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 detailReal-word experience with mepolizumab: Does it deliver what it has promised?
SCHLEICH, FLorence ULiege; Graff, Sophie ULiege; Nekoee Zahraei, Halehsadat ULiege et al

in Clinical and Experimental Allergy (2020)

Background: Randomized control trials performed in selected populations of severe eosinophilic asthmatics have shown that mepolizumab, an anti-IL5 therapy, was able to reduce exacerbations and OCS ... [more ▼]

Background: Randomized control trials performed in selected populations of severe eosinophilic asthmatics have shown that mepolizumab, an anti-IL5 therapy, was able to reduce exacerbations and OCS maintenance dose and in some studies, to improve asthma control and lung function. Objective: The aim of this study was to confirm the results of the RCTs in real-life in a population of 116 severe eosinophilic asthmatics treated with mepolizumab and who were followed up at the asthma clinic every month for at least 18 months. Severe asthmatics underwent FENO, lung function, asthma control and quality of life questionnaires, sputum induction and gave a blood sample at baseline, after 6 months and then every year. Results: We found a significant reduction in exacerbations by 85% after 6 months (P <.0001), which was maintained over time. We also found a significant and maintained reduction by 50% in the dose of oral corticosteroids (P <.001). Patients improved their ACT (+5.31pts, p<0.0001) ACQ (-1.13pts, P <.0001) and their AQLQ score (+1.24, P <.0001) at 6 months and this was maintained during follow-up. Only 37% reached asthma control (ACQ <1.5, ACT> 20). We observed a progressive increase in post-BD FEV1 that reached significance after 18 months (190ml or 11%, P <.01). Patients improving their FEV1had higher baseline sputum eosinophils than those not improving airway caliber. We found a significant reduction in sputum eosinophil counts by 60% after 6 months (P <.01) and a maintained reduction in blood eosinophil counts by 98% (P <.0001). Conclusion: In our real-life study, we confirm the results published in the RCTs showing a sharp reduction in exacerbation and oral corticosteroids dose and an improvement in asthma control and quality of life. Clinical relevance: Mepolizumab is efficient in severe eosinophilic asthma in real life. © 2020 John Wiley & Sons Ltd [less ▲]

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See detailThe influence of the conservation of respiratory epithelial samples on ciliary functional analysis
Bricmont, Noémie ULiege; Benchimol, Lionel ULiege; POIRRIER, Anne-Lise ULiege et al

Conference (2020)

Background: Primary ciliary dyskinesia(PCD) is an inherited otosinopulmonary ciliopathy in which respiratory cilia are stationary, or beat in a dyskinetic manner. Digital high speed videomicroscopy(DHSV ... [more ▼]

Background: Primary ciliary dyskinesia(PCD) is an inherited otosinopulmonary ciliopathy in which respiratory cilia are stationary, or beat in a dyskinetic manner. Digital high speed videomicroscopy(DHSV) allows ciliary functional analysis(CFA), including beat frequency(CBF) and pattern(CBP). DHSV is highly sensitive and specific for PCD diagnosis, but lacks standardization and evidence-based data. The technical process of ciliated epithelial samples before CFA varies among studies. Of importance, delay after sampling and temperature for samples conservation may impact CFA. However, these parameters have never been compared. Aims: To evaluate the stability of ciliary function over time when nasal brushing samples are conserved either in the fridge, or at room temperature. Methods: Ciliated epithelial samples were obtained by brushing the inferior nasal turbinate from 5 non-smoking healthy subjects. The samples were divided equally, and conserved either at 4°C or at 22°C. Beating cilia were recorded using DHSV at 37°C immediately(T0, then 9 hours after sampling(T9). CFA was assessed by CBF and the percentage of normal CBP. Results: There was no significant difference between CFA performed immediately or 9 hours after sampling, regardless of the sample storage temperature. Conclusion: This pilot study suggested that the stability of CFA may be preserved for 9 hours at 22°C and at 4°C. Larger studies are needed to confirm these preliminary results, notably in pathological conditions. [less ▲]

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See detailDevelopment of a Clinical Decision Support System for Severity Risk Prediction and Triage of COVID-19 Patients at Hospital Admission: an International Multicenter Study.
Wu, Guangyao; Yang, Pei; Xie, Yuanliang et al

in European Respiratory Journal (2020)

