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1.
Eur Respir J ; 63(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38423624

RESUMO

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.


Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergilose Pulmonar Invasiva , Adulto , Criança , Humanos , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Imunoglobulina E , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Itraconazol/uso terapêutico , Micologia , Prednisolona
2.
Alcohol Clin Exp Res (Hoboken) ; 48(4): 596-611, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38339830

RESUMO

BACKGROUND: Chronic alcohol consumption/misuse is a significant risk factor for pneumonia and lung infection leading to the development of chronic pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and lung fibrosis. In this study, we sought to delineate the mechanism of alcohol-associated lung disease. We did so by measuring in vitro mitochondrial, endoplasmic reticulum (ER) oxidative stress in human bronchial epithelial cells (hBECs) treated with ethanol and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters or FAEEs) metabolites. METHODS: Primary hBECs from a normal subject were treated with relevant concentrations of ethanol and its metabolites and incubated at 37°C for 24 h. Viability and cytotoxicity were determined using cell viability and lactate dehydrogenase (LDH) assay kits, respectively. Oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured by colorimetric reaction, and 4-hydroxynenonal (4HNE) by immunohistochemistry. Endoplasmic reticulum stress and dysregulated cellular bioenergetics were determined by western blot analysis. Mitochondrial stress and real-time ATP production rates were determined using a Seahorse Extracellular Flux analyzer. Amelioration of ethanol-induced oxidative/ER stress and mitochondrial energetics was determined using an AMPKα agonist. RESULTS: Human bronchial epithelial cells treated with ethanol, acetaldehyde, and FAEEs showed a concentration-dependent increase in the secretion of LDH, oxidative/ER stress, deactivation of AMPKα phosphorylation and mitochondrial stress (decreased spare respiratory capacity) with concomitant decreases in mitochondrial and glycolytic ATP production rates. FAEEs caused greater cytotoxicity, ER stress, and dysregulated cellular bioenergetics than those ethanol and its oxidative metabolite. AMPKα agonist-pretreated cells significantly ameliorated ethanol-induced oxidative/ER stress, deactivation of AMPKα, and dysregulated cellular bioenergetics. CONCLUSIONS: Findings of this study suggest that ethanol and its metabolites contribute to cytotoxicity, oxidative/ER stress, and dysregulation of cellular bioenergetics in hBECs. The attenuation of ethanol-induced ER/oxidative stress and mitochondrial respiration by an AMPKα agonist may reflect a potential for it to be developed as a therapeutic agent for chronic alcohol-associated lung disease.

3.
J Allergy Clin Immunol Pract ; 11(3): 896-905, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36581073

RESUMO

BACKGROUND: An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking. OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA. METHODS: We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease. RESULTS: In total, 49 studies (n = 267) were included in the qualitative synthesis and 14 case series (n = 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference, -2.09 [95% CI, -3.07 to -1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference, -14.62 [95% CI, -19.86 to -9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV1 % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated. CONCLUSIONS: Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.


Assuntos
Aspergilose Broncopulmonar Alérgica , Asma , Fibrose Cística , Humanos , Omalizumab/uso terapêutico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Fibrose Cística/tratamento farmacológico , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico
4.
Allergy Asthma Clin Immunol ; 18(1): 42, 2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35598022

RESUMO

Globally, a small proportion (5-12%) of asthma patients are estimated to have severe disease. However, severe asthma accounts for disproportionately high healthcare resource utilization. The Global Initiative for Asthma (GINA) management committee recommends treating patients with asthma with inhaled corticosteroids plus long-acting ß2-agonists and, when needed, adding a long-acting muscarinic receptor antagonist or biologic agent. Five biologics, targeting different effectors in the type 2 inflammatory pathway, are approved for asthma treatment. However, biologics have not been compared against each other or add-on inhaled therapies in head-to-head clinical trials. As a result, their positioning versus that of current and anticipated small-molecule strategies is largely unknown. Furthermore, with the emergence of biomarkers for predicting response to biologics, a more personalized treatment approach-currently lacking with inhaled therapies-may be possible. To gain perspective, we reviewed recent advances in asthma pathophysiology, phenotypes, and biomarkers; the place of biologics in the management and personalized treatment of severe asthma; and the future of biologics and small-molecule drugs. We propose an algorithm for the stepwise treatment of severe asthma based on recommendations in the GINA strategy document that accounts for the broad range of phenotypes targeted by inhaled therapies and the specificity of biologics. In the future, both biologics and small molecules will continue to play key roles in the individualized treatment of severe asthma. However, as targeted therapies, their application will continue to be focused on patients with certain phenotypes who meet the specific criteria for use as identified in pivotal clinical trials.

