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While the term asthma has long been known to describe heterogeneous groupings of patients, only recently have data evolved which enable a molecular understanding of the clinical differences. The evolution of transcriptomics (and other 'omics platforms) and improved statistical analyses in combination with large clinical cohorts opened the door for molecular characterization of pathobiologic processes associated with a range of asthma patients. When linked with data from animal models and clinical trials of targeted biologic therapies, emerging distinctions arose between patients with and without elevations in type 2 immune and inflammatory pathways, leading to the confirmation of a broad categorization of type 2-Hi asthma. Differences in the ratios, sources, and location of type 2 cytokines and their relation to additional immune pathway activation appear to distinguish several different (sub)molecular phenotypes, and perhaps endotypes of type 2-Hi asthma, which respond differently to broad and targeted anti-inflammatory therapies. Asthma in the absence of type 2 inflammation is much less well defined, without clear biomarkers, but is generally linked with poor responses to corticosteroids. Integration of "big data" from large cohorts, over time, using machine learning approaches, combined with validation and iterative learning in animal (and human) model systems is needed to identify the biomarkers and tightly defined molecular phenotypes/endotypes required to fulfill the promise of precision medicine.
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Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/patologia , Medicina de Precisão , Biomarcadores , Predisposição Genética para Doença , HumanosRESUMO
BACKGROUND: Epidemiologic studies have shown associations between traffic-related pollutants such as diesel particulate matter (PM) and asthma outcomes in children, but the inflammatory features associated with diesel PM exposure in children with asthma are not understood. OBJECTIVE: This study examined symptoms, exacerbations, and lung function measures in children with uncontrolled asthma and their associations with residential proximity to major roadways. Biomarker studies were performed to determine associations between diesel PM exposure and systemic inflammatory cytokines, circulating markers of T-cell activation and exhaustion, and metabolomic features. METHODS: Children 5 through 17 years of age with physician-diagnosed, uncontrolled asthma despite treatment with an asthma controller medication completed a research visit involving questionnaires, lung function testing, and venipuncture for biomarker studies. Geocoding was performed to quantify residential proximity to major roadways and pollutant exposure. RESULTS: Four hundred forty-seven children with uncontrolled asthma were enrolled. Children living closer to highly trafficked roadways were more disadvantaged and had more exposure to diesel PM, more exacerbations prompting an emergency department visit, and lower lung function measures. Children with the highest diesel PM exposure, compared to children with the lowest diesel PM exposure, also had blunted cytokine secretion and evidence of T cell exhaustion, as well as disturbances in several metabolites associated with glutathione formation and oxidative stress. CONCLUSION: Traffic-related diesel PM exposure in children with poorly controlled asthma is associated with poorer clinical outcomes and unique patterns of inflammation and oxidative stress. These findings argue for continued mitigation efforts to improve traffic-related air quality and health equity in children with asthma.
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BACKGROUND: Inhaled air pollutants are environmental determinants of health with negative impacts on human health. Air pollution has been linked to the incidence and progression of disease, with its effects unequally distributed across the population. Children compared to adults are a highly vulnerable group and suffer disproportionately from systemic environmental inequities exacerbated by social determinants. OBJECTIVE: To explore air pollution cluster patterns among 6- to 19-year-olds from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) and examine chemical cluster associations with social vulnerability. METHODS: NHANES data was extracted for 697 children and adolescents. Social vulnerability characteristics from questionnaires were assembled to construct a modified social vulnerability index (SVI). Thirty-four air pollutant exposure chemicals were measured in urine and available from the laboratory sub-sample A data. K-means clustering classified the sample into three groups: low, medium, and high chemical exposure groups. Logistic regression was used to examine associations between high chemical group membership and SVI after adjusting for age, biological sex, and BMI. Complex survey analysis was conducted using SAS v9.4 to reflect population effects. RESULTS: Air pollution clusters revealed significant differences in mean concentrations between groups for 31 analytes with minimal distinction in mixture profiles. SVI scores differed significantly between the three groups (P = .002), and with each point increase in their SVI, the odds of a child being assigned to the highest-chemical exposure group increased by 11.55% (95% CI: 1.02-1.31), after adjustment. CONCLUSION: Unsupervised clustering of environmental sub-sample specimens from NHANES provides an innovative, multi-pollutant model that can be used to explore exposure patterns in this population. Utilizing the modified SVI allows for the identification of children that may be highly susceptible to air pollution. It is imperative to interpret the research findings in light of historical structural and discriminatory inequalities to develop beneficial and sustainable solutions.
