Publications by authors named "Dominick E Shaw"

44 Publications

Corticosteroids and bone health in people with asthma: A systematic review and meta-analysis.

Respir Med 2021 Mar 26;181:106374. Epub 2021 Mar 26.

Division of Epidemiology and Public Health, Clinical Science Building, School of Medicine, University of Nottingham, Nottingham, NG5 1PB, UK.

Background: Understanding the potential deleterious effects of corticosteroids on bone health in people with asthma is important when making treatment decisions. There is a need for clearer evidence to better quantify the risk and effect size.

Methods: Databases were systematically searched to identify studies reporting on bone mineral density (BMD) measurement and risk of osteoporosis or fracture, comparing people with asthma exposed to inhaled (ICS) or oral (OCS) corticosteroids, with nonexposed people with asthma and healthy controls. Data were narratively synthesized, and a series of meta-analyses were performed using the random-effects inverse variance method.

Results: This review consists of 28 studies (six randomized control trials and 22 observational). There was no effect of ICS on bone loss both at spine and femoral neck in asthma. People with asthma receiving OCS were at greater risk of osteoporosis than nonexposed people with asthma (pooled HR = 1.76; 95%CI: 1.48 to 2.09; I=68%). Similarly, higher ICS exposure was associated with higher risk of osteoporosis (OR = 1.63; 95%CI: 1.33 to 1.99) and fracture (pooled OR = 1.19; 95%CI: 1.05 to 1.35; I=0%) when comparing people with asthma receiving ICS and not.

Conclusion: Patients with asthma exposed to OCS or high ICS doses become more susceptible to bone comorbidities. Striking the right balance between efficacy and safety of steroids in asthma is important to improve patients' quality of life.
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http://dx.doi.org/10.1016/j.rmed.2021.106374DOI Listing
March 2021

Balancing the needs of the many and the few: where next for adult asthma guidelines?

Lancet Respir Med 2021 Feb 24. Epub 2021 Feb 24.

Oxford Respiratory NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Asthma differs from many other chronic conditions in that most key management decisions are made in non-specialist settings, such as general practitioner surgeries and accident and emergency departments. Diagnosis in primary care relies on recognition of a characteristic pattern of symptoms and the occurrence of asthma attacks, sometimes supplemented by basic lung function tests. Ongoing management is guided by the assessment of symptoms and simple lung function measures of airflow obstruction, with little attempt made to personalise management. This approach is flawed because the inadequate specificity of symptoms, as well as the low sensitivity of variable airflow obstruction, means that a diagnosis of asthma is often difficult to exclude with confidence. Moreover, even if diagnosed correctly, dissociation between inflammation, airflow obstruction, and symptoms means that a generalised stepwise approach to managing asthma on the basis of symptoms is unlikely to be successful in a substantial proportion of patients. As a result, effective treatments are used inefficiently, and outcomes are often worse than they could be. Rather than use of either a population-based or personalised approach for the diagnosis and management of asthma, we recommend a new combined approach, in which treatment decisions are driven by objective assessment of key treatable mechanistic traits.
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http://dx.doi.org/10.1016/S2213-2600(21)00021-7DOI Listing
February 2021

Impact of COVID-19 on corticosteroids and antibiotics prescribing in England: an interrupted time series analysis.

J Public Health (Oxf) 2021 Feb 5. Epub 2021 Feb 5.

Division of Respiratory Medicine, Clinical Science Building, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.

Inhaled corticosteroids (ICS), prednisolone and antibiotics all play a crucial role in the management of respiratory diseases. The aim of this study was to analyse whether the declaration of the COVID-19 pandemic affected prescribing rates, as public health measures were implemented to reduce transmission of SARS-CoV-2. Monthly practise-level prescribing data published by NHS Digital were analysed. At the point, the COVID-19 outbreak was declared a pandemic, ICS prescriptions rose significantly. This was followed by a decrease in ICS and prednisolone prescribing in the following months. There was no difference in the antibiotic prescribing trend.
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http://dx.doi.org/10.1093/pubmed/fdab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928821PMC
February 2021

Risk of osteoporosis and fragility fractures in asthma due to oral and inhaled corticosteroids: two population-based nested case-control studies.

