Publications of Renaud LOUIS
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See detailExosomal Long Non-Coding RNAs in Lung Diseases
Poulet, Christophe ULiege; NJOCK, Makon-Sébastien ULiege; MOERMANS, Catherine ULiege et al

in International Journal of Molecular Sciences (2020), 21(10), 3580

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung ... [more ▼]

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung diseases. We present here a compilation of the current knowledge on lncRNAs commonly found in Chronic Obstructive Pulmonary Disease (COPD), asthma, Idiopathic Pulmonary Fibrosis (IPF), or lung cancers. We built interaction networks describing the mechanisms of action for COPD, asthma, and IPF, as well as private networks for H19, MALAT1, MEG3, FENDRR, CDKN2B-AS1, TUG1, HOTAIR, and GAS5 lncRNAs in lung cancers. We identified five signaling pathways targeted by these eight lncRNAs over the lung diseases mentioned above. These lncRNAs were involved in ten treatment resistances in lung cancers, with HOTAIR being itself described in seven resistances. Besides, five of them were previously described as promising biomarkers for the diagnosis and prognosis of asthma, COPD, and lung cancers. Additionally, we describe the exosomal-based studies on H19, MALAT1, HOTAIR, GAS5, UCA1, lnc-MMP2-2, GAPLINC, TBILA, AGAP2-AS1, and SOX2-OT. This review concludes on the need for additional studies describing the lncRNA mechanisms of action and confirming their potential as biomarkers, as well as their involvement in resistance to treatment, especially in non-cancerous lung diseases. [less ▲]

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See detailMultimodal Approaches for Untargeted Screening for Medical Applications of the Human Volatilome
Stefanuto, Pierre-Hugues ULiege; Zanella, Delphine ULiege; SCHLEICH, FLorence ULiege et al

Conference (2020, March)

The ballistic rise of analytical technologies has opened a large playground for all type of untargeted “omics” screening. In that trend, there is a rising interest for the characterization of the human ... [more ▼]

The ballistic rise of analytical technologies has opened a large playground for all type of untargeted “omics” screening. In that trend, there is a rising interest for the characterization of the human volatilome. Indeed, the characterization and the understanding of the volatile organic compounds (VOCs) production in different ex vivo matrices could open the route for improved diagnosis approach and new treatment. In the field of volatilomics, separation science based on multidimensional methods such as comprehensive two-dimensional gas chromatography (GC×GC) appeared as one of the methods of choice for the characterization complex VOC mixtures. At the price of high cost equipment and limited adaptability to routine medical usage, GC×GC offers the possibility to almost completely characterize a sample. For large scale screening, direct introduction instruments such as selected ion flow tube mass spectrometry (SIFT-MS) offered the capacity to perform both targeted and untargeted analyses within a few minutes. SIFT-MS can generate compositional patterns from direct sample introduction at the same time than other routine medical actions. These two orthogonal approaches for pathology screening should ideally conduct to identical sample classifications but have never been directly compared over an identical set of patients. In order to evaluate their complementarity, breath from 50 well-characterized asthmatic patients were analyzed by both approaches. Breath samples were collected using Tedlar bags. For GC×GC-HRTOFMS analyses, the bags were transferred onto thermal desorption tubes prior to injection. For SIFT-MS, the bags were directly emptied into the instrument. Next, data were analyzed using identical processing workflow. We observed that both approaches offered similar classification capacities. GC×GC-HRTOFMS allowed identifying the putative markers for comparison with previous studies and metabolic interpretation, while SIFT-MS offered a faster screening capacity. [less ▲]

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See detailIn vitro characterization of lung inflammation mechanisms
Focant, Jean-François ULiege; Zanella, Delphine ULiege; HENKET, Monique ULiege et al

Conference (2020, January)

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See detailAssessment of diagnostic accuracy of lung function indices and FeNO for a positive methacholine challenge
Bougard, Nicolas ULiege; Nekoee Zahraei, Halehsadat ULiege; SCHLEICH, FLorence ULiege et al

in Biochemical Pharmacology (2020)