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Poluentes Atmosféricos , Exposição Ambiental , Inquéritos Nutricionais , Humanos , Adolescente , Criança , Feminino , Masculino , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/urina , Análise por Conglomerados , Adulto Jovem , Exposição Ambiental/análise , Vulnerabilidade Social , Poluição do Ar/análiseRESUMO
BACKGROUND: Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. OBJECTIVE: We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n = 16; no sensitization, n = 36). METHODS: Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid [poly(I:C)] as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase, and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. RESULTS: A total of 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (ie, more myeloperoxidase and extracellular DNA) and less neutrophil proinflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (ie, M2) phenotype in sensitized children and a more proinflammatory (ie, M1) phenotype in nonsensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled health care were also higher in children without aeroallergen sensitization after enrollment. CONCLUSIONS: Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at type 2-high inflammation.
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Neutrófilos , Sons Respiratórios , Humanos , Pré-Escolar , Imunofenotipagem , Alérgenos , Inflamação/metabolismo , Citocinas/metabolismo , DNA/metabolismo , Peroxidase/metabolismoRESUMO
BACKGROUND: The asthma of some children remains poorly controlled, with recurrent exacerbations despite treatment with inhaled corticosteroids. Aside from prior exacerbations, there are currently no reliable predictors of exacerbation-prone asthma in these children and only a limited understanding of the potential underlying mechanisms. OBJECTIVE: We sought to quantify small molecules in the plasma of children with exacerbation-prone asthma through mass spectrometry-based metabolomics. We hypothesized that the plasma metabolome of these children would differ from that of children with non-exacerbation-prone asthma. METHODS: Plasma metabolites were extracted from 4 pediatric asthma cohorts (215 total subjects, with 41 having exacerbation-prone asthma) and detected with a mass spectrometer. High-confidence annotations were retained for univariate analysis and were confirmed by a sensitivity analysis in subjects receiving high-dose inhaled corticosteroids. Metabolites that varied by cohort were excluded. MetaboAnalyst software was used to identify pathways of interest. Concentrations were calculated by reference standardization. RESULTS: We identified 32 unique, cohort-independent metabolites that differed in children with exacerbation-prone asthma compared to children with non-exacerbation-prone asthma. Comparison of metabolite concentrations to literature-reported values for healthy children revealed that most metabolites were decreased in both asthma groups, but more so in exacerbation-prone asthma. Pathway analysis identified arginine, lysine, and methionine pathways as most impacted. CONCLUSIONS: Several plasma metabolites are perturbed in children with exacerbation-prone asthma and are largely related to arginine, lysine, and methionine pathways. While validation is needed, plasma metabolites may be potential biomarkers for exacerbation-prone asthma in children.
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Asma , Lisina , Criança , Humanos , Lisina/uso terapêutico , Metionina/uso terapêutico , Arginina , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , RacemetioninaRESUMO
BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.
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Asma , Masculino , Feminino , Criança , Humanos , Adulto , Volume Expiratório Forçado , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Broncodilatadores/farmacologia , Testes de Função Respiratória , Espirometria , PulmãoRESUMO
Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.
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Asma , Rhinovirus , Criança , Humanos , Animais , Camundongos , Pré-Escolar , Formação de Anticorpos , Anticorpos Neutralizantes , Reações CruzadasRESUMO
BACKGROUND: Social determinants of health have been inadequately studied in preschool children with wheezing and their caregivers but may influence the care received. OBJECTIVE: To evaluate the symptom and exacerbation experiences of wheezing preschool children and their caregivers, stratified by risk of social vulnerability, over 1 year of longitudinal follow-up. METHODS: A total of 79 caregivers and their preschool children with recurrent wheezing and at least 1 exacerbation in the previous year were stratified by a composite measure of social vulnerability into "low" (N = 19), "intermediate" (N = 27), and "high" (N = 33) risk groups. Outcome measures at the follow-up visits included child respiratory symptom scores, asthma control, caregiver-reported outcome measures of mental and social health, exacerbations, and health care utilization. The severity of exacerbations reflected by symptom scores and albuterol use and exacerbation-related caregiver quality of life were also assessed. RESULTS: Preschool children at high risk of social vulnerability had greater day-to-day symptom severity and more severe symptoms during acute exacerbations. High-risk caregivers were also distinguished by lower general life satisfaction at all visits and lower global and emotional quality of life during acute exacerbations which did not improve with exacerbation resolution. Rates of exacerbation or emergency department visits did not differ, but intermediate- and high-risk families were significantly less likely to seek unscheduled outpatient care. CONCLUSION: Social determinants of health influence wheezing outcomes in preschool children and their caregivers. These findings argue for routine assessment of social determinants of health during medical encounters and tailored interventions in high-risk families to promote health equity and improve respiratory outcomes.
