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Hewitt R, Farne H, Ritchie A, et al., 2016, The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma, Therapeutic Advances in Respiratory Disease, Vol: 10, Pages: 158-174, ISSN: 1753-4666
Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus–bacteria interactions and therapeutic advances.
Bousquet J, Barbara C, Bateman E, et al., 2016, AIRWAYS-ICPs (European Innovation Partnership on Active and Healthy Ageing) from concept to implementation, European Respiratory Journal, Vol: 47, Pages: 1028-1033, ISSN: 0903-1936
Jozwik A, Habibi MS, Paras A, et al., 2016, Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 7, ISSN: 2041-1723
Ritchie AI, Jackson DJ, Edwards MR, et al., 2016, Airway epithelial orchestration of innate immune function in response to virus infection. A focus on asthma, Annals of the American Thoracic Society, Vol: 13 Suppl 1, Pages: S55-S63, ISSN: 2329-6933
Heaney LG, Djukanovic R, Woodcock A, et al., 2016, Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK), Thorax, Vol: 71, Pages: 187-189, ISSN: 0040-6376
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
James AJ, Reinius LE, Verhoek M, et al., 2016, Increased YKL-40 and Chitotriosidase in Asthma and Chronic Obstructive Pulmonary Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 193, Pages: 131-142, ISSN: 1073-449X
Edwards MR, Facchinetti F, Civelli M, et al., 2016, Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines, Pharmacology Research and Perspectives, Vol: 4, ISSN: 2052-1707
Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose–response curve (1000–0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast.
Williams GR, Kubajewska I, Glanville NS, et al., 2016, The potential for a protective vaccine for rhinovirus infections., Expert Review of Vaccines, Vol: 15, Pages: 569-571, ISSN: 1744-8395
Rhinovirus (RV) infections impose a major disease burden as they cause around three out offour common colds and are responsible for the majority of acute exacerbations of chronicobstructive pulmonary disease (COPD) and asthma [1, 2]. RVs therefore are associated withan enormous economic cost in missed work or school and medical attention. Prophylacticvaccination against infection is arguably the most effective medical intervention everdeveloped, and has proven enormously effective in protecting against a large number ofdiseases. However, at the present time no effective vaccine exists for RVs. This is largelydue to the existence of 100 serotyped antigenically distinct RV strains - such variabilitymeans that a vaccine designed to elicit immune responses against a particular RV is unlikelyto be able to provide protection against the full range of virus subtypes successfully . Infact, this phenomenon was observed as early as 1965 when immunising with formalininactivated whole RV and is confirmed by the knowledge that the immunity induced followingRV infection does not significantly protect from future infection by different RV serotypes .More sophisticated attempts at immunisation with multiple inactivated RV serotypes alsofailed to induce significant cross-serotype protection . Thus, an effective cross-serotyperesponsive RV vaccine has remained elusive. The relatively recent description of a newclade of RV types (RV-C) has increased the number of identified strains/serotypes to ~160. Perhaps the quest for a RV vaccine has been dismissed as too difficult or evenimpossible, but new developments suggest that it may be feasible to generate a significantbreadth of immune protection.
Russell KE, Chung KF, Clarke CJ, et al., 2016, The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD., PLOS One, Vol: 11, ISSN: 1932-6203
INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
Footitt J, Mallia P, Durham AL, et al., 2016, Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD., Chest, Vol: 149, Pages: 62-73, ISSN: 1931-3543
BACKGROUND: Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. METHODS: Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. RESULTS: Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. CONCLUSIONS: O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
Johnston SL, Szigeti M, Cross M, et al., 2016, A Randomised, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy Of Oral Azithromycin (500 Mg Od) As A Supplement To Standard Care For Adult Patients With Acute Exacerbations Of Asthma (the Azalea Trial), Publisher: AMER THORACIC SOC
Telcian AG, Zdrenghea MT, Caramori G, et al., 2015, Soluble major histocompatibility complex class I-related chain B molecules are increased and correlate with clinical outcomes during rhinovirus infection in healthy subjects, Chest, Vol: 146, Pages: 32-40, ISSN: 1931-3543
BACKGROUND:Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma.METHODS:Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection.RESULTS:RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma.CONCLUSIONS:RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections.
Jozwik A, Habibi MS, Paras A, et al., 2015, RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 6, ISSN: 2041-1723
In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyze phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. These are more highly differentiated but express fewer cytotoxicity markers than in blood, but their abundance prior to infection correlates with protection from more severe disease.
Wolsk HM, Følsgaard NV, Birch S, et al., 2015, Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates., Journal of Infectious Diseases, Vol: 213, Pages: 1262-1270, ISSN: 1537-6613
BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was therefore to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic 1-month-old neonates from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for levels of 20 immune mediators related to type 1, type 2, type 17, and regulatory immune paths. The association between immune mediator levels and viruses was tested by conventional statistics and partial least square discriminant analysis. RESULTS: Picornaviruses were detected in 58 neonates (10.2%) and other viruses in 10 (1.8%). A general up-regulation of immune mediators was found in the neonates with picornavirus (P < .0001; partial least square discriminant analysis). The association was pronounced for type 1- and type 2-related markers and was unaffected by comprehensive confounder adjustment. Detection of picornavirus and bacteria was associated with an additive general up-regulating effect. CONCLUSIONS: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is relevant to understanding the immune potentiating effect of early life exposure to viruses.
