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BACKGROUND: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear. METHODS: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety. RESULTS: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups. CONCLUSIONS: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).
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Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-33/antagonistas & inibidores , Adulto , Idoso , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Receptores de Interleucina-4/antagonistas & inibidores , Falha de TratamentoRESUMO
BACKGROUND: There is evidence that global anthropogenic climate change may be impacting floral phenology and the temporal and spatial characteristics of aero-allergenic pollen. Given the extent of current and future climate uncertainty, there is a need to strengthen predictive pollen forecasts. METHODS: The study aims to use CatBoost (CB) and deep learning (DL) models for predicting the daily total pollen concentration up to 14 days in advance for 23 cities, covering all five continents. The model includes the projected environmental parameters, recent concentrations (1, 2 and 4 weeks), and the past environmental explanatory variables, and their future values. RESULTS: The best pollen forecasts include Mexico City (R2(DL_7) ≈ .7), and Santiago (R2(DL_7) ≈ .8) for the 7th forecast day, respectively; while the weakest pollen forecasts are made for Brisbane (R2(DL_7) ≈ .4) and Seoul (R2(DL_7) ≈ .1) for the 7th forecast day. The global order of the five most important environmental variables in determining the daily total pollen concentrations is, in decreasing order: the past daily total pollen concentration, future 2 m temperature, past 2 m temperature, past soil temperature in 28-100 cm depth, and past soil temperature in 0-7 cm depth. City-related clusters of the most similar distribution of feature importance values of the environmental variables only slightly change on consecutive forecast days for Caxias do Sul, Cape Town, Brisbane, and Mexico City, while they often change for Sydney, Santiago, and Busan. CONCLUSIONS: This new knowledge of the ecological relationships of the most remarkable variables importance for pollen forecast models according to clusters, cities and forecast days is important for developing and improving the accuracy of airborne pollen forecasts.
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Alérgenos , Previsões , Pólen , Pólen/imunologia , Previsões/métodos , Humanos , Mudança Climática , Modelos Teóricos , Monitoramento Ambiental/métodosRESUMO
BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. METHODS: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. RESULTS: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. CONCLUSIONS: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).
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Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Adolescente , Adulto , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Asma/classificação , Broncodilatadores/uso terapêutico , Criança , Método Duplo-Cego , Quimioterapia Combinada , Eosinofilia/induzido quimicamente , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Injeções Subcutâneas/efeitos adversos , Análise de Intenção de Tratamento , Interleucina-13 , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-4/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND: The phase 3 LIBERTY ASTHMA QUEST study (ClinicalTrials.gov: NCT02414854) in patients with uncontrolled, moderate-to-severe asthma has demonstrated the efficacy and safety of dupilumab 200 and 300â mg every 2â weeks versus placebo. This post hoc analysis assessed the effect of dupilumab on efficacy outcomes and asthma control across a range of historical exacerbation rates in patients with type 2-high asthma. METHODS: Annualised severe exacerbation rates over the 52-week treatment period, pre-bronchodilator forced expiratory volume in 1â s (FEV1) at weeks 12 and 52, and the five-item Asthma Control Questionnaire (ACQ-5) score at weeks 24 and 52 were assessed in patients with ≥1, ≥2 or ≥3 exacerbations in the previous year. Subgroups were stratified by baseline blood eosinophils ≥150 or ≥300â cells·µL-1 or baseline exhaled nitric oxide fraction ≥25â ppb and baseline inhaled corticosteroid (ICS) dose. RESULTS: Across all type 2-high subgroups, dupilumab versus placebo significantly reduced severe exacerbations by 54-90%, with greater improvements in patients with more exacerbations prior to study initiation. Similarly, improvements in FEV1 (least squares (LS) mean difference versus placebo: ≥1 exacerbations, 0.15-0.25â L; ≥2 exacerbations, 0.12-0.32â L; ≥3 exacerbations, 0.09-0.38â L; majority p<0.05) and ACQ-5 score (LS mean difference range: ≥1 exacerbations, -0.30 to -0.57; ≥2 exacerbations, -0.29 to -0.56; ≥3 exacerbations, -0.43 to -0.61; all p<0.05) were observed, irrespective of prior exacerbation history, across all subgroups. CONCLUSIONS: Dupilumab significantly reduced severe exacerbations and improved FEV1 and asthma control in patients with elevated type 2 biomarkers irrespective of exacerbation history and baseline ICS dose.