5.
Nanomedicine ; 40: 102476, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34743019

RESUMO

We report the design and adaptation of iron/iron oxide nanoparticle-based optical nanobiosensors for enzymes or cytokine/chemokines that are established biomarkers of lung diseases. These biomarkers comprise ADAM33, granzyme B, MMP-8, neutrophil elastase, arginase, chemokine (C-C motif) ligand 20 and interleukin-6. The synthesis of nanobiosensors for these seven biomarkers, their calibration with commercially available enzymes and cytokines/chemokines, as well as their validation using bronchoalveolar lavage (BAL) obtained from a mouse model of TLR3-mediated inflammation are discussed here. Exhaled Breath Condensate (EBC) is a minimally invasive approach for sampling airway fluid in the diagnosis and management of various lung diseases in humans (e.g., asthma, COPD and viral infections). We report the proof-of-concept of using human EBC in conjunction with nanobiosensors for diagnosis/monitoring airway inflammation. These findings suggest that, with nanosensor technology, human EBC can be utilized as a liquid biopsy to monitor inflammation/remodeling in lung disease.


Assuntos
Asma , Pneumopatias , Animais , Biomarcadores , Testes Respiratórios , Inflamação/diagnóstico , Camundongos
6.
Ann Am Thorac Soc ; 18(12): 1978-1987, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33891831

RESUMO

Rationale: Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma. Objectives: Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical interpretation. Methods:Post hoc analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined 1) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data (n = 2,612); 2) monthly variation using placebo-treated patient data (n = 713); 3) stability of eosinophil classification (<150, 150-299, and ⩾300 cells/µl) in placebo-treated patients with monthly measurements over a 1-year period (n = 751); and 4) impact of technical factors (laboratory-to-laboratory differences and time from collection to analysis). Results: Of intrinsic/extrinsic factors examined, nasal polyps increased eosinophil levels by 38%, whereas current smoking decreased levels by 23%. Substantial seasonal differences in eosinophil counts were observed, with differences of ∼20% between July and January. Eosinophil levels between 150 and 299 cells/µl were least stable, with 44% of patients remaining in the same classification for seven of 10 measurements versus 59% and 66% of patients in the <150 and ⩾300 cells/µl subgroups, respectively. Measurements at different laboratories showed high association (Spearman's correlation coefficient, R = 0.89); however, eosinophil counts were reduced, with longer time from collection to analysis, and variability increased with increasing eosinophil counts. Conclusions: Several intrinsic, extrinsic, and technical factors may influence, and should be considered in, clinical interpretation of eosinophil counts. Additionally, a single measurement may not be sufficient when using eosinophil counts for diagnosis/management of eosinophilic asthma.


Assuntos
Antiasmáticos , Asma , Eosinofilia Pulmonar , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Eosinófilos , Humanos , Contagem de Leucócitos , Eosinofilia Pulmonar/tratamento farmacológico
10.
Proc Natl Acad Sci U S A ; 117(4): 2187-2193, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932420

RESUMO

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3ß-hydroxysteroid dehydrogenase-1 (3ß-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3ß-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.


Assuntos
Asma/tratamento farmacológico , Asma/enzimologia , Glucocorticoides/administração & dosagem , Complexos Multienzimáticos/genética , Progesterona Redutase/genética , Esteroide Isomerases/genética , Adulto , Idoso , Alelos , Androgênios/metabolismo , Asma/genética , Asma/metabolismo , Estudos de Coortes , Resistência a Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/metabolismo , Progesterona Redutase/metabolismo , Esteroide Isomerases/metabolismo , Adulto Jovem
13.
J Proteomics ; 205: 103415, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195152

