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1.
Allergy ; 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38686450

RESUMEN

BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

2.
Allergy ; 77(10): 2974-2986, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35579040

RESUMEN

BACKGROUND: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. OBJECTIVES: To explore airway pathology in T2 biomarker-high and -low severe asthma. METHODS: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD2 and LTE4 measurements. RESULTS: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD2 and LTE4 , were increased in T2-high and T2-intermediate asthma compared with healthy controls. CONCLUSIONS: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530.


Asunto(s)
Asma , Eosinofilia , Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Biomarcadores , Citocinas/análisis , Eosinofilia/patología , Eosinófilos/metabolismo , Humanos , Inflamación/patología , Interleucina-4 , Interleucina-5/análisis , Esputo
3.
Am J Respir Crit Care Med ; 200(8): 982-991, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31106566

RESUMEN

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Asma/diagnóstico , Asma/fisiopatología , Asma/terapia , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Adulto , Anciano , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Modelos Anatómicos , Pruebas de Función Respiratoria/métodos , Espirometría/métodos
4.
J Immunol ; 198(8): 3307-3317, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28275137

RESUMEN

Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.


Asunto(s)
Antígenos CD/inmunología , Asma/inmunología , Moléculas de Adhesión Celular/inmunología , Células Epiteliales/inmunología , Neutrófilos/inmunología , Mucosa Respiratoria/inmunología , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas Ligadas a GPI/inmunología , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Transcriptoma
5.
BMC Pulm Med ; 19(1): 144, 2019 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-31395050

RESUMEN

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1ß, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.


Asunto(s)
Asma/inmunología , Asma/metabolismo , Citocinas/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Área Bajo la Curva , Biomarcadores/metabolismo , Niño , Progresión de la Enfermedad , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la Enfermedad , Esputo/inmunología , Esputo/metabolismo
6.
J Allergy Clin Immunol ; 142(5): 1457-1468, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29550052

RESUMEN

BACKGROUND: Asthma is a complex chronic disease underpinned by pathological changes within the airway wall. How variations in structural airway pathology and cellular inflammation contribute to the expression and severity of asthma are poorly understood. OBJECTIVES: Therefore we evaluated pathological heterogeneity using topological data analysis (TDA) with the aim of visualizing disease clusters and microclusters. METHODS: A discovery population of 202 adult patients (142 asthmatic patients and 60 healthy subjects) and an external replication population (59 patients with severe asthma) were evaluated. Pathology and gene expression were examined in bronchial biopsy samples. TDA was applied by using pathological variables alone to create pathology-driven visual networks. RESULTS: In the discovery cohort TDA identified 4 groups/networks with multiple microclusters/regions of interest that were masked by group-level statistics. Specifically, TDA group 1 consisted of a high proportion of healthy subjects, with a microcluster representing a topological continuum connecting healthy subjects to patients with mild-to-moderate asthma. Three additional TDA groups with moderate-to-severe asthma (Airway Smooth MuscleHigh, Reticular Basement MembraneHigh, and RemodelingLow groups) were identified and contained numerous microclusters with varying pathological and clinical features. Mutually exclusive TH2 and TH17 tissue gene expression signatures were identified in all pathological groups. Discovery and external replication applied to the severe asthma subgroup identified only highly similar "pathological data shapes" through analyses of persistent homology. CONCLUSIONS: We have identified and replicated novel pathological phenotypes of asthma using TDA. Our methodology is applicable to other complex chronic diseases.


Asunto(s)
Asma/patología , Bronquios/patología , Adulto , Remodelación de las Vías Aéreas (Respiratorias) , Asma/genética , Bronquios/metabolismo , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Fenotipo
7.
Eur Respir J ; 48(1): 92-103, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27230444

RESUMEN

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.


Asunto(s)
Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/diagnóstico por imagen , Tomografía Computarizada por Rayos X/normas , Adulto , Anciano , Europa (Continente) , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Sistema Respiratorio/fisiopatología , Espirometría
8.
J Allergy Clin Immunol ; 134(2): 287-94, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24928647

RESUMEN

BACKGROUND: Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. OBJECTIVES: We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. METHODS: Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. RESULTS: FEV1 decrease was -25.7 mL/y in the overall population. Postbronchodilator FEV1 was also dependent on exacerbations, age of onset, height, age, sex, and log10 sputum eosinophil percentages (P < .001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, -14.0 mL/y), (2) eosinophilic with high variation (mean decrease, -40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, -19.2 mL/y). CONCLUSION: The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV1 decrease.


