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PR Toolkit

Guidance and resources to help professionals promote recruitment

Author: U-BIOPRED
Publication type: Project Resources
Published: 2011

Prevalence and phenotypic characteristics of severe adult-onset asthma in the U-BIOPRED cohort

A recent study has shown that severe adult-onset asthma is a distinct clinical phenotype, characterized by absence of atopy, nasal polyposis, persistent eosinophilic airway inflammation and higher blood neutrophil counts [Amelink et al, JACI 2013]. The aim of the present study was to assess the prevalence and phenotypic characteristics of adult-onset disease amongst patients with severe asthma. 

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Author: Hekking PW Bel EH
Publication type: Academic Publication
Published: 2014
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Project update booklet 2012

An overview of the project and progress report (up to August 2012)

Author: U-BIOPRED
Publication type: Project Resources
Published: 2012
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Reclassification of bronchodilator reversibility in the U-BIOPRED adult asthma cohort using z-scores

Bronchodilator reversibility (BDR) is a hallmark feature of asthma. In the May 2017 issue of CHEST, Quanjer et al1 raised two valuable points to consider in the interpretation of BDR.

1.The current European Respiratory Society/American Thoracic Society criteria for BDR2 (ie, >12% and >200 mL increase in FEV1 and/or FVC) leads to a bias in that the likelihood of BDR increases with deteriorating pulmonary function. Consequently, the authors propose new criteria for BDR that is based on z scores, which eliminates this artifact: ΔzFEV1 > 0.78 or ΔzFVC > 0.64.
2.FVC BDR, unlike FEV1 BDR, increases with asthma severity and hence should be interpreted independently to FEV1 BDR.
We applied the newly proposed BDR criteria to the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult asthma cohort3 to: (1) determine the influence of these new criteria on the prevalence of BDR and (2) explore the difference in clinical characteristics between individuals with FEV1 BDR and FVC BDR. A total of 499 people with asthma underwent BDR testing. Global Lung Function Initiative 2012 reference equations were used to calculate z scores.4 Full methodology is presented elsewhere.3
Using the European Respiratory Society/American Thoracic Society BDR criteria,2 55% of the asthma cohort displayed BDR. The reevaluation of BDR using ΔzFEV1 > 0.78 or ΔzFVC > 0.64 resulted in the reclassification of 12% of the population: 9% no longer having BDR and 3% now fulfilling BDR criteria. A further 10% with BDR changed classification on the type of BDR they displayed.
We compared the clinical characteristics between the new BDR classifications. Individuals with FVC BDR only and both FEV1 and FVC BDR had worse lung function, higher BMI, and poorer asthma control and quality of life compared with individuals with FEV1 BDR only

Authors: Simpson AJ, Fowler SJ, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2018
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Recruitment flyer

A flyer promoting recruitment

Author: U-BIOPRED
Publication type: Project Resources
Published: 2012

Rhinovirus application on the background of allergic airway inflammation in a chronic house dust mite model

Human rhinovirus (HRV) is most prominently associated with asthma exacerbations in humans. The U-BIOPRED project of the Innovative Medicine Initiative (IMI) aims to define biomarkers of asthma exacerbations for distinct phenotypes to enable a better prediction of therapeutic efficacy.   

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Author: Rochlitzer S
Publication type: Academic Publication
Published: 2012
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Rhinovirus infection in chronic mouse asthma model

Severe asthma and viral-induced asthma exacerbations represent a high unmet medical need as no therapy is currently available for these patients. HRV (human rhinovirus) is prominently associated with asthma exacerbations in humans. The aim of the present study was to establish a mouse model of severe asthma with additional rhinovirus infection to investigate the interplay between chronic allergic airway inflammation and acute respiratory viral infection.

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Author: Rochlitzer S Hoymann HG
Publication type: Academic Publication
Published: 2014

Rhinovirus infection in human and mouse precision cut lung slices

Human rhinovirus (HRV) is the main cause of respiratory tract infection and has been linked to exacerbations of chronic lung diseases e.g. allergic asthma. However, reliable models of HRV induced exacerbations of severe chronic asthma are not available. The aim of this study was to evaluate the potential use of precision cut lung slices (PCLS) for analysis of HRV infection in mouse and human. 