RESUMO

Small molecule inhibitors of the epigenetic regulator bromodomain-containing protein 4 (BRD4) are potential therapeutics for viral and allergen-induced airway remodeling. A limitation of their preclinical advancement is the lack of detailed understanding of mechanisms of action and biomarkers of effect. We report a systems-level pharmacoproteomics in a standardized murine model of toll-like receptor TLR3-NFκB/RelA innate inflammation in the absence or presence of a highly selective BRD4 inhibitor (ZL0454) or nonselective bromodomain and extraterminal domain inhibitor (JQ1). Proteomics of bronchoalveolar lavage fluid (BALF) secretome and exosomal proteins from this murine model revealed increased, selective, capillary leak associated with pericyte-myofibroblast transition, a phenomenon blocked by BRD4 inhibitors. BALF proteomics also suggested that ZL0454 better reduced the vascular leakage and extracellular matrix deposition than JQ1. A significant subset of inflammation-mediated remodeling factors was also identified in a mouse model of idiopathic pulmonary fibrosis produced by bleomycin. BALF exosome analysis indicated that BRD4 inhibitors reduced the induction of exosomes enriched in coagulation factors whose presence correlated with interstitial fibrin deposition. Finally, BALF samples from humans with severe asthma demonstrated similar upregulations of ORM2, APCS, SPARCL1, FGA, and FN1, suggesting their potential as biomarkers for early detection of airway remodeling and/or monitoring of therapy response. SIGNIFICANCE: Repetitive and chronic viral upper respiratory tract infections trigger toll-like receptor (TLR)3-NFκB/RelA mediated airway remodeling which is linked to a progressive decline in pulmonary function in patients with asthma and chronic obstructive pulmonary disease. Small molecule inhibitors of the epigenetic regulator bromodomain-containing protein 4 (BRD4) are potential therapeutics for viral and allergen-induced airway remodeling. A limitation of their preclinical advancement is the lack of detailed understanding of mechanisms of action and biomarkers of effect. Our study revealed that the activation of (TLR)3-NFκB/RelA pathway in the lung induced an elevation in coagulation, complement, and platelet factors, indicating the increased vascular leak during airway remodeling. The mechanism of vascular leakage was chronic inflammation-induced pericyte-myofibroblast transition, which was blocked by BRD4 inhibitors. Finally, proteomics analysis of the bronchoalveolar lavage fluid samples from humans with severe asthma demonstrated similar findings that we observed in the animal model.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Biomarcadores Farmacológicos/análise , Vasos Sanguíneos/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Citoproteção/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Animais , Asma/metabolismo , Asma/patologia , Azepinas/farmacologia , Biomarcadores Farmacológicos/metabolismo , Bleomicina , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/farmacologia , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Sulfonamidas/farmacologia , Receptor 3 Toll-Like/fisiologia , Triazóis/farmacologia
14.
Alcohol Clin Exp Res ; 43(8): 1682-1694, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31211863

RESUMO

BACKGROUND: Chronic alcohol consumption impairs alveolar macrophage's (AM) function and increases risk for developing lung infection and pneumonia. However, the mechanism and metabolic basis of alcohol-induced AM dysfunction leading to lung infection are not well defined, but may include altered ethanol (EtOH) and reactive oxygen species metabolism and cellular energetics. Therefore, oxidative stress, endoplasmic reticulum (ER) stress, the formation of fatty acid ethyl esters [FAEEs, nonoxidative metabolites of EtOH], AMP-activated protein kinase (AMPK) signaling, and phagocytic function were examined in freshly isolated AM incubated with EtOH. METHODS: AMs separated from bronchoalveolar lavage fluid samples obtained from normal volunteers were incubated with EtOH for 24 hours. AMPK signaling and ER stress were assessed using Western blotting, FAEEs by GC-MS, oxidative stress by immunofluorescence using antibodies to 4-hydroxynonenal, and phagocytosis by latex beads. Oxidative stress was also measured in EtOH-treated AMs with/without AMPK activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)] or inhibitor (Compound C), and in AMs incubated with FAEEs. mRNA expression for interleukins (IL-6 and IL-8), monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-ß was measured in AM treated with EtOH or FAEEs using RT-PCR. RESULTS: EtOH exposure to AM increased oxidative stress, ER stress, and synthesis of FAEEs, decreased phosphorylated AMPK, and impaired phagocytosis. Attenuation or exacerbation of EtOH-induced oxidative stress by AICAR or Compound C, respectively, suggests a link between AMPK signaling, EtOH metabolism, and related oxidative stress. The formation of FAEEs may contribute to EtOH-induced oxidative stress as FAEEs also produced concentration-dependent oxidative stress. An increased mRNA expression of IL-6, IL-8, and MCP-1 by FAEEs is key finding to suggest a metabolic basis of EtOH-induced inflammatory response. CONCLUSIONS: EtOH-induced impaired phagocytosis, oxidative stress, ER stress, and dysregulated AMPK signaling are plausibly associated with the formation of FAEEs and may participate in the pathogenesis of nonspecific pulmonary inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Etanol/efeitos adversos , Etanol/farmacocinética , Macrófagos Alveolares/metabolismo , Fagocitose/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Quimiocina CCL2/biossíntese , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ésteres/metabolismo , Etanol/antagonistas & inibidores , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Humanos , Interleucinas/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ribonucleotídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/biossíntese
15.
J Allergy Clin Immunol ; 143(4): 1380-1394.e9, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30321559