Demonstration of bronchial hyperresponsiveness is a key feature in asthma diagnosis. Methacholine challenge has proved to be a highly sensitive test to diagnose asthma in patients with chronic respiratory ... [more ▼]

Demonstration of bronchial hyperresponsiveness is a key feature in asthma diagnosis. Methacholine challenge has proved to be a highly sensitive test to diagnose asthma in patients with chronic respiratory symptoms and preserved baseline lung function (FEV1 > 70% pred.) but is time consuming and may sometimes reveal unpleasant to the patient. We conducted a retrospective study on 270 patients recruited from the University Asthma Clinic of Liege. We have compared the values of several lung function indices and fractional exhaled nitric oxide (FeNO) in predicting a provocative methacholine concentration ≤16 mg/ml on a discovery cohort of 129 patients (57 already on ICS) and on a validation cohort of 141 patients (66 already on ICS). In the discovery study (n = 129), 85 patients (66%) had a positive methacholine challenge with PC20M ≤ 16 mg/ml. Those patients had lower baseline % predicted FEV1 (92% vs. 100%; p < 0.01), lower FEV1/FVC ratio (79% vs. 82%; p < 0.05), higher RV/TLC ratio (114% vs. 100%; p < 0,0001), lower SGaw (specific conductance) (0.76 vs. 0.95; p < 0,001) and higher FeNO (29 ppb vs. 19 ppb; p < 0,01). When performing ROC curve the RV/TLC ratio provided the greatest AUC (0.74, p < 0.001), sGAW had intermediate AUC of 0.69 (p < 0.001) while FeNO, FEV1 and FEV1/FVC ratio were modestly predictive (AUC of 0.65 (p < 0.05), 0,67 (p < 0.001) and 0,63 (p < 0.001). These results were confirmed in the validation study (n = 141). Based on a logistic regression analysis, significant variables associated with positive methacholine challenge were FeNO and RV/TLC (% Pred). A combined application of FeNO and RV/TLC (% Pred) for predicting the PC20M had a specificity of 85%, a sensitivity of 59% and an AUC of 0.79. In the validation study, three variables (RV/TLC, FeNO and FEV1) were independently associated with positive methacholine challenge and the combination of these three variables yielded a specificity of 77%, a sensitivity of 39% and an AUC of 0.77. The RV/TLC ratio combined to FeNO may be of interest to predict significant methacholine bronchial hyperresponsiveness. © 2020 Elsevier Inc. [less ▲]

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See detailMissing Value Imputation in Cluster Analysis
Nekoee Zahraei, Halehsadat ULiege; Louis, Renaud ULiege; Donneau, Anne-Françoise ULiege

Scientific conference (2019, July 24)

Introduction The problem of missing values is unavoidable in clinical research. In literature, missing value has been investigated by extensive methods. One of the most attractive methods for handling ... [more ▼]

Introduction The problem of missing values is unavoidable in clinical research. In literature, missing value has been investigated by extensive methods. One of the most attractive methods for handling missing data is multiple imputation (MI). However, applying MI method within the framework of clustering involves several difficulties and limitations. Objective Many classical clustering algorithms cannot deal with missing values, therefore, in this study, we proposed a new procedure for applying multiple imputation and variable reduction when the main goal is cluster analysis on the dataset contains missing values. The important part of this new procedure is to combine the clustering for each imputed dataset to produce the best result of the subject clustering in terms of classification. Therefore, we propose a clustering combination algorithm with a novel framework. Method The proposed procedure starts by applying a multiple imputation technique, then uses factor analysis of mixed data (FAMD) for reducing the complexity of high-dimensional data. In the clustering step, several methods (k-means, hierarchical and model-based) are used for clustering imputed datasets. In the final merging step, we propose to use indices which have been developed to determine the optimal number of clusters to offer the best permutation of clustering for assigning the subject to the cluster. The derived results are compared with previous methods (majority vote and fuzzy k-means). The main difficulty in this procedure is that the cluster analysis involves many technical decisions, therefore, various algorithms are defined and compared. Results Simulation studies are conducted to illustrate the usefulness of our methodology against commonly used alternative models. Also, the practicality is examined by analyzing chronic obstructive pulmonary disease (COPD) that are taken from the Pneumology Department of the University hospital of Liege, which aimed to identify clinical phenotypes among adults suffering from COPD. Conclusions In conclusion, our proposed procedure is very practical and flexible to allow the user to compare several methods in clustering and merging step. [less ▲]

