Assuntos
Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma , Humanos , Feminino , Prevalência , Masculino , Pessoa de Meia-Idade , Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma/diagnóstico , Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma/epidemiologia , Idoso , Pulmão/fisiopatologia , Asma/epidemiologia , Asma/diagnóstico , Estudos de Coortes , Adulto , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/diagnósticoAssuntos
Produtos Biológicos , Rinite , Humanos , Cavidade Nasal , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVE: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. METHODS: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. RESULTS: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. CONCLUSION: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.
Assuntos
Asma , Eosinofilia , Humanos , Óxido Nítrico , Multimorbidade , Asma/diagnóstico , Asma/epidemiologia , EosinófilosRESUMO
BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), which is characterized by partial loss of smell (hyposmia) or total loss of smell (anosmia), is commonly associated with asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). CRSwNP worsens disease severity and quality of life. The objective of this real-world study was to determine whether biological treatments prescribed for severe asthma can improve olfaction in patients with CRSwNP. A further objective was to compare the improvement in in olfaction in N-ERD and non-N-ERD subgroups. METHODS: We performed a multicenter, noninterventional, retrospective, observational study of 206 patients with severe asthma and CRSwNP undergoing biological treatment (omalizumab, mepolizumab, benralizumab, or reslizumab). RESULTS: Olfaction improved after treatment with all 4 monoclonal antibodies (omalizumab [35.8%], mepolizumab [35.4%], reslizumab [35.7%], and benralizumab [39.1%]), with no differences between the groups. Olfaction was more likely to improve in patients with atopy, more frequent use of short-course systemic corticosteroids, and larger polyp size. The proportion of patients whose olfaction improved was similar between the N-ERD (37%) and non-N-ERD (35.7%) groups. CONCLUSIONS: This is the first real-world study to compare improvement in olfaction among patients undergoing long-term treatment with omalizumab, mepolizumab, reslizumab, or benralizumab for severe asthma and associated CRSwNP. Approximately 4 out of 10 patients reported a subjective improvement in olfaction (with nonsignificant differences between biologic drugs). No differences were found for improved olfaction between the N-ERD and non-N-ERD groups.
Assuntos
Asma , Produtos Biológicos , Pólipos Nasais , Rinite , Sinusite , Humanos , Omalizumab/uso terapêutico , Pólipos Nasais/complicações , Pólipos Nasais/tratamento farmacológico , Olfato , Produtos Biológicos/uso terapêutico , Anosmia/complicações , Anosmia/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Asma/complicações , Asma/tratamento farmacológico , Imunossupressores/uso terapêutico , Sinusite/complicações , Sinusite/tratamento farmacológico , Doença Crônica , Rinite/complicações , Rinite/tratamento farmacológicoAssuntos
Anafilaxia , Humanos , Anafilaxia/diagnóstico , Anafilaxia/etiologia , Grão Comestível/efeitos adversos , Milhetes , SementesRESUMO
Five biological drugs are currently marketed for treatment of uncontrolled severe asthma. They all block type 2 inflammatory pathways by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/IL-13 pathway (dupilumab). Hypereosinophilia has been observed in 4%-25% of patients treated with dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. Cases of EGPA have been reported with all biologics, including anti-IL-5 agents, and with leukotriene receptor antagonists in publications or in the EudraVigilance database. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti-IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti-IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. Blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/µL), in which case an anti-IL-5/IL-5R agent is preferable. Furthermore, when switching from an anti-IL-5/5R to an anti-IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation. This approach can prevent the development of EGPA and other types of symptomatic hypereosinophilia while maintaining control of nasal polyposis. In the near future, it will be possible to use a new generation of biological therapies for the treatment of severe asthma. These act at a higher level of the inflammatory cascade, as is the case of the antialarmins tezepelumab and itepekimab.