Schögler A, Stokes AB, Casaulta C, et al., 2015, Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection, Journal of Cystic Fibrosis, Vol: 15, Pages: 332-339, ISSN: 1873-5010
Rhinoviruses (RVs) are associated with exacerbations of cystic fibrosis (CF), asthma and COPD. There is growing evidence suggesting the involvement of the interferon (IFN) pathway in RV-associated morbidity in asthma and COPD. The mechanisms of RV-triggered exacerbations in CF are poorly understood. In a pilot study, we assessed the antiviral response of CF and healthy bronchial epithelial cells (BECs) to RV infection, we measured the levels of IFNs, pattern recognition receptors (PRRs) and IFN-stimulated genes (ISGs) upon infection with major and minor group RVs and poly(IC) stimulation. Major group RV infection of CF BECs resulted in a trend towards a diminished IFN response at the level of IFNs, PRRs and ISGs in comparison to healthy BECs. Contrary to major group RV, the IFN pathway induction upon minor group RV infection was significantly increased at the level of IFNs and PRRs in CF BECs compared to healthy BECs.
Carlsson CJ, Vissing NH, Sevelsted A, et al., 2015, Duration of wheezy episodes in early childhood is independent of the microbial trigger, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 1208-1214.e5, ISSN: 1097-6825
BackgroundWheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger.ObjectiveWe sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger.MethodsTwo hundred eighty-three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth.ResultsEight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species.ConclusionsThe duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes.
De La Rosa GM, Delaney EM, Webb-Murphy JA, et al., 2015, Interactive effects of stress and individual differences on alcohol use and posttraumatic stress disorder among personnel deployed to Guantanamo Bay, ADDICTIVE BEHAVIORS, Vol: 50, Pages: 128-134, ISSN: 0306-4603
Ritchie AI, Farne HA, Singanayagam A, et al., 2015, Pathogenesis of Viral Infection in Exacerbations of Airway Disease., Annals of the American Thoracic Society, Vol: 12, Pages: S115-S132, ISSN: 2329-6933
Chronic airway diseases are a significant cause of morbidity and mortality worldwide, and their prevalence is predicted to increase in the future. Respiratory viruses are the most common cause of acute pulmonary infection, and there is clear evidence of their role in acute exacerbations of inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. Studies have reported impaired host responses to virus infection in these diseases, and a better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus-induced exacerbations. The aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in acute exacerbations of chronic pulmonary diseases and to discuss exciting areas for future research and novel treatments.
Bousquet J, Schunemann HJ, Fonseca J, et al., 2015, MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation, Allergy, Vol: 70, Pages: 1372-1392, ISSN: 0105-4538
Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.
Eccles R, Winther B, Johnston SL, et al., 2015, Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial, Respiratory Research, Vol: 16, ISSN: 1465-993X
ota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previousclinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms.Methods: This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patientswith self-diagnosed colds of <48 h’ duration that were confirmed by baseline cold symptom scores. Patients wereto self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptominformation for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2–4 (TSS2–4).Results: Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo).Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients(55.7 %). Mean ± SE for TSS2–4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratoryanalyses after unblinding (TSS2–4 excluding a patient with aberrantly high symptom scores [TSS2–4, ex 1pt]; mean ofTSS over Days 1–4 [TSS1–4]; change in TSS1–4 relative to baseline [TSS1–4, rel]) demonstrated treatment differences infavor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirusat baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 %reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates.Conclusions: The primary endpoint did not demonstrate a statistically significant difference between I-C andplacebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction
Dhariwal J, Kitson J, Jones RE, et al., 2015, Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundPractical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide(LPS) is a component of the cell wall of Gram negative bacteria and a potentactivator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasalmucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levelsin mucosal lining fluid (MLF).MethodsWe performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy nonatopicsubjects (n = 14 per protocol). Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl) orplacebo were administered by a single nasal spray to each nostril. Using the recently developedmethod of nasosorption with synthetic adsorptive matrices (SAM), a series of sampleswere taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassayin MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantifiedfrom nasal epithelial curettage samples taken before and after challenge.ResultsTopical nasal LPS was well tolerated, causing no symptoms and no visible changes to thenasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1α) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μgLPS). At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05). Dose-relatedchanges in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophilsappeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levelsshowed prominent cytokine and chemokine responses to relatively low LPS doses (10μgand 30μg LPS).
