Bafadhel Group Publications

Criner GJ, Martinez FJ, Aaron S, Agusti A, Anzueto A, Bafadhel M, Barnes PJ, Bourbeau J, Chen R, Ewig J et al. 2018. Current Controversies in Chronic Obstructive Pulmonary Disease: A Report from the GOLD Scientific Committee. Ann Am Thorac Soc, | Read more

Russell REK, Bafadhel M. 2018. Investigating blood eosinophil count thresholds in patients with COPD. Lancet Respir Med, 6 (11), pp. 823-824. | Read more

Bafadhel M. 2018. Symptomatic COPD: is it time for triple therapy? Lancet Respir Med, 6 (10), pp. 728-729. | Read more

Camp J, Cane JL, Bafadhel M. 2018. Shall We Focus on the Eosinophil to Guide Treatment with Systemic Corticosteroids during Acute Exacerbations of COPD?: PRO. Med Sci (Basel), 6 (3), pp. 74-74. | Show Abstract | Read more

In an era of precision medicine, it seems regressive that we do not use stratified approaches to direct treatment of oral corticosteroids during an exacerbation of chronic obstructive pulmonary disease (COPD). This is despite evidence suggesting that 40% of COPD patients have eosinophilic inflammation and this is an indicator of corticosteroid response. Treatments with oral corticosteroids are not always effective and not without harm, with significant and increased risk of hyperglycemia, sepsis, and fractures. Eosinophils are innate immune cells with an incompletely understood role in the pathology of airway disease. They are detected at increased levels in some patients and can be measured using non-invasive methods during states of exacerbation and stable periods. Despite the eosinophil having an unknown mechanism in COPD, it has been shown to be a marker of length of stay in severe hospitalized exacerbations, a predictor of risk of future exacerbation and exacerbation type. Although limited, promising data has come from one prospective clinical trial investigating the eosinophil as a biomarker to direct systemic corticosteroid treatment. This identified that there were statistically significant and clinically worsened symptoms in patients with low eosinophil levels who were prescribed prednisolone, demonstrating the potential utility of the eosinophil. In an era of precision medicine our patients' needs are best served by accurate diagnosis, correct identification of maximal treatment response and the abolition of harm. The peripheral blood eosinophil count could be used towards reaching these aims.

Hilvering B, Hinks TSC, Stöger L, Marchi E, Salimi M, Shrimanker R, Liu W, Chen W, Luo J, Go S et al. 2018. Synergistic activation of pro-inflammatory type-2 CD8+ T lymphocytes by lipid mediators in severe eosinophilic asthma. Mucosal Immunol, 11 (5), pp. 1408-1419. | Show Abstract | Read more

Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia-a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines, which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, Kebadze T, Cohen S, Newbold P, Rapley L et al. 2018. Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles. J Allergy Clin Immunol, 141 (6), pp. 2027-2036.e12. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters.

Hurst JR, Bafadhel M, Bolton CE, Quint JK, Sapey E, Wilkinson TMA. 2018. COPD exacerbations: transforming outcomes through research. Lancet Respir Med, 6 (3), pp. 172-174. | Citations: 1 (European Pubmed Central) | Read more

Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, Fagerås M. 2018. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med, 6 (2), pp. 117-126. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease (COPD) who will experience fewer exacerbations when taking inhaled corticosteroids (ICS). Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response. We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD. METHODS: We analysed data from three AstraZeneca randomised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts. Patients with any history of asthma were excluded. Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design. The trials are registered with ClinicalTrials.gov, NCT00206167, NCT00206154, and NCT00419744. FINDINGS: 4528 patients were studied. A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone. At eosinophil counts of 0·10 × 109 cells per L or more, a significant treatment effect was recorded for exacerbation reduction with budesonide-formoterol compared with formoterol alone (rate ratio 0·75, 95% CI 0·57-0·99; pinteraction=0·015). Interactions were observed between eosinophil count and the treatment effects of budesonide-formoterol over formoterol on St George's Respiratory Questionnaire (pinteraction=0·0043) and pre-bronchodilator FEV1 (linear effect p<0·0001, pinteraction=0·067). Only eosinophil count and smoking history were independent predictors of response to budesonide-formoterol in reducing exacerbations (eosinophil count, pinteraction=0·013; smoking history, pinteraction=0·015). INTERPRETATION: In patients with COPD treated with formoterol, blood eosinophil count predicts exacerbation risk and the clinical response to ICS. FUNDING: AstraZeneca.

Agustí A, Bafadhel M, Beasley R, Bel EH, Faner R, Gibson PG, Louis R, McDonald VM, Sterk PJ, Thomas M et al. 2017. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J, 50 (4), pp. 1701655-1701655. | Citations: 15 (Scopus) | Show Abstract | Read more

On February 21, 2017, a European Respiratory Society research seminar held in Barcelona discussed how to best apply precision medicine to chronic airway diseases such as asthma and chronic obstructive pulmonary disease. It is now clear that both are complex and heterogeneous diseases, that often overlap and that both require individualised assessment and treatment. This paper summarises the presentations and discussions that took place during the seminar. Specifically, we discussed the need for a new taxonomy of human diseases, the role of different players in this scenario (exposome, genes, endotypes, phenotypes, biomarkers and treatable traits) and a number of unanswered key questions in the field. We also addressed how to deploy airway precision medicine in clinical practice today, both in primary and specialised care. Finally, we debated the type of research needed to move the field forward.

