RESUMEN
Summary: Background.Diagnosis of anisakis allergy (AA) is based on the skin prick test (SPT) and specific IgE (sIgE) determination. Anyway, false positivity cases are due to cross reactivity with numerous allergens. The aim of the study was to evaluate the reliability of a comprehensive diagnostic algorithm for the AA. Methods.An observational study was conducted on a sample of consecutive subjects accessing the allergology outpatient ambulatories of two hospitals located in Western Sicily. All the recruited outpatients were tested by Skin Prick Test performed using anisakis extracts by ALK-Abellò (Madrid, Spain). Specific IgE dosage for anisakis extracts was then performed by using ImmunoCAP250 (Immunodiagnostics Uppsala, Sweden). Consequently, outpatients who tested positive to first line tests underwent sIgE testing for ascaris and tropomyosin. Lastly, outpatients positive to the first line were invited to be further tested by basophil activation test (BAT) by using Flow CAST kit and anisakis commercial extract (Bühlmann Laboratories AG, Schönenbuch, Switzerland), as confirmatory analysis. Results.One hundred and eleven outpatients with an anamnesis suggestive of sensitization to anisakis (AS) and 466 subjects with chronic urticaria (CU) were recruited in the study. Of these, 22 with AS and 41 with CU showed a sensitization to anisakis allergens. The diagnostic algorithm revealed that 8.8% of outpatients who tested positive to sIgE determination were affected by CU, while 82.5% of all the sIgE positivity was related to cross-reactivity. Overall, a genuine anisakis seroprevalence of 2.3% was documented. Within a sub-sample of 15 subjects with clinical symptoms related to AA, n. 8 showed a real positivity after BAT. A greater response to A. pegreffii allergens as compared to A. simplex was reported. Conclusions.Our preliminary findings support the high clinical specificity of BAT for AA diagnosis, suggesting implementing this method in a comprehensive diagnostic algorithm.
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Anisakiasis/diagnóstico , Anisakis/fisiología , Urticaria Crónica/diagnóstico , Hipersensibilidad/diagnóstico , Adolescente , Adulto , Algoritmos , Alérgenos/inmunología , Animales , Anisakiasis/epidemiología , Antígenos Helmínticos/inmunología , Prueba de Desgranulación de los Basófilos , Urticaria Crónica/inmunología , Femenino , Humanos , Hipersensibilidad/epidemiología , Inmunoglobulina E/sangre , Italia/epidemiología , Masculino , Región Mediterránea , Persona de Mediana Edad , Estudios Seroepidemiológicos , Pruebas Cutáneas , Adulto JovenRESUMEN
Inflammation and cellular senescence (also called inflammaging) are involved in the pathogenesis of premature lung aging, a key driver of chronic obstructive pulmonary disease (COPD). Downregulation of histone deacetylases and FoxO3 expression, activation of the ERK 1/2 pathway and IL-8 increase are hallmarks of lung inflammaging. The effects of Budesonide (BUD), Aclidinium (ACL) and Formoterol (FO) on lung inflammaging are unknown. This study was aimed to assess the effects of BUD, ACL and FO in bronchial epithelial cells exposed to cigarette smoke extract (CSE) by evaluating: a) Expression of TLR4 and survivin and LPS binding by flow cytometry; b) expression of HDAC2, HDAC3, SIRT1 and FoxO3 and activation of the ERK 1/2 pathway by western blot; c) IL-8 mRNA levels and release by Real Time-PCR and ELISA, respectively. Reported results show that CSE increased TLR4 and survivin, LPS binding, ERK 1/2 activation, IL-8 release and mRNA levels but decreased SIRT1, HDAC2, HDAC3 and FoxO3 nuclear expression. Combined therapy with BUD, ACL and FO counteracted the effects of CSE on LPS binding, FoxO3 nuclear expression, ERK 1/2 activation, survivin and IL-8 release and mRNA levels. These findings suggest a new role of combination therapy with BUD, ACL and FO in counteracting inflammaging processes induced by cigarette smoke exposure.