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Antiasmáticos , Asma , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.1093/biosci/biz140.].
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BACKGROUND: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). OBJECTIVE: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. METHODS: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. RESULTS: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and ≥1 perennial aeroallergen specific immunoglobulin E (IgE) level ≥0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P < .05 for both) and improved FEV1 at week 12 by 0.14 L and 0.18 L (P < .01 for both); greater efficacy was observed in patients with elevated baseline blood eosinophil counts (≥300 cells/µL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. CONCLUSION: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitis-specific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR.
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Antialérgicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Rinite Alérgica Perene/tratamento farmacológico , Adulto , Biomarcadores , Método Duplo-Cego , Eosinófilos/citologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Receptores Tipo II de Interleucina-4/antagonistas & inibidoresRESUMO
BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated. RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo. CONCLUSIONS: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
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Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Eosinofilia/complicações , Subunidade alfa de Receptor de Interleucina-4/imunologia , Adolescente , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Asma/imunologia , Asma/fisiopatologia , Biomarcadores/sangue , Feminino , Volume Expiratório Forçado , Glucocorticoides/uso terapêutico , Humanos , Injeções Subcutâneas , Análise de Intenção de Tratamento , Contagem de Leucócitos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Células Th2 , Adulto JovemRESUMO
BACKGROUND: Intranasal corticosteroids are generally considered the most effective medication class for controlling allergic rhinitis. Previous comparative studies with oral antihistamines have been only partially informative due to a variety of variables encountered during their execution. OBJECTIVE: To compare fluticasone propionate nasal spray (FPNS) with the second-generation antihistamine cetirizine (oral tablet) and with placebo in a head-to-head study in a 2-week treatment study during fall ragweed season. METHODS: A total of 978 subjects were screened for this study. Six hundred and eighty-two subjects were randomized into the study (170 subjects, FPNS 200 mcg once daily; 170, cetirizine 10 mg once daily; 171, FPNS placebo; 171, cetirizine placebo) and comprised the intent-to-treat population. A 1-week placebo run-in was followed by a 2-week active treatment period during which time a total nasal symptom score (TNSS), total ocular symptom score, and the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire were collected. RESULTS: The primary efficacy end point was the mean change from baseline over the entire treatment period in A.M. reflective TNSS. The TNSS was the sum of the four individual nasal congestion, nasal itching, rhinorrhea, and sneezing scores, in which each symptom was scored on a scale of 0 to 3. Both FPNS and cetirizine improved the primary end point when compared with placebo during the active treatment period. Although there was a trend that favored FPNS with regard to the primary and secondary end points, there was not a statistical difference between the two treatments. CONCLUSION: FPNS and cetirizine were equally effective in treating fall seasonal allergic rhinitis during a 2-week head-to-head treatment investigation. Clinical trial NCT01916226,
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Ambrosia/efeitos adversos , Cetirizina/administração & dosagem , Fluticasona/administração & dosagem , Sprays Nasais , Rinite Alérgica Sazonal/tratamento farmacológico , Rinite Alérgica Sazonal/etiologia , Estações do Ano , Adolescente , Adulto , Cetirizina/efeitos adversos , Feminino , Fluticasona/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
A fundamental aspect of climate change is the potential shifts in flowering phenology and pollen initiation associated with milder winters and warmer seasonal air temperature. Earlier floral anthesis has been suggested, in turn, to have a role in human disease by increasing time of exposure to pollen that causes allergic rhinitis and related asthma. However, earlier floral initiation does not necessarily alter the temporal duration of the pollen season, and, to date, no consistent continental trend in pollen season length has been demonstrated. Here we report that duration of the ragweed (Ambrosia spp.) pollen season has been increasing in recent decades as a function of latitude in North America. Latitudinal effects on increasing season length were associated primarily with a delay in first frost of the fall season and lengthening of the frost free period. Overall, these data indicate a significant increase in the length of the ragweed pollen season by as much as 13-27 d at latitudes above ~44°N since 1995. This is consistent with recent Intergovernmental Panel on Climate Change projections regarding enhanced warming as a function of latitude. If similar warming trends accompany long-term climate change, greater exposure times to seasonal allergens may occur with subsequent effects on public health.