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Author: Rochlitzer S Braun A
Publication type: Academic Publication
Published: 2013

Safety of the COX-2 inhibitor etoricoxib in allergen-challenged asthmatics

Prostaglandins (PG) that constrict and relax airways are biosynthesised in reactions catalysed by either cyclooxygenase isoenzymes 1 or 2 (COX-1 and COX-2). In mice models of asthma, COX-2 inhibition aggravates airway hyperresponsiveness (AHR). It is unclear if inhibition of COX-2 in subjects with asthma selectively removes PGs that make asthmatic responses better or worse.

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Authors: Balgoma D, Daham K
Publication type: Academic Publication
Published: 2012

Session: Asthma and COPD: diseases with different phenotypes

Current therapeutic options fail to prevent or reverse irreversible obstruction, which occurs in some patients with asthma. Careful phenotyping of these patients will allow more detailed understanding of the underlying pathophysiology, such as the accompanying inflammatory pathways. This can promote the development of targeted prophylaxis or treatment. 

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Author: Wagener A H
Publication type: Academic Publication
Published: 2013
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Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study

The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild-moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups.In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm-2) compared with both severe asthma groups (SAn: 17.4 mm-2, p<0.001; SAs/ex: 22.2 mm-2, p=0.01) and with the MMA group (21.2 mm-2, p=0.01). The number of CD4+ lymphocytes was decreased in the SAs/ex group (4.7 mm-2) compared with the SAn (11.6 mm-2, p=0.002), MMA (10.1 mm-2, p=0.008) and HC (10.6 mm-2, p<0.001) groups. No other differences were observed.Affymetrix microarray analysis identified seven probe sets in the bronchial brushing samples that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1); the remaining two are unnamed.We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.

Authors: Wilson SJ, Ward JA, Sousa AR, Corfield J, Bansal AT, De Meulder B, Lefaudeux D, Auffray C, Loza MJ, Baribaud F, Fitch N, Sterk PJ, Chung KF, Gibeon D, Sun K, Guo YK, Adcock IM, Djukanovic R, Dahlen B, Chanez P, Shaw D, Krug N, Hohlfield J, Sandstrom T, Howarth PH, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2016

Severe asthma patients on oral corticosteroid therapy as a distinct phenotype: the European U-BIOPRED cohort

A relatively important proportion of patients with severe asthma end up using a daily dose of oral corticosteroids (OCS) in addition to their high dose of inhaled corticosteroids (ICS). We have determined whether oral CS-dependent severe asthma is a distinct phenotype from those only on ICS.

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Author: Chung F
Publication type: Academic Publication
Published: 2014
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Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship.

610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort.

When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1–47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD.

This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

Authors: Tariq K, Schofield JPR, Nicholas B, Burg D, Brandsma J, Bansal AT, Wilson SJ, Lutter R, Fowler SJ, Bakke PS, Caruso M, Dahlen B, Horvath I, Krug N, Montuschi P, Sanak M, Sandstrom T, Geiser T, Pandis I, Sousa AR, Adcock IM, Shaw D, Auffray C, Howarth PH, Sterk PJ, Chung KF, Skipp P, Dimitrov B, Djukanovic R, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2019
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Sputum transcriptomics reveal upregulation of IL-1 receptor family members in severe asthma

BACKGROUND:

Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy.

OBJECTIVE:

We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma.

METHODS:

Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA.

RESULTS:

Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma.

CONCLUSION:

IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.

Authors: Rossios C, Pavlidis S, Hoda U, Kuo CS, Wiegman C, Sun K, Loza MJ, Baribaud F, Durham AL, Ojo O, Rowe A, Bansal AT, Auffray C, Sousa AR, Corfield J, Djukanovic R, Guo YK, Sterk PJ, Chung KF, Adcock IM, U-BIOPRED
Publication type: Academic Publication
Published: 2018
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Stratification of asthma phenotypes by airway proteomic signatures.

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 to predict treatment responses and a need for better understanding of the underlying mechanisms.

OBJECTIVE:

Identify molecular sub-phenotypes of asthma defined by proteomic signatures for improved stratification.

METHODS:

Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyse the proteomes of sputum supernatants from 246 participants (206 asthmatics) 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, proteotypes, based on similarity in proteomics features, representing discrete molecular sub-phenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined three of these as highly eosinophilic, three as highly neutrophilic, and two as highly atopic with relatively low granulocytic inflammation. For each of these three 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 by quantifying granulocytic inflammation and gives additional insight into their underlying mechanisms which could become targets for novel therapies.

