S140 Interim results from a prospective study of tablet and web-based audiometry to detect ototoxicity in adults with cystic fibrosis (vol 73, pg A87, 2018), THORAX, Vol: 74, Pages: 723-723, ISSN: 0040-6376
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.
Somayaji R, Parkins MD, Shah A, et al., 2019, Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: a systematic review, Journal of Cystic Fibrosis, Vol: 18, Pages: 236-243, ISSN: 1569-1993
BackgroundAntimicrobial susceptibility testing (AST) is a cornerstone of infection management. Cystic fibrosis (CF) treatment guidelines recommend AST to select antimicrobial treatments for CF airway infection but its utility in this setting has never been objectively demonstrated.MethodsWe conducted a systematic review of primary published articles designed to address two PICO (patient, intervention, comparator, outcome) questions: 1) “For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection predictable from AST results available at treatment initiation?” and 2) “For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection affected by the method used to guide antimicrobial selection?” Relationships between AST results and clinical response (changes in pulmonary function, weight, signs and symptoms of respiratory tract infection, and time to next event) were assessed for each article and results were compared across articles when possible.ResultsTwenty-five articles describing the results of 20 separate studies, most of which described Pseudomonas aeruginosa treatment, were identified. Thirteen studies described pulmonary exacerbation (PEx) treatment and seven described ‘maintenance’ of chronic bacterial airways infection. In only three of 16 studies addressing PICO question #1 was there a suggestion that baseline bacterial isolate antimicrobial susceptibility was associated with clinical response to treatment. None of the four studies addressing PICO question #2 suggested that antimicrobial selection methods influenced clinical outcomes.ConclusionsThere is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment, suggesting a need for careful consideration of current AST use by the CF community.
Shteinberg M, Shah A, Elborn JS, 2019, New insights into immunological responses to infection in bronchiectasis, European Respiratory Journal, Vol: 53, Pages: 1-4, ISSN: 0903-1936
Zusag M, Desai SR, Di Paolo M, et al., 2019, SAPSAM - SPARSELY ANNOTATED PATHOLOGICAL SIGN ACTIVATION MAPS - A NOVEL APPROACH TO TRAIN CONVOLUTIONAL NEURAL NETWORKS ON LUNG CT SCANS USING BINARY LABELS ONLY, 16th IEEE International Symposium on Biomedical Imaging (ISBI), Publisher: IEEE, Pages: 298-302, ISSN: 1945-7928
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.
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.
Armstrong-James DPH, Bercusson A, Colley T, et al., 2018, Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis, Blood, Vol: 132, Pages: 1985-1988, ISSN: 1528-0020
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