BACKGROUND: The outbreak of the coronavirus disease 2019 (COVID-19) has globally strained medical resources and caused significant mortality. OBJECTIVE: To develop and validate machine-learning model ... [more ▼]

BACKGROUND: The outbreak of the coronavirus disease 2019 (COVID-19) has globally strained medical resources and caused significant mortality. OBJECTIVE: To develop and validate machine-learning model based on clinical features for severity risk assessment and triage for COVID-19 patients at hospital admission. METHOD: 725 patients were used to train and validate the model including a retrospective cohort of 299 hospitalised COVID-19 patients at Wuhan, China, from December 23, 2019, to February 13, 2020, and five cohorts with 426 patients from eight centers in China, Italy, and Belgium, from February 20, 2020, to March 21, 2020. The main outcome was the onset of severe or critical illness during hospitalisation. Model performances were quantified using the area under the receiver operating characteristic curve (AUC) and metrics derived from the confusion-matrix. RESULTS: The median age was 50.0 years and 137 (45.8%) were men in the retrospective cohort. The median age was 62.0 years and 236 (55.4%) were men in five cohorts. The model was prospectively validated on five cohorts yielding AUCs ranging from 0.84 to 0.89, with accuracies ranging from 74.4% to 87.5%, sensitivities ranging from 75.0% to 96.9%, and specificities ranging from 57.5% to 88.0%, all of which performed better than the pneumonia severity index. The cut-off values of the low, medium, and high-risk probabilities were 0.21 and 0.80. The online-calculators can be found at www.covid19risk.ai. CONCLUSION: The machine-learning model, nomogram, and online-calculator might be useful to access the onset of severe and critical illness among COVID-19 patients and triage at hospital admission. [less ▲]

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See detailMulti-matrices screening for untargeted volatilomics by GC×GC-TOFMS
Zanella, Delphine ULiege; HENKET, Monique ULiege; SCHLEICH, FLorence ULiege et al

in European Respiratory Journal. Supplement (2019), 54

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See detailBreath analysis for asthma phenotyping and beyond
Zanella, Delphine ULiege; Stefanuto, Pierre-Hugues ULiege; SCHLEICH, FLorence ULiege et al

Conference (2019, September)

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See detailMultimodal breath-based asthma phenotyping using GCxGC-HRTOFMS and SIFT-MS approaches
Stefanuto, Pierre-Hugues ULiege; Zanella, Delphine ULiege; Vercammen, Joeri et al

Conference (2019, September)

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See detailTime-course of upper respiratory tract viral infection and COPD exacerbation.
Stolz, Daiana; Papakonstantinou, Eleni; Grize, Leticia et al

in European Respiratory Journal (2019)

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of COPD (AECOPD). We aimed to evaluate, longitudinally, the association between upper ... [more ▼]

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of COPD (AECOPD). We aimed to evaluate, longitudinally, the association between upper respiratory tract infections (URTI) caused by viruses and AECOPD.Detection of 18 viruses was performed in naso- and oromicronpharyngeal swabs in 450 COPD patients (GOLD 2-4), followed for a mean of 27 months, at stable periods (n=1909), at URTI onset (n=391), 10 days after the URTI (n=356) and at AECOPD (n=177) using a multiplex nucleic acid amplification testing.Evidence of at least one respiratory virus was significantly higher at URTI onset (52.7%), at 10 days following a URTI (15.2%) and at exacerbation (38.4%), compared with the stable period (5.3%, p<0.001). At stable visits rhinovirus accounted for 54.2% of all viral infections, followed by coronavirus (20.5%). None of the viruses could be identified in two consecutive stable visits. Patients with viral infection at URTI onset did not have a higher incidence of exacerbation, compared with patients without viral infection (p=0.993). Tauhe incidence of any viral infection at AECOPD was similar between URTI-related AECOPD and non-URTI-related AECOPD (p=0.359). Only 24% of the patients that had a URTI-related AECOPD had the same virus at URTI and AECOPD. Detection of parainfluenza 3 at URTI onset was associated with higher risk of AECOPD (p=0.003). Rhinovirus and coronavirus were the most frequently detected viruses at AECOPD visits accounting for 35.7% and 25.9% of all viral infections, respectively.The prevalence of viral infection at the stable period of COPD is low. The risk of exacerbation following the onset of URTI symptoms depends on the particular virus associated with the event and was significant only for parainfluenza 3. [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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