Thorax 2021 01 21;76(1):21-28. Epub 2020 Oct 21.

School of Medicine, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.

Background: Inhaled (ICS) and oral (OCS) corticosteroids are used widely in asthma; however, the risk of osteoporosis and fragility fracture (FF) due to corticosteroids in asthma is not well-established.

Methods: We conducted two nested case-control studies using linked data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases. Using an asthma cohort, we separately identified patients with osteoporosis or FF and gender-, age- and practice-matched controls. Conditional logistic regression was used to determine the association between ICS and OCS exposure, and the risk of osteoporosis or FF. The prevalence of patients receiving at least one bisphosphonate was also calculated.

Results: There was a dose-response relationship between both cumulative dose and number of OCS/ICS prescriptions within the previous year, and risk of osteoporosis or FF. After adjusting for confounders, people receiving more OCS prescriptions (≥9 vs 0) had a 4.50 (95% CI 3.21 to 6.11) and 2.16 (95% CI 1.56 to 3.32) increased risk of osteoporosis and FF, respectively. For ICS (≥11 vs 0) the ORs were 1.60 (95% CI 1.22 to 2.10) and 1.31 (95% CI 1.02 to 1.68). The cumulative dose had a similar impact, with those receiving more OCS or ICS being at greater risk. The prevalence of patients taking ≥9 OCS and at least one bisphosphonate prescription was just 50.6% and 48.4% for osteoporosis and FF, respectively.

Conclusions: The findings suggest that exposure to OCS or ICS is an independent risk factors for bone health in patients with asthma. Steroid administration at the lowest possible level to maintain asthma control is recommended.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215664DOI Listing
January 2021

Incidence of osteoporosis and fragility fractures in asthma: a UK population-based matched cohort study.

Eur Respir J 2021 Jan 21;57(1). Epub 2021 Jan 21.

Division of Respiratory Medicine, School of Medicine, University of Nottingham, Nottingham, UK.

Introduction: Osteoporosis and fragility fractures are associated with corticosteroids which are the mainstay treatment for asthma; however, these bone comorbidities within asthma need to be better described.

Methods: A matched cohort study was conducted using the UK Clinical Practice Research Database (CPRD). Adults with an incident asthma code were identified and matched, with up to four randomly selected people without asthma, by age, sex and practice. Osteoporosis and fragility fracture incidence rates were calculated, and Cox regression was performed comparing hazard rates to the general population. We report the impact of age, sex, glucocorticoids and the risk of specific fractures.

Results: Patients with asthma had a higher risk of osteoporosis (adjusted hazard ratio (aHR) 1.18, 95% CI 1.13-1.23) and were 12% (aHR 1.12, 95% CI 1.07-1.16) more likely to sustain fragility fractures than the general population. Age modified the effect of asthma on osteoporosis and fragility fractures, such that the effect was stronger in younger people (p<0.0001). The vertebra (aHR 1.40, 95% CI 1.33-1.48) and forearm/wrist (aHR 1.27, 95% CI 1.22-1.32) were the sites linked with a larger incidence. A dose-response relationship between oral corticosteroids (OCS) and osteoporosis was observed, whereas the risk of fragility fractures increased in those with six or more OCS courses per year. Regular use of inhaled corticosteroids (ICS) increased the risk of both bone conditions.

Conclusions: Patients with asthma are more likely to develop osteoporosis or sustain fragility fractures than the general population, with a particular concern in younger people and those more frequently using OCS and ICS.
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http://dx.doi.org/10.1183/13993003.01251-2020DOI Listing
January 2021

Urinary Leukotriene E and Prostaglandin D Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Am J Respir Crit Care Med 2021 01;203(1):37-53

Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics.