Hambleton K, Connolly CM, Borg C, Davies JH, Jeffers HP, Russell RE, Bafadhel M. 2017. Comparison of the peripheral blood eosinophil count using near-patient testing and standard automated laboratory measurement in healthy, asthmatic and COPD subjects. Int J Chron Obstruct Pulmon Dis, 12 pp. 2771-2775. | Citations: 1 (European Pubmed Central) | Show Abstract | Read more

Near-patient testing (NPT) allows clinical decisions to be made in a rapid and convenient manner and is often cost effective. In COPD the peripheral blood eosinophil count has been demonstrated to have utility in providing prognostic information and predicting response to treatment during an acute exacerbation. For this potential to be achieved having a reliable NPT of blood eosinophil count would be extremely useful. Therefore, we investigated the use of the HemoCue® WBC Diff System and evaluated its sensitivity and specificity in healthy, asthmatic and COPD subjects. This method requires a simple skin prick of blood and was compared to standard venepuncture laboratory analysis. The HemoCue® WBC Diff System measured the peripheral blood eosinophil count in healthy, asthma and COPD subjects with very close correlation to the eosinophil count as measured by standard venepuncture. The correlations were unaffected by disease status. This method for the measurement of the peripheral blood eosinophil count has the potential to provide rapid near-patient results and thus influence the speed of management decisions in the treatment of airway diseases.

Bafadhel M, Pavord ID, Russell REK. 2017. Eosinophils in COPD: just another biomarker? Lancet Respir Med, 5 (9), pp. 747-759. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

Eosinophils are innate immune cells that, under certain conditions, can be recruited to the lungs, where they have an incompletely understood role in health and disease. Eosinophils have been found in the airways, tissues, and circulation of patients with COPD, during both stable disease and exacerbations. Epidemiological studies and post-hoc analyses of clinical trials of corticosteroid treatment for COPD have shown that the blood eosinophil count is associated with the risk of COPD exacerbations, mortality, decline in FEV1, and response to both inhaled and systemic corticosteroids. Further studies are urgently needed to explore the contribution of eosinophils to the mechanism of disease in COPD and to identify their association with levels of clinical risk. In this review, we explore the role of the eosinophil as a biomarker and mediator of disease in COPD.

Haldar K, Bafadhel M, Lau K, Berg A, Kwambana B, Kebadze T, Ramsheh MY, Barker B, Haldar P, Johnston S et al. 2017. Microbiome balance in sputum determined by PCR stratifies COPD exacerbations and shows potential for selective use of antibiotics. PLoS One, 12 (8), pp. e0182833. | Citations: 4 (European Pubmed Central) | Show Abstract | Read more

BACKGROUND: While a subgroup of patients with exacerbations of chronic obstructive pulmonary disease (COPD) clearly benefit from antibiotics, their identification remains challenging. We hypothesised that selective assessment of the balance between the two dominant bacterial groups (Gammaproteobacteria (G) and Firmicutes (F)) in COPD sputum samples might reveal a subgroup with a bacterial community structure change at exacerbation that was restored to baseline on recovery and potentially reflects effective antibiotic treatment. METHODS: Phylogenetically specific 16S rRNA genes were determined by quantitative real time PCR to derive a G:F ratio in serial sputum samples from 66 extensively-phenotyped COPD exacerbation episodes. RESULTS: Cluster analysis based on Euclidean distance measures, generated across the 4 visit times (stable and exacerbation day: 0,14 and 42) for the 66 exacerbation episodes, revealed three subgroups designated HG, HF, and GF reflecting predominance or equivalence of the two target bacterial groups. While the other subgroups showed no change at exacerbation, the HG cluster (n = 20) was characterized by G:F ratios that increased significantly at exacerbation and returned to baseline on recovery (p<0.00001); ratios in the HG group also correlated positively with inflammatory markers and negatively with FEV1. At exacerbation G:F showed a significant receiver-operator-characteristic curve to identify the HG subgroup (AUC 0.90, p<0.0001). CONCLUSIONS: The G:F ratio at exacerbation can be determined on a timescale compatible with decisions regarding clinical management. We propose that the G:F ratio has potential for use as a biomarker enabling selective use of antibiotics in COPD exacerbations and hence warrants further clinical evaluation.

Kerkhof M, Sonnappa S, Postma DS, Brusselle G, Agustí A, Anzueto A, Jones R, Papi A, Pavord I, Pizzichini E et al. 2017. Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J, 50 (1), pp. 1700761-1700761. | Citations: 9 (Web of Science Lite) | Read more

Simpson JL, Bafadhel M. 2017. Alternatives to induced sputum for identifying inflammatory subtypes of asthma. Respirology, 22 (4), pp. 624-625. | Citations: 1 (European Pubmed Central) | Read more

Thulborn SJ, Dilpazir M, Haldar K, Mistry V, Brightling CE, Barer MR, Bafadhel M. 2017. Investigating the role of pentraxin 3 as a biomarker for bacterial infection in subjects with COPD. Int J Chron Obstruct Pulmon Dis, 12 pp. 1199-1205. | Citations: 2 (European Pubmed Central) | Show Abstract | Read more

BACKGROUND: Pentraxin 3 (PTX3) is an acute phase protein, involved in antibacterial resistance. Recent studies have shown PTX3 levels to be elevated in the presence of a bacterial infection and in a murine sepsis model. OBJECTIVE: We aim to investigate if sputum PTX3 can be used as a biomarker for bacterial infection in subjects with COPD. MATERIALS AND METHODS: Sputum samples from 142 COPD patients (102 men) with a mean (range) age of 69 years (45-85) and mean (SD) post-bronchodilator percentage predicted forced expiratory volume in 1 second (FEV1) of 50% (19) were analyzed for PTX3, using a commercial assay at stable state and during an exacerbation. Association with bacteria, from culture, quantitative real-time polymerase chain reaction (qPCR) and colony-forming units (CFU) was investigated. RESULTS: The geometric mean (95% CI) PTX3 level at stable state was 50.5 ng/mL (41.4-61.7). PTX3 levels correlated with absolute neutrophil count in sputum (r=0.37; P<0.01), but not FEV1 or health status. There was a weak correlation between PTX3 and bacterial load (CFU: r=0.29, P<0.01; 16S qPCR: r=0.18, P=0.05). PTX3 was a poor predictor of bacterial colonization (defined as >105 CFU/mL at stable state) with a receiver-operating characteristic (ROC) area under the curve (AUC) of 0.59 and 95% confidence interval (CI) 0.43-0.76 (P=0.21). During an exacerbation, there was a modest increase in PTX3 (fold difference 0.15, 95% of difference 0.02-0.29; P=0.02), and PTX3 fared better at identifying a bacteria-associated exacerbation (ROC AUC 0.65, 95% CI 0.52-0.78, P=0.03). CONCLUSION: PTX3 is associated with bacterial infection in patients with COPD, but its utility as a biomarker for identifying a bacteria-associated exacerbation warrants further studies.