Schoegler A, Stokes AB, Casaulta C, et al., 2015, Differential interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Selroos O, Kupczyk M, Kuna P, et al., 2015, National and regional asthma programmes in Europe., European Respiratory Review, Vol: 24, Pages: 474-483, ISSN: 1600-0617
This review presents seven national asthma programmes to support the European Asthma Research and Innovation Partnership in developing strategies to reduce asthma mortality and morbidity across Europe. From published data it appears that in order to influence asthma care, national/regional asthma programmes are more effective than conventional treatment guidelines. An asthma programme should start with the universal commitments of stakeholders at all levels and the programme has to be endorsed by political and governmental bodies. When the national problems have been identified, the goals of the programme have to be clearly defined with measures to evaluate progress. An action plan has to be developed, including defined re-allocation of patients and existing resources, if necessary, between primary care and specialised healthcare units or hospital centres. Patients should be involved in guided self-management education and structured follow-up in relation to disease severity. The three evaluated programmes show that, thanks to rigorous efforts, it is possible to improve patients' quality of life and reduce hospitalisation, asthma mortality, sick leave and disability pensions. The direct and indirect costs, both for the individual patient and for society, can be significantly reduced. The results can form the basis for development of further programme activities in Europe.
Hatchwell L, Collison A, Girkin J, et al., 2015, Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia, Thorax, Vol: 70, Pages: 854-861, ISSN: 0040-6376
Background Asthma exacerbations represent asignificant disease burden and are commonly caused byrhinovirus (RV), which is sensed by Toll-like receptors(TLR) such as TLR7. Some asthmatics have impairedinterferon (IFN) responses to RV, but the underlyingmechanisms of this clinically relevant observation arepoorly understood.Objectives To investigate the importance of intactTLR7 signalling in vivo during RV exacerbation usingmouse models of house dust mite (HDM)-inducedallergic airways disease exacerbated by a superimposedRV infection.Methods Wild-type and TLR7-deficient (Tlr7−/−) BALB/c mice were intranasally sensitised and challenged withHDM prior to infection with RV1B. In some experiments,mice were administered recombinant IFN or adoptivelytransferred with plasmacytoid dendritic cells (pDC).Results Allergic Tlr7−/− mice displayed impaired IFNrelease upon RV1B infection, increased virus replicationand exaggerated eosinophilic inflammation and airwayshyper reactivity. Treatment with exogenous IFN oradoptive transfer of TLR7-competent pDCs blocked theseexaggerated inflammatory responses and boosted IFNγrelease in the absence of host TLR7 signalling. TLR7expression in the lungs was suppressed by allergicinflammation and by interleukin (IL)-5-inducedeosinophilia in the absence of allergy. Subjects withmoderate-to-severe asthma and eosinophilic but notneutrophilic airways inflammation, despite inhaledsteroids, showed reduced TLR7 and IFNλ2/3 expressionin endobronchial biopsies. Furthermore, TLR7 expressioninversely correlated with percentage of sputumeosinophils.Conclusions This implicates IL-5-induced airwayseosinophilia as a negative regulator of TLR7 expressionand antiviral responses, which provides a molecularmechanism underpinning the effect of eosinophiltargetingtreatments for the prevention of asthmaexacerbations.
Singanayagam A, Glanville N, Walton RP, et al., 2015, A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD, Clinical Science, Vol: 129, Pages: 245-258, ISSN: 1470-8736
Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF)-α, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon γ-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with pot
Jackson DJ, Trujillo-Torralbo M-B, del-Rosario J, et al., 2015, The influence of asthma control on the severity of virus-induced asthma exacerbations, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 497-500.e3, ISSN: 1097-6825
Gielen V, Sykes A, Zhu J, et al., 2015, Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 177-188e.11, ISSN: 1097-6825
BackgroundRhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.ObjectiveWe sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.MethodsWe assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.ResultsWe report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.ConclusionWe describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
Bonnelykke K, Vissing NH, Sevelsted A, et al., 2015, Association between respiratory infections in early life and later asthma is independent of virus type, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 81-86.e4, ISSN: 1097-6825
Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent.ObjectiveWe sought to study the association between specific infections in early life and development of asthma later in childhood.MethodsThree hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years.ResultsIn unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma.ConclusionThe number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory trac
Jackson DJ, Glanville N, Trujillo-Torralbo M-B, et al., 2015, Interleukin-18 Is Associated With Protection Against Rhinovirus-Induced Colds and Asthma Exacerbations, Clinical Infectious Diseases, Vol: 60, Pages: 1528-1531, ISSN: 1537-6591
Rhinoviruses cause the common cold and exacerbations of asthma. Animal models of infection have identified a protective role for interleukin-18 (IL-18). Following experimental rhinovirus infection, we observed increased respiratory symptoms in healthy and asthmatic subjects with low nasal and bronchial IL-18 levels.
Girkin J, Hatchwell L, Foster P, et al., 2015, CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection, Journal of Immunology, Vol: 194, Pages: 4924-4930, ISSN: 1550-6606
Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B–infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7–targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in nonallergic mice. Neutralizing CCL7 also reduced activation of NF-κB p65 and p50 subunits, as well as airway hyperreactivity (AHR) in nonallergic mice. However, neither NF-κB subunit activation nor AHR was abolished with infection of allergic mice after neutralizing CCL7, despite a reduction in the number of neutrophils, macrophages, and eosinophils. IRF-7 small interfering RNA primarily suppressed IFN-α and IFN-β levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF-7 in RV-induced inflammation and IFN responses and link NF-κB signaling to the development of AHR.
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