New approaches are needed to guide personalized treatment of asthma. To test if urinary eicosanoid metabolites can direct asthma phenotyping. Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE and the PGD metabolite 2,3-dinor-11β-PGF. High concentrations of LTE and PGD metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).
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http://dx.doi.org/10.1164/rccm.201909-1869OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781128PMC
January 2021

Phenotypic and functional translation of IL33 genetics in asthma.

J Allergy Clin Immunol 2021 Jan 19;147(1):144-157. Epub 2020 May 19.

Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown.

Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.

Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs.

Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function.

Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.04.051DOI Listing
January 2021

A retrospective database study of oral corticosteroid and bisphosphonate prescribing patterns in England.

NPJ Prim Care Respir Med 2020 02 13;30(1). Epub 2020 Feb 13.

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.

Exposure to oral corticosteroids (OCS) is associated with an increased risk of osteoporosis and fragility fractures. Guidelines suggest bisphosphonate (BP) therapy as the first-line treatment of glucocorticoid-induced osteoporosis (GIOP). This population study used publicly available data, including prescription annual cost analysis and monthly practice-level data. Our aim was to examine the prescribing of OCS and BP at practice level and investigate reasons for variation using a mixed-effect negative binomial regression analysis. There was a rise in OCS and BP prescriptions of 55% and 1200% from 1998 to 2018, respectively. Of the 6586 included practices, the median (IQR) of OCS and BP prescriptions were 120.8 (84.8-160.4) and 107.7 (73.8-147.4) per 1000 patients, respectively. Asthma and chronic obstructive pulmonary disease (COPD) were significantly associated with OCS use (p < 0.0001), but only COPD was associated with BP use (p < 0.0001). Higher OCS prescribing rates were associated with higher BP prescribing rates (5th to 1st quintile-IRR = 1.99; 95% CI: 1.88-2.10). Practice list size, deprivation and advanced age were all associated with both drugs (p < 0.0001). In conclusion, although OCS use is positively associated with BP prescription, variation among practices and CCGs exists. The variation in prescribing suggests there is still a need to improve GIOP prevention.
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http://dx.doi.org/10.1038/s41533-020-0162-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018734PMC
February 2020

Changes in asthma mortality in England and Wales since 2001.

Thorax 2019 12 13;74(12):1174-1175. Epub 2019 Sep 13.

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.

The number of deaths from asthma in England and Wales has not changed significantly over the last decade. This lack of improvement has received attention from both national asthma guidelines and the media. We examined asthma death data from the Office for National Statistics, stratified by age band. Every 5-year age band below the age of 80 years has seen a large reduction in mortality between 2001 and 2017, whereas numbers of asthma deaths have increased by 81% for people aged 80 years or above. This increase in older people dying from asthma requires explanation.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213350DOI Listing
December 2019

IL-17-high asthma with features of a psoriasis immunophenotype.

J Allergy Clin Immunol 2019 11 15;144(5):1198-1213. Epub 2019 Apr 15.

Respiratory, Inflammation, Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required.

Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.

Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes.

Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin.

Conclusion: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
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http://dx.doi.org/10.1016/j.jaci.2019.03.027DOI Listing
November 2019

Stratification of asthma phenotypes by airway proteomic signatures.

J Allergy Clin Immunol 2019 07 28;144(1):70-82. Epub 2019 Mar 28.

NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Electronic address:

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms.

Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification.

Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms.

Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.

Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
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http://dx.doi.org/10.1016/j.jaci.2019.03.013DOI Listing
July 2019

Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers.

Metabolomics 2018 09 17;14(10):123. Epub 2018 Sep 17.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Lung epithelial lining fluid (ELF)-sampled through sputum induction-is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood.

Objectives: To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort.

Methods: Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes.

Results: The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender.

Conclusions: We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.
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http://dx.doi.org/10.1007/s11306-018-1412-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153688PMC
September 2018

Idiopathic chronic productive cough and response to open-label macrolide therapy: An observational study.

Respirology 2019 06 5;24(6):558-565. Epub 2019 Feb 5.

The Asthma Centre, Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham City Hospital, Nottingham, UK.

