[Asthma in clinical practice: from inflammatory phenotypes to personalized treatment]. / L'asthme bronchique en pratique clinique : des phénotypes inflammatoires au traitement personnalisé.

Asthma is a chronic inflammatory disease of the airways. Classification of asthma in different phenotypes has therapeutic implications and may lead to personalized medicine. Induced sputum is the gold standard for asthma phenotyping but is complex, time-consuming and not widely available. The combination of different biomarkers such as exhaled nitric oxide, blood eosinophils and total serum IgE levels allows the prediction of inflammatory phenotype in 58% of asthmatic patients when sputum is not available. We recently demonstrated the interest of measuring volatile organic compounds in exhaled breath to phenotype asthma. These compounds could play an important role in the future to predict the response to expensive biologicals available in severe asthma to reduce exacerbations and the use of systemic corticosteroids.

: L'asthme est une pathologie inflammatoire chronique des voies respiratoires. Classer l'asthme en différents phénotypes inflammatoires a des implications thérapeutiques importantes et peut conduire à un traitement personnalisé. Le gold standard pour l'établissement du phénotype inflammatoire est l'analyse de l'expectoration induite qui est une technique complexe, difficilement accessible en routine. La combinaison de plusieurs biomarqueurs d'intérêt tels le monoxyde d'azote dans l'air exhalé, l'éosinophilie systémique et le taux d'IgE sérique permet de prédire correctement le phénotype inflammatoire dans 58% des cas. Récemment, nous avons également mis en évidence l'intérêt de la détection de molécules dans l'haleine. Ces composés organiques volatiles pourraient représenter des biomarqueurs futurs de la réponse au traitement, spécialement dans l'asthme sévère, pour lequel des traitements ciblés coûteux sont actuellement disponibles en vue de réduire les exacerbations et le recours aux corticostéroïdes oraux.

Asthma in elderly is characterized by increased sputum neutrophils, lower airway caliber variability and air trapping.

BACKGROUND: Elderly asthmatics represent an important group that is often excluded from clinical studies. In this study we wanted to present characteristics of asthmatics older than 70 years old as compared to younger patients. METHODS: We conducted a retrospective analysis on a series of 758 asthmatics subdivided in three groups: lower than 40, between 40 and 70 and older than 70. All the patients who had a successful sputum induction were included in the study. RESULTS: Older patients had a higher Body Mass Index, had less active smokers and were more often treated with Long Acting anti-Muscarinic Agents. We found a significant increase in sputum neutrophil counts with ageing. There was no significant difference in blood inflammatory cell counts whatever the age group. Forced expiratory volume in one second (FEV1) and FEV1/FVC values were significantly lower in elderly who had lower bronchial hyperresponsiveness and signs of air trapping. We found a lower occurrence of the allergic component in advanced ages. Asthmatics older than 70 years old had later onset of the disease and a significant longer disease duration. CONCLUSION: Our study highlights that asthmatics older than 70 years old have higher bronchial neutrophilic inflammation, a poorer lung function, signs of air trapping and lower airway variability. The role of immunosenescence inducing chronic low-grade inflammation in this asthma subtype remains to be elucidated.

Asthmatics with concordant eosinophilic disease classified according to their serum IgE status.

BACKGROUND: Eosinophilic inflammation has long been associated with asthma. Looking at systemic and airway eosinophilia, we have recently identified a group of patients exhibiting diffuse eosinophilic inflammation. Among the mechanisms governing eosinophilic inflammation, IgE-mediated mast cell activation is a key event leading to eosinophilia in atopic asthmatics. METHODS: We conducted a retrospective study on our asthma clinic database containing more than 1500 patients and identified 205 asthmatics with successful sputum induction and concordant eosinophilic phenotype. This phenotype was defined as a sputum eosinophil count≥3% and a blood eosinophils concentration≥400cells/mm3. IgE-high atopic phenotype was characterized by the presence of at least one positive specific IgE (>0.35kU/L) to common aeroallergens and a raised total serum IgE (≥113kU/L). RESULTS: The largest group of asthmatics displaying concordant eosinophilic phenotype had a raised total serum IgE and atopy (45%). IgE-low non-atopic concordant eosinophilic asthma was a predominantly late onset disease, exhibited a more intense airway eosinophilic inflammation (P<0.05), required more often maintenance treatment with oral corticosteroids (P<0.05) but, surprisingly, had a reduced level of bronchial hyperresponsiveness to methacholine (P<0.05) despite similar baseline airway calibre impairment. CONCLUSION: The more severe airway eosinophilic inflammation in IgE-low non-atopic asthmatics despite similar treatment with ICS and a higher burden of OCS points to a certain corticosteroid resistance in this asthma phenotype.