Asunto(s)
Asma/fisiopatología , Eosinofilia/fisiopatología , Pulmón/fisiopatología , Adulto , Asma/complicaciones , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Eosinofilia/complicaciones , Eosinofilia/tratamiento farmacológico , Femenino , Volumen Espiratorio Forzado , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Estudios Longitudinales , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Esputo/química , Esputo/citología
9.
J Allergy Clin Immunol ; 134(1): 33-9, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24290286

RESUMEN

BACKGROUND: IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. OBJECTIVES: We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. METHODS: Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. RESULTS: Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. CONCLUSION: We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.


Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Asma/tratamiento farmacológico , Inmunoglobulina E/sangre , Voriconazol/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Aspergilosis/complicaciones , Aspergilosis/microbiología , Aspergilosis/patología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/fisiología , Asma/complicaciones , Asma/microbiología , Asma/patología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento
10.
BMC Pulm Med ; 14: 112, 2014 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-25007795

RESUMEN

BACKGROUND: Eosinophilic airway inflammation is observed in 10-30% of COPD subjects. Whether increased eosinophils or impairment in their clearance by macrophages is associated with the severity and frequency of exacerbations is unknown. METHODS: We categorised 103 COPD subjects into 4 groups determined by the upper limit of normal for their cytoplasmic macrophage red hue (<6%), an indirect measure of macrophage efferocytosis of eosinophils, and area under the curve sputum eosinophil count (≥ 3%/year). Eosinophil efferocytosis by monocyte-derived macrophages was studied in 17 COPD subjects and 8 normal controls. RESULTS: There were no differences in baseline lung function, health status or exacerbation frequency between the groups: A-low red hue, high sputum eosinophils (n=10), B-high red hue, high sputum eosinophils (n=16), C-low red hue, low sputum eosinophils (n=19) and D- high red hue, low sputum eosinophils (n=58). Positive bacterial culture was lower in groups A (10%) and B (6%) compared to C (44%) and D (21%) (p=0.01). The fall in FEV1 from stable to exacerbation was greatest in group A (ΔFEV1 [95 % CI] -0.41 L [-0.65 to -0.17]) versus group B (-0.16 L [-0.32 to -0.011]), C (-0.11 L [-0.23 to -0.002]) and D (-0.16 L [-0.22 to -0.10]; p=0.02). Macrophage efferocytosis of eosinophils was impaired in COPD versus controls (86 [75 to 92]% versus 93 [88 to 96]%; p=0.028); was most marked in group A (71 [70 to 84]%; p=0.0295) and was inversely correlated with exacerbation frequency (r=-0.63; p=0.006). CONCLUSIONS: Macrophage efferocytosis of eosinophils is impaired in COPD and is related to the severity and frequency of COPD exacerbations.


Asunto(s)
Citofagocitosis/fisiología , Eosinofilia/fisiopatología , Eosinófilos , Macrófagos/fisiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Color , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Índice de Severidad de la Enfermedad , Esputo/citología
12.
J Allergy Clin Immunol ; 129(1): 104-11.e1-9, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21975173

RESUMEN

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP-OX40 ligand (OX40L)-T cell axis and a TSLP-mast cell axis. Whether these pathways are active in human asthma is unknown. OBJECTIVE: We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways. METHODS: In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, T(H)2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR. RESULTS: There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a T(H)2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects. CONCLUSION: TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and T(H)2 inflammation.


Asunto(s)
Asma/inmunología , Citocinas/metabolismo , Asma/genética , Asma/metabolismo , Citocinas/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Eosinofilia/inmunología , Eosinofilia/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamación/inmunología , Inflamación/patología , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ligando OX40/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Linfopoyetina del Estroma Tímico
13.
N Engl J Med ; 360(10): 973-84, 2009 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-19264686

RESUMEN

BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Interleucina-5/inmunología , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Asma/fisiopatología , Biomarcadores/análisis , Biomarcadores/sangre , Método Doble Ciego , Quimioterapia Combinada , Eosinófilos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Hospitalización/estadística & datos numéricos , Humanos , Interleucina-5/antagonistas & inhibidores , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Calidad de Vida , Prevención Secundaria , Esputo/inmunología , Resultado del Tratamiento , Adulto Joven
14.
Prim Care Respir J ; 21(3): 283-7, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22786814

