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The role of fibrocytes in chronic obstructive pulmonary disease (COPD) is unknown. We sought to enumerate blood and tissue fibrocytes in COPD and determine the association of blood fibrocytes with clinical features of disease.Utilizing flow cytometry to identify circulating, collagen type 1Blood and tissue fibrocytes were not increased compared to control subjects nor were blood fibrocytes associated with lung function or qCT, but were increased in eosinophilic COPD. Myeloid-derived suppressor cell-like fibrocytes were increased in COPD compared to controls [2.3 (1.1-4.9), P = 0.038]. Our path analysis model showed that collagen type 1 intensity for MDSC-like fibrocytes was positively associated with lung function through associations with air trapping, predominately in the upper lobes.We have demonstrated that two circulating populations of fibrocyte exist in COPD, with distinct clinical associations, but are not prevalent in proximal or small airway tissue. Blood MDSC-like fibrocytes, however, are increased and associated with preserved lung function through a small airway-dependent mechanism in COPD.

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.

Background Sputum and blood eosinophil counts predict corticosteroid effects in COPD patients. Bacterial infection causes increased airway neutrophilic inflammation. The relationship of eosinophil counts with airway bacterial load in COPD patients is uncertain. We tested the hypothesis that bacterial load and eosinophil counts are inversely related. Methods COPD patients were seen at stable state and exacerbation onset. Sputum was processed for quantitative polymerase chain reaction detection of the potentially pathogenic microorganisms (PPM) H. influenzae, M. catarrhalis and S. pneumoniae. PPM positive was defined as total load ≥1 × 104copies/ml. Sputum and whole blood were analysed for differential cell counts. Results At baseline, bacterial counts were not related to blood eosinophils, but sputum eosinophil % was significantly lower in patients with PPM positive compared to PPM negative samples (medians: 0.5% vs. 1.25% respectively, p = 0.01). Patients with PPM positive samples during an exacerbation had significantly lower blood eosinophil counts at exacerbation compared to baseline (medians: 0.17 × 109/L vs. 0.23 × 109/L respectively, p = 0.008), while no blood eosinophil change was observed with PPM negative samples. Conclusions These findings indicate an inverse relationship between bacterial infection and eosinophil counts. Bacterial infection may influence corticosteroid responsiveness by altering the profile of neutrophilic and eosinophilic inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0570-5) contains supplementary material, which is available to authorized users.

Background The characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression. Methods Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used. Results One hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B. Conclusions Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0384-8) contains supplementary material, which is available to authorized users.

Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction (post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio

Background: A reduced blood eosinophil count can occur during bacterial sepsis. Little is known about the relationship between blood eosinophil counts and bacterial infection in COPD. Aims: To investigate the relationship between blood eosinophil counts and bacterial load during COPD exacerbations. Methods: As part of the COPDMAP consortium, sputum and blood samples were collected at baseline and exacerbation (E). 109 COPD patients were included in this analysis. Potentially pathogenic microorganism (PPM) load was measured in sputum using qPCR. A PPM +ve sample was defined as genome copies/ml of ≥1x10 4 . Blood eosinophil counts were measured. Statistical analysis was performed using the Wilcoxon signed rank test, Mann Whitney U test and Spearman9s correlation test. Results: Patients with PPM +ve samples at E had a significantly lower blood eosinophil count at E compared to baseline (medians: 0.17x10 9 /L vs 0.23x10 9 /L respectively, p= 0.008). Patients with PPM -ve samples at E had no change in blood eosinophil counts at E compared to baseline. The median change in blood eosinophil count from baseline to E was significantly different in the PPM +ve patients compared to PPM -ve patients (-0.02 x10 9 /L vs 0.04x10 9 /L respectively, p= 0.038). An increase in bacterial load was associated with a decrease in eosinophil count at E; rho= -0.28, p=0.02, for Δ blood eosinophil count and Δ in bacterial load measured between baseline and E. Conclusion: A decrease in blood eosinophil count occurs in COPD exacerbations with bacteria presence. Our results suggest an inverse relationship between blood eosinophils and airway bacteria; this may be relevant to the use of blood eosinophil counts to predict response to corticosteroids.

Introduction: The role of fibrocytes in COPD is unknown. We sought to enumerate blood and tissue fibrocytes in COPD and determine the association of blood fibrocytes with clinical features of disease. Methods: Utilising flow cytometry to identify circulating, collagen type-1 + cells we found two populations 1) CD45 + CD34 + (fibrocytes) and 2) CD45 + CD34 - (myeloid-derived suppressor cell [MDSC]-like fibrocytes) in 41 stable COPD and 19 control subjects. Lung resection material, from a separate group of subjects, with (n=11) or without (n=11) COPD was collected for tissue fibrocyte detection. We examined circulating fibrocyte populations for correlations with clinical parameters including quantitative computed tomography (qCT) and determined pathways of association between correlated variables using a structural equation model. Results: Blood and tissue fibrocytes were not increased compared to control subjects nor were blood fibrocytes associated with lung function or qCT, but were increased in eosinophilic COPD. MDSC-like fibrocytes were increased in COPD compared to controls (3-fold [1.2-7.7], p= 0.025). Our structural equation model showed that collagen type-1 intensity for MDSC-like fibrocytes was positively associated with lung function through associations with air trapping (standardised β co-efficient -0.39, p= 0.015) predominately in the upper lobes. Conclusion: We have demonstrated that two circulating populations of fibrocyte exist in COPD, with distinct clinical associations, but are not prevalent in proximal or small airway airway tissue. Blood MDSC-like fibrocytes, however, are increased and associated with preserved lung function in COPD.