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Ambrosia , Pólen , Estações do Ano , Temperatura , Asma/etiologia , Clima , Humanos , América do Norte , Rinite Alérgica Sazonal/etiologiaRESUMO
Some patients with allergic rhinitis (AR) may prefer a "dry" intranasal corticosteroid aerosol to avoid certain sensory perceptions such as the "wet feeling in the nose" and the "dripping down the throat" associated with aqueous nasal sprays. A nonaqueous hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol with an established efficacy and safety profile was approved to treat the nasal symptoms associated with AR in adult and adolescent patients. This study was designed to evaluate ease of use and patient satisfaction with the BDP nasal aerosol device in patients with perennial AR (PAR). In this phase 3, randomized, double-blind, parallel-group, placebo-controlled study, eligible patients (≥12 years of age) with PAR were randomly assigned to receive BDP nasal aerosol at 320 micrograms/day or placebo for 6 weeks. At the end of the treatment period, patients assessed device ease of use and satisfaction with the device using a questionnaire with a 5-point representative scale (not at all, not very, neither nor, somewhat, very [certain/easy/satisfactory]). Nearly all patients (89.7%) reported that the BDP nasal aerosol device with integrated dose counter was "very easy" or "somewhat easy" to use. The majority of patients (87.5%) also indicated that it was "very easy" or "somewhat easy" to tell when the device was empty, compared with only 42.3% who were "very certain" or "somewhat certain" of being able to tell when previously used aqueous nasal spray devices were empty. Overall, patient satisfaction with the BDP nasal aerosol device was high: 65.7% responded that they were "very satisfied" or "somewhat satisfied" and only 3.6% were "not satisfied at all" or "not very satisfied." These results indicate that the majority of patients considered the BDP nasal aerosol device easy to use and reported a high degree of satisfaction with the device compared with other nasal sprays they had used in the past.
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Beclometasona/administração & dosagem , Satisfação do Paciente/estatística & dados numéricos , Rinite Alérgica Perene/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Aerossóis , Idoso , Idoso de 80 Anos ou mais , Criança , Prestação Integrada de Cuidados de Saúde/estatística & dados numéricos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Studies examining how Australian Aboriginal people will accept, adapt and adhere to interventions such as continuous positive airway pressure (CPAP) therapy in the management of obstructive sleep apnoea (OSA) are sparsely reported. METHODS: In this study, clinical, demographic, polysomnographic (PSG) and CPAP data were utilised to assess and predict acceptance and adherence to CPAP therapy among adult Aboriginal Australians diagnosed to have OSA. RESULTS: Of the 649 Aboriginal patients with OSA, 49% accepted to trial CPAP therapy. Patients who accepted to trial CPAP showed more severe OSA (65vs.35% with severe OSA), reported higher daytime sleepiness (median 10vs.9), and had a higher BMI (83vs.73% obese). Of those who accepted to trial CPAP, 62% adapted to therapy (used the device for more than 30 days). Patients who adapted had more severe OSA (71vs.54% with severe OSA), and were more likely to live in urban areas (63vs.40%). Of those who adapted, 32% were adherent to therapy. Adherent patients were more likely to live in urban areas (84vs.53%), though there was no difference in OSA severity between adherent and non-adherent patients. In multivariate models remote location and more severe OSA predicted CPAP acceptance, while urban location and more severe OSA predicted adaptation, and urban location and higher oxygen saturation nadir predicted adherence. CONCLUSIONS: Acceptance to trial CPAP therapy was observed in the presence of symptomatic and severe OSA. However, long term adherence to CPAP therapy was significantly influenced by patients' residential location, with patients residing in remote/rural settings demonstrating significantly lower adherence rates.