[Yoga to improve asthma control in severe asthmatics treated with biologics]. / Le yoga en vue d'améliorer le contrôle symptomatique des patients asthmatiques sévères traités par biologiques.

We conducted a prospective observational study to evaluate the efficacy of yoga in poorly controlled severe asthmatic patients treated with maximal inhaled therapy and biologics. The objective of yoga was to improve breathing consciousness, exercising controlled ventilation with and without retention, abdominal breathing observation, improvement of inspiratory and expiratory muscles, opening of the chest, diaphragm exercises and relaxation. We measured exhaled nitric oxide, forced expiratory volume in one second, forced vital capacity, asthma control and quality of life questionnaires, anxiety and depression questionnaires before and after the tenth yoga course (performed twice a week). Half of the patients who were invited to participate to the study declined due to organization problems. Two patients were excluded due to bronchitis and arthralgia respectively. The analysis of the data from 12 participants revealed significant improvement in asthma control and asthma quality of life questionnaires and a reduction of anxiety.The regular practice of yoga in severe asthmatics insufficiently controlled despite maximal inhaled treatment and biotherapy seems to be an interesting complementary option to improve asthma control. Our results must be confirmed in larger randomized controlled trials.

Nous avons conduit une étude pilote prospective observationnelle en vue d'évaluer l'efficacité de la pratique du yoga chez le patient asthmatique sévère insuffisamment contrôlé sous traitement de fond inhalé maximal et traitement biologique. L'objectif des séances de yoga était la prise de conscience de la respiration habituelle, le travail de la respiration contrôlée avec et sans temps de rétention, l'observation de la respiration abdominale, le travail des muscles inspiratoires et expiratoires, l'ouverture de la cage thoracique, le travail du diaphragme et la relaxation. Nous avons évalué le monoxyde d'azote dans l'air exhalé, le volume expiré maximal par seconde, la capacité vitale forcée, l'indice de Tiffeneau, les questionnaires de contrôle de l'asthme, de qualité de vie et d'anxiété et dépression avant la première séance et après la dixième séance de yoga (réalisées à raison de deux fois par semaine). La moitié des patients invités à participer à l'étude a refusé l'inclusion suite à des problèmes organisationnels. Deux patients ont été exclus, respectivement, suite à une surinfection bronchique et à des douleurs ostéo-articulaires. L'analyse des données des 12 participants a révélé une amélioration significative des questionnaires de contrôle, de qualité de vie et d'anxiété. La pratique régulière du yoga chez le patient asthmatique sévère insuffisamment contrôlé sur le plan symptomatique sous traitement de fond maximal semble donc être une option complémentaire intéressante. Les résultats de notre étude doivent être confirmés dans une étude contrôlée randomisée à plus large échelle.

[Asthma : the contribution of biotherapies]. / Une décennie d'avancées dans l'asthme : l'apport des biothérapies.

Asthma is a chronic heterogeneous airway disease. There are different asthma inflammatory phenotypes with various responses to treatment and different disease severities. When asthma requires chronic systemic corticosteroids or hospitalizations despite maximal inhaled therapies in asthmatic patients in whom comorbidities have been managed and who are considered as compliant, the pulmonologist may propose biological treatment to reduce exacerbations and the dose of systemic corticosteroids. During the last ten years, the number of biologics for the management of type-2 severe asthma has increased. Anti-IgE monoclonal antibodies (omalizumab) are available for more than ten years and recommended in severe allergic asthma. New biologics are now available to block IL-5 (mepolizumab, reslizumab) or its receptor (benralizumab). These treatments allow a reduction of exacerbations and of the dose of systemic corticosteroids, an improvement in asthma control, in asthma quality of life and for some of them, an increase in lung function. New biologics will soon be available in Belgium for the management of severe asthma. In addition to the improvement of asthma control in severe asthma, biological treatments have improved the understanding of the mechanisms leading to severe asthma.