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See detailBiomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study.
Maher, Toby M.; Stowasser, Susanne; Nishioka, Yasuhiko et al

in Lancet Respiratory Medicine (2019)

BACKGROUND: A hallmark of idiopathic pulmonary fibrosis is the excess accumulation of extracellular matrix in the lungs. Degradation of extracellular matrix generates free-circulating protein fragments ... [more ▼]

BACKGROUND: A hallmark of idiopathic pulmonary fibrosis is the excess accumulation of extracellular matrix in the lungs. Degradation of extracellular matrix generates free-circulating protein fragments called neoepitopes. The aim of the INMARK trial was to investigate changes in neoepitopes as predictors of disease progression in patients with idiopathic pulmonary fibrosis and the effect of nintedanib on these biomarkers. METHODS: In this randomised, double-blind, placebo-controlled trial, patients with a diagnosis of idiopathic pulmonary fibrosis within the past 3 years and forced vital capacity (FVC) of 80% predicted or higher were eligible to participate. Patients were recruited from hospitals, private practices, clinical research units, and academic medical centres. Patients were randomly assigned (1:2) with the use of a pseudo-random number generator to receive oral nintedanib 150 mg twice a day or placebo for 12 weeks in a double-blind fashion, followed by open-label nintedanib for 40 weeks. The primary endpoint was the rate of change in C-reactive protein (CRP) degraded by matrix metalloproteinases 1 and 8 (CRPM) from baseline to week 12 in the intention-to-treat population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02788474, and with the European Clinical Trials Database, number 2015-003148-38. FINDINGS: Between June 27, 2016, and May 15, 2017, 347 patients were randomly assigned to the nintedanib group (n=116) or to the placebo group (n=231). One patient from the placebo group was not treated owing to a randomisation error. At baseline, mean FVC was 97.5% (SD 13.5) predicted. In the double-blind period, 116 patients received nintedanib and 230 patients received placebo. The rate of change in CRPM from baseline to week 12 was -2.57 x 10(-3) ng/mL/month in the nintedanib group and -1.90 x 10(-3) ng/mL/month in the placebo group (between-group difference -0.66 x 10(-3) ng/mL/month [95% CI -6.21 x 10(-3) to 4.88 x 10(-3)]; p=0.8146). The adjusted rate of change in FVC over 12 weeks was 5.9 mL in the nintedanib group and -70.2 mL in the placebo group (difference 76.1 mL/12 weeks [31.7 to 120.4]). In patients who received placebo for 12 weeks followed by open-label nintedanib, rising concentrations of CRPM over 12 weeks were associated with disease progression (absolute decline in FVC >/=10% predicted or death) over 52 weeks. In the double-blind period, serious adverse events were reported in eight (7%) patients given nintedanib and 18 (8%) patients given placebo. Grade 3 diarrhoea was reported in two (2%) patients in the nintedanib group and two (1%) patients in the placebo group. No patients had grade 4 diarrhoea. INTERPRETATION: In patients with idiopathic pulmonary fibrosis and preserved lung function, treatment with nintedanib versus placebo for 12 weeks did not affect the rate of change in CRPM but was associated with a reduced rate of decline in FVC. These results suggest that change in CRPM is not a marker of response to nintedanib in patients with idiopathic pulmonary fibrosis. FUNDING: Boehringer Ingelheim. [less ▲]

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See detailGranulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer.
SIBILLE, Anne ULiege; Alfieri, Romain ULiege; MALAISE, Olivier ULiege et al

in Frontiers in oncology (2019), 9

Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of ... [more ▼]

Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of toxicity in terms of potential predictive value and long-term effects. Materials and Methods: We report the first case of granulomatosis with polyangiitis (GPA) in a patient treated with an anti-Programmed Death protein-1 (PD-1) antibody for advanced non-small-cell lung cancer (NSCLC). Results: After a single dose of this drug the patient showed severe myositis associated with a high anti-PR3 anti-neutrophil cytoplasmic antibody titer. Discontinuation of the anti-PD-1 and introduction of corticoids led to a remission of the irAE. Regarding tumor a partial response was noted. A year later a neutrophilic, sterile pleural exudate and cutaneous lesions appeared with the pathological findings of neutrophilic vasculitis. Retreatment with corticoids induced a new remission of symptoms. It remains unclear whether GPA was preexisting and clinically silent but revealed by the use of ICI or primarily induced by this treatment. Conclusions: irAE are rare when anti-PD-1 antibodies are used in monotherapy. They present with a distinct clinical picture and temporal course and require specific treatment. Patients with irAE usually have a favorable oncological outcome. [less ▲]

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See detailDEVELOPMENT OF ADVANCED PROCESSING WORKFLOW FOR UNTARGETED VOLATILOMICS BY GC×GC-TOFMS
Stefanuto, Pierre-Hugues ULiege; Zanella, Delphine ULiege; Fucito, Maurine et al

Conference (2019, June)

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See detailGC×GC-TOFMS and SIFT-MS approaches for clinical breath-based asthma phenotyping
Stefanuto, Pierre-Hugues ULiege; Zanella, Delphine ULiege; Vercammen, Joeri et al

Conference (2019, June)

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See detailIncrease in blood eosinophils during follow-up is associated with lung function decline in adult asthma.
Graff, Sophie ULiege; Demarche, Sophie ULiege; HENKET, Monique ULiege et al

in Respiratory Medicine (2019), 152

BACKGROUND: Asthma is associated with accelerated rate of lung function (FEV1) decline. OBJECTIVE: To determine predictive factors associated with FEV1 decline in adult asthma. METHODS: A retrospective ... [more ▼]

BACKGROUND: Asthma is associated with accelerated rate of lung function (FEV1) decline. OBJECTIVE: To determine predictive factors associated with FEV1 decline in adult asthma. METHODS: A retrospective study was conducted in 229 asthmatics recruited from the University Asthma Clinic of Liege. Subjects had at least two visits with post-bronchodilation (post-BD) FEV1 and minimum one year between them. A multivariable linear regression analysis was conducted in order to come up with factors associated with lung function decline. RESULTS: Post-BD FEV1 decline in % predicted. y(-1) was 0.2 (95%CI -2.0 to 2.8) in the overall population. Our population was made up of mild to moderate asthmatics [1] for 58%, aged 50 (41-60) years old, 62% were female and 59% were atopic. Median ICS dose was 1000mug beclomethasone equivalent (CFC)/day with 81% treated at baseline. Time between visits was 46.8+/-32.1 months. The univariate linear regression analysis revealed a negative association between % predicted FEV1 decline and baseline ACQ (p<0.0001) and blood eosinophils (% and/mm(3)) (p<0.0001 and p<0.0001). A positive association was found between % predicted FEV1 decline and baseline pre-BD FEV1 (mL) values (p=0.001), blood neutrophils (%) (p=0.02), change in blood eosinophils (%) (p<0.0001), time between visits (months) (p<0.0001). The predictive variables for accelerated decline highlighted by the multivariable analysis (r(2)=0.39) were change in blood eosinophils (%) over time (p=0.002) and time between visits (months) (p<0.0001). CONCLUSION: These findings highlight a new value for blood eosinophil counts as their increase over time predicts greater lung function decline in asthma. [less ▲]

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See detailIt needs more than just eosinophils to cause emphysema in COPD.
SCHLEICH, FLorence ULiege; Louis, Renaud ULiege

in European Respiratory Journal (2019)

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See detailArtificial intelligence outperforms pulmonologists in the interpretation of pulmonary function tests.
Topalovic, Marko; Das, Nilakash; Burgel, Pierre-Regis et al

in European Respiratory Journal (2019), 53(4),

The interpretation of pulmonary function tests (PFTs) to diagnose respiratory diseases is built on expert opinion that relies on the recognition of patterns and the clinical context for detection of ... [more ▼]