RESUMO

BACKGROUND: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease in pulmonary function, producing morbidity. Cat dander is an aeroallergen associated with asthma risk. OBJECTIVE: We sought to elucidate the mechanism of cat dander-induced inflammation-remodeling. METHODS: We identified remodeling in mucosal samples from allergic asthma by using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)-BRD4 interaction was measured by using a proximity ligation assay in situ. RESULTS: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase-NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB-RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. CONCLUSIONS: NF-κB-inducible BRD4 activity mediates cat dander-induced inflammation and remodeling. Therapeutic modulation of the NF-κB-BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/patologia , Proteínas de Ciclo Celular/metabolismo , Inflamação/imunologia , Mucosa Respiratória/patologia , Fatores de Transcrição/metabolismo , Animais , Asma/imunologia , Asma/metabolismo , Gatos , Alérgenos Animais/imunologia , Transição Epitelial-Mesenquimal/imunologia , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo
16.
J Asthma ; 55(7): 695-704, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28837382

RESUMO

OBJECTIVE: Previous single-center studies have reported that up to 40% of children hospitalized for asthma will be readmitted. The study objectives are to investigate the prevalence and timing of 30-day readmissions in children hospitalized with asthma, and to identify factors associated with 30-day readmissions. METHODS: Data (n = 12,842) for children aged 6-18 years hospitalized for asthma were obtained from the 2013 Nationwide Readmission Database (NRD). The primary study outcome was time to readmission within 30 days after discharge attributable to any cause. Several predictors associated with the risk of admission were included: patient (age, sex, median household income, insurance type, county location, and pediatric chronic complex condition), admission (type, day, emergency services utilization, length of stay (LOS), and discharge disposition), and hospital (ownership, bed size, and teaching status). Cox's proportional hazards model was used to identify predictors. RESULTS: Of 12,842 asthma-related index hospitalizations, 2.5% were readmitted within 30-days post-discharge. Time to event models identified significantly higher risk of readmission among asthmatic children aged 12-18 years, those who resided in micropolitan counties, those with >4-days LOS during index hospitalization, those who were hospitalized in an urban hospital, who had unfavorable discharge (hazard ratio 2.53, 95% confidence interval 1.33-4.79), and those who were diagnosed with a pediatric complex chronic condition, respectively, than children in respective referent categories. CONCLUSION: A multi-dimensional approach including effective asthma discharge action plans and follow-up processes, home-based asthma education, and neighborhood/community-level efforts to address disparities should be integrated into the routine clinical care of asthma children.


Assuntos
Asma/terapia , Readmissão do Paciente/estatística & dados numéricos , Adolescente , Criança , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Renda/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Masculino , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Estados Unidos
17.
JAMA ; 318(3): 279-290, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28719697

RESUMO

Importance: Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, monitoring, and treatment can improve functioning and quality of life in adult patients with asthma. Observations: Asthma is a heterogeneous clinical syndrome primarily affecting the lower respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough. The diagnosis of asthma requires these symptoms and demonstration of reversible airway obstruction using spirometry. Identifying clinically important allergen sensitivities is useful. Inhaled short-acting ß2-agonists provide rapid relief of acute symptoms, but maintenance with daily inhaled corticosteroids is the standard of care for persistent asthma. Combination therapy, including inhaled corticosteroids and long-acting ß2-agonists, is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of inhaled long-acting ß2-agonists alone is not appropriate. Other controller approaches include long-acting muscarinic antagonists (eg, tiotropium), and biological agents directed against proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab). Conclusions and Relevance: Asthma is characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. Management of persistent asthma requires avoidance of aggravating environmental factors, use of short-acting ß2-agonists for rapid relief of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as long-acting bronchodilators and biologics, may be required in moderate and severe asthma. Patients with severe asthma generally benefit from consultation with an asthma specialist for consideration of additional treatment, including injectable biologic agents.


Assuntos
Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Administração por Inalação , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/efeitos adversos , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Obstrução das Vias Respiratórias/fisiopatologia , Antiasmáticos/efeitos adversos , Asma/fisiopatologia , Produtos Biológicos/uso terapêutico , Hiper-Reatividade Brônquica/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Inflamação , Masculino , Antagonistas Muscarínicos/uso terapêutico , Prognóstico
18.
J Proteome Res ; 16(8): 2663-2679, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28679203