Authors: Schofield JPR, Burg D, Nicholas B, Strazzeri F, Brandsma J, Staycova D, Folisi C, Bansal AT, Xian Y, Guo YK, Rowe A, Corfield J, Wilson SJ, Ward JA, Lutter R, Shaw DE, Bakke PS, Caruso M, Dahlen SE, Fowler SJ, Horvath I, Howarth PH, Krug N, Montuschi P, Sanak M, Sandstrom T, Sun K, Pandis I, Riley JH, Auffray C, De Meulder B, Lefaudeux D, Sousa AR, Adcock IM, Chung KF, Sterk PJ, Skipp P, Djukanovic R, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2019
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Susceptibility to influenza virus infection of bronchial biopsies in asthma

Influenza causes significant morbidity and mortality, especially in patients with chronic lung diseases.1 Infection results in inflammatory cell influx and leads to either resolution or increased lung immunopathology and resulting morbidity,2 especially in patients with chronic airways diseases where viruses exacerbate inflammation and, subsequently, symptoms.
Those with asthma are more susceptible to influenza and are, therefore, the most common population hospitalized, although, interestingly, they are less likely to develop severe disease or die than those without asthma.3 The mechanisms underlying the increased susceptibility to viral infections in those with asthma are poorly understood, but it has been suggested that the skewing toward TH2 immunity results in deficient TH1 antiviral immunity.4 Understanding of antiviral immunity in asthma is also complicated by the immunosuppressive effects of inhaled corticosteroids (ICSs) or oral corticosteroids, standard treatments in asthma.5 The effectiveness of ICSs during exacerbations is unclear because doubling their dose at the time of upper respiratory tract infection fails to prevent asthma exacerbations.6 Corticosteroids may protect against severe outcomes in those with asthma with influenza infection, whereas systemic corticosteroids in individuals without asthma cause delayed viral clearance.7
The primary aim of our study was to compare the susceptibility and inflammatory responses to influenza virus infection of ICS treated patients with asthma and healthy individuals. We hypothesized that these patients with asthma are more susceptible to influenza infection and that their inflammatory responses during infection are elevated, thereby contributing to asthma exacerbations. In view of ethical and safety difficulties of studying influenza infection in vivo, especially in patients with asthma, the airway responses were studied in bronchial biopsies infected ex vivo, using a bronchial biopsy explant model.8 To mimic in vivo conditions of viral exposure, bronchial biopsies from patients with asthma regularly treated with ICSs were exposed to influenza virus in the presence of exogenous ICS, fluticasone propionate (FP), whereas biopsies from healthy subjects were infected in the absence of this corticosteroid.
Twenty-four hours after ex vivo infection, biopsies were enzymatically dispersed with collagenase, allowing quantification of infected cells and activation markers by multicolor flow cytometry (see details in this article’s Online Repository at www.jacionline.org). In these conditions, epithelial cell infection was not different between health and asthma (Fig 1, Ai), whereas viral shedding was significantly reduced in explants from patients with asthma (Fig 1, Aii). T-lymphocyte activation induced by infection (measured by fold-induction of cell surface HLA-DR expression) was suppressed in the biopsies from patients with asthma (Fig 1, Bi); HLA-DR expression on epithelial cells was unchanged (Fig 1, Bii). Secreted mediator responses, including innate defence (IFN-, C-X-C motif chemokine 10 [CXCL-10]), chemokines (CXCL-8, monocyte chemoattractant protein 1, macrophage inflammatory protein 1), and proinflammatory cytokines (IL-1, IL-6, TNF-α) were also all blunted in those with asthma when compared with healthy controls (Fig 1, C). Type I interferons were not present in sufficient quantity to measure; however, the finding of lower CXCL-10 quantities in asthmatic explants was consistent with deficient innate antiviral defences in asthma.
Because subjects with asthma in our study were on regular ICSs, the effects on influenza susceptibility of which are unknown, we also sought to determine whether the differences seen in the primary comparator groups reflected the effects of FP or disease. Ex vivo treatment of steroid-naive bronchial explants from healthy participants with FP increased the percentage of virally infected epithelial cells (Fig 2, Ai) without (in contrast to asthmatic explants) affecting viral shedding (Fig 2, Aii) or activation of T lymphocytes (Fig 2, Bi), but epithelial cell surface induction of HLA-DR was suppressed (Fig 2, Bii). We have previously observed elevation of this panel ofmediators with influenza infection in healthy subjects, with the exception of IL-8.8 As expected, FP treatment significantly inhibited the secretion of these mediators (Fig 2, C).
This study points to important differences between asthma and health in respect of influenza virus handling. However, our hypothesis that the elevated morbidity and mortality caused by influenza infection in people with asthma is associated with increased susceptibility to infection was not fully supported because the initial infection rate was no different between asthma and health (judged by similar proportions of infected epithelial cells). Nevertheless, the blunted inflammatory, including innate immune, responses and T-cell activation (judged by lesser induction of cell surface HLA-DR expression) to infection in ICS-treated patients with asthma do argue in favor of deficient anti-influenza immunity in these patients. Although the reduced viral shedding in asthmatic tissues (when compared with healthy tissues) could be viewed as a positive phenomenon that limits virus spread, alternatively, it could account for prolonged viral retention, with consequential prolonged recovery and increased risk of viremia. Prolonged viral shedding appears to be a consistent problem associated with systemic corticosteroid therapy in patients hospitalized with influenza, in contrast to antiviral agents that enhance virus clearance.7
For ethical and safety reasons, it was impossible to wash out the effects of regular treatment with ICS on the asthmatic explant responses to infection. Accepting that the effects of corticosteroids likely differ between healthy and asthmatic tissue, we thought it useful to study the impact of FP treatment on explants from healthy subjects. In contrast to asthma, this showed that FP increased epithelial infection rates, while viral shedding and T-cell activation were unaffected. Similar to asthma, mediator secretion was suppressed. We also found that MHC class II (HLA-DR) induction in healthy airway tissue epithelial cells was suppressed by ex vivo FP treatment. We have previously observed influenza infection-mediated elevation in HLA-DR on the surface of primary bronchial epithelial cells,9 an effect replicated in bronchial epithelial cells of our explants, probably occurring in both models as a result of infection-induced secretion of IFN-, and suggestive that respiratory epithelial cells potentiate cytotoxic T-cell activity.
Corticosteroid suppression of this effect may reflect suppression of innate antiviral mediators including IFN-, and could have implications for clearance of virally infected cells from the lungs. In summary, the present study shows blunted responses of ICS treated patients with mild/moderate asthma to influenza virus infection but is unable to differentiate between the impact of corticosteroid and disease itself. The lack of effect of corticosteroids in explants from healthy participants suggests that reduced viral shedding and defective T-cell activation observed in patients with asthma may be independent of corticosteroid treatment. Further study is needed to elucidate the underlying mechanisms.