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Bronquios/efectos de los fármacos , Budesonida/administración & dosificación , Senescencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Fumarato de Formoterol/administración & dosificación , Inflamación/prevención & control , Nicotiana/efectos adversos , Humo/efectos adversos , Tropanos/administración & dosificación , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Proteína Forkhead Box O3/metabolismo , Humanos , Lipopolisacáridos/metabolismo , Sirtuina 1/análisis , Receptor Toll-Like 4/análisisRESUMEN
BACKGROUND: Alterations in the nasal epithelial barrier homeostasis and increased interleukin 33 (IL-33) expression contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). AIMS: As Notch-1 signaling is crucial in repair processes of mucosa, the current study assessed Notch-1/Jagged-1 signaling and IL-33 in the epithelium of nasal polyps biopsies from allergic (A-CRSwNP; n = 9) and not allergic (NA-CRSwNP; n = 9) subjects by immunohistochemistry. We also assessed, in a model of nasal epithelial cells, the effects of stimulation of Notch-1 with Jagged-1 on the expression of IL-33 (by flow cytometry, immunofluorescence, and immunocytochemistry), Jagged-1 (by flow cytometry), and p-CREB transcription factor (by western blot analysis). RESULTS: Ex vivo (a) in normal epithelium, the expression of Notch-1 and IL-33 were higher in NA-CRSwNP than in A-CRSwNP; (b) in metaplastic epithelium, the expression of Notch-1, Jagged-1, and IL-33 were higher in NA-CRSwNP than in A-CRSwNP; (c) in hyperplastic epithelium, the expression of Notch-1, Jagged-1, and IL-33 were higher in A-CRSwNP than in NA-CRSwNP; and (d) in basal epithelial cells, no differences were observed in the expression of Jagged-1, IL-33, and Notch-1. The expression of Notch-1 significantly correlated with the expression of IL-33. In vitro, stimulation of Notch-1 with Jagged-1 induced the expression of (a) Jagged-1; (b) IL-33; and (c) p-CREB transcription factor. The inhibitor of Notch-1, DAPT, reduced all the effects of Jagged-1 on nasal epithelial cells. CONCLUSIONS: The data herein provided support, for the first time, a putative role of Notch-1/Jagged-1 signaling in the overexpression of IL-33 in the epithelium of nasal polyps from patients with CRSwNP.
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Células Epiteliales/metabolismo , Interleucina-33/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasales/metabolismo , Receptor Notch1/metabolismo , Rinitis Alérgica/metabolismo , Sinusitis/metabolismo , Adulto , Línea Celular , Enfermedad Crónica , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Humanos , Proteína Jagged-1/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Nasal/inmunología , Mucosa Nasal/patología , Pólipos Nasales/inmunología , Pólipos Nasales/patología , Fosforilación , Rinitis Alérgica/inmunología , Rinitis Alérgica/patología , Transducción de Señal , Sinusitis/inmunología , Sinusitis/patología , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Cigarette smoke, the principal risk factor for chronic obstructive pulmonary disease (COPD), negatively influences the effectiveness of the immune system's response to a pathogen. The antibiotic ceftaroline exerts immune-modulatory effects in bronchial epithelial cells exposed to cigarette smoke. AIMS AND METHODS: The present study aims to assess the effects of ceftaroline on TLR2 and TLR4 expression, LPS binding and TNF-α and human beta defensin (HBD2) release in an undifferentiated and PMA-differentiated human monocyte cell line (THP-1) exposed or not to cigarette smoke extracts (CSE). TLR2, TLR4, and LPS binding were assessed by flow cytometry, TNF-α and HBD2 release were evaluated by ELISA. RESULTS: The constitutive expression of TLR2 and TLR4 and LPS binding were higher in differentiated compared to undifferentiated THP-1 cells. In undifferentiated THP-1 cells, CSE increased TLR2 and TLR4 protein levels, LPS binding and TNF-α release and reduced HBD2 release and ceftaroline counteracted all these effects. In differentiated THP-1, CSE did not significantly affect TLR2 and TLR4 expression and LPS binding but reduced HBD2 release and increased TNF-α release. Ceftaroline counteracted the effects of CSE on HBD2 release in differentiated THP-1. CONCLUSION: Ceftaroline counteracts the effect of CSE in immune cells by increasing the effectiveness of the innate immune system. This effect may also assist in reducing pathogen activity and recurrent exacerbations in COPD patients.