The interpretation of pulmonary function tests (PFTs) to diagnose respiratory diseases is built on expert opinion that relies on the recognition of patterns and the clinical context for detection of specific diseases. In this study, we aimed to explore the accuracy and interrater variability of pulmonologists when interpreting PFTs compared with artificial intelligence (AI)-based software that was developed and validated in more than 1500 historical patient cases.120 pulmonologists from 16 European hospitals evaluated 50 cases with PFT and clinical information, resulting in 6000 independent interpretations. The AI software examined the same data. American Thoracic Society/European Respiratory Society guidelines were used as the gold standard for PFT pattern interpretation. The gold standard for diagnosis was derived from clinical history, PFT and all additional tests.The pattern recognition of PFTs by pulmonologists (senior 73%, junior 27%) matched the guidelines in 74.4+/-5.9% of the cases (range 56-88%). The interrater variability of kappa=0.67 pointed to a common agreement. Pulmonologists made correct diagnoses in 44.6+/-8.7% of the cases (range 24-62%) with a large interrater variability (kappa=0.35). The AI-based software perfectly matched the PFT pattern interpretations (100%) and assigned a correct diagnosis in 82% of all cases (p<0.0001 for both measures).The interpretation of PFTs by pulmonologists leads to marked variations and errors. AI-based software provides more accurate interpretations and may serve as a powerful decision support tool to improve clinical practice. [less ▲]

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See detailSerum levels of hyaluronic acid are associated with COPD severity and predict survival.
Papakonstantinou, Eleni; Bonovolias, Ioannis; Roth, Michael et al

in European Respiratory Journal (2019), 53(3),

Hyaluronic acid (HA) and its degradation products play an important role in lung pathophysiology and airway remodelling in chronic obstructive pulmonary disease (COPD).We investigated if HA and its ... [more ▼]

Hyaluronic acid (HA) and its degradation products play an important role in lung pathophysiology and airway remodelling in chronic obstructive pulmonary disease (COPD).We investigated if HA and its degrading enzyme hyaluronidase (HYAL)-1 are associated with COPD severity and outcome.Serum HA was assessed in a discovery cohort of 80 COPD patients at stable state and exacerbations. HA, HYAL-1 and HYAL-1 enzymatic activity were evaluated at stable state, exacerbations and 4 weeks after exacerbations in 638 COPD patients from the PROMISE validation cohort.In the discovery cohort, serum HA was higher at exacerbations compared with the stable state (p=0.015). In the validation cohort, HA was higher at moderate and severe exacerbations than at baseline (p<0.001), and remained higher after 4 weeks (p<0.001). HA was strongly predictive for overall survival since it was associated with time to death (p<0.001) independently of adjusted Charlson score, annual exacerbation rate and BODE (body mass, airflow obstruction, dyspnoea, exercise capacity) index. Serum HYAL-1 was increased at moderate (p=0.004) and severe (p=0.003) exacerbations, but decreased after 4 weeks (p<0.001). HYAL-1 enzymatic activity at stable state was inversely correlated with FEV1 % pred (p=0.034) and survival time (p=0.017).Serum HA is associated with COPD severity and predicts overall survival. Degradation of HA is associated with airflow limitation and impairment of lung function. [less ▲]

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See detailGuidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma.
Bousquet, J.; Bedbrook, A.; Czarlewski, W. et al

in Clinical and translational allergy (2019), 9

Aims: Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with ... [more ▼]

Aims: Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases. Methods: MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients. Stakeholders: Include patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors. Results: MASK is deployed in 23 countries and 17 languages. 26,000 users have registered. EU grants 2018: MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour). Lessons learnt: (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases. [less ▲]

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See detailAllergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.
Bousquet, Jean; Hellings, Peter W.; Agache, Ioana et al

in The Journal of allergy and clinical immunology (2019), 143(3), 864-879

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and ... [more ▼]

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional. [less ▲]

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