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Pressão Positiva Contínua nas Vias Aéreas , Apneia Obstrutiva do Sono , Adulto , Humanos , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Polissonografia , Austrália , Cooperação do PacienteRESUMO
BACKGROUND: Aboriginal Australians are reported to have higher presence of chronic respiratory diseases. However, comprehensive evidence surrounding this is sparse. Hence, a systematic review was undertaken to appraise the current state of knowledge on respiratory health in the adult Aboriginal Australians, in particular among the three most common respiratory disorders: asthma, bronchiectasis and chronic obstructive pulmonary disease (COPD). METHODS: A systematic review of primary literature published between January 2012 and October 2022, using the databases PubMed and Scopus, was conducted. Studies were included if they reported adult Aboriginal Australian prevalence's or outcomes related to asthma, bronchiectasis or COPD, and excluded if adult data were not reported separately, if Aboriginal Australian data were not reported separately or if respiratory disorders were combined into a single group. Risk of bias was assessed by both Joanne Briggs Institute checklists and Hoys' bias assessment. Summary data pertaining to prevalence, lung function, symptoms, sputum cultures and mortality for each of asthma, bronchiectasis and COPD were extracted from the included studies. RESULTS: Thirty-seven studies were included, involving approximately 33 364 participants (71% female). Eighteen studies reported on asthma, 21 on bronchiectasis and 30 on COPD. The majority of studies (94%) involved patients from hospitals or respiratory clinics and were retrospective in nature. Across studies, the estimated prevalence of asthma was 15.4%, bronchiectasis was 9.4% and COPD was 13.7%, although there was significant geographical variation. Only a minority of studies reported on clinical manifestations (n=7) or symptoms (n=4), and studies reporting on lung function parameters (n=17) showed significant impairment, in particular among those with concurrent bronchiectasis and COPD. Airway exacerbation frequency and hospital admission rates including mortality are high. DISCUSSION: Although risk of bias globally was assessed as low, and study quality as high, there was limited diversity of studies with most reporting on referred populations, and the majority originating from two centres in the Northern Territory. The states with the greatest Aboriginal Australian population (Victoria and New South Wales) reported the lowest number of studies and patients. This limits the generalisability of results to the wider Aboriginal Australian population due to significant environmental, cultural and socioeconomic variation across the population. Regardless, Aboriginal Australians appear to display a high prevalence, alongside quite advanced and complex chronic respiratory diseases. There is however significant heterogeneity of prevalence, risk factors and outcomes geographically and by patient population. Further collaborative efforts are required to address specific diagnostic and management pathways in order to close the health gap secondary to respiratory disorders in this population.
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Asma , Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Transtornos Respiratórios , Humanos , Adulto , Feminino , Masculino , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Estudos Retrospectivos , Austrália/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Asma/epidemiologia , Bronquiectasia/epidemiologiaRESUMO
Exposure to air pollutants is known to exacerbate asthma, with prior studies focused on associations between single pollutant exposure and asthma exacerbations. As air pollutants often exist as a complex mixture, there is a gap in understanding the association between complex air pollutant mixtures and asthma exacerbations. We evaluated the association between the air pollutant mixture (52 pollutants) and pediatric asthma exacerbations. Method: This study focused on children (age ≤ 19 years) who lived in Douglas County, Nebraska, during 2016-2019. A seasonal-scale joint association between the outdoor air pollutant mixture adjusting for potential confounders (temperature, precipitation, wind speed, and wind direction) in relation to pediatric asthma exacerbation-related emergency department (ED) visits was evaluated using the generalized weighted quantile sum (qWQS) regression with repeated holdout validation. Results: We observed associations between air pollutant mixture and pediatric asthma exacerbations during spring (lagged by 5 days), summer (lag 0-5 days), and fall (lag 1-3 days) seasons. The estimate of the joint outdoor air pollutant mixture effect was higher during the summer season (adjusted-ßWQS = 1.11, 95% confidence interval [CI]: 0.66, 1.55), followed by spring (adjusted-ßWQS = 0.40, 95% CI: 0.16, 0.62) and fall (adjusted-ßWQS = 0.20, 95% CI: 0.06, 0.33) seasons. Among the air pollutants, PM2.5, pollen, and mold contributed higher weight to the air pollutant mixture. Conclusion: There were associations between outdoor air pollutant mixture and pediatric asthma exacerbations during the spring, summer, and fall seasons. Among the 52 outdoor air pollutant metrics investigated, PM2.5, pollen (sycamore, grass, cedar), and mold (Helminthosporium, Peronospora, and Erysiphe) contributed the highest weight to the air pollutant mixture.