RESUMEN

BACKGROUND: Most patients with asthma are managed exclusively in primary care. Little is known about the patterns of airway dysfunction in these patients and how these relate to other aspects of the disease. AIMS: We set out to assess this in a cross-sectional study of 262 patients. METHODS: Symptoms, spirometry, airway responsiveness, reversibility, and airway inflammation were all assessed. Exacerbations requiring oral corticosteroids in the preceding year were enumerated. RESULTS: Patients had heterogeneous patterns of airway dysfunction. Those with a post-bronchodilator forced expiratory volume in 1 sec/ forced vital capacity ratio of <0.7 had more exacerbations in the previous year (2.2 vs. 0.8; mean difference 1.4; 95% CI 0.4 to 2.4; p=0.007). Patients with normal results had less inflammation (proportion with a sputum eosinophil count of >1.9%, 20% vs. 48%, χ²=14.8, df=3; p<0.001) and fewer exacerbations (0.5 vs. 1.4; mean difference -0.9; 95% CI -1.4 to -0.4; p=0.001) but similar symptom scores (6.2 vs. 6.9; p=0.2) compared with patients with any abnormality. CONCLUSIONS: Patients with a diagnosis of asthma have mixed patterns of physiological impairment; many have no airflow obstruction or airway hyper-responsiveness. The physiological characterisation of asthma is not related to symptoms and is of little value in predicting exacerbations or eosinophilic airway inflammation.


Asunto(s)
Asma/complicaciones , Asma/fisiopatología , Asma/diagnóstico , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Primaria de Salud
15.
Sci Transl Med ; 14(671): eabl5849, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36383685

RESUMEN

Acute cardiorespiratory breathlessness accounts for one in eight of all emergency hospitalizations. Early, noninvasive diagnostic testing is a clinical priority that allows rapid triage and treatment. Here, we sought to find and replicate diagnostic breath volatile organic compound (VOC) biomarkers of acute cardiorespiratory disease and understand breath metabolite network enrichment in acute disease, with a view to gaining mechanistic insight of breath biochemical derangements. We collected and analyzed exhaled breath samples from 277 participants presenting acute cardiorespiratory exacerbations and aged-matched healthy volunteers. Topological data analysis phenotypes differentiated acute disease from health and acute cardiorespiratory exacerbation subtypes (acute heart failure, acute asthma, acute chronic obstructive pulmonary disease, and community-acquired pneumonia). A multibiomarker score (101 breath biomarkers) demonstrated good diagnostic sensitivity and specificity (≥80%) in both discovery and replication sets and was associated with all-cause mortality at 2 years. In addition, VOC biomarker scores differentiated metabolic subgroups of cardiorespiratory exacerbation. Louvain clustering of VOCs coupled with metabolite enrichment and similarity assessment revealed highly specific enrichment patterns in all acute disease subgroups, for example, selective enrichment of correlated C5-7 hydrocarbons and C3-5 carbonyls in heart failure and selective depletion of correlated aldehydes in acute asthma. This study identified breath VOCs that differentiate acute cardiorespiratory exacerbations and associated subtypes and metabolic clusters of disease-associated VOCs.


Asunto(s)
Asma , Insuficiencia Cardíaca , Compuestos Orgánicos Volátiles , Humanos , Pruebas Respiratorias , Compuestos Orgánicos Volátiles/análisis , Enfermedad Aguda , Disnea/diagnóstico , Asma/diagnóstico , Biomarcadores/metabolismo , Insuficiencia Cardíaca/diagnóstico
16.
Am J Respir Crit Care Med ; 182(11): 1362-8, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20639442

RESUMEN

RATIONALE: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear. OBJECTIVES: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma. METHODS: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data. MEASUREMENTS AND MAIN RESULTS: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV1 % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024). CONCLUSIONS: A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.


Asunto(s)
Aspergillus fumigatus/inmunología , Asma/inmunología , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/inmunología , Pulmón/fisiopatología , Adulto , Asma/complicaciones , Asma/fisiopatología , Bronquiectasia/etiología , Bronquiectasia/inmunología , Estudios de Cohortes , Femenino , Volumen Espiratorio Forzado/inmunología , Humanos , Hipersensibilidad Inmediata/complicaciones , Pulmón/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Pruebas de Función Respiratoria/métodos , Índice de Severidad de la Enfermedad , Esputo/inmunología
17.
ERJ Open Res ; 7(3)2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34235208

