Joshua Agbetile

University of Leicester, Leiscester, England, United Kingdom

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Publications (14)95.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. Objectives: We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. Methods: Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. Results: FEV1 decrease was -25.7 mL/y in the overall population. Postbronchodilator FEV1 was also dependent on exacerbations, age of onset, height, age, sex, and log(10) sputum eosinophil percentages (P < .001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, -14.0 mL/y), (2) eosinophilic with high variation (mean decrease, -40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, -19.2 mL/y). Conclusion: The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV1 decrease.
    Journal of Allergy and Clinical Immunology 06/2014; 134(2). DOI:10.1016/j.jaci.2014.04.005 · 11.25 Impact Factor
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    ABSTRACT: IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.
    The Journal of allergy and clinical immunology 11/2013; 68(Suppl 3). DOI:10.1016/j.jaci.2013.09.050 · 11.25 Impact Factor
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    ABSTRACT: Bacteria are often isolated in stable chronic obstructive pulmonary disease (COPD). Whether fungi are also commonly present and associated with clinical and pathological features of disease is uncertain. We investigated the frequency of filamentous fungal culture and IgE sensitization to Aspergillus fumigatus and the relationship to clinical outcomes in COPD subjects.COPD subjects were recruited to enter a 1 year observational study. Assessments of lung function, allergen testing and sputum analysis for inflammation, bacteria and fungus were undertaken in COPD subjects and healthy smoking and non-smoking controls.Filamentous fungi were cultured at baseline in 49% (63/128) of COPD subjects of which 75% (47/63) were A. fumigatus. Fungus was cultured in 3/22 controls (2 were A. fumigatus). The total sputum cell count and inhaled corticosteroid dosage were significantly increased in COPD patients with a positive filamentous fungal culture at baseline (p<0.05). Sensitization to A. fumigatus was present in 13% of COPD subjects and was associated with worse lung function (FEV1 % predicted 39% versus 51%; p=0.01), but not related to filamentous fungal culture.A. fumigatus sensitization is related to poor lung function. Positive filamentous fungal culture is a common feature of COPD. The clinical significance of this remains uncertain.
    European Respiratory Journal 04/2013; 43(1). DOI:10.1183/09031936.00162912 · 7.13 Impact Factor
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    ABSTRACT: Indoor bioaerosols, such as mold spores, have been associated with respiratory symptoms in patients with asthma; however, dose-response relationships and guidelines on acceptable levels are lacking. Furthermore, a causal link between mold exposure and respiratory infections or asthma remains to be established. The aim of this study was to determine indoor concentrations of Aspergillus fumigatus and a subset of clinically relevant fungi in homes of people with asthma, in relation to markers of airways colonization and sensitization. Air and dust samples were collected from the living room of 58 properties. Fungal concentrations were quantified using mold-specific quantitative PCR and compared with traditional microscopic analysis of air samples. Isolation of A. fumigatus from sputum was associated with higher airborne concentrations of the fungus in patient homes (P = 0.04), and a similar trend was shown with Aspergillus/Penicillium-type concentrations analyzed by microscopy (P = 0.058). No association was found between airborne levels of A. fumigatus and sensitization to this fungus, or dustborne levels of A. fumigatus and either isolation from sputum or sensitization. The results of this study suggest that the home environmentshould be considered as a potential source of fungal exposure and elevated home levels may predispose people with asthma to airways colonization. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
    Indoor Air 11/2012; 23(4). DOI:10.1111/ina.12020 · 4.20 Impact Factor
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    ABSTRACT: Fungal sensitization is common in severe asthma, but the clinical relevance of this and the relationship with airway colonization by fungi remain unclear. The range of fungi that may colonize the airways in asthma is unknown. To provide a comprehensive analysis on the range of filamentous fungi isolated in sputum from people with asthma and report the relationship with their clinico-immunological features of their disease. We recruited 126 subjects with a diagnosis of asthma, 94% with moderate-severe disease, and 18 healthy volunteers. At a single stable visit, subjects underwent spirometry; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel; specific IgE to Aspergillus fumigatus. Fungi were identified by morphology and species identity was confirmed by sequencing. Four patients had allergic bronchopulmonary aspergillosis. Forty-eight percent of asthma subjects were IgE-sensitized to one fungal allergen and 22% to ≥ 2. Twenty-seven different taxa of filamentous fungi were isolated from 54% of their sputa, more than one species being detected in 17%. This compared with 3 (17%) healthy controls culturing any fungus (P < 0.01). Aspergillus species were most frequently cultured in isolation followed by Penicillium species. Post-bronchodilator FEV (1) (% predicted) in the subjects with asthma was 71(± 25) in those with a positive fungal culture vs. 83 (± 25) in those culture-negative, (P < 0.01). Numerous thermotolerant fungi other than A. fumigatus can be cultured from sputum of people with moderate-to-severe asthma; a positive culture is associated with an impaired post-bronchodilator FEV (1) , which might be partly responsible for the development of fixed airflow obstruction in asthma. Sensitization to these fungi is also common.