Background And Objective: Adult patients with chronic productive cough of unknown cause are commonly seen in respiratory clinics. We have previously described a subgroup of these patients who have a short-lived response to standard antibiotic treatment but a prolonged response to 3 months of low-dose azithromycin therapy.

Methods: This observational study describes the physiological, radiological and pathological features of this patient cohort along with their response to a 12-week open-label trial of 250 mg azithromycin thrice weekly.

Results: A total of 30 subjects with a mean age of 57 were recruited. The majority demonstrated airway dilatation on high-resolution computed tomography (HRCT) scan without evidence of established bronchiectasis (n = 21) and non-specific chronic inflammatory changes on bronchial biopsy (n = 15/17). Twenty-nine subjects completed 3 months of azithromycin with a significant improvement in median Leicester Cough Questionnaire (LCQ) score (-6.3 points, P < 0.00001), reduction in median 24-h sputum volume (-5.8 mL, P = 0.0003) and improvement in sputum colour (P = 0.003). Patients responsive to azithromycin (n = 22) demonstrated neutrophilic or paucigranulocytic airway inflammation, whereas five subjects with eosinophilic airways inflammation did not respond symptomatically to azithromycin.

Conclusion: We describe a cohort of patients with chronic productive cough not adequately described by existing disease labels whose symptoms responded well to low-dose azithromycin. Many of the features are similar to the paediatric condition protracted bacterial bronchitis.
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http://dx.doi.org/10.1111/resp.13483DOI Listing
June 2019

Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort.

PLoS One 2018 21;13(9):e0203874. Epub 2018 Sep 21.

Department of Clinical and Experimental Medicine - University of Catania, Catania, Italy.

Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150501PMC
March 2019

FeNO monitoring to adjust treatment in asthma: has it come of age?

Authors:
Dominick E Shaw

Thorax 2018 12 12;73(12):1095-1096. Epub 2018 Aug 12.

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http://dx.doi.org/10.1136/thoraxjnl-2018-211761DOI Listing
December 2018

Investigating the discriminative value of Early Warning Scores in patients with respiratory disease using a retrospective cohort analysis of admissions to Nottingham University Hospitals Trust over a 2-year period.

BMJ Open 2018 07 30;8(7):e020269. Epub 2018 Jul 30.

Respiratory Research Unit, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.

Objective: Early Warning Scores (EWSs) are used to monitor patients for signs of imminent deterioration. Although used in respiratory disease, EWSs have not been well studied in this population, despite the underlying cardiopulmonary pathophysiology often present. We examined the performance of two scoring systems in patients with respiratory disease.

Design: Retrospective cohort analysis of vital signs observations of all patients admitted to a respiratory unit over a 2-year period. Scores were linked to outcome data to establish the performance of the National EWS (NEWS) compared results to a locally adapted EWS.

Setting: Nottingham University Hospitals National Health Service Trust respiratory wards. Data were collected from an integrated electronic observation and task allocation system employing a local EWS, also generating mandatory referrals to clinical staff at set scoring thresholds.

Outcome Measures: Projected workload, and sensitivity and specificity of the scores in predicting mortality based on outcome within 24 hours of a score being recorded.

Results: 8812 individual patient episodes occurred during the study period. Overall, mortality was 5.9%. Applying NEWS retrospectively (vs local EWS) generated an eightfold increase in mandatory escalations, but had higher sensitivity in predicting mortality at the protocol cut points.

Conclusions: This study highlights issues surrounding use of scoring systems in patients with respiratory disease. NEWS demonstrated higher sensitivity for predicting death within 24 hours, offset by reduced specificity. The consequent workload generated may compromise the ability of the clinical team to respond to patients needing immediate input. The locally adapted EWS has higher specificity but lower sensitivity. Statistical evaluation suggests this may lead to missed opportunities for intervention, however, this does not account for clinical concern independent of the scores, nor ability to respond to alerts based on workload. Further research into the role of warning scores and the impact of chronic pathophysiology is urgently needed.
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http://dx.doi.org/10.1136/bmjopen-2017-020269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067348PMC
July 2018

Impact of straight to test pathways on time to diagnosis in oesophageal and gastric cancer.