Background The characteristics and natural history of GOLD B patients are not well described. Aims Objectives To assess the clinical characteristics and natural history of GOLD B patients over one year in a multicentre cohort of COPD patients in the COPDMAP study. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression. Methods 370 COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 minute walk test and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U test were used as appropriate. Results 107 (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers ( p =0.031), had chronic bronchitis ( p =0.0003) and cardiovascular comorbidities ( p =0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p =0.019 and CAT, 21.0 v 14.0, p =0.006) and lower FEV 1 (60% v 69% p =0.014) at baseline compared to stable patients who remained in GOLD B. Conclusions Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.

INTRODUCTION: Physical Activity (PA) is an important factor to measure in patients with COPD (chronic obstructive pulmonary disease) because low PA is associated with poorer long-term outcomes. However, the optimum way to analyse and report PA data; or if PA is associated with other clinical characteristics, is unknown in COPD. METHOD: We explored PA within a secondary care COPD cohort (COPDMAP). Sensewear Armband PA monitors (SWM) were used to obtain readings over 7 days for 55 patients. Clinical characteristics including spirometry were also recorded. PA variables were used in a factor analysis to determine underlying patterns of activity within the cohort and verified in two further separate cohorts. RESULTS: PA variables were positively correlated with each other (p 1. 9General Daily Activity9, 9GDA9 associated with the number of 2 min bouts of moderate activity in 24hr, factor loading (FL) =0.94. 2. 9Purposeful Physical Activity9, 9PPA9 associated with number of 20 min bouts of moderate activity per 24 hours, FL=0.84. CONCLUSIONS: We have found two distinct types of activity within a secondary care COPD cohort; that of 9General Daily Activity9 9GDA9 and 9Purposeful Physical Activity9, 9PPA9. These have distinct clinical associates.

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−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−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.

COPD (chronic obstructive pulmonary disease) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within lung, do not define different airway inflammatory patterns, nor do they define different physiological changes or differences in structure as can be defined by imaging. Over recent years, there has been interest in describing this heterogeneity and using this information to subgroup patients into COPD phenotypes. Most approaches to phenotyping have considered disease at a single scale and have not integrated information from different scales (e.g. organ–whole person, tissue–organ, cell–tissue and gene–cell) of disease to provide multi-dimensional phenotypes. Integration of disease biology with clinical expression is critical to improve understanding of this disease. When combined with biostatistical modelling, this information may lead to identification of new drug targets, new end points for clinical trials and targeted treatment for subgroups of COPD patients. It is hoped this will ultimately improve COPD outcomes and represent a move towards personalised medicine. In the present review, we will consider these aspects of multi-dimensional phenotyping in more detail.

Bacterial infection of the respiratory tract is amongst the commonest presentations to primary and secondary care. In addition to supportive care the mainstay of pharmacotherapy is antibiotics. Antibiotic treatment of bacterial infections of the respiratory tract needs to consider patient factors such as age, co-morbidities, location, previous antibiotic use, microbiological results and allergy. The emergence of multi-drug-resistant bacteria, partly a consequence of inappropriate antibiotic use, has both focussed the need for careful management of bacterial infection and presented a new therapeutic challenge. The choice of antibiotic for respiratory infections needs to be within national guidelines modified by local susceptibility profiles. Bacterial infections of the respiratory tract affect all levels of the airway tree and can be simply classified by their anatomical location for example: epiglottitis, exacerbations of chronic obstructive pulmonary disease and bronchiectasis and pneumonia. As with all pharmacotherapy alongside the benefit the potential side effects of the treatment needs to be considered. This is particularly important for the 6-month treatment of tuberculosis, which should only be managed by a specialist. The majority of bacterial infections of the respiratory tract respond well to therapy, but it is important to recognize that this remains a major cause of mortality.

Mona Bafadhel,1 Koirobi Haldar,2 Bethan Barker,2,3 Hemu Patel,4 Vijay Mistry,2,3 Michael R Barer,2–4 Ian D Pavord,1 Christopher E Brightling2,3 1Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Department of Infection, Immunity and Inflammation, University of Leicester, 3Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, University of Leicester, 4Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, UK 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 (>106 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 >106 copies/mL. Samples that had qPCR copy numbers >106/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P106/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. Keywords: H. influenzae, qPCR, sputum

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 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.