Assuntos
Asma , Síndrome de Churg-Strauss , Eosinofilia , Granulomatose com Poliangiite , Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Síndrome de Churg-Strauss/diagnóstico , Eosinofilia/tratamento farmacológico , Granulomatose com Poliangiite/diagnóstico , Humanos , Interleucina-13 , Interleucina-4 , Interleucina-5RESUMO
BACKGROUND AND OBJECTIVES: Asthma is a chronic inflammatory condition of the airways with a complex pathophysiology. Stratification of asthma subtypes into phenotypes and endotypes should move the field forward, making treatment more effective and personalized. Eosinophils are the key inflammatory cells involved in severe eosinophilic asthma. Given the health threat posed by eosinophilic asthma, there is a need for reliable biomarkers to identify affected patients and treat them properly with novel biologics. microRNAs (miRNAs) are a promising diagnostic tool. The aim of this study was to identify serum miRNAs that can phenotype asthma patients. METHODS: Serum miRNAs of patients with eosinophilic asthma (N=40) and patients with noneosinophilic asthma (N=36) were evaluated using next-generation sequencing, specifically miRNAs-seq, and selected miRNAs were validated using RT-qPCR. Pathway enrichment analysis of deregulated miRNAs was performed. RESULTS: Next-generation sequencing revealed 15 miRNAs that were expressed differentially between eosinophilic and noneosinophilic asthma patients, although no differences were observed in the miRNome between atopic and nonatopic asthma patients. Of the 15 miRNAs expressed differentially between eosinophilic and noneosinophilic asthma patients, hsa-miR-26a-1-3p and hsa-miR-376a-3p were validated by RT-qPCR. Expression levels of these 2 miRNAs were higher in eosinophilic than in noneosinophilic asthma patients. Furthermore, expression values of hsa-miR-26a-1-3p correlated inversely with peripheral blood eosinophil count, and hsa-miR-376a-3p expression values correlated with FeNO values and the number of exacerbations. Additionally, in silico pathway enrichment analysis revealed that these 2 miRNAs regulate signaling pathways associated with the pathogenesis of asthma. CONCLUSIONS: hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used to differentiate between eosinophilic and noneosinophilic asthma.
Assuntos
Asma , MicroRNAs , Humanos , MicroRNAs/genética , Sequenciamento de Nucleotídeos em Larga Escala , Biomarcadores , Fenótipo , Asma/diagnóstico , Asma/genéticaRESUMO
Eosinophils were discovered more than 140 years ago. These polymorphonuclear leukocytes have a very active metabolism and contain numerous intracellular secretory granules that enable multiple effects on both health and disease status. Classically, eosinophils have been considered important immune cells in the pathogenesis of inflammatory processes (eg, parasitic helminth infections) and allergic or pulmonary diseases (eg, asthma) and are always associated with a type 2 immune response. Furthermore, in recent years, eosinophils have been linked to the immune response by conferring host protection against fungi, bacteria, and viruses, which they recognize through several molecules, such as toll-like receptors and the retinoic acid-inducible gene 1-like receptor. The immune protection provided by eosinophils is exerted through multiple mechanisms and properties. Eosinophils contain numerous cytoplasmatic granules that release cationic proteins, cytokines, chemokines, and other molecules, all of which contribute to their functioning. In addition to the competence of eosinophils as effector cells, their capabilities as antigen-presenting cells enable them to act in multiple situations, thus promoting diverse aspects of the immune response. This review summarizes various aspects of eosinophil biology, with emphasis on the mechanisms used and roles played by eosinophils in host defence against viral infections and response to vaccines. The review focuses on respiratory viruses, such as the new coronavirus, SARS-CoV-2.