RESUMEN

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic has claimed over two and a half million lives worldwide so far. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is perceived to be seasonally recurrent, and a rapid noninvasive biomarker to accurately diagnose patients early on in their disease course will be necessary to meet the operational demands for COVID-19 control in the coming years. OBJECTIVE: The aim of this study was to evaluate the role of exhaled breath volatile biomarkers in identifying patients with suspected or confirmed COVID-19 infection, based on their underlying PCR status and clinical probability. METHODS: A prospective, real-world, observational study was carried out, recruiting adult patients with suspected or confirmed COVID-19 infection. Breath samples were collected using a standard breath collection bag, modified with appropriate filters to comply with local infection control recommendations, and samples were analysed using gas chromatography-mass spectrometry (TD-GC-MS). RESULTS: 81 patients were recruited between April 29 and July 10, 2020, of whom 52 out of 81 (64%) tested positive for COVID-19 by reverse transcription-polymerase chain reaction (RT-PCR). A regression analysis identified a set of seven exhaled breath features (benzaldehyde, 1-propanol, 3,6-methylundecane, camphene, beta-cubebene, iodobenzene and an unidentified compound) that separated PCR-positive patients with an area under the curve (AUC): 0.836, sensitivity: 68%, specificity: 85%. CONCLUSIONS: GC-MS-detected exhaled breath biomarkers were able to identify PCR-positive COVID-19 patients. External replication of these compounds is warranted to validate these results.

18.
J Breath Res ; 15(2)2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33227714

RESUMEN

The headspace of a biological sample contains exogenous volatile organic compounds (VOCs) present within the sampling environment which represent the background signal. This study aimed to characterise the background signal generated from a headspace sampling system in a clinical site, to evaluate intra- and inter-day variation of background VOC and to understand the impact of a sample itself upon commonly reported background VOC using sputum headspace samples from severe asthmatics. The headspace, in absence of a biological sample, was collected hourly from 11am to 3pm within a day (time of clinical samples acquisition), and from Monday to Friday in a week, and analysed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Chemometric analysis identified 1120 features, 37 of which were present in at least the 80% of all the samples. The analyses of intra- and inter-day background variations were performed on 13 of the most abundant features, ubiquitously present in headspace samples. The concentration ratios relative to background were reported for the selected abundant VOC in 36 asthmatic sputum samples, acquired from 36 stable severe asthma patients recruited at Glenfield Hospital, Leicester, UK. The results identified no significant intra- or inter-day variations in compounds levels and no systematic bias ofz-scores, with the exclusion of benzothiazole, whose abundance increased linearly between 11am and 3pm with a maximal intra-day fold change of 2.13. Many of the identified background features are reported in literature as components of headspace of biological samples and are considered potential biomarkers for several diseases. The selected background features were identified in headspace of all severe asthma sputum samples, albeit with varying levels of enrichment relative to background. Our observations support the need to consider the background signal derived from the headspace sampling system when developing and validating headspace biomarker signatures using clinical samples.


Asunto(s)
Asma , Compuestos Orgánicos Volátiles , Asma/diagnóstico , Pruebas Respiratorias , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Esputo/química , Compuestos Orgánicos Volátiles/análisis
20.
J Allergy Clin Immunol Pract ; 8(10): 3418-3427, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32531482

RESUMEN

BACKGROUND: Currently, the acceptability and efficacy of pulmonary rehabilitation for adults with severe asthma is unknown. OBJECTIVE: To investigate the feasibility of performing a randomized controlled trial of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC). METHODS: Adults with severe asthma were recruited and randomized 2:1 to AT-PR and UC. The primary outcomes were recruitment, retention, and serious adverse event rates. Secondary outcome measures included those for a future trial assessing the feasibility of collecting data. Assessments were performed at baseline, 12 weeks, and 9 months including measures of physical performance, health-related quality of life, and asthma control. A recruitment rate of 30% was estimated with 95% CI of ±7%, a retention rate of 75% ± 14% if we recruited 40 patients to AT-PR, and a serious adverse event rate of 2.5%. RESULTS: Sixty-one (26%) of 238 eligible patients were recruited (38 women; mean age, 54 ± 13 years; body mass index, 32 ± 7 kg/m2; FEV1, 1.9 ± 0.7 L; FEV1/forced vital capacity, 69% ± 11%). Fifty-one patients were randomized to AT-PR (n = 34) and UC (n = 17). The retention rate was 62% for the AT-PR group and 53% for the UC group, with a serious adverse event rate of 3.3% related to the study visits. Overall collection of the outcome measures was feasible. The results of the AT-PR group were suggestive of improvements in exercise performance, health-related quality of life, and asthma control, but the UC group results were either unchanged or worsened. CONCLUSIONS: Both recruitment and retention rates were within the a priori estimated 95% CI. Our results indicate that AT-PR may be efficacious for adults with severe asthma but any future intervention and trial design would need further modifications to improve acceptability and retention rate.


Asunto(s)
Asma , Calidad de Vida , Adulto , Anciano , Asma/epidemiología , Ejercicio Físico , Estudios de Factibilidad , Femenino , Humanos , Persona de Mediana Edad , Capacidad Vital
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