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Antibacterianos/farmacología , Cefalosporinas/farmacología , Inmunidad Innata/efectos de los fármacos , Inmunocompetencia , Factores Inmunológicos/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Humo/efectos adversos , Fumar/efectos adversos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Huésped-Patógeno , Humanos , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Fumar/inmunología , Receptor Toll-Like 2/efectos de los fármacos , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , beta-Defensinas/inmunología , beta-Defensinas/metabolismo , CeftarolinaRESUMEN
BACKGROUND: The addition of long-acting beta2-agonists (LABAs) to corticosteroids improves asthma control. Cigarette smoke exposure, increasing oxidative stress, may negatively affect corticosteroid responses. The anti-inflammatory effects of formoterol (FO) and fluticasone propionate (FP) in human bronchial epithelial cells exposed to cigarette smoke extracts (CSE) are unknown. AIMS: This study explored whether FP, alone and in combination with FO, in human bronchial epithelial cellline (16-HBE) and primary bronchial epithelial cells (NHBE), counteracted some CSE-mediated effects and in particular some of the molecular mechanisms of corticosteroid resistance. METHODS: 16-HBE and NHBE were stimulated with CSE, FP and FO alone or combined. HDAC3 and HDAC2 activity, nuclear translocation of GR and NF-κB, pERK1/2/tERK1/2 ratio, IL-8, TNF-α, IL-1ß mRNA expression, and mitochondrial ROS were evaluated. Actin reorganization in neutrophils was assessed by fluorescence microscopy using the phalloidin method. RESULTS: In 16-HBE, CSE decreased expression/activity of HDAC3, activity of HDAC2, nuclear translocation of GR and increased nuclear NF-κB expression, pERK 1/2/tERK1/2 ratio, and mRNA expression of inflammatory cytokines. In NHBE, CSE increased mRNA expression of inflammatory cytokines and supernatants from CSE exposed NHBE increased actin reorganization in neutrophils. FP combined with FO reverted all these phenomena in CSE stimulated 16-HBE cells as well as in NHBE cells. CONCLUSIONS: The present study provides compelling evidences that FP combined with FO may contribute to revert some processes related to steroid resistance induced by oxidative stress due to cigarette smoke exposure increasing the anti-inflammatory effects of FP.
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Antiinflamatorios/farmacología , Bronquios/metabolismo , Fumar Cigarrillos/efectos adversos , Células Epiteliales/metabolismo , Fluticasona/farmacología , Fumarato de Formoterol/farmacología , Histonas/metabolismo , Acetilación/efectos de los fármacos , Bronquios/patología , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
The tobacco smoking habit interferes with the innate host defence system against infections. Recurrent infections accelerated the functional respiratory decline. The present study assessed the effects of ceftaroline on TLR2 and TLR4 and on pro-inflammatory responses in airway epithelial cells (16HBE cell line and primary bronchial epithelial cells) with or without cigarette smoke extracts (CSE 10%). TLR2, TLR4, LPS binding and human beta defensin 2 (HBD2) were assessed by flow cytometry, NFkB nuclear translocation by western blot analysis, IL-8 and HBD2 mRNA by Real Time PCR; the localization of NFkB on the HBD2 and IL-8 promoters by ChiP Assay. CSE increased TLR4, TLR2 expression, LPS binding and IL-8 mRNA; CSE decreased HBD2 (protein and mRNA), activated NFkB and promoted the localization of NFkB on IL-8 promoter and not on HBD2 promoter. Ceftaroline counteracted the CSE effect on TLR2 expression, on LPS binding, on IL-8 mRNA, HBD2 and NFkB in 16HBE. The effects of ceftaroline on HBD2 protein and on IL-8 mRNA were confirmed in primary bronchial epithelial cells. In conclusion, ceftaroline is able to counteract the effects of CSE on the innate immunity and pro-inflammatory responses modulating TLR2, LPS binding, NFkB activation and activity, HBD2 and IL-8 expression in bronchial epithelial cells.
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Antiinflamatorios no Esteroideos/farmacología , Bronquiolitis/prevención & control , Cefalosporinas/farmacología , Inmunidad Innata/efectos de los fármacos , Profármacos/farmacología , Mucosa Respiratoria/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Transporte Activo de Núcleo Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Bronquiolos/efectos de los fármacos , Bronquiolos/inmunología , Bronquiolos/metabolismo , Bronquiolos/patología , Bronquiolitis/etiología , Bronquiolitis/inmunología , Bronquiolitis/metabolismo , Línea Celular , Línea Celular Transformada , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Lipopolisacáridos/metabolismo , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , beta-Defensinas/genética , beta-Defensinas/metabolismo , CeftarolinaRESUMEN
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.