RESUMO

Activated eosinophils contribute to airway dysfunction and tissue remodeling in asthma and thus are considered to be important factors in asthma pathology. We report here comparative proteomic and phosphoproteomic changes upon activation of eosinophils using eight cytokines individually and in selected cytokine combinations in time-course reactions. Differential protein and phosphoprotein expressions were determined by mass spectrometry after 2-dimensional gel electrophoresis (2DGE) and by LC-MS/MS. We found that each cytokine-stimulation produced significantly different changes in the eosinophil proteome and phosphoproteome, with phosphoproteomic changes being more pronounced and having an earlier onset. Furthermore, we observed that IL-5, GM-CSF, and IL-3 showed the greatest change in protein expression and phosphorylation, and this expression differed markedly from those of the other five cytokines evaluated. Comprehensive univariate and multivariate statistical analyses were employed to evaluate the comparative results. We also monitored eosinophil activation using flow cytometry (FC) analysis of CD69. In agreement with our proteomic studies, FC indicated that IL-5, GM-CSF, and IL-3 were more effective than the other five cytokines studied in stimulating a cell surface CD69 increase indicative of eosinophil activation. Moreover, selected combinations of cytokines revealed proteomic patterns with many proteins in common with single cytokine expression patterns but also showed a greater effect of the two cytokines employed, indicating a more complex signaling pathway that was reflective of a more typical inflammatory pathology.


Assuntos
Citocinas/farmacologia , Eosinófilos/efeitos dos fármacos , Fosfoproteínas/análise , Proteínas/análise , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Asma/sangue , Células Cultivadas , Citocinas/metabolismo , Eletroforese em Gel Bidimensional , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Interleucina-3/farmacologia , Interleucina-5/farmacologia , Lectinas Tipo C/análise , Masculino , Proteômica/métodos , Espectrometria de Massas em Tandem , Fatores de Tempo
19.
Immunol Allergy Clin North Am ; 37(2): 345-355, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28366481

RESUMO

Chronic obstructive pulmonary disease (COPD) is common worldwide. The predominant cause in most COPD is environmental exposure to toxicants. The inflammatory processes in COPD are multifactorial, complex, and interacting, leading to many potential therapeutic targets. Although most typically associated with neutrophilic/macrophagic inflammation (type 1), it is now known that COPD can also be associated with eosinophilic inflammation (type 2), particularly in exacerbations. Accordingly, there is an active program of investigation of highly selective biologic therapeutic agents in the management of COPD. This review summarizes clinical trials of the use of these novel agents in the management of COPD.


Assuntos
Terapia Biológica , Doença Pulmonar Obstrutiva Crônica/terapia , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Humanos , Terapia de Alvo Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Resultado do Tratamento
20.
J Allergy Clin Immunol ; 140(1): 257-265.e11, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28069248

RESUMO

BACKGROUND: African American subjects have a greater burden from asthma compared with white subjects. Whether the pattern of airway inflammation differs between African American and white subjects is unclear. OBJECTIVE: We sought to compare sputum airway inflammatory phenotypes of African American and white subjects treated or not with inhaled corticosteroids (ICSs; ICS+ and ICS-, respectively). METHODS: We performed a secondary analysis of self-identified African American and white subjects with asthma enrolled in clinical trials conducted by the National Heart, Lung, and Blood Institute-sponsored Asthma Clinical Research Network and AsthmaNet. Demographics, clinical characteristics, and sputum cytology after sputum induction were examined. We used a sputum eosinophil 2% cut point to define subjects with either an eosinophilic (≥2%) or noneosinophilic (<2%) inflammatory phenotype. RESULTS: Among 1018 participants, African American subjects (n = 264) had a lower FEV1 percent predicted (80% vs 85%, P < .01), greater total IgE levels (197 vs 120 IU/mL, P < .01), and a greater proportion with uncontrolled asthma (43% vs 28%, P < .01) compared with white subjects (n = 754). There were 922 subjects in the ICS+ group (248 African American and 674 white subjects) and 298 subjects in the ICS- group (49 African American and 249 white subjects). Eosinophilic airway inflammation was not significantly different between African American and white subjects in either group (percentage with eosinophilic phenotype: ICS+ group: 19% vs 16%, P = .28; ICS- group: 39% vs 35%, P = .65; respectively). However, when adjusted for confounding factors, African American subjects were more likely to exhibit eosinophilic airway inflammation than white subjects in the ICS+ group (odds ratio, 1.58; 95% CI, 1.01-2.48; P = .046) but not in the ICS- group (P = .984). CONCLUSION: African American subjects exhibit greater eosinophilic airway inflammation, which might explain the greater asthma burden in this population.


Assuntos
Asma/epidemiologia , População Negra , Eosinofilia/epidemiologia , População Branca , Corticosteroides/uso terapêutico , Adulto , Asma/tratamento farmacológico , Asma/imunologia , Asma/fisiopatologia , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Eosinofilia/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Imunoglobulina E/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Fenótipo , Escarro/citologia , Adulto Jovem
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