    Clinical & Experimental Allergy 05/2012; 42(5):782-91. DOI:10.1111/j.1365-2222.2012.03987.x · 4.32 Impact Factor
  • Thorax 12/2011; 66(Suppl 4):A43-A43. DOI:10.1136/thoraxjnl-2011-201054b.91 · 8.56 Impact Factor
  • J. Agbetile · S. Singh · P. Bradding · I. Pavord · R. Green
    Winter Meeting of the British-Thoracic-Society; 12/2011
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    ABSTRACT: Colonization of the airways by filamentous fungi can occur in asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. A recent study found IgE sensitization to Aspergillus fumigatus to be associated with reduced lung function. Significantly higher rates of A. fumigatus were detected in sputum from asthmatics sensitized to this fungus compared to non-sensitized asthmatics. The rate of positive cultures was far higher than equivalent historical samples analysed by the local clinical laboratory following protocols recommended by the UK Health Protection Agency (HPA). This study compares the HPA procedure with our sputum processing method, whereby sputum plugs are separated from saliva and aliquots of approximately 150 mg are inoculated directly onto potato dextrose agar. A total of 55 sputum samples from 41 patients with COPD were analyzed, comparing fungal recovery of five dilutions of sputa on two media. Isolation of A. fumigatus in culture was significantly higher using the research approach compared to the HPA standard method for mycological investigations (P < 0.001). There was also a significant difference in the recovery rate of A. fumigatus (P < 0.05) between media. This highlights the need for a standardized approach to fungal detection which is more sensitive than the method recommended by the HPA.
    Medical mycology: official publication of the International Society for Human and Animal Mycology 10/2011; 50(4):433-8. DOI:10.3109/13693786.2011.615762 · 2.26 Impact Factor
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    Joshua Agbetile · Ruth Green
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    ABSTRACT: It is increasingly recognized that large proportions of patients with asthma remain poorly controlled with daily symptoms, limitation in activities, or severe exacerbations despite traditional treatment with inhaled corticosteroids and other agents. This suggests that there is considerable scope for the refinement of traditional guidelines on the use of inhaled therapies in asthma and also a need for the development of novel therapeutic agents, particularly for the treatment of severe asthma. This review aims to discuss a range of emerging treatment approaches in asthma. Firstly, we will set the scene by highlighting the importance of achieving good asthma control in a patient-focused manner and discussing recent work that has furthered our understanding of asthma phenotypes and paved the way for patient-specific treatments. Secondly, we will review new strategies to better use the existing therapies such as inhaled corticosteroids and long-acting β(2)-agonists that remain the mainstay of treatment for most patients. Finally, we will review the novel therapies that are becoming available, both pharmacological and interventional, and discuss their likely place in the management of this complex disease.
    Journal of Asthma and Allergy 01/2011; 4:1-12. DOI:10.2147/JAA.S8671
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    ABSTRACT: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear. Objectives: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma. We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data. A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV₁ % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024). A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.
    American Journal of Respiratory and Critical Care Medicine 12/2010; 182(11):1362-8. DOI:10.1164/rccm.201001-0087OC · 11.99 Impact Factor
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    ABSTRACT: Introduction and objectives IgE sensitisation to fungal allergens is common in severe asthma, but the clinical relevance of this, and the relationship to airway colonisation with fungi, is not known. Many of the fungi that can grow at body temperature are filamentous moulds from the genera Aspergillus and Pencillium. We report here the relationship between lung function and fungal sputum culture in patients with severe asthma. Methods We recruited 126 patients attending a tertiary referral centre with a diagnosis of asthma and 18 healthy volunteers. 93% of patients were on GINA treatment step 4 or higher. At a single stable visit subjects underwent: spirometry with reversibility to 200 μg salbutamol; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel (+ve ≥3 mm); specific IgE to Aspergillus fumigatus by CAP (positive >0.35 kU/l). Fungi were identified by morphology and species identity confirmed by sequencing regions of the nuclear ribosomal operon. Results Patients had a mean age of 56 years (21–84 years); 48% were males with median ICS dose of 800 μg Fluticasone equivalent. 60% were atopic to common aeroallergens, 45% were IgE sensitised to one fungal allergen and 27% to ≥2 fungal allergens. 64% of patients cultured a mould in their sputum, 7% more than one species. This compared with three healthy subjects (17%) culturing any mould (p<0.01). Aspergillus species were most frequently cultured (n=58) followed by Penicillium species (n=15) and Thermoascus species (n=2), others (n=8). Four fungal genera were cultured from healthy volunteers sputum,-Aspergillus, Penicillium, Coprinus and one other. Post bronchodilator FEV1% predicted was 71% in those with a positive fungal culture vs 84% in those who were culture negative, (p<0.01). There were no differences in the sputum cell differential between culture positive and negative patients. Conclusions In addition to IgE fungal sensitisation, sputum culture focused towards detection of moulds is frequently positive and associated with impaired post-bronchodilator FEV1. Colonisation of the airways with mould in asthma could be responsible for the development of fixed airflow obstruction.
