[Preventive effects of allergen immunotherapy to pneumallergens]. / Prévention des manifestations allergiques par une immunothérapie aux pneumallergènes.

Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized patients. It can be administered either by subcutaneous or by sublingual route. The purpose of the treatment is to modulate the immune response to a specific allergen and to alter the course of the disease over a long-term period. Numerous studies and meta-analyses have demonstrated its efficacy in terms of symptoms and quality of life improvement as well as reduction of the allergic march. Indication of allergen immunotherapy includes moderate to severe allergic rhinitis and mild to moderate allergic asthma from GINA step 3. Early intervention in sensitized patients is nowadays promoted.

L'immunothérapie allergénique représente, encore aujourd'hui, le seul traitement curatif des allergies respiratoires. Elle consiste en l'administration répétée d'extraits allergéniques auxquels le patient est allergique. Elle peut se faire par voie sous-cutanée ou sublinguale. L'objectif est de moduler la réponse immunitaire afin de réduire les symptômes de l'allergie et de modifier le cours de la maladie allergique avec des effets perdurant sur le long terme. De nombreuses études et méta-analyses ont prouvé son efficacité en termes d'amélioration symptomatique, d'amélioration de la qualité de vie mais également de la réduction de l'évolution de la marche allergique. L'immunothérapie allergénique est indiquée dans le traitement de la rhinite allergique modérée à sévère et de l'asthme allergique dès le palier 3 du GINA («Global Initiative for Asthma¼). Une utilisation plus précoce est de plus en plus mise en avant pour bénéficier des effets préventifs de la modulation immunitaire.

[Dupilumab : a new treatment for severe T2 high asthma]. / Dupilumab, Dupixent® :un nouveau traitement pour l'asthme sévère avec un profil «T2 high¼.

Severe asthma often features a T2 high profile regulated by cytokines such as interleukins IL-4, IL-5 and IL-13. Dupilumab (Dupixent®) is humanized monoclonal antibody directed against the α subunit of the receptor for IL-4 and IL-13. Here we summarise the immunogical background of severe asthma which supports the use of dupilumab and the pivotal randomised controlled trials which have established the efficacy of dupilumab in treating people with severe asthma. Dupilumab reduces the exacerbation rate, has corticosteroids sparing effect, provides sustained improvement in expiratory flow rates and improved asthma control and quality of life with a reassuring safety profile. Dupilumab reduces the levels of FeNO values and of serum IgE but not those of circulating eosinophils. We also report on a few real life data with dupilumab supporting its clinical effectiveness.

L'asthme sévère est souvent caractérisé par un profil immunologique dit «T2 high¼ régulé par des cytokines telles que les interleukines IL-4, IL-5 et IL-13. Le dupilumab (Dupixent®) est un anticorps monoclonal humanisé dirigé contre la sous-unité α du récepteur à l'IL-4 et à l'IL-13. Nous présentons ici les bases immunologiques qui annoncent son efficacité dans le traitement de l'asthme sévère et les grandes études contrôlées qui ont validé son efficacité. Le dupilumab réduit la fréquence des exacerbations, permet une épargne en corticoïdes systémiques, améliore les débits expiratoires, le contrôle de la maladie et la qualité de vie des personnes asthmatiques, sans donner lieu à des effets secondaires notables. Il réduit le taux de FeNO et des IgE sériques, mais pas celui des éosinophiles circulants. Nous donnons également un aperçu de quelques données obtenues en vie réelle pour souligner son utilité en clinique.

Evidence for 2 clusters among patients with noneosinophilic asthma.