Bafadhel M, Greening NJ, Harvey-Dunstan TC, Williams JEA, Morgan MD, Brightling CE, Hussain SF, Pavord ID, Singh SJ, Steiner MC. 2016. Blood Eosinophils and Outcomes in Severe Hospitalized Exacerbations of COPD. Chest, 150 (2), pp. 320-328. | Citations: 40 (Scopus) | Show Abstract | Read more

BACKGROUND: Patients with moderate exacerbations of COPD and the eosinophilic phenotype have better outcomes with prednisolone. Whether this outcome is similar in patients hospitalized with a severe exacerbation of COPD is unclear. We investigated the rate of recovery of eosinophilic and noneosinophilic exacerbations in patients participating in a multicenter randomized controlled trial assessing health outcomes in hospitalized exacerbations. METHODS: Patients were recruited at presentation to the hospital with an exacerbation of COPD. They were stratified into groups according to eosinophilic exacerbations if the peripheral blood eosinophil count on admission was ≥ 200 cells/μL and/or ≥ 2% of the total leukocyte count. Admission details, serum C-reactive protein levels, length of stay, and subsequent rehospitalization data were compared between groups. RESULTS: A total of 243 patients with COPD (117 men) with a mean age of 71 years (range, 45-93 years) were recruited. The inpatient mortality rate was 3% (median time to death, 12 days; range, 9-16 days). The median absolute eosinophil count was 100 cells/μL (range, 10-1,500 cells/μL), and 25% met our criteria for an eosinophilic exacerbation; in this population, the mean length of stay (in days) was shorter than in patients with noneosinophilic exacerbations (5.0 [range, 1-19] vs 6.5 [range, 1-33]; P = .015) following treatment with oral corticosteroids and independent of treatment prior to admission. Readmission rates at 12 months were similar between groups. CONCLUSIONS: The study patients presenting to the hospital with a severe eosinophilic exacerbation of COPD had a shorter length of stay. The exacerbations were usually not associated with elevated C-reactive protein levels, suggesting that better treatment stratification of exacerbations can be used. TRIAL REGISTRY: http://www.isrctn.com/ISRCTN05557928.

Wright A, Mahaut-Smith M, Symon F, Sylvius N, Ran S, Bafadhel M, Muessel M, Bradding P, Wardlaw A, Vial C. 2016. Impaired P2X1 Receptor-Mediated Adhesion in Eosinophils from Asthmatic Patients. J Immunol, 196 (12), pp. 4877-4884. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Eosinophils play an important role in the pathogenesis of asthma and can be activated by extracellular nucleotides released following cell damage or inflammation. For example, increased ATP concentrations were reported in bronchoalveolar lavage fluids of asthmatic patients. Although eosinophils are known to express several subtypes of P2 receptors for extracellular nucleotides, their function and contribution to asthma remain unclear. In this article, we show that transcripts for P2X1, P2X4, and P2X5 receptors were expressed in healthy and asthmatic eosinophils. The P2X receptor agonist α,β-methylene ATP (α,β-meATP; 10 μM) evoked rapidly activating and desensitizing inward currents (peak 18 ± 3 pA/pF at -60 mV) in healthy eosinophils, typical of P2X1 homomeric receptors, which were abolished by the selective P2X1 antagonist NF449 (1 μM) (3 ± 2 pA/pF). α,β-meATP-evoked currents were smaller in eosinophils from asthmatic patients (8 ± 2 versus 27 ± 5 pA/pF for healthy) but were enhanced following treatment with a high concentration of the nucleotidase apyrase (17 ± 5 pA/pF for 10 IU/ml and 11 ± 3 pA/pF for 0.32 IU/ml), indicating that the channels are partially desensitized by extracellular nucleotides. α,β-meATP (10 μM) increased the expression of CD11b activated form in eosinophils from healthy, but not asthmatic, donors (143 ± 21% and 108 ± 11% of control response, respectively). Furthermore, α,β-meATP increased healthy (18 ± 2% compared with control 10 ± 1%) but not asthmatic (13 ± 1% versus 10 ± 0% for control) eosinophil adhesion. Healthy human eosinophils express functional P2X1 receptors whose activation leads to eosinophil αMβ2 integrin-dependent adhesion. P2X1 responses are constitutively reduced in asthmatic compared with healthy eosinophils, probably as the result of an increase in extracellular nucleotide concentration.

Hambleton K, Bafadhel M, Russell R. 2016. Chronic obstructive pulmonary disease: management of chronic disease Medicine, 44 (5), pp. 310-313. | Show Abstract | Read more

© 2016 Elsevier Ltd. All rights reserved. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, affecting an estimated 3 million people in the UK. The most common cause is tobacco smoke. Patients with COPD experience a high symptom burden, worsened during disease instability (termed exacerbations or 'lung attacks'), and a multidisciplinary approach should be adopted to manage this chronic lung disease. Diagnosis requires clinical and functional assessment to tailor treatments towards symptoms; the most common and debilitating of these are breathlessness, cough and sputum production. Breathlessness develops as a result of irreversible airway narrowing (obstruction), and spirometry is used alongside imaging to guide both diagnosis and treatment. To date, smoking cessation is the single most important intervention in delaying disease progression and should be a focus at every patient interaction. COPD is treated by a combination of pharmacological and non-pharmacological treatments, including pulmonary rehabilitation and self-management plans, allowing control over some of the symptom burden. Holistic management in COPD requires effective communication between all those involved in patient care, crossing secondary and primary care boundaries.