BMJ Open Qual 2018 21;7(3):e000328. Epub 2018 Jul 21.

East Midlands Academic Health Science Network, Nottingham, UK.

Background: Cancer survival in the UK has doubled in the last 40 years; however, 1-year and 5-year survival rates are still lower than other countries. One cause may be a delay between referral into secondary care and subsequent investigation. We set out to evaluate the impact of a straight to test pathway (STTP) on time to diagnosis for upper gastrointestinal (UGI) cancer.

Methods: Six hospital Trusts across the East Midlands Clinical Network introduced a STTP enabling general practitioners to refer patients with suspected UGI cancer (oesophageal/gastric) for immediate investigation, without the need to see a hospital specialist first. Data were collected for all patients referred between 2013 and 2015 with suspected UGI cancer and stratified by STTP or traditional referral pathway. Overall time from referral to diagnosis was compared. Data from two Trusts who did not implement STTP acted as control.

Results: 340 patients followed the STTP pathway and 495 followed the traditional route. STTP saved a mean of 7 days from referral to treatment (with a 95% CI of 3 to 11 days, p<0.008) and a mean of 16 days from referral to diagnosis, when compared with a traditional referral pathway. The number of diagnostic tests performed using STTP or traditional referral pathways were similar.

Conclusion: A STTP is associated with an overall reduction of 1 week from referral to treatment for UGI cancer. The approach is feasible and did not require more resource. Larger studies are required to assess whether this time saving translates into improved cancer outcomes.
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http://dx.doi.org/10.1136/bmjoq-2018-000328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059286PMC
July 2018

Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.

J Allergy Clin Immunol 2019 02 11;143(2):577-590. Epub 2018 Jun 11.

Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.

Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.

Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.

Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.

Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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http://dx.doi.org/10.1016/j.jaci.2018.05.026DOI Listing
February 2019

Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome.

J Proteome Res 2018 06 23;17(6):2072-2091. Epub 2018 May 23.

Centre for Proteomic Research, Biological Sciences , University of Southampton , Southampton SO17 1BJ , U.K.

Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMS applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in ≥40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in ≥3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMS is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.
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http://dx.doi.org/10.1021/acs.jproteome.8b00018DOI Listing
June 2018

A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial.

Trials 2018 Jan 4;19(1). Epub 2018 Jan 4.

Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.

Background: Patients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.

Methods/design: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.

Discussion: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.

Trial Registration: ClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.
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http://dx.doi.org/10.1186/s13063-017-2384-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753571PMC
January 2018

Accurate identification of hospital admissions from care homes; development and validation of an automated algorithm.

Age Ageing 2018 05;47(3):387-391

East Midlands Academic Health Science Network, Clinical Sciences Building, Nottingham City Hospital Campus, Hucknall Road, Nottingham, UK.

Background: measuring the complex needs of care home residents is crucial for resource allocation. Hospital patient administration systems (PAS) may not accurately identify admissions from care homes.

Objective: to develop and validate an accurate, practical method of identifying care home resident hospital admission using routinely collected PAS data.

Method: admissions data between 2011 and 2012 (n = 103,105) to an acute Trust were modelled to develop an automated tool which compared the hospital PAS address details with the Care Quality Commission's (CQC) database, producing a likelihood of care home residency. This tool and the Nuffield method (CQC postcode match only) were validated against a manual check of a random sample of admissions (n = 2,000). A dataset from a separate Trust was analysed to assess generalisability.

Results: the hospital PAS was inaccurate; none of the admissions from a care home identified on manual check had a care home source of admission recorded on the PAS. Both methods performed well; the automated tool had a higher positive predictive value than the Nuffield method (100% 95% confidence interval (CI) 98.23-100% versus 87.10% 95%CI 82.28-91.00%), meaning those coded as care home residents were more likely to actually be from a care home. Our automated tool had a high level of agreement 99.2% with the second Trust's data (Kappa 0.86 P < 0.001).