Authors: Nicholas B, Dudley S, Tariq K, Howarth PH, Lunn K, Pink S, Sterk PJ, Adcock IM, Monk P, Djukanovic R, U-BIOPRED Study Group
Publication type: Academic Publication
Published: 2017
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Systems medicine and integrated care to combat chronic noncommunicable diseases

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century.

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Author: Auffray C
Publication type: Academic Publication
Published: 2011
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Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms

The development of computational approaches in systems biology has reached a state of maturity that allows their transition to systems medicine. Despite this progress, intuitive visualisation and context-dependent knowledge representation still present a major bottleneck. In this paper, we describe the Disease Maps Project, an effort towards a community-driven computationally readable comprehensive representation of disease mechanisms. We outline the key principles and the framework required for the success of this initiative, including use of best practices, standards and protocols. We apply a modular approach to ensure efficient sharing and reuse of resources for projects dedicated to specific diseases. Community-wide use of disease maps will accelerate the conduct of biomedical research and lead to new disease ontologies defined from mechanism-based disease endotypes rather than phenotypes.

Authors: Mazein A, Ostaszewski M, Kuperstein I, Watterson S, Le Novere N, Lefaudeux D, De Meulder B, Pellet J, Balaur I, Saqi M, Nogueira MM, He F, PArton A, Lemonnier N, Gawron P, Gebel S, Hainaut P, Ollert M, Dogrusoz, Barillot E, Zinovyev A, Schneider R, Balling R, Auffray C
Publication type: Academic Publication
Published: 2018
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