A sputum eosinophilia is observed in 10–40% of COPD subjects. The blood eosinophil count is a biomarker of sputum eosinophilia, but whether it is associated with bronchial submucosal eosinophils is unclear. In 20 COPD subjects and 21 controls we assessed the number of bronchial submucosal eosinophils and reticular basement membrane thickening and found these were positively correlated with the blood eosinophil percentage. In COPD, blood eosinophils are a good biomarker of bronchial eosinophilia and remodelling.

A system of electronic discharge summaries was developed. It replaced conventional discharge prescriptions and dictated discharge summaries. We conducted a prospective case-control study of 102 consecutive patients admitted to our hospital under the care of one consultant physician. Patients discharged after 1 December 2004 were discharged using the new computerised system (50 patients) while patients admitted under the same medical team, but to another ward were discharged using the conventional paper discharge system (52 patients). Patients in the electronic group and the conventional group were similar in age (mean 67 years versus 58 years, P>0.05) and duration of hospital stay (6 days versus 1 day, P>0.05). The mean time taken to produce an electronic discharge summary was immediate (0 days) which was significantly (P

1. Regarding COPD: 1. It is predicted to be the third leading cause of death worldwide by 2030 2. It is diagnosed by clinical symptoms and forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio

Background Stable COPD patients are colonised if potentially pathogenic organisms are identified on sputum culture. Associations between colonisation and clinical features such as exacerbation frequency and airway inflammation have been suggested. There is however limited data describing the reproducibility of sputum microbiology results in clinically stable COPD patients. Aims Examine repeatability of sputum microbiology in subjects with stable COPD over time. Methods Subjects with COPD were enrolled into an observational study and seen at baseline and at stable visits after 3 and 6 months. Sputum was obtained and samples were divided and analysed over time using standard culture, semi-quantitative bacterial count (colony forming units, CFU), PCR for potentially pathogenic organisms [ (Haemophilus influenzae (HI), Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Moraxella catarrhalis (MC)] and quantitative bacterial 16S analysis. Results 63 subjects provided paired sputum samples; 52 were male with a mean (SD) FEV1 (L) and FEV1/FVC ratio (%) of 1.48(0.54) and 53% (12.8) respectively. 40% were current smokers with an exacerbation frequency of 3 in the preceding year. Results for standard culture were divided into two groups (culture positive or negative). Results are expressed as Kappa values (95% CI). There was moderate agreement after 3 months, Kappa = 0.48 (0.24 to 0.71); and after 6 months, Kappa = 0.50 (0.25 to 0.76). Individual PCR revealed fair agreement after both time intervals. After 3 months, HI=0.17(–0.08 to 0.43), SA=0.27(–0.03 to 0.56), SP=0.30(0.06 to 0.53), MC=0.19(–0.04 to 0.43). After 6 months, HI=0.09(–0.18 to 0.35), SA=0.10(–0.22 to 0.43), SP=0.37(0.13 to 0.62) and MC= –0.14(–0.4 to 0.11). Quantitative bacterial analysis demonstrated no differences (mean difference; 95% CI) at 3 or 6 months in bacterial load measured by CFU (–0.18; –0.41 to 0.04, p=0.11 and –0.06; –0.32 to 0.2, p=0.65 respectively) or 16S (–0.03; –0.28 to 0.33, p=0.86 and –0.1; –0.42 to 0.22, p=0.54 respectively). Discussions These results demonstrate that sputum microbiological assessment in stable COPD is complex. Further longitudinal assessments of sputum microbiology and associations with clinical features are needed.

A 55-year-old Caucasian man who worked in the recycling industry presented with a 7-month history of non-productive cough and no other symptoms. He had no significant previous medical history and took no medications. He had never smoked and had no history of travel outside the UK. He described symptoms of a lower respiratory tract infection 5 months previously which had been treated with antibiotics and steroids. A chest x-ray at the time had shown consolidation consistent with infection which had subsequently resolved. Physical examination was normal. Spirometry and transfer factor were normal. Full blood count showed isolated eosinophilia of 12.7×10−9/l. The blood film revealed an unremarkable cell morphology. The erythrocyte sedimentation rate was elevated at 92 mm/h. Urea and electrolytes, …

Patients with cystic fibrosis (CF) suffer recurrent bacterial pulmonary infections, but viral infections can also cause acute clinical deterioration.1 Certain patient groups suffer increased morbidity following pandemic (H1N1) 2009 influenza (swine flu),2 but there are few previous reports of outcomes in individuals with CF.3 4 The West Midlands, along with Greater London, has had the highest incidence of H1N1 influenza in the UK.5 We therefore examined the outcomes of patients diagnosed with H1N1 influenza at the West Midlands Adult CF Centre. From June 2009 to April 2010 all adults with CF at our regional centre with potential H1N1 influenza had nasopharyngeal swabs tested …