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Antiinflamatorios no Esteroideos/efectos adversos , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad Respiratoria/epidemiología , Hipersensibilidad Respiratoria/etiología , Adolescente , Adulto , Anciano , Comorbilidad , Estudios Transversales , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Vigilancia de la Población , Prevalencia , Hipersensibilidad Respiratoria/diagnóstico , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Cigarette smoke may accelerate cellular senescence by increasing oxidative stress. Altered proliferation and altered expression of anti-aging factors, including SIRT1 and FoxO3, characterise cellular senescence. The effects of carbocysteine on the SIRT1/FoxO3 axis and on downstream molecular mechanisms in human bronchial epithelial cells exposed to cigarette smoke are largely unknown. AIMS: Aim of this study was to explore whether carbocysteine modulated SIRT1/FoxO3 axis, and downstream molecular mechanisms associated to cellular senescence, in a bronchial epithelial cell line (16-HBE) exposed to cigarette smoke. METHODS: 16HBE cells were stimulated with/without cigarette smoke extracts (CSE) and carbocysteine. Flow cytometry and clonogenic assay were used to assess cell proliferation; western blot analysis was used for assessing nuclear expression of SIRT1 and FoxO3. The nuclear co-localization of SIRT1 and FoxO3 was assessed by fluorescence microscopy. Beta galactosidase (a senescence marker) and SIRT1 activity were assessed by specific staining and colorimetric assays, respectively. ChiP Assay and flow cytometry were used for assessing survivin gene regulation and protein expression, respectively. RESULTS: CSE decreased cell proliferation, the nuclear expression of SIRT1 and FoxO3 and increased beta galactosidase staining. CSE, reduced SIRT1 activity and FoxO3 localization on survivin promoter thus increasing survivin expression. In CSE stimulated bronchial epithelial cells carbocysteine reverted these phenomena by increasing cell proliferation, and SIRT1 and FoxO3 nuclear expression, and by reducing beta galactosidase staining and survivin expression. CONCLUSIONS: The study shows for the first time that carbocysteine may revert some senescence processes induced by oxidative stress due to cigarette smoke exposure.
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Carbocisteína/farmacología , Proteína Forkhead Box O3/metabolismo , Nicotiana/efectos adversos , Sirtuina 1/metabolismo , Humo/efectos adversos , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Proteína Forkhead Box O3/efectos de los fármacos , Humanos , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/efectos de los fármacosRESUMEN
BACKGROUND: Lung fibroblasts are crucial for the integrity of alveolar structure. Cigarette smoking, the major risk factor for chronic obstructive pulmonary disease, impairs the repair functions of lung fibroblasts. AIMS: The study simultaneously assessed for the first time cell cycle, p53, p21, p38, ERK 1/2 and IL-8. MAIN METHODS: Primary foetal lung fibroblasts (HFL-1) and primary lung fibroblasts from former (n = 5) and current (n = 5) smokers with/without cigarette smoke extracts (CSEs) and inhibitors of p38 and ERK1/2 were studied for cell cycle events and for marker expression by flow-cytometry, western-blot analysis and ELISA. KEY FINDINGS: CSE exposure did not induce caspase 3 cleavage or DNA laddering but reduced S phase, and increased G1 and G2/M in HFL-1. Furthermore CSE increased: p53 and p21 expression; p38 and ERK 1/2 pathway activation; and IL-8 release. Inhibitors of p38 and ERK 1/2 reversed the effects of CSE on cell cycle and on IL-8 release. ERK 1/2 inhibitor was able to reverse the effects of CSE on p21 expression. Primary lung fibroblasts from current smokers had higher ERK 1/2 activation in comparison to normal primary fibroblasts and higher percentage of cells in G1 phase and lower percentage of cells in S phase in comparison to former smoker fibroblasts. SIGNIFICANCE: Cigarette smoke may affect the reparative potential of lung fibroblasts altering the expression of p53 and p21 and the progression of the cell cycle to S phase. All these events are promoted by the activation of pro-inflammatory pathways.