BACKGROUND: Although asthma is often seen as an eosinophilic disease associated with atopy, patients with noneosinophilic asthma represent a substantial part of the population with asthma. OBJECTIVE: To apply an unsupervised clustering method in a cohort of 588 patients with noneosinophilic asthma (sputum eosinophils < 3%) recruited from an asthma clinic of a secondary care center. METHODS: Our cluster analysis of the whole cohort identified 2 subgroups as cluster 1 (n = 417) and cluster 2 (n = 171). RESULTS: Cluster 1 comprised a predominantly female group with late disease onset, a low proportion of atopy (24%), and a substantial smoking history (53%). In this cluster, treatment burden was low (<50% of inhaled corticosteroid users); asthma control and quality of life were poor, with median Asthma Control Test, Asthma Control Questionnaire, and Asthma Quality of Life scores of 16, 1.7, and 4.5, respectively, whereas lung function was preserved with a median postbronchodilation forced expiratory volume in 1 second of 93% predicted. Cluster 2 was a predominantly male group, almost exclusively comprising patients with atopy (99%) with early disease onset and a moderate treatment burden (median inhaled corticosteroids dose 800 µg/d equivalent beclomethasone). In cluster 2, asthma was partially controlled, with median Asthma Control Test and Asthma Control Questionnaire scores reaching 18 and 1.3, respectively, and lung function well preserved with a median postbronchodilation of 95% predicted. Although systemic and airway neutrophilic inflammation was the dominant pattern in cluster 1, cluster 2 essentially comprised paucigranulocytic asthma with moderately elevated fraction exhaled nitric oxide. CONCLUSION: Noneosinophilic asthma splits into 2 clusters distinguishing by disease onset, atopic status, smoking history, systemic and airway inflammation, and disease control and quality of life.

Patients With Asthma Only Sensitized to Staphylococcus aureus Enterotoxins Have More Exacerbations, Airflow Limitation, and Higher Levels of Sputum IL-5 and IgE.

BACKGROUND: Staphylococcus aureus enterotoxins (SE) may act as superantigens and induce an intense T-cell activation, causing local production of polyclonal IgE and resultant eosinophil activation. OBJECTIVE: To assess whether asthma with sensitization to SE but not to common aeroallergens (AAs) displays different inflammatory characteristics. METHODS: We conducted a prospective study on a series of 110 consecutive patients with asthma recruited from the University Asthma Clinic of Liège. We compared clinical, functional, and inflammatory characteristics of this general population of patients with asthma categorized into 4 groups according to sensitization to AAs and/or SE. We also compared sputum supernatant cytokines in patients sensitized to SE or not. RESULTS: Patients with asthma sensitized only to AAs represented 30%, while 29% were sensitized to both AAs and SE. One-fifth of the population had no specific IgE. Sensitization to SE but not to AA (21%) was associated with later onset of disease, higher rate of exacerbations, nasal polyps, and more severe airway obstruction. As for airway type 2 biomarkers, patients presenting with specific IgE against SE displayed higher fractional exhaled nitric oxide, sputum IgE, and sputum IL-5 levels but not IL-4. We confirm that the presence of specific IgE against SE is associated with elevated serum IgE to levels well above those observed in patients sensitized only to AAs. CONCLUSIONS: Our study suggests that asthma specialists should measure specific IgE against SE during the phenotyping process because it may allow the identification of a subgroup of patients with more asthma exacerbations, more nasal polyposis and chronic sinusitis, lower lung function, and more intense type 2 inflammation.

[Dyspnea «sine materia¼]. / La dyspnée «sine materia¼.

Dyspnea is a symptom of respiratory discomfort commonly encountered in clinical practice which, in most of the cases, relates to a cardiopulmonary or a metabolic disorder. Its genesis is complex and results from numerous interactions within cortical and limbic brain areas following intero- and nociceptive stimuli. The term dyspnea «sine materia¼ points to a state where no clear underlying cardiopulmonary or metabolic pathology has been identified and we include here the hyperventilation syndrome and the physical deconditioning. Treatment of dyspnea «sine materia¼ is based on behavioural psychotherapy and on reathtletisation programme in case of physical deconditioning.