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Cuidadores , Qualidade de Vida , Humanos , Pré-Escolar , Cuidadores/psicologia , Sons Respiratórios , Promoção da Saúde , Determinantes Sociais da SaúdeRESUMO
BACKGROUND: Severe, refractory asthma is a life-threatening emergency that may be treated with isoflurane and extracorporeal life support. The objective of this study was to describe the clinical response to isoflurane and outcomes after discharge of children who received isoflurane and/or extracorporeal life-support for near-fatal asthma. METHODS: This was a retrospective descriptive study using electronic medical record data from two pediatric intensive care units within a single healthcare system in Atlanta, GA. RESULTS: Forty-five children received isoflurane, and 14 children received extracorporeal life support, 9 without a trial of isoflurane. Hypercarbia and acidosis improved within four hours of starting isoflurane. Four children died during the index admission for asthma. Twenty-seven percent had a change in Functional Status Score of three or more points from baseline to PICU discharge. Patients had median percent predicted FEV1 and FEV1/FVC ratios pre- and post-bronchodilator values below normal pediatric values. CONCLUSION: Children who received isoflurane and/or ECLS had a high frequency of previous PICU admission and intubation. Improvement in ventilation and acidosis occurred within the first four hours of starting isoflurane. Children who required isoflurane or ECLS may develop long-lasting deficits in their functional status. Children with near-fatal asthma are a high-risk group and require improved follow-up in the year following PICU discharge.
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Asma , Oxigenação por Membrana Extracorpórea , Isoflurano , Estado Asmático , Criança , Humanos , Estado Asmático/tratamento farmacológico , Isoflurano/uso terapêutico , Asma/tratamento farmacológico , Estudos Retrospectivos , Unidades de Terapia Intensiva PediátricaRESUMO
PURPOSE: People living with cystic fibrosis (CF) experience impaired quality of life, but the extent to which pulmonary function is associated with quality of life in CF remains unclear METHODS: Using baseline data from a trial of specialist palliative care in adults with CF, we examined the association between pulmonary obstruction and quality of life (measured with the Functional Assessment of Chronic Illness Therapy Total Score). RESULTS: Among 262 participants, median age was 33, and 78% were on modulator therapy. The median quality of life score was higher in those with mild obstruction (135, IQR 110-156) compared to moderate (125, IQR 109-146) and severe obstruction (120, IQR 106-136). In an unadjusted model, we observed a non-significant trend toward lower quality of life with increased obstruction-compared to participants with mild obstruction, those with moderate obstruction had quality of life score 7.46 points lower (95% CI -15.03 to 0.10) and those with severe obstruction had a score 9.98 points lower (95% CI -21.76 to 1.80). However, this association was no longer statistically significant in the adjusted model, which may reflect confounding due to sex, age, BMI, and modulator therapy. Comorbidities (depression and anxiety) and social determinants of health (financial insecurity and education) were also associated with quality of life. CONCLUSION: Advancing our understanding of patient-centered markers of quality of life, rather than focusing on pulmonary function alone, may help identify novel interventions to improve quality of life in this patient population.
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Fibrose Cística , Adulto , Humanos , Ansiedade/epidemiologia , Ansiedade/etiologia , Transtornos de Ansiedade , Fibrose Cística/complicações , Fibrose Cística/terapia , Pulmão , Qualidade de Vida , Ensaios Clínicos como AssuntoRESUMO
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.
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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 JovemRESUMO
BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).
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Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Eosinófilos , Glucocorticoides/uso terapêutico , Furoato de Mometasona/uso terapêutico , Escarro/imunologia , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Asma/imunologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Contagem de Leucócitos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).
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Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Asma/tratamento farmacológico , Negro ou Afro-Americano , Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Glucocorticoides/administração & dosagem , Xinafoato de Salmeterol/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
OBJECTIVES: Poverty, racial bias, and disparities are linked to adverse health outcomes for children in the United States. The social vulnerability and child opportunity indices are composite measures of the social, economic, education, health, and environmental qualities that affect human health for every U.S. census tract. Composite measures of social vulnerability and child opportunity were compared for neighborhood hot spots, where PICU admissions for acute respiratory failure requiring invasive mechanical ventilation were at the 90th percentile or greater per 1,000 children, versus non-hot spots. DESIGN: Population-based ecological study. SETTING: Two urban free-standing children's hospital PICUs consisting of a 36-bed quaternary academic and a 56-bed tertiary community center, in Atlanta, GA. PATIENTS: Mechanically ventilated children who were 17 years of age or younger with a geocodable Georgia residential address admitted to a PICU for at least 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Residential addresses were geocoded and spatially joined to census tracts. Composite measures of social vulnerability and childhood opportunity, PICU readmission rates, and hospital length of stay were compared between neighborhood hot spots versus non-hot spots. There were 340 of 3,514 children (9.7%) who lived within a hot spot. Hot spots were associated with a higher (worse) composite social vulnerability index ranking, reflecting differences in socioeconomic status, household composition and disability, and housing type and transportation. Hot spots also had a lower (worse) composite childhood opportunity index percentile ranking, reflecting differences in the education, health and environment, and social and economic domains. Higher social vulnerability and lower childhood opportunity were not associated with readmission rates but were associated with longer total median duration of hospital days per 1,000 children in a census tract. CONCLUSIONS: Social determinants of health identified by geospatial analyses are associated with acute respiratory failure requiring invasive mechanical ventilation in critically ill children. Interventions addressing the neighborhood social vulnerability and child opportunity are needed to decrease disparities in intensive care admissions for acute respiratory failure requiring mechanical ventilation.
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Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Criança , Cuidados Críticos , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Respiração Artificial , Insuficiência Respiratória/terapia , Estudos Retrospectivos , Determinantes Sociais da SaúdeRESUMO
Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.
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Corticosteroides/normas , Corticosteroides/uso terapêutico , Antiasmáticos/normas , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Óxido Nítrico/análise , Guias de Prática Clínica como Assunto , Humanos , Estados UnidosRESUMO
Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.
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Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Infusões Parenterais , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.
Assuntos
Anticorpos Neutralizantes/sangue , Asma/fisiopatologia , Suscetibilidade a Doenças , Infecções por Picornaviridae/fisiopatologia , Sons Respiratórios/fisiopatologia , Rhinovirus/genética , Rhinovirus/patogenicidade , Adolescente , Fatores Etários , Asma/epidemiologia , Asma/virologia , Austrália/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Variação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Infecções por Picornaviridae/epidemiologia , Infecções por Picornaviridae/imunologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).
Assuntos
Antiasmáticos/administração & dosagem , Asma/prevenção & controle , Fluticasona/administração & dosagem , Administração por Inalação , Albuterol/administração & dosagem , Antiasmáticos/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluticasona/efeitos adversos , Crescimento/efeitos dos fármacos , Humanos , Masculino , Pico do Fluxo ExpiratórioRESUMO
AIM: To describe diabetes nurses' perspectives on the impact of the COVID-19 pandemic on people with diabetes and diabetes services across Europe. METHODS: An online survey developed using a rapid Delphi method. The survey was translated into 17 different languages and disseminated electronically in 27 countries via national diabetes nurse networks. RESULTS: Survey responses from 1829 diabetes nurses were included in the analysis. The responses indicated that 28% (n = 504) and 48% (n = 873) of diabetes nurses felt the COVID-19 pandemic had impacted 'a lot' on the physical and psychological risks of people with diabetes, respectively. The following clinical problems were identified as having increased 'a lot': anxiety 82% (n = 1486); diabetes distress 65% (n = 1189); depression 49% (n = 893); acute hyperglycaemia 39% (n = 710) and foot complications 18% (n = 323). Forty-seven percent (n = 771) of respondents identified that the level of care provided to people with diabetes had declined either extremely or quite severely. Self-management support, diabetes education and psychological support were rated by diabetes nurse respondents as having declined extremely or quite severely during the COVID-19 pandemic by 31% (n = 499), 63% (n = 1,027) and 34% (n = 551), respectively. CONCLUSION: The findings show that diabetes nurses across Europe have seen significant increases in both physical and psychological problems in their patient populations during COVID-19. The data also show that clinical diabetes services have been significantly disrupted. As the COVID-19 situation continues, we need to adapt care systems with some urgency to minimise the impact of the pandemic on the diabetes population.
Assuntos
COVID-19 , Atenção à Saúde , Diabetes Mellitus/fisiopatologia , Enfermeiros Especialistas , Angústia Psicológica , Ansiedade/psicologia , Atitude do Pessoal de Saúde , Depressão/psicologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/enfermagem , Diabetes Mellitus/psicologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/enfermagem , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/enfermagem , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/psicologia , Pé Diabético/fisiopatologia , Europa (Continente) , Humanos , Hiperglicemia/metabolismo , SARS-CoV-2 , Autogestão , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma. OBJECTIVE: We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence. METHODS: Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually. RESULTS: At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P < .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/µL. CONCLUSIONS: In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.