Bafadhel M, Russell REK. 2016. Are COPD and cardiovascular disease fundamentally intertwined? Eur Respir J, 47 (5), pp. 1307-1309. | Citations: 2 (European Pubmed Central) | Read more

Jackson VE, Ntalla I, Sayers I, Morris R, Whincup P, Casas J-P, Amuzu A, Choi M, Dale C, Kumari M et al. 2016. Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12. Thorax, 71 (6), pp. 501-509. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)). CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Wang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D, Miller BE, Tal-Singer R, Johnston SL, Ramsheh MY, Barer MR et al. 2016. Lung microbiome dynamics in COPD exacerbations. Eur Respir J, 47 (4), pp. 1082-1092. | Citations: 54 (Web of Science Lite) | Show Abstract | Read more

Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.

Pahlke S, Hilvering B, Thulborn S, Bafadhel M. 2015. The identification of distinct immunophenotypical subgroups in a COPD patient population based on predominating T-lymphocyte subsets European Respiratory Journal, 46 (suppl 59), pp. PA376-PA376. | Read more

Thulborn S, Cane J, Ceroni A, Brightling C, Pavord I, Bafadhel M. 2015. The detection of free-living H. influenzae in the airways of patients with COPD European Respiratory Journal, 46 (suppl 59), pp. PA566-PA566. | Read more

Dilpazir M, Thulborn S, Brightling C, Bafadhel M. 2015. Investigation the role of pentraxin-3 in the innate immune system in patients with COPD European Respiratory Journal, 46 (suppl 59), pp. PA3972-PA3972. | Read more

Hynes G, Brightling C, Bafadhel M. 2015. Fractional exhaled nitric oxide in chronic obstructive pulmonary disease European Respiratory Journal, 46 (suppl 59), pp. PA3993-PA3993. | Read more

Wright AKA, Mistry V, Richardson M, Shelley M, Thornton T, Terry S, Barker B, Bafadhel M, Brightling C. 2015. Toll-like receptor 9 dependent interferon-α release is impaired in severe asthma but is not associated with exacerbation frequency Immunobiology, 220 (7), pp. 859-864. | Citations: 6 (Scopus) | Show Abstract | Read more

© 2015 Elsevier GmbH. Patients with asthma and chronic obstructive pulmonary disease (COPD) are susceptible to exacerbations, often caused by microbial pathogens. We hypothesised that intracellular Toll-like receptor (TLR) function in blood mononuclear cells (PBMCs) from these subjects would be impaired and that this impairment is related to exacerbation frequency. PBMCs stimulated with a TLR-9 agonist (but not TLR-3 or 7/8) produced significantly less IFN-α in asthma (26 [3-696]. pg/ml) compared to control (943 [164-1651]) and COPD (597 [127-1186]) subjects (p= 0.0019) but this was not related to the number of exacerbations per year in asthma or COPD. In COPD, IFN-α levels were related to KCO (% predicted) in COPD (r= -0.41, p= 0.01). IFN-α was derived from plasmacytoid dendritic cells (pDCs) and their frequency was lower in asthma compared to control subjects (control 0.48% [0.33-0.64] versus asthma 0.29% [0.13-0.34], p= 0.019) whereas pDC function per se was not significantly impaired between groups. The mechanism underlying reduced IFN-α production and the clinical consequences in severe asthma remains to be established.

Bafadhel M, Haldar K, Barker B, Patel H, Mistry V, Barer MR, Pavord ID, Brightling CE. 2015. Airway bacteria measured by quantitative polymerase chain reaction and culture in patients with stable COPD: relationship with neutrophilic airway inflammation, exacerbation frequency, and lung function. Int J Chron Obstruct Pulmon Dis, 10 pp. 1075-1083. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes. METHODS: Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed. FINDINGS: Sputum was qPCR-positive (>10(6) copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]). Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >10(6) copies/mL. Samples that had qPCR copy numbers >10(6)/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P<0.001), were repeatable within subjects, and were >10(6)/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life. INTERPRETATION: qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods.

Brightling CE, Pavord ID, Bafadhel M. 2015. Inhaled glucocorticoids and COPD exacerbations. N Engl J Med, 372 (1), pp. 93. | Citations: 7 (Web of Science Lite) | Read more

Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Newby C et al. 2015. Biological clustering supports both "dutch" and "british" hypotheses of asthma and chronic obstructive pulmonary disease Journal of Allergy and Clinical Immunology, 135 (1), pp. 63-72. | Citations: 66 (Scopus) | Show Abstract | Read more

© 2014 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma and Immunology. Conclusions Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.Results Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study.Background Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.Objective We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis.Methods We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD).

Brightling CE, Pavord ID, Bafadhel M. 2015. Inhaled Glucocorticoids and COPD Exacerbations New England Journal of Medicine, 372 (1), pp. 92-94. | Read more

Wright AKA, Mistry V, Richardson M, Shelley M, Thornton T, Terry S, Barker B, Bafadhel M, Brightling C. 2015. Toll-like receptor 9 dependent interferon-α release is impaired in severe asthma but is not associated with exacerbation frequency. Immunobiology, 220 (7), pp. 859-864. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

Patients with asthma and chronic obstructive pulmonary disease (COPD) are susceptible to exacerbations, often caused by microbial pathogens. We hypothesised that intracellular Toll-like receptor (TLR) function in blood mononuclear cells (PBMCs) from these subjects would be impaired and that this impairment is related to exacerbation frequency. PBMCs stimulated with a TLR-9 agonist (but not TLR-3 or 7/8) produced significantly less IFN-α in asthma (26 [3-696]pg/ml) compared to control (943 [164-1651]) and COPD (597 [127-1186]) subjects (p = 0.0019) but this was not related to the number of exacerbations per year in asthma or COPD. In COPD, IFN-α levels were related to KCO (% predicted) in COPD (r = -0.41, p = 0.01). IFN-α was derived from plasmacytoid dendritic cells (pDCs) and their frequency was lower in asthma compared to control subjects (control 0.48% [0.33-0.64] versus asthma 0.29% [0.13-0.34], p = 0.019) whereas pDC function per se was not significantly impaired between groups. The mechanism underlying reduced IFN-α production and the clinical consequences in severe asthma remains to be established.