La dyspnée est un symptôme d'inconfort respiratoire extrêmement courant en médecine qui traduit, le plus souvent, un désordre cardiorespiratoire ou métabolique. Sa genèse est complexe et résulte de l'intégration, au niveau du cortex et du système limbique, de messages intéro- et nociceptifs. Par dyspnée «sine materia¼, nous entendons ici une dyspnée sans pathologie cardiorespiratoire ou métabolique sous-jacente avérée et nous y incluons celle du syndrome d'hyperventilation et du déconditionnement physique. La prise en charge de la dyspnée «sine materia¼ et, notamment, celle du syndrome d'hyperventilation repose sur la psychothérapie comportementale et la gestion du déconditionnement physique par des programmes de réathlétisation.

Cytokine-targeted therapies for asthma and COPD.

Asthma affects over 300 million people worldwide and its prevalence is increasing. COPD is the third leading cause of death globally. Asthma and COPD are complex inflammatory diseases of the airways in which impaired host defences lead to increased susceptibility to pathogens, pollutants and allergens. There is a constant interplay between host and the environment. Environmental exposures can alter the lung microbiome and influence the development of sensitisation by disrupting normal immunoregulation. The underlying airway inflammation in severe asthma is heterogeneous, with upregulation of type 2 cytokines in most cases but increased neutrophilic inflammation and activated T-helper 17 mediated immunity in others. COPD may also comprise several different phentoypes that are driven by different molecular mechanisms or endotypes. This disease heterogeneity is affected by comorbidities, treatments and environmental exposures. Recent intervention trials have shed light on the pathways beyond type 2 inflammation that can lead to beneficial outcomes versus potentially deleterious effects. We have made a great deal of progress over the last 10 years in terms of immunology and the pathophysiology of asthma and this has led to the development of novel treatments and major improvements in severe asthma outcomes. In COPD, however, no targeted treatments have demonstrated great improvements. This article reviews the mechanism of action and efficacy of the available biologics in asthma and COPD.

Bronchodilation Test with Inhaled Salbutamol Versus Bronchial Methacholine Challenge to Make an Asthma Diagnosis: Do They Provide the Same Information?

BACKGROUND: Methacholine bronchial challenge and bronchodilation to salbutamol are key tests in clinical practice to make asthma diagnosis. OBJECTIVE: To assess the concordance between the 2 tests and to see whether they actually identify the same population of asthmatics. METHOD: We conducted a retrospective study using our asthma clinic database to see how methacholine bronchial challenge compared to bronchodilation to salbutamol in untreated patients with recurrent or chronic symptoms suspicious of asthma. We identified 194 untreated patients with baseline forced expiratory volume in 1 second (FEV1) ≥70% predicted who had both a bronchodilation test with salbutamol and a methacholine bronchial challenge 7 to 14 days apart. A positive bronchial challenge was a provocative concentration of methacholine causing a 20% fall in FEV1 ≤16 mg/mL, whereas a positive bronchodilation test was a reversibility to 400 µg inhaled salbutamol ≥12% from baseline and 200 mL. RESULTS: Overall, asthma diagnosis was confirmed in 91% of cases leaving 9% of subjects with double negative tests. Isolated positive methacholine challenge was found in 71% of subjects, double positive tests in 17%, whereas isolated significant bronchodilation to salbutamol was rare (3%). There was no correlation between provocative concentration of methacholine causing a fall in FEV1 of 20% (PC20M) and the magnitude of salbutamol reversibility (P = .10). Baseline FEV1/forced vital capacity ratio inversely correlated with reversibility to salbutamol (P < .001) but not with PC20M (P = .1). No difference was found between the groups regarding demographic and immunoinflammatory features, including the proportion of eosinophilic asthma. CONCLUSION: We conclude that methacholine challenge outperforms reversibility to salbutamol to diagnose asthma without selecting patients with distinct inflammatory profile. Baseline airway obstruction predicts magnitude of reversibility but not hyperresponsiveness.