[Modeling T2 high severe asthma using human induced pluripotent stem cells (hiPSC)]. / Modélisation de l'asthme sévère par la technologie des cellules humaines souches pluripotentes induites (hiPSC).

Severe asthma patients with persistent airflow obstruction are characterized by functional obstruction due to mucus plugs containing mucins, fibrin, and eosinophil derived Charcot- Leyden crystals. The molecular mechanisms underlying this endotype are not clearly understood. Developing new models is crucial to respiratory research insofar as critical differences exist between human and rodent airway epithelium. We (and other teams) have shown that it is possible to reconstitute in vitro a complex and functional airway epithelium displaying all the features described in vivo from human-induced pluripotent stem cells (hiPSC). Our aim is to establish a human in vitro model of severe asthma that will recapitulate airway epithelium remodeling and mucus plugs.

[Adverse events in biologics for severe asthma]. / Effets indésirables des biothérapies de l'asthme sévère.

INTRODUCTION: Asthma is a pathology that remains severe and is inadequately controlled in 4% of patients. Identification of multiple pathophysiological mechanisms has led to the development of biomedicines, of which there are currently five available in France, with a safety profile that appears favorable but remains uncertain due to a lack of real-life experience with these new molecules. STATE OF KNOWLEDGE: Although relatively benign, the adverse effects of biologics are diverse. Headache, joint pain, skin reactions at the injection site, fever and asthenia are commonly observed during the different treatments. Ophthalmological complications seem restricted to dupilumab, with numerous cases of keratitis and conjunctivitis in patients with atopic dermatitis. Several respiratory complications have also been observed, essentially consisting in pharyngitis and other upper respiratory infections. Hypereosinophilia may occur, mainly with dupilumab, requiring investigation of systemic repercussions or vasculitis. Allergic reactions are uncommon but require careful monitoring during initial injections. CONCLUSION: Biologics for severe asthma are recent drugs with a favorable safety profile, but with little real-life experience, justifying increased vigilance by prescribing physicians.

[Anti-IL-5 in severe asthma associated with eosinophilic granulomatosis with polyangiitis. Real-life study]. / Anti-IL-5 dans l'asthme sévère associé à une granulomatose éosinophilique avec polyangéite. Étude en vie réelle.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of necrotizing vasculitis affecting small vessels and typically characterized by severe glucocorticoid (GC)-dependent eosinophilic asthma. While mepolizumab, which is indicated at a dose of 100mg/4weeks in severe eosinophilic asthma, has been shown to be an effective treatment for EGPA-related asthma at a dose of 300mg/4weeks, it was only recently approved at this dose. METHODS: This retrospective, single-center, observational study was conducted to investigate over a 5-year period (2014-2019) the effect of mepolizumab 100mg/4weeks at 12months in patients with EGPA and glucocorticoid-dependant severe asthma. Response to treatment was defined as reduction in daily dose of oral corticosteroids to at most 5mg/day or reduction in annual exacerbation by at least 50%. RESULTS: Thirty patients were included, of whom twenty-three were treated (two were not fully evaluable). Among the 21 evaluable treated patients, 13 (62%) had responded at 12months. At baseline, non-responders had lower FEV1 levels and lower blood eosinophil levels than responders. CONCLUSIONS: Mepolizumab at a "severe asthma" dose (100mg/4weeks) is effective in treatment of GC-dependent severe asthma in most patients with EGPA.

[Introduction of an anticholinesterase drug in the context of myasthenia, in a severe asthmatic patient]. / Introduction d'un anticholinestérasique dans le contexte d'une myasthénie, chez une patiente asthmatique sévère.

Association of asthma with myasthenia gravis presents a twofold peculiarity. First, as dyspnea characterizes both conditions, diagnostic orientation is difficult. Second, from a therapeutic standpoint, the initiation of anticholinesterase treatment requires a multidisciplinary approach due to possible contraindication for asthma. We report on the case of a patient monitored for severe asthma and treated with biotherapy, and also monitored for myasthenia gravis, and treated with anticholinesterase.

[Markers of severity and predictors of response to treatment in severe asthma]. / Marqueurs de sévérité et marqueurs prédictifs de réponse au traitement dans l'asthme sévère.