    Thorax 11/2010; 65(Suppl 4):A61-A62. DOI:10.1136/thx.2010.150946.37 · 8.56 Impact Factor
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    ABSTRACT: Background Severe asthma is a multidimensional disease, with recent evidence supporting the notion that eosinophilic airway inflammation (EAI) is an important driver for exacerbations. In addition EAI has been shown to be associated with airflow limitation in cross sectional studies. However, it remains to be established whether EAI may drive FEV1 decline. Methods The severe asthma registry at Glenfield hospital, Leicester, was screened for patients with a physician diagnosis of asthma and at least 5 years of longitudinal data recording sputum eosinophils, pre- and post-bronchodilator spirometry, inhaled corticosteroid usage as well as standard demographic indices during stable scheduled follow-up visits. Linear mixed effects models were used to investigate the effect of log sputum eosinophils as a time varying covariate on decline of post bronchodilator FEV1. Models were iteratively compared and refined using standard information criteria. Other fixed effects in the final model were, time and the interaction terms for time * log sputum eosinophils and time *daily dose of inhaled corticosteroids and pack years smoked. Individual variations in the slopes and intercepts of time and time*log sputum eosinophils were considered by adding them iteratively as random effects. A first-order autoregressive correlation structure was used to model covariance of random effects. Results 92 patients, 46% male with severe asthma were identified from a registry cohort of 686 between 2000 and 2009. The mean (sem) age was 54(12.9) years and age of onset 23 (2.1) years. The mean (range) duration of follow-up and number of visits were 6 years (4.6–10.5), 2.7/year. We found a significant interaction between sputum eosinophils, time and post bronchodilator FEV1. Indicating a net decline (95% CI) of −16.8 mls(25.8–7.8 mls) /annum/log unit increase in sputum eosinophils (F(1, 43.4); p<0.0001). In contrast there was a net decline 95%CI of −0.015 mls (0.029 to 0.0014 mls)/annum/mcg of inhaled beclamethasonediproprionate daily (F(1,726); p=0.031). Conclusion Eosinophilic airway inflammation is associated with a significant decline in FEV1 in severe asthma.
    Thorax 11/2010; 65(Suppl 4):A61-A61. DOI:10.1136/thx.2010.150946.34 · 8.56 Impact Factor
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    ABSTRACT: Introduction and Objectives 10% of patients with asthma have disease that is refractory to conventional therapy. Two important factors in this group of patients are non-adherence to prescribed treatment and steroid insensitive airway inflammation. We report on our experience using intramuscular (IM) triamcinolone to evaluate such patients. Methods We identified 28 patients who were on BTS step 5 treatment for asthma and at risk of fatal or near fatal events, who were given IM triamcinolone in the Glenfield difficult asthma clinic. The primary reason for administration of IM triamcinolone was to evaluate whether these patients had evidence of steroid insensitivity or were potentially non adherent. Adherence was assessed objectively prior to commencing triamcinolone. Juniper asthma control questionnaire (JACQ), fraction of exhaled nitric oxide (FeNO), blood eosinophils, sputum eosinophils, FEV1 (pre bronchodilator) were measured at baseline and whilst on triamcinolone. Results Triamcinolone was administered monthly at a dose of 40–80 mg for a median (range) course of 4 (1–19) months. Patient demographics were: 75% (21) female, mean age 40 y, mean BMI 29.1, median dose of ICS (BDP equivalent) 2000 mcg, median dose of maintenance prednisolone 20 mg, 29% (8) had previously been ventilated. Adherence was objectively assessed in 93% (26) with non-adherence demonstrated in 77% (20), either by prescription refill check or drug assays. Significant improvements were seen whilst on triamcinolone in the mean JACQ score from 3.66 to 2.52 (p=0.0003), geometric mean FeNO from 52.3 ppb to 17.8 ppb (p=0.0034), mean blood eosinophils from 0.59×109/l to 0.22×109/l (p=0.0032), geometric mean sputum eosinophil count from 12.93% to 1.24% (p<0.0001) and in pre bronchodilator FEV1 from 54% to 67% predicted (p=0.0003). Of 28 patients receiving IM triamcinolone, 68% (19) showed significant improvement in 2 or more disease markers, 7% (2) showed improvement in 1 disease marker, 18% (5) had an equivocal response and 7% (2) demonstrated no response to parenteral steroid. No significant adverse events were reported. Conclusions This study shows that IM triamcinolone is a useful tool that may identify non-adherence in difficult-to-control asthmatic patients prescribed maintenance oral corticosteroids. Absolute steroid resistance is uncommon in this group.
    Thorax 11/2010; 65(Suppl 4):A152-A152. DOI:10.1136/thx.2010.151043.27 · 8.56 Impact Factor
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    ABSTRACT: This paper was published as Clinical and Experimental Allergy, 2009, 39 (12), p. 1946: British Society for Allergy and Clinical Immunology Annual Conference 2009 Abstracts, A12. It is available from http://www3.interscience.wiley.com/journal/122683542/issue. Doi: 10.1111/j.1365-2222.2009.03389.x Metadata only entry