Conclusions: care home status is not routinely or accurately captured. Automated matching offers an accurate, repeatable, scalable method to identify care home residency and could be used as a tool to benchmark how care home residents use acute hospital resources across the National Health Service.
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http://dx.doi.org/10.1093/ageing/afx182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920300PMC
May 2018

Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma.

Eur Respir J 2017 09 27;50(3). Epub 2017 Sep 27.

Dept of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands.

A proportion of severe asthma patients suffers from persistent airflow limitation (PAL), often associated with more symptoms and exacerbations. Little is known about the underlying mechanisms. Here, our aim was to discover unexplored potential mechanisms using Gene Set Variation Analysis (GSVA), a sensitive technique that can detect underlying pathways in heterogeneous samples.Severe asthma patients from the U-BIOPRED cohort with PAL (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal) were compared with those without PAL. Gene expression was assessed on the total RNA of sputum cells, nasal brushings, and endobronchial brushings and biopsies. GSVA was applied to identify differentially enriched predefined gene signatures based on all available gene expression publications and data on airways disease.Differentially enriched gene signatures were identified in nasal brushings (n=1), sputum (n=9), bronchial brushings (n=1) and bronchial biopsies (n=4) that were associated with response to inhaled steroids, eosinophils, interleukin-13, interferon-α, specific CD4 T-cells and airway remodelling.PAL in severe asthma has distinguishable underlying gene networks that are associated with treatment, inflammatory pathways and airway remodelling. These findings point towards targets for the therapy of PAL in severe asthma.
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http://dx.doi.org/10.1183/13993003.02298-2016DOI Listing
September 2017

Comparable reductions in hyperpnoea-induced bronchoconstriction and markers of airway inflammation after supplementation with 6·2 and 3·1 g/d of long-chain n-3 PUFA in adults with asthma.

Br J Nutr 2017 May 13;117(10):1379-1389. Epub 2017 Jun 13.

1Exercise and Health Research Group,Department of Sport Science,Sport, Health and Performance Enhancement (SHAPE) Research Centre,Nottingham Trent University,Nottingham NG11 8NS,UK.

Although high dose n-3 PUFA supplementation reduces exercise- and hyperpnoea-induced bronchoconstriction (EIB/HIB), there are concurrent issues with cost, compliance and gastrointestinal discomfort. It is thus pertinent to establish the efficacy of lower n-3 PUFA doses. Eight male adults with asthma and HIB and eight controls without asthma were randomly supplemented with two n-3 PUFA doses (6·2 g/d (3·7 g EPA and 2·5 g DHA) and 3·1 g/d (1·8 g EPA and 1·3 g DHA)) and a placebo, each for 21 d followed by 14 d washout. A eucapnic voluntary hyperpnoea (EVH) challenge was performed before and after treatments. Outcome measures remained unchanged in the control group. In the HIB group, the peak fall in forced expiratory volume in 1 s (FEV1) after EVH at day 0 (-1005 (sd 520) ml, -30 (sd 18) %) was unchanged after placebo. The peak fall in FEV1 was similarly reduced from day 0 to day 21 of 6·2 g/d n-3 PUFA (-1000 (sd 460) ml, -29 (sd 17) % v. -690 (sd 460) ml, -20 (sd 15) %) and 3·1 g/d n-3 PUFA (-970 (sd 480) ml, -28 (sd 18) % v. -700 (sd 420) ml, -21 (sd 15) %) (P<0·001). Baseline fraction of exhaled nitric oxide was reduced by 24 % (P=0·020) and 31 % (P=0·018) after 6·2 and 3·1 g/d n-3 PUFA, respectively. Peak increases in 9α, 11β PGF2 after EVH were reduced by 65 % (P=0·009) and 56 % (P=0·041) after 6·2 and 3·1 g/d n-3 PUFA, respectively. In conclusion, 3·1 g/d n-3 PUFA supplementation attenuated HIB and markers of airway inflammation to a similar extent as a higher dose. Lower doses of n-3 PUFA thus represent a potentially beneficial adjunct treatment for adults with asthma and EIB.
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http://dx.doi.org/10.1017/S0007114517001246DOI Listing
May 2017

Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity.