Asthma is a multifactorial disease with complex pathophysiology. Knowledge of its immunopathology and inflammatory mechanisms is progressing and has led to the development over recent years of increasingly targeted therapeutic strategies. The objective of this review is to pinpoint the different predictive markers of asthma severity and therapeutic response. Obesity, nasal polyposis, gastroesophageal reflux disease and intolerance to aspirin have all been considered as clinical markers associated with asthma severity, as have functional markers such as bronchial obstruction, low FEV1, small daily variations in FEV1, and high FeNO. While sinonasal polyposis and allergic comorbidities are associated with better response to omalizumab, nasal polyposis or long-term systemic steroid use are associated with better response to antibodies targeting the IL5 pathway. Elevated total IgE concentrations and eosinophil counts are classic biological markers regularly found in severe asthma. Blood eosinophils are predictive biomarkers of response to anti-IgE, anti-IL5, anti-IL5R and anti-IL4R biotherapies. Dupilumab is particularly effective in a subgroup of patients with marked type 2 inflammation (long-term systemic corticosteroid therapy, eosinophilia≥150/µl or FENO>20 ppb). Chest imaging may help to identify severe patients by seeking out bronchial wall thickening and bronchial dilation. Study of the patient's environment is crucial insofar as exposure to tobacco, dust mites and molds, as well as outdoor and indoor air pollutants (cleaning products), can trigger asthma exacerbation. Wider and more systematic use of markers of severity or response to treatment could foster increasingly targeted and tailored approaches to severe asthma.

[A new pathophysiological element in severe asthma: GTPase Rac]. / Un nouvel acteur physiopathologique dans l'asthme sévère : la GTPase Rac.

Asthma is a chronic airway condition defined by hyperresponsiveness, bronchial remodeling and chronic inflammation. A significant proportion of severe asthmatic patients remain uncontrolled despite recent therapeutic breakthroughs (biotherapies). Better understanding of the signaling pathways involved in the pathophysiological mechanisms underlying severe asthma could successfully address this unmet need. Rac GTPase acts as a molecular switch and has already been convincingly associated with airway hyperresponsiveness and bronchial remodeling in asthma. Having been elucidated by acquired knowledge regarding other pathologies. Its role in the inflammation mechanisms characterizing asthma is currently under specific evaluation.

[Bronchial thermoplasty for severe asthma]. / Place de thermoplastie bronchique dans la prise en charge de l'asthme sévère.

Bronchial thermoplasty has been developed over the past fifteen years and is the first endoscopic technique approved in the management of severe asthma. This procedure uses radiofrequency applied to the airway wall to target bronchial smooth muscle. Patients treated in randomized controlled trials have experienced significant decreases in the use of rescue medications, urgent care visits, and exacerbations rate. The lack of reliable predictive markers of response to this expensive, minimally-invasive technique currently makes it a last-line treatment option. We review the principles and supposed mechanisms of action of this treatment, the results from the main trials and clinical registry data and discuss the place of bronchial thermoplasty in the current management of severe asthma. We also discuss perspectives to better characterize the mechanisms of action and identify the responder phenotype, the main challenge of current studies.

[Severe adult asthma and treatment adherence: Results of the FASE-CPHG study]. / Asthme sévère de l'adulte et observance : résultats de l'étude FASE-CPHG.

INTRODUCTION: Data on severe asthma in France are scarce. The aim of this study was to evaluate adherence to asthma treatments and its determinants in a population of severe asthmatics. METHODS: From May 2016 to June 2017, the French Collège des Pneumologues des Hôpitaux Généraux organized a large-scale prospective, cross-sectional, multicenter study on this topic; 1502 patients with severe asthma were included. RESULTS: The average number of substantive treatments was 2.5±1.1. Assessed by self-questionnaire in 1289 patients, overall adherence was 64.8%, in good agreement with the findings of the pneumologist in charge (p<0.0001). Control of asthma according to the GINA criteria was more successful in compliant patients (p<0.01). In univariate analysis, the most compliant participants were frequent exacerbator patients (p=0.02), those with nasal polyposis (p=0.01) and those receiving an anticholinergic agent (p<0.01), anti-IgE biotherapy (p<0.0001) or oral corticosteroids (p<0.01). The least compliant participants were younger (p<0.0001), active smokers (p<0.001), with shorter average disease duration (24.2±15.7 vs 29.1±18.7 years, p<0.0001) and a lower number of substantive asthma treatments (2.2±1 vs 2.6±1, p<0.0001). In multivariate analysis, age, length of disease and anti-IgE treatment were the only factors affecting therapeutic compliance. CONCLUSION: In this large-scale study of severe asthmatic patients, 64.8% were compliant according to the MMAS-4© self-administered questionnaire and appeared to be better monitored according to the criteria defined in our study. Overall, adherence was more satisfactory among older patients and those whose disease had been evolving over a long period of time or were receiving anti-IgE biotherapy.

Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma.

BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan®), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups.

[Physical activity in severe asthma: Results of the FASE-CPHG Study]. / Activité physique et asthme sévère : résultats de l'étude FASE-CPHG.

INTRODUCTION: Data on physical activity in severe asthma are scarce. From May 2016 to June 2017, 1502 adult patients with severe asthma visiting a pulmonologist practicing in one of the 104 non-academic hospitals participating in the study were included in this prospective, cross-sectional, multicenter study, provided they gave consent. Physical activity was classified according to 4 levels: 1 (no activity), 2 (occasional), 3 (regular), or 4 (frequent). Clinical and therapeutic parameters were described according to these levels. RESULTS: Respectively, 440, 528, 323, and 99 patients had physical activity of level 1, 2, 3, and 4. The percentage of patients with controlled asthma increased with physical activity. Treatment adherence did not differ with physical activity. Percentages of obese patients, patients with FEV1 <60%, and patients with anxiety, depressive syndrome, gastro-esophageal reflux disease, arterial hypertension, diabetes, obstructive sleep apnoea-hypopnoea syndrome, and osteoporosis decreased with physical activity. Respiratory rehabilitation was offered to only 5% of patients. CONCLUSIONS: In this large study, physical activity is associated with disease control in severe asthma and with less comorbidity. Its practice should be encouraged and respiratory rehabilitation offered more often.

[Woman's asthma throughout life: Towards a personalized management?] / Asthme de la femme au fil du temps : vers une prise en charge personnalisée ?

In a woman's life, asthma can affect her in a variety of ways, with the onset of premenstrual asthma currently under-diagnosed. It is estimated that about 20% of women with asthma have premenstrual asthma, which is more common in patients with severe asthma. Women with asthma are at high risk of exacerbations and of severe asthma. Asthma is the most common chronic disease during pregnancy with potential maternal and foetal complications. Asthma medications are safe for the foetus and it is essential to continue pre-existing treatment and adapt it to the progress of asthma during the pregnancy. Sex steroids modulate the structure and function of bronchial and immune cells. Understanding their role in asthma pathogenesis is complicated by the ambivalent effects of bronchodilating and pro-inflammatory oestrogens as well as the diversity of response to their association with progesterone. Menopausal asthma is a clinical entity and is part of one of the phenotypes of severe non-allergic and low steroid-sensitive asthma. Targeted assessment of the domestic and professional environment allows optimization of asthma management.

[Patients in the IDEAL cohort: A snapshot of severe asthma in France]. / Les patients de la cohorte IDEAL : une photographie de l'asthme sévère en France.

INTRODUCTION: This paper reports the French data from a post-hoc analysis of the international IDEAL study, which aimed to describe a recent cohort of patients with severe asthma, the impact of the disease on quality of life, as well as the population of patients eligible for treatment with omalizumab, mepolizumab and reslizumab. METHODS: Eligible patients were≥12 years of age, with severe asthma (GINA steps 4 and 5). RESULTS: A total of 129 patients were included in this post-hoc analysis. Their mean age was 53 years, the majority were overweight, they were mainly women (64%) and had at least one medical comorbidity (85%). More than half had suffered from asthma for more than 25 years and were non-smokers. Lung function was moderately impaired. Blood eosinophil count was≥150 cells/µL in 66% of patients,≥300 cells/µL in 34% of patients, and≥500 cells/µL in 12% of patients. One out of three patients was currently treated with omalizumab and 24% had maintenance oral corticosteroids. Asthma was poorly controlled with a negative impact on quality of life (ACQ≥1.5) in 67% of patients. In this population 40% of patients were eligible for omalizumab, 27% for mepolizumab and 2% for reslizumab. CONCLUSIONS: These findings show that a considerable proportion of patients with severe asthma remain uncontrolled and are not eligible for any of the available biological treatments. This underlines the need for therapeutic innovations in this disease.

[Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma]. / Benralizumab: Der IL-5-Rezeptor als Ziel bei schwerem eosinophilem Asthma.

Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma Abstract. For patients with difficult-to-control, severe bronchial asthma, highly effective, targeted treatment options are available in addition to inhaled medication. In the presence of eosinophilia, inhibition of the interleukin-5 (IL­5) axis with specific monoclonal antibodies promises to be an effective alternative to continuous systemic steroid therapy with few side effects. This review summarizes the data on benralizumab, a specific antibody against the IL-5 receptor alpha preventing receptor stimulation by IL-5 and activating a NK-cell mediated cytotoxic reaction with apoptosis of eosinophils. The s.c.-application of benralizumab leads within days to a virtually complete depletion of blood eosinophils with consecutive improvement in lung function and stabilization of asthma. For selected severe asthmatics, this is a promising therapy option.

[Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma]. / Benralizumab: Cibler le récepteur de l'IL-5 dans l'asthme sévère éosinophile.

Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma Abstract. Abstract:For patients with difficult-to-control, severe bronchial asthma, highly effective, targeted treatment options are available in addition to inhaled medication. In the presence of eosinophilia, inhibition of the interleukin-5 (IL-5) axis with specific monoclonal antibodies promises to be an effective alternative to continuous systemic steroid therapy with few side effects. This review summarizes the data on benralizumab, a specific antibody against the IL-5 receptor alpha preventing receptor stimulation by IL-5 and activating a NK-cell mediated cytotoxic reaction with apoptosis of eosinophils. The s.c.-application of benralizumab leads within days to a virtually complete depletion of blood eosinophils with consecutive improvement in lung function and stabilization of asthma. For selected severe asthmatics, this is a promising therapy option.

[Update in severe asthma physiopathology and treatments]. / Actualités physiopathologiques et thérapeutiques dans l'asthme sévère.

Asthma is an inflammatory airway disease which presentation is highly heterogeneous. Last two decades provided new clinical and basic data concerning asthma physiopathology that make global understanding much complex. Phenotypes based on clinical settings and paraclinical investigations from large cohorts confirm old paradigm (eosinophilic vs. non-eosinophilic asthma) but also introduce new concepts (obesity-related asthma, late onset asthma, etc.). Conversely, improvement of big data analytics allows to initiate new cohorts aiming at better understanding the pathophysiology underlying those phenotypes and unraveling new ones. However, clinical and therapeutic impacts of those big data need to be further detailed. In parallel, biotherapies and innovative techniques as bronchial thermoplasty become available for severe asthmatic patients who did not respond to specific treatment in the past. Development of a personalized medicine in severe asthma becomes an important challenge for tomorrow. This review will focus on new pathophysiological concepts arisen from large cohorts and new therapeutic strategies available and in progress for severe asthma.

[Omalizumab: Beyond anti-IgE properties]. / Mécanismes d'action de l'omalizumab : au-delà de l'action anti-IgE.

INTRODUCTION: Omalizumab is used as a treatment for severe allergic asthma. Its intended mechanism of action is based on its anti-IgE proprieties. However, recent studies have highlighted other mechanisms of action. STATE OF THE ART: Omalizumab treatment is associated with a decrease in the number of dendritic cells, T and B lymphocytes and eosinophils. This anti-inflammatory activity is characterized by a decrease in the levels of several cytokines involved in the recruitment, activation and survival of eosinophils and mastocytes, and in a Th2 orientation of the immune response. A modulation of bronchial remodeling by omalizumab has recently been shown. A decrease in the production of extracellular matrix components and in the proliferation of smooth muscle cells could be involved in this modulation. These mechanisms of action could explain in part the clinical efficiency of omalizumab in non-allergic conditions such as non-allergic asthma, non-allergic urticaria or nasal polyposis. CONCLUSION: A precise knowledge of the mechanisms of action of omalizumab could allow the identification of biomarkers predictive of efficacy of this treatment. These could be useful tools in the phenotyping of severe asthma.

[Severe uncontrolled asthma in patients over 75 years old: Treatment with omalizumab]. / Asthme sévère mal contrôlé de sujets de plus de 75 ans : traitement par omalizumab.

INTRODUCTION: With an aging population and an increase in the prevalence of asthma, this disease is becoming more common in the elderly. Nevertheless, the management of severe asthma can be complex, due to an increased risk of uncontrolled disease in patients over 65 years old and partly to the inherent characteristics of old age: comorbidities, underestimation of the role of allergies, poor adherence, difficulties with inhalation devices, etc. CASE REPORTS: We report two cases of women over 75 with severe persistent allergic asthma not controlled by high doses of inhaled corticosteroids and long-acting beta-2-agonists in whom treatment with omalizumab was initiated. Following treatment with omalizumab a decrease in the number and severity of exacerbations, improved asthma control and dose reduction or discontinuation of systemic corticosteroids were observed. The tolerance of omalizumab was good in both cases. CONCLUSIONS: Omalizumab is to be considered an effective and well-tolerated therapeutic option for elderly patients with inadequately controlled severe allergic asthma.

[Bronchial thermoplasty in the treatment of severe adult asthma]. / La thermoplastie bronchique dans le traitement de l'asthme sévère de l'adulte.

Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma.