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Vestbo J.,University of Manchester | Vestbo J.,University of Southern Denmark | Hurd S.S.,Global Initiative for Chronic Obstructive Lung Disease | Agusti A.G.,University of Barcelona | And 10 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Chronic obstructive pulmonary disease (COPD) is a global health problem, and since 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents themaincontents of thesecond5-year revision of theGOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry isrequired for the clinical diagnosis ofCOPDto avoid misdiagnosis and to ensure proper evaluation of severity of airflowlimitation. Thedocumenthighlights that theassessment of thepatientwith COPDshould always includeassessment of (1)symptoms,(2)severityof airflow limitation, (3) history of exacerbations, and (4) comorbidities. Thefirst threepointscanbeusedtoevaluatelevelof symptomsandrisk of futureexacerbations, andthis isdoneinawaythatsplitspatientswith COPD into four categories-A, B, C, and D. Nonpharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority, and a separate section in the document addresses management of comorbidities aswell asCOPDin the presence of comorbidities. The revised document also contains a newsection on exacerbations of COPD. TheGOLDinitiative will continue tobringCOPDto the attention of all relevant shareholdersandwillhopefullyinspire futurenationaland local guidelines on the management of COPD. Copyright © 2013 by the American Thoracic Society.

Bush A.,UK National Heart and Lung Institute | Bush A.,Royal Brompton Hospital | Zar H.J.,University of Cape Town
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of Review: In 2009, an expert panel met to propose a WHO definition of asthma severity and control, and criteria for describing exacerbations and their severity, which would be globally applicable. This review addresses their findings in the context of recent literature, and assesses the usefulness of these definitions in children in particular. Recent Findings: Severe asthma was defined by the level of current clinical control and risks as: 'Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'. Severe asthma includes three groups, with different public health messages and challenges: untreated severe asthma, due to undiagnosed asthma or unavailability of therapy, difficult-to-treat severe asthma (due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or co-morbidity), and treatment-resistant severe asthma, including asthma for which control is not achieved despite the highest level of recommended treatment or asthma which is controlled only with the highest level of recommended treatment. Summary: These definitions will enable more precise measurement of the burden of severe childhood asthma globally. International collaborations in epidemiological and mechanistic studies, and randomized controlled trials of treatment, will be facilitated. However, both pathophysiology and severity are influenced by a number of factors with wide global variation; international comparisons should be interpreted with caution. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Joshi M.S.,Oxford Brookes University | Lalvani A.,UK National Heart and Lung Institute
Ethnicity and Health | Year: 2010

Objectives: Malaria is a serious disease hazard facing travellers to tropical countries. On average around 2000 cases of malaria are annually imported into the UK, with an over-representation of ethnic minority members. The current research examined adherence to chemoprophylaxis among UK South Asians travelling to malarial regions in South Asia and East Africa. Design: Four hundred South Asians were interviewed with a questionnaire investigating use of malaria prophylaxis, knowledge of malaria, risk perceptions and reasons for inadequate or zero adherence to chemoprophylaxis. Two hundred interviews were conducted in 1994, and a further 200 interviews in 2004. Participants were recruited from areas of known ethnic density in Leicester, London and Oxford. Results: In 1994, although 49% embarked on taking anti-malaria tablets, only 22% took tablets for 2 or more weeks upon return to the UK (and only 6% for the medically advisory period of 4 weeks). In 2004, 32% embarked on taking tablets but only 9% took tablets for 2 or more weeks upon returning to the UK (and only 2.5% for 4 weeks). Good adherence was associated with greater knowledge about the symptoms and transmission of malaria, and being more likely to define the trip as a 'holiday' rather than as a visit to 'family and friends'. Zero adherence was associated with a failure to recognise the potential severity and critical nature of malaria. Common reasons for partial and zero adherence were the perception that the personal risk of getting malaria was low and an erroneous belief in immunity. Conclusions: The specific cognitions available to ethnic minority members travelling 'home' contribute to a very low use of chemoprophylaxis, thus placing them at a heightened risk of acquiring malaria. Health messages need to stress that malaria is a serious health hazard and that emigres visiting malarial regions cannot rely on personal immunity. © 2010 Taylor & Fra ncis.

Steiner M.C.,University of Leicester | Roubenoff R.,Novartis | Tal-Singer R.,Glaxosmithkline | Polkey M.I.,UK National Heart and Lung Institute
Thorax | Year: 2012

Skeletal muscle dysfunction is a prevalent and clinically important systemic manifestation of chronic obstructive pulmonary disease (COPD) that predicts morbidity and mortality. Skeletal muscle retains its plasticity in response to anabolic stimuli such as exercise in COPD and is therefore a promising target for novel pharmacological therapies aimed at reducing disability and healthcare utilisation and improving mortality. In this article, we outline the steps the academic and pharmaceutical communities need to undertake for such therapeutic advances to be realised. Copyright Article author (or their employer) 2012.