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Ciclo Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Humo/efectos adversos , Fumar/metabolismo , Caspasa 3/metabolismo , Células Cultivadas , Fragmentación del ADN/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Interleucina-8/metabolismo , Pulmón , Fumar/patología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.
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Algoritmos , Asma/clasificación , Biomarcadores/análisis , Administración por Inhalación , Adolescente , Adulto , Anciano , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Estudios de Cohortes , Método Doble Ciego , Eosinófilos/inmunología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Fenotipo , Pruebas de Función Respiratoria , Esputo/inmunología , Adulto JovenRESUMEN
RATIONALE: There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. METHODS: In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. RESULTS: A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. CONCLUSIONS: People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.
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Obstrucción de las Vías Aéreas/epidemiología , Asma/complicaciones , Rinitis/complicaciones , Sinusitis/complicaciones , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Casos y Controles , Enfermedad Crónica , Estudios Transversales , Recolección de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
BACKGROUND: Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures. OBJECTIVE: We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects. METHODS: Within the Global Allergy and Asthma European Network (GA(2) LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18-75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index (BMI). RESULTS: Skin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders. CONCLUSION: Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses.
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Contaminantes Atmosféricos/efectos adversos , Alérgenos/inmunología , Hipersensibilidad/epidemiología , Hipersensibilidad/inmunología , Adolescente , Adulto , Anciano , Alérgenos/clasificación , Animales , Femenino , Salud Global/estadística & datos numéricos , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Prevalencia , Vigilancia en Salud Pública , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. OBJECTIVE: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. METHODS: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. RESULTS: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 µg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). CONCLUSION AND CLINICAL RELEVANCE: We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.
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Asma , Eosinófilos , Glucocorticoides/administración & dosificación , Índice de Severidad de la Enfermedad , Esputo/metabolismo , Administración por Inhalación , Administración Oral , Adolescente , Adulto , Anciano , Asma/tratamiento farmacológico , Asma/metabolismo , Asma/patología , Asma/fisiopatología , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Monitoreo FisiológicoRESUMEN
BACKGROUND: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. OBJECTIVE: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. METHODS: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. RESULTS: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. CONCLUSION: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.
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Alérgenos/inmunología , Pruebas Cutáneas/normas , Adolescente , Adulto , Alérgenos/administración & dosificación , Animales , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/inmunología , Masculino , Persona de Mediana Edad , Pruebas Cutáneas/métodos , Adulto JovenRESUMEN
TGF-beta-targeting structural and inflammatory cells has been implicated in the mechanisms leading to the inflammatory and restructuring processes in asthma, suggesting an impact of TGF-beta1 signaling on the development and persistency of this disease. We investigated the potential early involvement of TGF-beta1 activity in the immunological and molecular mechanisms underlying progression of inflammation in childhood asthma. We evaluated the levels of TGF-beta1 in induced sputum supernatants (ISSs) and the expression of small mother cell against decapentaplegic (Smad) 2 and Smad7 proteins in induced sputum cells (ISCs) from children with intermittent asthma (IA), moderate asthma (MA) and control subjects (C). Furthermore, we investigated the regulatory role of TGF-beta1 activity on eosinophil and neutrophil adhesion to epithelial cells using adhesion assay, and on the granulocyte expression of adhesion molecule CD11b/CD18 Macrophage-1 antigen (MAC-1), by flow cytometry. We found that the levels of TGF-beta1 are increased in ISSs of IA and MA in comparison to C, concomitantly to the activation of intracellular signaling TGFbeta/Smads pathway in ISCs. In MA, TGF-beta1 levels correlated with the number of sputum eosinophils and neutrophils. Furthermore, we showed the ability of sputum TGF-beta1 to promote eosinophil and neutrophil adhesion to epithelial cells, and to increase the expression of MAC-1 on the granulocyte surface. This study shows the activation of TGFbeta/Smad signaling pathway in the airways of children with IA and, despite the regular ICS treatment, in children with MA, and provides evidence for the contribution of TGF-beta1 in the regulation of granulocyte activation and trafficking.