L'asthme est une maladie hétérogène chronique des voies aériennes. Il existe, en effet, différents phénotypes inflammatoires d'asthme induisant une réponse variable aux traitements et différents degrés de sévérité. Lorsque l'asthme est sévère et requiert le recours aux corticostéroïdes systémiques ou à des hospitalisations malgré un traitement de fond maximal chez un patient asthmatique bon observant dont les comorbidités ont été prises en charge, le pneumologue peut proposer un traitement biologique en vue de réduire les exacerbations et la dose de corticostéroïdes systémiques. Au cours des dix dernières années, les traitements biologiques dans la prise en charge de l'asthme sévère de type 2 se sont étoffés. A côté du traitement par anti-IgE (omalizumab), disponible depuis plus de 10 ans et recommandé dans l'asthme sévère extrinsèque, d'autres traitements bloquant l'IL-5 (mépolizumab, reslizumab) ou son récepteur (benralizumab) ont vu le jour. Ces traitements permettent une réduction des exacerbations et de la dose de corticostéroïdes systémiques, une amélioration du contrôle, des paramètres de qualité de vie et, pour certains d'entre eux, de la fonction respiratoire. D'autres traitements ciblés prometteurs seront bientôt disponibles en Belgique. En plus d'améliorer le contrôle symptomatique des patients asthmatiques sévères, les traitements biologiques ont permis de mieux comprendre les mécanismes conduisant au développement d'un asthme sévère.

Predictors of a good response to inhaled corticosteroids in obesity-associated asthma.

INTRODUCTION: Asthma in obese subjects is poorly understood. According to GINA guidelines, pulmonologists increase ICS in case of poor asthma control but lung volume restriction may also worsen respiratory symptoms in obese asthmatics leading to overtreatment in this subpopulation. METHODS: We conducted a retrospective study on 1217 asthmatics recruited from University Hospital of Liege. 92 patients with a BMI ≥30 came at least two times at the asthma clinic (mean interval: 335 days). In this obese population, we identified predictors of good (decrease in ACQ ≥0.5) versus poor response (rise in ACQ ≥0.5) to ICS step-up therapy. RESULTS: Obese asthmatics had a poorer asthma control and quality of life as compared to non-obese and exhibited reduced FVC, higher levels of blood leucocytes and markers of systemic inflammation. The proportion of asthma inflammatory phenotypes was similar to that observed in a general population of asthmatics. Among uncontrolled obese asthmatics receiving ICS step-up therapy, 53% improved their asthma control while 31% had a worsening of their asthma. Uncontrolled obese asthmatics showing a good response to increase in ICS had higher ACQ, lower CRP levels, higher sputum eosinophil counts and higher FeNO levels at visit 1. Uncontrolled obese asthmatics that worsened after increasing the dose of ICS had lower FVC, lower sputum eosinophil counts and higher sputum neutrophil counts. CONCLUSION: We observed poorer asthma control in obese asthmatics despite similar bronchial inflammation. Managing obese asthmatics according to ACQ alone seems to underestimate asthma control and the contribution of restriction to dyspnea. Increasing the dose of ICS in the absence of sputum eosinophilic inflammation or in the presence of restriction or bronchial neutrophilia led to poorer asthma control. In those patients, management of obesity should be the first choice.

Assessment of diagnostic accuracy of lung function indices and FeNO for a positive methacholine challenge.

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.

Effectiveness of omalizumab on patient reported outcomes, lung function, and inflammatory markers in severe allergic asthma.

BACKGROUND: Omalizumab arose as a therapeutic option in patients suffering from moderate to severe refractory allergic asthma. It acts as a humanized monoclonal antibody neutralizing circulating IgE antibodies. Randomized clinical trials and real life clinical studies have already confirmed benefits, cost-effectiveness and applicability of the medication. METHOD: Our study retrospectively reports on the clinical outcomes and airway inflammation in 157 severe allergic asthmatics who were initiated with omalizumab between 2007 and 2019. RESULTS: After 4 months of therapy, 76% of the patients were judged to have benefited from omalizumab and were admitted to prolonged treatment. During follow-up, we observed an improvement in asthma control, quality of life and spirometric performance. There was also a sustained reduction in exacerbation rate over the years. As for T2 biomarkers, FeNO significantly decreased and, in a subgroup of patients who had repeated sputum inductions, there was also significant reduction in sputum eosinophils but no change in blood eosinophil count. Lastly, we found a correlation between high FeNO levels at baseline and reduction in ACQ scores at 1 year. CONCLUSION: We conclude that omalizumab shows effectiveness in severe allergic asthma in a real life setting, by reducing exacerbation rate, improving patient perspective outcomes and airway calibre, together with reducing type-2 airway inflammation.