Gollwitzer E.S.,University of Lausanne | Saglani S.,UK National Heart and Lung Institute | Trompette A.,University of Lausanne | Yadava K.,University of Lausanne | And 5 more authors.
Nature Medicine | Year: 2014

Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4 + Foxp3 + CD25 + Helios + regulatory T (T reg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios a ̂' T reg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization 10 or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of T reg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood. © 2014 Nature America, Inc. All rights reserved.

Barnes P.J.,Imperial College London | Barnes P.J.,UK National Heart and Lung Institute
Respiration | Year: 2010

Inhaled corticosteroids (ICS) are now very widely used in high doses in the management of COPD patients. In sharp contrast to the situation in asthma, ICS provide little or no benefit in COPD patients and may have long-term detrimental effects. High doses of ICS fail to reduce disease progression or mortality, even when combined with a long-acting β2-agonist (LABA). Several trials have demonstrated that ICS reduce exacerbations by 20-25%, particularly in patients with more severe disease, but these studies are confounded by poor trial design and more appropriate analysis shows no benefit. Indeed, the benefit of combination inhalers seems to be largely due to the effect of the LABA, and long-acting bronchodilators - including tiotropium - provide similar benefits in reducing exacerbations. However, there may be some COPD patients, for example those with concomitant asthma, who benefit from ICS. Yet it has not been possible to identify any clinical factors that predict corticosteroid responsiveness in COPD patients in the large clinical trials. There is increasing evidence that high doses of ICS may have detrimental effects on bones and may increase the risk of pneumonia. ICS fail to suppress inflammation in COPD patients because there is a marked reduction in histone deacetylase-2, the nuclear enzyme that corticosteroids require to switch off activated inflammatory genes. In the future, alternative anti-inflammatory treatments will be needed for COPD or therapeutic strategies which reverse the molecular pathways that causes corticosteroid resistance. © 2010 S. Karger AG, Basel.

Chaturvedi N.,UK National Heart and Lung Institute
Journal of the American Heart Association | Year: 2012

Stroke mortality rate is higher in South Asians than in Europeans, despite equivalent or lower resting blood pressure (BP). Elevated recovery BP after exercise predicts stroke, independently of resting values. We hypothesized that South Asians would have adverse postexercise hemodynamics and sought explanations for this. A population-based sample of 147 European and 145 South Asian middle-aged men and women performed the Dundee 3-minute step test. Cardiovascular risk factors were measured. BP, heart rate, and rate-pressure product, a measure of myocardial oxygen consumption, were compared. With 90% power and 5% significance, we could detect a difference of 0.38 of a standard deviation in any outcome measure. Resting systolic BP was similar in South Asians (144 mm Hg) and Europeans (142 mm Hg) (P=0.2), as was exercise BP (P=0.4). However, recovery systolic BP at 3 minutes after exercise was higher in South Asians by 4.3 mm Hg (95% confidence interval [CI], 0.2 to 8.3 mm Hg; P=0.04). This effect persisted when adjusted for exercise BP and work effort (5.4 mm Hg [95% CI, 2.2 to 8.7 mm Hg; P=0.001]). Adjustment for baroreflex insensitivity and greater aortic stiffness in South Asians contributes greatly to attenuating this ethnic difference (1.9 mm Hg [95% CI, -0.9 to 4.6 mm Hg; P=0.4]). Similarly, rate-pressure product recovery after exercise was impaired in South Asians by 735 mm Hg/min (95% CI, 137 to 1334 mm Hg/min; P=0.02); again, adjustment for baroreflex insensitivity and aortic stiffness attenuated this difference (261 mm Hg/min [95% CI, -39 to 561 mm Hg/min; P=0.3]). Postexercise recovery of BP and rate-pressure product is impaired in South Asians compared to Europeans even though resting and exercise BP are similar. This is associated with the autonomic dysfunction and aortic stiffness in South Asians.