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Asma/metabolismo , Pulmón/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Administración por Inhalación , Adolescente , Corticoesteroides/administración & dosificación , Factores de Edad , Asma/diagnóstico , Asma/tratamiento farmacológico , Asma/inmunología , Asma/fisiopatología , Broncodilatadores/administración & dosificación , Estudios de Casos y Controles , Adhesión Celular , Línea Celular , Niño , Eosinófilos/inmunología , Eosinófilos/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino , Granulocitos/inmunología , Granulocitos/metabolismo , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/fisiopatología , Antígeno de Macrófago-1/metabolismo , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fosforilación , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Proteína smad7/metabolismo , Esputo/metabolismoRESUMEN
BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammation of the nose and of the paranasal sinuses. The involvement of the respiratory epithelium in the mechanisms of CRS is poorly understood. AIMS: Among proteins expressed by nasal epithelial cells in CRS, IL-19 may have key functions. We here aimed to determine the expression and regulation of IL-19. METHODS: Nasal biopsies from normal subjects (n = 12), subjects with CRS but without nasal polyps (NP) (CRSsNP, n = 12) and with CRS with NP (CRSwNP, n = 15) were collected. Human Asthma Gene Array and real-time PCR were used to evaluate gene expression, western blot analysis and immunohistochemistry for protein expression. Results for IL-19 were confirmed by real-time PCR. The constitutive and stimulated (LPS, TGF ß) expression of IL-19 and cell proliferation were evaluated in a nasal epithelial cell line (RPMI 2650). RESULTS: Human Asthma Gene Array showed an increased IL-19 gene expression in NP from patients with CRS in comparison with normal subjects. Real-time PCR confirmed the IL-19 mRNA up-regulation in patients with CRSwNP and showed an up-regulation of IL-19, at lower extent, in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) in comparison with normal subjects. Western blot analysis confirmed that IL-19 is increased also at protein level in patients with CRSwNP in comparison with normal subjects. In NP, IL-19 is highly expressed in the metaplastic nasal epithelium when compared to normal or hyperplastic epithelium. LPS stimulation increased IL-19 expression, and recombinant IL-19 increased cell proliferation in nasal epithelial cells. CONCLUSIONS: IL-19 is overexpressed in the epithelium in CRSwNP and increases epithelial cell proliferation.
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Interleucinas/metabolismo , Mucosa Nasal/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Adolescente , Adulto , Enfermedad Crónica , Células Epiteliales/metabolismo , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Interleucinas/genética , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Nasal/metabolismo , Pólipos Nasales/genética , ARN Mensajero/metabolismo , Rinitis/genética , Sinusitis/genética , Adulto JovenRESUMEN
BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.
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Asma/complicaciones , Asma/epidemiología , Rinitis/complicaciones , Rinitis/epidemiología , Sinusitis/complicaciones , Sinusitis/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Recolección de Datos , Europa (Continente)/epidemiología , Femenino , Humanos , Hipersensibilidad/complicaciones , Masculino , Persona de Mediana Edad , Pólipos Nasales/complicaciones , Prevalencia , Adulto JovenRESUMEN
A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.
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Asma/microbiología , Infecciones Bacterianas/complicaciones , Infecciones del Sistema Respiratorio/complicaciones , Virosis/complicaciones , Enfermedad Aguda , Asma/complicaciones , Asma/epidemiología , Infecciones Bacterianas/epidemiología , Humanos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/microbiología , Virosis/epidemiologíaRESUMEN
BACKGROUND: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic, endoscopic, and radiologic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and validity of a symptom-based definition of CRS using data from the GA(2) LEN European survey. METHODS: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, allergic rhinitis, and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in prevalence of CRS between two study points, the standardized absolute repeatability, and the chance-corrected repeatability (kappa) were determined. In two centers, 342 participants underwent nasal endoscopy. The association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. RESULTS: There was a decrease in prevalence of CRS between the two study phases, and this was consistent across all centers (-3.0%, 95% CI: -5.0 to -1.0%, I(2) = 0). There was fair to moderate agreement between the two occasions (kappa = 39.6). Symptom-based CRS was significantly associated with positive endoscopy in nonallergic subjects, and with self-reported doctor-diagnosed CRS in all subjects, irrespective of the presence of allergic rhinitis. CONCLUSION: Our findings suggest that a symptom-based definition of CRS, according to the epidemiological part of the EP3OS criteria, has a moderate reliability over time, is stable between study centers, is not influenced by the presence of allergic rhinitis, and is suitable for the assessment of geographic variation in prevalence of CRS.