Barker BL, McKenna S, Mistry V, Pancholi M, Patel H, Haldar K, Barer MR, Pavord ID, Steiner MC, Brightling CE, Bafadhel M. 2014. Systemic and pulmonary inflammation is independent of skeletal muscle changes in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 9 pp. 975-981. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. OBJECTIVES: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. METHODS: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m(2) and/or fat-free mass index (FFMI) less than 15 or 17 kg/m(2) in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. RESULTS: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics. CONCLUSION: Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD.

Brightling CE, Bleecker ER, Panettieri RA, Bafadhel M, She D, Ward CK, Xu X, Birrell C, van der Merwe R. 2014. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med, 2 (11), pp. 891-901. | Citations: 127 (Scopus) | Show Abstract | Read more

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278. FINDINGS: We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related. INTERPRETATION: Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia. FUNDING: MedImmune.

Barker BL, Haldar K, Patel H, Pavord ID, Barer MR, Brightling CE, Bafadhel M. 2015. Association between pathogens detected using quantitative polymerase chain reaction with airway inflammation in COPD at stable state and exacerbations. Chest, 147 (1), pp. 46-55. | Citations: 18 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Relationships between airway inflammation and respiratory potentially pathogenic microorganisms (PPMs) quantified using quantitative polymerase chain reaction (qPCR) in subjects with COPD are unclear. Our aim was to evaluate mediators of airway inflammation and their association with PPMs in subjects with COPD at stable state and during exacerbations. METHODS: Sputum from 120 stable subjects with COPD was analyzed for bacteriology (colony-forming units; total 16S; and qPCR targeting Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae), differential cell counts, and inflammatory mediators using the Meso-Scale Discovery Platform. Subjects were classified as colonized if any PPM was identified above the threshold of detection by qPCR. Symptoms were quantified using the visual analog scale. RESULTS: At stable state, 60% of subjects were qPCR positive for H influenzae, 48% for M catarrhalis, and 28% for S pneumoniae. Elevated sputum concentrations of IL-1β, IL-10, and tumor necrosis factor (TNF)-α were detected in samples qPCR positive for either H influenzae or M catarrhalis. Bacterial loads of H influenzae positively correlated with IL-1β, IL-8, IL-10, TNF-α, and symptoms; and M catarrhalis correlated with IL-10 and TNF-α. H influenzae qPCR bacterial load was an independent predictor of sputum TNF-α and IL-1β. In 55 subjects with paired exacerbation data, qPCR bacterial load fold change at exacerbation in M catarrhalis but not H influenzae correlated to changes in sputum TNF-α and IL-1β concentrations. CONCLUSIONS: At stable state, H influenzae is associated with increased airway inflammation in COPD. The relationship between bacterial load changes of specific pathogens and airway inflammation at exacerbation and recovery warrants further investigation.

Eltboli O, Bafadhel M, Hollins F, Wright A, Hargadon B, Kulkarni N, Brightling C. 2014. COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils. BMC Pulm Med, 14 (1), pp. 112. | Citations: 19 (Scopus) | Show Abstract | Read more

BACKGROUND: Eosinophilic airway inflammation is observed in 10-30% of COPD subjects. Whether increased eosinophils or impairment in their clearance by macrophages is associated with the severity and frequency of exacerbations is unknown. METHODS: We categorised 103 COPD subjects into 4 groups determined by the upper limit of normal for their cytoplasmic macrophage red hue (<6%), an indirect measure of macrophage efferocytosis of eosinophils, and area under the curve sputum eosinophil count (≥ 3%/year). Eosinophil efferocytosis by monocyte-derived macrophages was studied in 17 COPD subjects and 8 normal controls. RESULTS: There were no differences in baseline lung function, health status or exacerbation frequency between the groups: A-low red hue, high sputum eosinophils (n=10), B-high red hue, high sputum eosinophils (n=16), C-low red hue, low sputum eosinophils (n=19) and D- high red hue, low sputum eosinophils (n=58). Positive bacterial culture was lower in groups A (10%) and B (6%) compared to C (44%) and D (21%) (p=0.01). The fall in FEV1 from stable to exacerbation was greatest in group A (ΔFEV1 [95 % CI] -0.41 L [-0.65 to -0.17]) versus group B (-0.16 L [-0.32 to -0.011]), C (-0.11 L [-0.23 to -0.002]) and D (-0.16 L [-0.22 to -0.10]; p=0.02). Macrophage efferocytosis of eosinophils was impaired in COPD versus controls (86 [75 to 92]% versus 93 [88 to 96]%; p=0.028); was most marked in group A (71 [70 to 84]%; p=0.0295) and was inversely correlated with exacerbation frequency (r=-0.63; p=0.006). CONCLUSIONS: Macrophage efferocytosis of eosinophils is impaired in COPD and is related to the severity and frequency of COPD exacerbations.

Bafadhel M, Davies L, Calverley PMA, Aaron SD, Brightling CE, Pavord ID. 2014. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J, 44 (3), pp. 789-791. | Citations: 66 (Scopus) | Read more

Jones RCM, Price D, Ryan D, Sims EJ, von Ziegenweidt J, Mascarenhas L, Burden A, Halpin DMG, Winter R, Hill S et al. 2014. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med, 2 (4), pp. 267-276. | Citations: 60 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies. METHODS: We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667. FINDINGS: We assessed data for 38,859 patients. Opportunities for diagnosis were missed in 32,900 (85%) of 38,859 patients in the 5 years immediately preceding diagnosis of COPD; in 12,856 (58%) of 22,286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry. INTERPRETATION: Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities. FUNDING: UK Department of Health, Research in Real Life.