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COVID-19/imunologia , Eosinófilos/imunologia , SARS-CoV-2 , Animais , HumanosAssuntos
Asma/complicações , Asma/epidemiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Asma/diagnóstico , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Prevalência , Vigilância em Saúde Pública , SARS-CoV-2 , Espanha/epidemiologiaAssuntos
Alérgenos/imunologia , Antígenos de Plantas/imunologia , Fagopyrum/imunologia , Hipersensibilidade Alimentar/diagnóstico , Administração Oral , Culinária , Eritema , Humanos , Imunização , Imunoglobulina E/metabolismo , Masculino , Pessoa de Meia-Idade , Prurido , Testes Cutâneos , Distúrbios do PaladarAssuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Asma/diagnóstico , Biomarcadores , MicroRNA Circulante/sangue , Humanos , MicroRNAs/sangue , Testes de Função RespiratóriaRESUMO
Eosinophils are terminal polymorphonuclear cells with a high number of cytoplasmic granules that originate in bone marrow. Some are exosomes, which contain multiple molecules, such as specific eosinophilic proteins, cytokines, chemokines, enzymes, and lipid mediators that contribute to the effector role of these cells. Moreover, exosomes present a large number of receptors that allow them to interact with multiple cell types. Eosinophils play an important role in defense against infestations and are a key element in asthma and allergic diseases. Eosinophils are recruited to the inflamed area in response to stimuli, modulating the immune response through the release to the extracellular medium of their granule-derived content. Various mechanisms of degranulation have been identified. Polymorphonuclear leukocytes contain multivesicular bodies that generate exosomes that are secreted into the extracellular environment. Eosinophilic exosomes participate in multiple processes and mechanisms. Eosinophils participate actively in asthma and are hallmarks of the disease. The cells migrate to the inflammatory focus and contribute to epithelial damage and airway remodeling. Given their relevance in this pathology, new therapeutic tools have been developed that target mainly eosinophils and their receptors. In this manuscript, we provide a global, updated vision of the biology of eosinophils and the role of eosinophils in respiratory diseases, particularly asthma. We also summarize asthma treatments linked to eosinophils and new therapeutic strategies based on biological products in which eosinophils and their receptors are the main targets.
Assuntos
Eosinófilos/imunologia , Animais , Asma/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Humanos , Hipersensibilidade/imunologia , Inflamação/imunologiaRESUMO
BACKGROUND: Eosinophils, a central factor in asthma pathogenesis, have the ability to secrete exosomes. However, the precise role played by exosomes in the biological processes leading up to asthma has not been fully defined. OBJECTIVE: We hypothesized that exosomes released by eosinophils contribute to asthma pathogenesis by activating structural lung cells. METHODS: Eosinophils from asthmatic patients and healthy volunteers were purified from peripheral blood, and exosomes were isolated from eosinophils of asthmatic and healthy individuals. All experiments were performed with eosinophil-derived exosomes from healthy and asthmatic subjects. Epithelial damage was evaluated using primary small airway epithelial cell lines through 2 types of apoptosis assays, that is, flow cytometry and TUNEL assay with confocal microscopy. Additionally, the epithelial repair was analysed by performing wound healing assays with epithelial cells. Functional studies such as proliferation and inhibition-proliferation assays were carried out in primary bronchial smooth muscle cell lines. Also, gene expression analysis of pro-inflammatory molecules was evaluated by real-time PCR on epithelial and muscle cells. Lastly, protein expression of epithelial and muscle cell signalling factors was estimated by Western blot. RESULTS: Asthmatic eosinophil-derived exosomes induced an increase in epithelial cell apoptosis at 24 hour and 48 hour, impeding wound closure. In addition, muscle cell proliferation was increased at 72 hours after exosome addition and was linked with higher phosphorylation of ERK1/2. We also found higher expression of several genes when both cell types were cultured in the presence of exosomes from asthmatics: CCR3 and VEGFA in muscle cells, and CCL26, TNF and POSTN in epithelial cells. Healthy eosinophil-derived exosomes did not exert any effect over these cell types. CONCLUSIONS AND CLINICAL RELEVANCE: Eosinophil-derived exosomes from asthmatic patients participate actively in the development of the pathological features of asthma via structural lung cells.