Am J Respir Crit Care Med 2017 04;195(8):1000-1009

1 Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.

Rationale: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma.

Objectives: To investigate whether MMP-1 could be activated by mast cells and increase asthma severity.

Methods: Patients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed.

Measurements And Main Results: Airway smooth muscle cells generated pro-MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro-MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV and worsening asthma symptoms.

Conclusions: MMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness.
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http://dx.doi.org/10.1164/rccm.201604-0822OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422648PMC
April 2017

Step 4: stick or twist? A review of asthma therapy.

BMJ Open Respir Res 2016 5;3(1):e000143. Epub 2016 Sep 5.

Division of Respiratory Medicine , University of Nottingham, Nottingham City Hospital , Nottingham , UK.

Many people with asthma do not achieve disease control, despite bronchodilators and inhaled corticosteroid therapy. People with uncontrolled asthma are at higher risk of an asthma attack and death, with mortality rates estimated at 1000 deaths/year in England and Wales. The recent National Review of Asthma Deaths (NRAD) report, 'Why asthma still kills', recommended that patients at step 4 or 5 of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidance must be referred to a specialist asthma service. This article reviews the 2014 evidence base for therapy of asthma patients at BTS/SIGN step 4 of the treatment cascade, in response to key findings of the NRAD report and lack of preferred treatment option at this step.
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http://dx.doi.org/10.1136/bmjresp-2016-000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020663PMC
September 2016

A prebiotic galactooligosaccharide mixture reduces severity of hyperpnoea-induced bronchoconstriction and markers of airway inflammation.

Br J Nutr 2016 Sep;116(5):798-804

1Exercise and Health Research Group,Department of Sport Science,Sport, Health and Performance Enhancement (SHAPE) Research Centre,Nottingham Trent University,Nottingham NG11 8NS,UK.

Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (-880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (-940 (sd 460) v. -570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB.
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http://dx.doi.org/10.1017/S0007114516002762DOI Listing
September 2016

Using venous blood gas analysis in the assessment of COPD exacerbations: a prospective cohort study.

Thorax 2016 Mar 1;71(3):210-5. Epub 2015 Dec 1.

Respiratory Research Unit, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK Medical Informatics, East Midlands Academic Health Sciences Network, Nottingham, UK.

Introduction: Identifying acute hypercapnic respiratory failure is crucial in the initial management of acute exacerbations of COPD. Guidelines recommend obtaining arterial blood samples but these are more difficult to obtain than venous. We assessed whether blood gas values derived from venous blood could replace arterial at initial assessment.

Methods: Patients requiring hospital treatment for an exacerbation of COPD had paired arterial and venous samples taken. Bland-Altman analyses were performed to assess agreement between arterial and venous pH, CO2 and HCO3-. The relationship between SpO2 and SaO2 was assessed. The number of attempts and pain scores for each sample were measured.

Results: 234 patients were studied. There was good agreement between arterial and venous measures of pH and HC)3- (mean difference 0.03 and -0.04, limits of agreement -0.05 to 0.11 and -2.90 to 2.82, respectively), and between SaO2 and SpO2 (in patients with an SpO2 of >80%). Arterial sampling required more attempts and was more painful than venous (mean pain score 4 (IQR 2-5) and 1 (IQR 0-2), respectively, p<0.001).

Conclusions: Arterial sampling is more difficult and more painful than venous sampling. There is good agreement between pH and HCO3- values derived from venous and arterial blood, and between pulse oximetry and arterial blood gas oxygen saturations. These agreements could allow the initial assessment of COPD exacerbations to be based on venous blood gas analysis and pulse oximetry, simplifying the care pathway and improving the patient experience.
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http://dx.doi.org/10.1136/thoraxjnl-2015-207573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789825PMC
March 2016