Siva R, Bafadhel M, Monteiro W, Brightling CE, Pavord ID. 2014. Effect of levofloxacin on neutrophilic airway inflammation in stable COPD: a randomized, double-blind, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis, 9 pp. 179-186. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

RATIONALE: Airway inflammation persists after smoking cessation in established chronic obstructive pulmonary disease (COPD), suggesting that other factors drive the airway inflammatory response. OBJECTIVES: We tested the hypothesis that high levels of bacterial colonization are associated with increased levels of neutrophilic airway inflammation in stable COPD by examining the cross-sectional relationship between these measurements and by conducting a randomized, double-blind, placebo-controlled study of the effect of levofloxacin in patients with stable COPD. METHODS: Patients were randomized to receive either levofloxacin 500 mg daily or placebo for 7 days and underwent sputum induction for a differential cell count and quantitative bacterial analysis at baseline and at days 7, 14, and 28. RESULTS: Sputum percentage neutrophil count correlated with airway bacterial load at baseline (r=0.56; P=0.003). Levofloxacin reduced bacterial load compared with placebo by 4.9-fold (95% confidence interval, 1.4-25.7; P=0.02) at day 7 but had no effect at any point on any marker of neutrophilic airway inflammation. In patients with a baseline bacterial load of more than 10(6) cfu/mL, levofloxacin treatment was associated with a 26.5% (95% confidence interval, 1.8%-51.3%; P=0.04) greater reduction in the percentage neutrophil count compared with placebo at day 7. Change in percentage neutrophil count correlated significantly with baseline airway bacterial load and change in airway bacterial load. CONCLUSION: In stable COPD, levofloxacin treatment causes a short-term reduction in bacterial load. This is associated with a reduction in neutrophilic airway inflammation in patients with high bacterial loads. Further studies are required to investigate whether this effect is clinically advantageous.

Russell R, Bafadhel M. 2014. Respimat vs HandiHaler: a lesson in asking the right question Prescriber, 25 (3), pp. 7-8. | Read more

Russell R, Bafadhel M. 2014. Flu vaccine reduces risk of adverse CV events in high-risk patients Prescriber, 25 (3), pp. 34-34. | Read more

Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Newby C et al. 2015. Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol, 135 (1), pp. 63-72. | Citations: 62 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. OBJECTIVE: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. METHODS: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). RESULTS: Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. CONCLUSIONS: Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.

Bafadhel M. 2014. Eosinophilic Chronic Obstructive Pulmonary Disease is Not Associated with Helminth Infection or Exposure Journal of Pulmonary & Respiratory Medicine, 04 (02), | Read more

Hopkinson N, Wallis C, Higgins B, Gaduzo S, Sherrington R, Keilty S, Stern M, Britton J, Bush A, Moxham J et al. 2013. Children must be protected from the tobacco industry's marketing tactics. BMJ, 347 (dec09 14), pp. f7358. | Citations: 1 (European Pubmed Central) | Read more

Pavord ID, Bafadhel M. 2013. Exhaled nitric oxide and blood eosinophilia: independent markers of preventable risk. J Allergy Clin Immunol, 132 (4), pp. 828-829. | Citations: 21 (Web of Science Lite) | Read more

Pavord ID, Bafadhel M. 2013. Exhaled nitric oxide and blood eosinophilia: Independent markers of preventable risk Journal of Allergy and Clinical Immunology, 132 (4), pp. 828-829. | Citations: 21 (Scopus) | Read more

Bafadhel M, McKenna S, Agbetile J, Fairs A, Desai D, Mistry V, Morley JP, Pancholi M, Pavord ID, Wardlaw AJ et al. 2014. Aspergillus fumigatus during stable state and exacerbations of COPD. Eur Respir J, 43 (1), pp. 64-71. | Citations: 48 (Scopus) | Show Abstract | Read more

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 sensitisation 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 nonsmoking controls. Filamentous fungi were cultured at baseline in 49% (63 out of 128) of COPD subjects, of which 75% (47 out of 63) were A. fumigatus. Fungus was cultured in three out of 22 controls (two 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). Sensitisation to A. fumigatus was present in 13% of COPD subjects and was associated with worse lung function (forced expiratory volume in 1 s 39% predicted versus 51% predicted; p=0.01), but not related to filamentous fungal culture. A. fumigatus sensitisation is related to poor lung function. Positive filamentous fungal culture is a common feature of COPD. The clinical significance of this remains uncertain.

Desai D, Newby C, Symon FA, Haldar P, Shah S, Gupta S, Bafadhel M, Singapuri A, Siddiqui S, Woods J et al. 2013. Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med, 188 (6), pp. 657-663. | Citations: 90 (Scopus) | Show Abstract | Read more

RATIONALE: The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.

Barker BL, Patel H, Haldar K, Mistry V, Pancholi M, Barer M, Brightling CE, Bafadhel M. 2012. ASSESSING THE REPEATABILITY OF BACTERIAL DETECTION IN STABLE COPD USING SEVERAL METHODS THORAX, 67 (Suppl 2), pp. A156-A157. | Read more

Barker BL, Mistry V, Pancholi M, Brightling CE, Bafadhel M. 2012. ARE SPUTUM AND BLOOD BIOMARKERS OF INFLAMMATION REPEATABLE IN STABLE COPD? THORAX, 67 (Suppl 2), pp. A155-A156. | Citations: 1 (Web of Science Lite) | Read more

Wan YI, Shrine NRG, Soler Artigas M, Wain LV, Blakey JD, Moffatt MF, Bush A, Chung KF, Cookson WOCM, Strachan DP et al. 2012. Genome-wide association study to identify genetic determinants of severe asthma. Thorax, 67 (9), pp. 762-768. | Citations: 88 (Scopus) | Show Abstract | Read more

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. 2012. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med, 186 (1), pp. 48-55. | Citations: 225 (Web of Science Lite) | Show Abstract | Read more

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES: Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS: Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS: There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS: The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

Wan YI, Soler-Artigas M, Shrine NRG, Wain LV, Tobin MD, Moffatt MF, Bush A, Cookson WO, Strachan D, Heaney L et al. 2011. Genome-Wide Association Study To Identify Genetic Determinants Of Severe Asthma (AUGOSA) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183 | Show Abstract | Read more

Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective: To identify common genetic variants affecting susceptibility to severe asthma. Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480?889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10 (-8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10 (-8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study. Copyright Article author (or their employer) 2012.

