Research LettersNon-eosinophilic cor ticosteroid unresponsive asthma
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Cited by (445)
Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes
2023, Journal of Allergy and Clinical ImmunologyAirway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation.
We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment.
In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion.
Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, −0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, −0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33.
Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation
2023, Allergology InternationalThe physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical–physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma.
A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT.
More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics.
The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.
Toward a Predict and Prevent Approach in Obstructive Airway Diseases
2023, Journal of Allergy and Clinical Immunology: In PracticeAsthma and chronic obstructive pulmonary disease are currently diagnosed and treated after the demonstration of variable airflow limitation and symptoms. Under this framework, undiagnosed and unchecked airway inflammation is associated with recurrent acute attacks, airway remodeling, airflow limitation, adverse effects of corticosteroids, and impaired quality of life, ultimately leading to the collection of side effects termed “people remodeling.” This one-size-fits-all damage control approach aims to control symptoms and treat exacerbations rather than modify the underlying disease process. The advent of highly effective therapies targeting proximal drivers of airway inflammation calls for a paradigm shift; upstream-acting therapies offer potential to alter the disease course and achieve clinical remission. We propose moving away from downstream firefighting and toward a “predict and prevent” model, measuring inflammation and providing anti-inflammatory therapy early, without waiting for further clinical deterioration. Much in the same way that high blood pressure and cholesterol are used to predict and prevent heart attacks, in asthma, elevated blood eosinophils and/or exhaled nitric oxide can be used to predict and prevent asthma attacks. We also advocate moving research further upstream by identifying patients with subclinical airway inflammation or disease who may be at risk of progressing to airflow limitation and associated morbidities and intervening early to prevent them. In summary, we call for a predict and prevent approach in obstructive airway disease.
Eosinophilic and noneosinophilic asthma: Beyond severe asthma
2023, Asthma in the 21st Century: New Research AdvancesInflammation in asthma can be generally classified as eosinophilic or noneosinophilic. Eosinophilic asthma is defined by the presence of eosinophils in the airway or blood. Because eosinophils are highly biologically active, the presence of activated eosinophils in tissue and release of toxins and mediators can contribute to the severity of asthma, and are therefore an appropriate therapeutic target for some individuals. Eosinophilia frequently coexists with additional immune pathways including IgE-mediated inflammation and abnormalities of arachidonic acid metabolism. In contrast, noneosinophilic asthma can be characterized by the presence of neutrophilic inflammation or the relative lack of granulocytic inflammation with prominent airway remodeling. These noneosinophilic types of asthma may be less responsive to usual therapies, including corticosteroids and anti-eosinophil targeted biologics, and therefore also contribute to severe disease. This chapter highlights the biological mechanisms believed to underlie the recognized eosinophilic and noneosinophilic asthma phenotypes, their clinical features, and discusses implications for future treatments. This chapter also highlights emerging features of eosinophilic and noneosinophilic inflammation in asthma, including the role of neutrophil and eosinophil extracellular traps, the inflammasome, and the lipoxins.
Determining asthma endotypes and outcomes: Complementing existing clinical practice with modern machine learning
2022, Cell Reports MedicineThere is unprecedented opportunity to use machine learning to integrate high-dimensional molecular data with clinical characteristics to accurately diagnose and manage disease. Asthma is a complex and heterogeneous disease and cannot be solely explained by an aberrant type 2 (T2) immune response. Available and emerging multi-omics datasets of asthma show dysregulation of different biological pathways including those linked to T2 mechanisms. While T2-directed biologics have been life changing for many patients, they have not proven effective for many others despite similar biomarker profiles. Thus, there is a great need to close this gap to understand asthma heterogeneity, which can be achieved by harnessing and integrating the rich multi-omics asthma datasets and the corresponding clinical data. This article presents a compendium of machine learning approaches that can be utilized to bridge the gap between predictive biomarkers and actual causal signatures that are validated in clinical trials to ultimately establish true asthma endotypes.
Use of systemic glucocorticoids for the treatment of severe asthma: Spanish Multidisciplinary Consensus
2022, Open Respiratory ArchivesLos glucocorticoides sistémicos (GCS) se han utilizado ampliamente para tratar el asma desde que se describió por primera vez su eficacia en esta enfermedad. Actualmente sabemos que su uso está asociado con la aparición de efectos adversos (EA), como la osteoporosis o la insuficiencia suprarrenal. Este es un estudio observacional basado en la metodología Delphi. El cuestionario constaba de 4 bloques principales: generalidades de los GCS; tratamiento de mantenimiento; tratamiento en ciclos cortos, y EA.
Un panel de 48 expertos profesionales alergólogos y neumólogos respondieron a 2 rondas de un cuestionario de 68 enunciados.
Se consensuaron definiciones y hubo acuerdos sobre el uso apropiado de los GCS en el tratamiento del asma grave. Los expertos consensuaron que el uso de los GCS se debe minimizar en lo posible y estuvieron de acuerdo en un esquema de retirada gradual y progresivo en caso de terapias de mantenimiento. Además, destacaron la necesidad de estandarizar el procedimiento de control de la medida de GCS administrado tanto en ciclos cortos como en terapias de mantenimiento a fin de controlar mejor la carga acumulada de los pacientes que reciben dicho tratamiento y evitar la aparición de EA.
Este documento de consenso pretende aunar las recomendaciones de los expertos en el manejo del asma respaldadas por la evidencia científica con el objetivo de impulsar la reducción en el uso de GCS en el ámbito español.
Since their effectiveness was initially demonstrated, oral corticosteroids (OCS) have been routinely used to treat asthma. We now know that their usage is linked to the development of side effects such osteoporosis and adrenal insufficiency. This is an observational study based on Delphi methodology. The questionnaire was divided into 4 sections: OCS generalities, maintenance treatment, short-term treatment, and adverse events.
Two rounds of a 68-item questionnaire were completed by a panel of 48 allergists and pneumologists.
Definitions were agreed upon, as was the proper use of OCS in the treatment of severe asthma. The experts agreed that the use of OCS should be minimized as much as possible and that in the event of maintenance treatments, a slow and progressive tapering strategy should be used. They also emphasized the importance of standardizing the technique for measuring the amount of SCG delivered in both cases.
This consensus document attempts to bring together scientifically supported suggestions from specialists in the management of asthma to reduce the use of OCS in Spain.