Singanayagam A.,UK National Heart and Lung Institute
Current Opinion in Pulmonary Medicine | Year: 2016

PURPOSE OF REVIEW: The emergence of next-generation 16S rRNA sequencing techniques has facilitated a more detailed study of the bodyʼs microbiota and led to renewed interest in the association between microbial exposure and asthma inception. In this review, we evaluate the evidence that the respiratory tract and intestinal microbiota contribute to asthma pathogenesis and progression. RECENT FINDINGS: Human studies have revealed associations between the presence of potentially pathogenic bacteria in the respiratory tract in early life and subsequent risk of allergic sensitization and asthma. Similarly, alterations in the intestinal microbiota of neonates have also been shown to precede the development of asthma. Emerging evidence suggests that the lung microbiota is dysregulated in asthma with specific changes in bacterial diversity and community composition according to severity and phenotype. Studies using germ-free mice have been invaluable in moving our understanding from correlation to causation by demonstrating a mechanistic link between the neonatal microbiota and the development of allergic airway inflammation. SUMMARY: An expanding body of literature supports the hypothesis that early life microbial exposures and bacterial communities within the lung and/or intestine play an important role in shaping early immunological development. Perturbations in the microbiota may promote immune defects associated with the development of asthma and allergic sensitization. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Calderon M.A.,UK National Heart and Lung Institute
Cochrane database of systematic reviews (Online) | Year: 2011

Allergic ocular symptoms, although frequently trivialised, are common and represent an important comorbidity of allergic rhinitis. Sublingual Immunotherapy (SLIT) is an effective and well-tolerated treatment for allergic rhinitis, but its effects on symptoms of ocular allergy have not been well established. To evaluate the efficacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirements and conjunctival immediate allergen sensitivity. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1950 to January 2011), EMBASE (January 1980 to January 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews, (January 1979 to January 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (January 2011), ClinicalTrials.gov (www.clinicaltrials.gov) (January 2011), the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.actr.org.au) (July 2010), SCOPUS (November 2008) and the UK Clinical Trials Gateway (January 2010). There were no language or date restrictions in the search for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19 January 2011. Randomised controlled trials (RCTs), double-masked and placebo controlled, which evaluated the efficacy of SLIT in patients with symptoms of allergic rhinoconjunctivitis (ARC) or allergic conjunctivitis (AC). The primary outcome was the total ocular symptom scores. Secondary endpoints included individual ocular symptom scores (such as itchy eyes, red eyes, watery eyes, swollen eyes), ocular medication scores (eye drops) and conjunctival immediate allergen sensitivity (CIAS). Data were analysed and reported as standardised mean differences (SMDs) using Review Manager software. Forty-two trials (n = 3958 total participants; n= 2011 SLIT and n = 1947 placebo) had available data to evaluate the efficacy of SLIT on AC and were included in the meta-analyses. Heterogeneity among studies (I(2) statistic) was around 50% or below for all endpoints. Sublingual immunotherapy induced a significant reduction in both total ocular symptom scores (SMD -0.41; 95% confidence interval (CI) -0.53 to -0.28; P < 0.00001; I(2) = 59%) and individual ocular symptom scores for red eyes (SMD -0.33; 95% CI -0.45 to -0.22; P < 0.00001; I(2) = 27%), itchy eyes (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001; I(2) = 46%) and watery eyes (SMD -0.23; 95% CI -0.34 to -0.11; P < 0.0001; I(2) = 42%) compared to placebo. Those participants having active treatment showed an increase in the threshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05; I(2) = 43%). No significant reduction was observed in ocular eye drops use (SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13; I(2) = 34%). Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC. There were however some concerns about the overall quality of the evidence-base, this relating to inadequate descriptions of allocation concealment in some studies, statistical heterogeneity and the possibility of publication bias. There is a need for further large rigorously designed studies that study long-term effectiveness after discontinuation of treatment and establish the cost-effectiveness of SLIT.

Mercado N.,UK National Heart and Lung Institute | To Y.,UK National Heart and Lung Institute | Ito K.,UK National Heart and Lung Institute | Barnes P.J.,UK National Heart and Lung Institute
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-δ (PI3Kδ). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. The aim of this study was to identify the molecular mechanism whereby nortriptyline increases corticosteroid sensitivity. Phosphorylation of Akt, a footprint of PI3K activation, and HDAC activity were evaluated by Western blotting and fluorescent activity assay in U937 monocytic cells. Corticosteroid sensitivity was evaluated by the inhibition of tumor necrosis factor α (TNFα)-induced interleukin 8 (IL-8) production by budesonide. Hydrogen peroxide (H 2O 2) or cigarette smoke extract (CSE) increased the level of phosphorylated Akt (pAkt) and reduced HDAC activity. Pretreatment with nortriptyline inhibited pAkt induced by CSE and H 2O 2 as well as restored HDAC activity that had been decreased by H 2O 2 and CSE. In addition, nortriptyline inhibited PI3Kδ activity, but had no effect on the PI3Kα and PI3Kγ isoforms. Although CSE reduced the effects of budesonide on TNFα-induced IL-8 production in U937 cells, nortriptyline reversed CSE-induced corticosteroid insensitivity. Nortriptyline restores corticosteroid sensitivity induced by oxidative stress via direct inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD and severe asthma. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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