Russell R, Norcliffe J, Bafadhel M. 2012. Chronic obstructive pulmonary disease: management of chronic disease Medicine, 40 (5), pp. 262-266. | Show Abstract | Read more

Chronic obstructive pulmonary disease (COPD) is the disease that has been described as the epidemic of our time. Cigarette smoking is the major cause of the disease and smoking cessation is the most effective intervention in both preventing disease development and progression. Once established, COPD causes irreversible airways obstruction that often results in breathlessness. The management of this condition involves initially an accurate diagnosis and a clinical and functional assessment. The primary confirmatory investigation is spirometry, although other tests such as chest X-ray are helpful in excluding other diseases. Treatment is aimed at preventing acute attacks (exacerbations) of disease and stopping disease progression. After smoking cessation, the most effective therapy is pulmonary rehabilitation, a multidisciplinary series of exercise and education sessions, which have been shown to be clinically and cost effective. Drug therapy reduces breathlessness and reduces attack rates. An effective approach to COPD requires cooperation of all healthcare providers working across primary and secondary care boundaries. Many agencies will and should be involved, including GPs, palliative care services, district nurses, hospital specialist services and social services. Patients can be educated about their disease and empowered to self manage, so that they can use health service providers in a more effective manner. © 2012 Elsevier Ltd. All rights reserved.

Pashley CH, Fairs A, Morley JP, Tailor S, Agbetile J, Bafadhel M, Brightling CE, Wardlaw AJ. 2012. Routine processing procedures for isolating filamentous fungi from respiratory sputum samples may underestimate fungal prevalence. Med Mycol, 50 (4), pp. 433-438. | Citations: 54 (Scopus) | Show Abstract | Read more

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.

Bafadhel M, McCormick M, Saha S, McKenna S, Shelley M, Hargadon B, Mistry V, Reid C, Parker D, Dodson P et al. 2012. Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration, 83 (1), pp. 36-44. | Citations: 69 (Scopus) | Show Abstract | Read more

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown. OBJECTIVES: To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD. METHODS: Subjects with asthma and COPD (n = 54 and n = 49) were studied. Clinical characteristics and sputum were collected at entry into the study. A 2-step sputum processing method was performed for supernatant and cytospin preparation. Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. RESULTS: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1β, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3-5.4), p = 0.01; TNFRI, 2.1 (1.3-5.4), p = 0.03; TNFRII, 2.6 (1.2-5.6), p = 0.02]. In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. CONCLUSION: Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated.

Bafadhel M, Brightling CE. 2011. Procalcitonin vs Clinical and Chest Film Findings to Diagnose Community-Acquired Pneumonia in Patients With Acute Asthma or Acute Exacerbations of Chronic Bronchitis Response CHEST, 140 (6), pp. 1668-1668. | Read more

Bafadhel M, Brightling CE, Siddiqui S. 2011. Visual vs Automated Assessment of Emphysema Response CHEST, 140 (5), pp. 1385-1385. | Read more

Bafadhel M, Brightling C. 2011. Serum Procalcitonin and Infective Exacerbations of Asthma Response CHEST, 140 (5), pp. 1390-1391. | Read more

Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A et al. 2011. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med, 184 (6), pp. 662-671. | Citations: 371 (Scopus) | Show Abstract | Read more

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83–0.95); serum CXCL10, 0.83 (95% CI, 0.70–0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78–0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

Bafadhel M, Umar I, Gupta S, Raj JV, Vara DD, Entwisle JJ, Pavord ID, Brightling CE, Siddiqui S. 2011. The role of CT scanning in multidimensional phenotyping of COPD. Chest, 140 (3), pp. 634-642. | Citations: 59 (Scopus) | Show Abstract | Read more

BACKGROUND: COPD is a heterogeneous disease characterized by airflow obstruction and diagnosed by lung function. CT imaging is emerging as an important, noninvasive tool in phenotyping COPD. However, the use of CT imaging in defining the disease heterogeneity above lung function is not fully known. METHODS: Seventy-five patients with COPD (58 men, 17 women) were studied with CT imaging and with measures of airway inflammation. Airway physiology and health status were also determined. RESULTS: The presence of emphysema (EM), bronchiectasis (BE), and bronchial wall thickening (BWT) was found in 67%, 27%, and 27% of subjects, respectively. The presence of EM was associated with lower lung function (mean difference % FEV(1), -20%; 95% CI, -28 to -11; P < .001). There was no difference in airway inflammation, exacerbation frequency, or bacterial load in patients with EM alone or with BE and/or BWT ± EM. The diffusing capacity of the lung for carbon monoxide/alveolar volume ratio was the most sensitive and specific parameter in identifying EM (area under the receiver operator characteristic curve, 0.87; 95% CI, 0.79-0.96). Physiologic cluster analysis identified three clusters, two of which were EM predominant and the third characterized by a heterogeneous combination of EM and BE. CONCLUSIONS: The application of CT imaging can be useful as a tool in the multidimensional approach to phenotyping patients with COPD.

Bafadhel M, Clark TW, Reid C, Medina M-J, Batham S, Barer MR, Nicholson KG, Brightling CE. 2011. Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD. Chest, 139 (6), pp. 1410-1418. | Citations: 93 (Scopus) | Show Abstract | Read more

BACKGROUND: Antibiotic overuse in respiratory illness is common and is associated with drug resistance and hospital-acquired infection. Biomarkers that can identify bacterial infections may reduce antibiotic prescription. We aimed to compare the usefulness of the biomarkers procalcitonin and C-reactive protein (CRP) in patients with pneumonia or exacerbations of asthma or COPD. METHODS: Patients with a diagnosis of community-acquired pneumonia or exacerbation of asthma or COPD were recruited during the winter months of 2006 to 2008. Demographics, clinical data, and blood samples were collected. Procalcitonin and CRP concentrations were measured from available sera. RESULTS: Sixty-two patients with pneumonia, 96 with asthma, and 161 with COPD were studied. Serum procalcitonin and CRP concentrations were strongly correlated (Spearman rank correlation coefficient [rs] = 0.56, P < .001). Patients with pneumonia had increased procalcitonin and CRP levels (median [interquartile range] 1.27 ng/mL [2.36], 191 mg/L [159]) compared with those with asthma (0.03 ng/mL [0.04], 9 mg/L [21]) and COPD (0.05 ng/mL [0.06], 16 mg/L [34]). The area under the receiver operating characteristic curve (95% CI) for distinguishing between patients with pneumonia (antibiotics required) and exacerbations of asthma (antibiotics not required), for procalcitonin and CRP was 0.93 (0.88-0.98) and 0.96 (0.93-1.00). A CRP value > 48 mg/L had a sensitivity of 91% (95% CI, 80%-97%) and specificity of 93% (95% CI, 86%-98%) for identifying patients with pneumonia. CONCLUSIONS: Procalcitonin and CRP levels can both independently distinguish pneumonia from exacerbations of asthma. CRP levels could be used to guide antibiotic therapy and reduce antibiotic overuse in hospitalized patients with acute respiratory illness.

Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, McCormick M, Woods J, May R, Sleeman MA et al. 2010. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest, 138 (5), pp. 1140-1147. | Citations: 211 (Scopus) | Show Abstract | Read more

BACKGROUND: Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain. METHODS: We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD. RESULTS: The median (interquartile range) IL-17A cells/mm² submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04). In COPD, IL-17A(+) cells/mm² submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046). IL-17F(+) cells/mm² submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV₁% predicted (r = -0.5, P = .008) and FEV(1)/FVC (r = -0.4, P = .04). CONCLUSIONS: Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation.

Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, GABRIEL Consortium. 2010. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med, 363 (13), pp. 1211-1221. | Citations: 1022 (Scopus) | Show Abstract | Read more

BACKGROUND: Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS: We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS: We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS: Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)

Bafadhel M, Singapuri A, Terry S, Hargadon B, Monteiro W, Green RH, Bradding PH, Wardlaw AJ, Pavord ID, Brightling CE. 2010. Body mass and fat mass in refractory asthma: an observational 1 year follow-up study. J Allergy (Cairo), 2010 pp. 251758. | Citations: 3 (European Pubmed Central) | Show Abstract | Read more

Background. Asthma and obesity are common; however the impact of obesity upon asthma remains uncertain. Objectives. To assess relationships between obesity and fat mass with airway inflammation, lung function, and disease control in patients with refractory asthma. Methods. 151 refractory asthma patients were characterised for measures of airway inflammation, lung function, Juniper asthma control questionnaire (JACQ), body mass index (BMI), and fat mass index (FMI) derived from dual energy X-ray absorptiometry. Patients were reassessed over 12 months. Results. 74% of patients had an elevated BMI. BMI and FMI correlated (r = 0.9, P < .001). FMI and JACQ correlated in men (r = 0.3, P = .01). After 12 months 23% lost weight. Weight change over 12 months correlated with FEV(1) change (r = -0.3, P = .03), but not with change in JACQ or exacerbations. Conclusion. Increased fat mass is common in refractory asthma and is associated with asthma symptom control in men. Loss of weight is associated with improvement in lung function in refractory asthma.

Bafadhel M, Saha S, Siva R, McCormick M, Monteiro W, Rugman P, Dodson P, Pavord ID, Newbold P, Brightling CE. 2009. Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. Respiration, 78 (3), pp. 256-262. | Citations: 32 (Scopus) | Show Abstract | Read more

BACKGROUND: Airway inflammation in chronic obstructive pulmonary disease (COPD) is predominately neutrophilic, but some subjects demonstrate eosinophilic airway inflammation. Whether these inflammatory phenotypes have differential cytokine and chemokine expression is unknown. OBJECTIVES: To assess the sputum concentrations of cytokines and chemokines and their response to oral corticosteroid therapy in COPD subjects with or without a sputum eosinophilia. METHODS: Cytokine and chemokine concentrations were measured using the meso-scale device platform. To assess validity, recovery of exogenous spikes was examined. The concentrations of the validated mediators were measured in COPD sputum from subjects with or without a sputum eosinophilia. In a subgroup with a sputum eosinophilia, the response to oral prednisolone 10 mg for 1 month was examined. RESULTS: The recovery in sputum of exogenous spiked mediators was >80% in 11/26 cytokines and chemokines. In supernatants from eosinophilic (n = 39) versus non-eosinophilic (n = 59) sputa, the geometric mean (95% CI) concentration was increased for IL-5 [9.0 (4.5-18) pg/ml vs. 3.6 (2.7-6.3) pg/ml, p = 0.03]. IL-5 alone was correlated with sputum eosinophil counts (r = 0.33, p = 0.001), and was attenuated following treatment with prednisolone [n = 9; mean difference 2.3 pg/ml (0.2-4.3), p = 0.032]. CONCLUSION: We have validated the use of the meso-scale device platform for cytokine and chemokine measurements in the sputum supernatants in COPD. Sputum IL-5 was associated with a sputum eosinophilia and was attenuated following oral corticosteroid therapy. Whether this cytokine is important in the pathogenesis of COPD in a subgroup of patients warrants further investigation.

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