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BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is higher among Indigenous Australians than that of non-Indigenous Australians. However, no studies have investigated COPD disease awareness and knowledge among Indigenous Australians. In this study, we assessed the COPD disease awareness among Indigenous and non-Indigenous patients in the Top End Health Service region of the Northern Territory of Australia. METHODS: Of a total convenience sample of 100 adults, 86 patients consented to participate in this study over a 15-month period. A structured interview was conducted to identify participant's level of knowledge about COPD, medications, self-management, healthcare interaction and utilisations. RESULTS: Most (69%) participants were Indigenous and men (52%). Indigenous patients were significantly younger (mean 56 vs 68 years p<0.001), with a higher proportion of remote residence and current smoking. COPD knowledge across the cohort was low, with 68% of Indigenous and 19% of non-Indigenous participants reporting they 'know nothing/had never heard of COPD'. Most patients self-reported use of puffers/inhalers and were able to identify medication used; however, adherence to therapy was observed in only 18%. Shortness of breath was the most common symptom for hospital presentation (83%) and 69% of Indigenous patients reported seeking medical attention during an exacerbation. Self-management and COPD action plans were poorly implemented. A significant proportion (49%) reported ≥2 hospital admissions in the preceding 12 months. During exacerbation, although the majority of Indigenous patients were transferred to a tertiary centre from remote communities, patient's preference was to be managed in their respective local communities. CONCLUSIONS: Awareness and understanding of COPD are low in this cohort on several domains. Tailored and culturally appropriate initiatives for both patients and health professionals alike are required to improve COPD disease management among Indigenous population. This will not only improve quality of life but also reduce recurrent hospitalisation, healthcare cost and utilisation.
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Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Adulto , Hospitalização , Hospitais , Humanos , Masculino , Northern Territory/epidemiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/terapiaRESUMO
BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed. OBJECTIVE: This post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose. METHODS: The OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d. RESULTS: Dupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups. CONCLUSIONS: In patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function.
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Antiasmáticos , Asma , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados , Broncodilatadores/uso terapêutico , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Esteroides/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available. METHODS: TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12-84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV1, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028. FINDINGS: Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5-25·9%), injection-site erythema (2·2-23·4%), and bronchitis (9·3-19·0%). Serious asthma exacerbations (0·5-3·6%) and pneumonia (0·7-2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277-0·327) across parent study and treatment groups, pre-bronchodilator FEV1 improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV1 and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks. INTERPRETATION: Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population. FUNDING: Sanofi and Regeneron Pharmaceuticals.
Assuntos
Antiasmáticos , Asma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiasmáticos/efeitos adversos , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Asma/tratamento farmacológico , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
Objective.Understanding and differentiating brain states is an important task in the field of cognitive neuroscience with applications in health diagnostics, such as detecting neurotypical development vs. autism spectrum or coma/vegetative state vs. locked-in state. Electroencephalography (EEG) analysis is a particularly useful tool for this task as EEG data can detect millisecond-level changes in brain activity across a range of frequencies in a non-invasive and relatively inexpensive fashion. The goal of this study is to apply machine learning methods to EEG data in order to classify visual language comprehension across multiple participants.Approach.26-channel EEG was recorded for 24 Deaf participants while they watched videos of sign language sentences played in time-direct and time-reverse formats to simulate interpretable vs. uninterpretable sign language, respectively. Sparse optimal scoring (SOS) was applied to EEG data in order to classify which type of video a participant was watching, time-direct or time-reversed. The use of SOS also served to reduce the dimensionality of the features to improve model interpretability.Main results.The analysis of frequency-domain EEG data resulted in an average out-of-sample classification accuracy of 98.89%, which was far superior to the time-domain analysis. This high classification accuracy suggests this model can accurately identify common neural responses to visual linguistic stimuli.Significance.The significance of this work is in determining necessary and sufficient neural features for classifying the high-level neural process of visual language comprehension across multiple participants.
Assuntos
Compreensão , Eletroencefalografia , Encéfalo/fisiologia , Humanos , Idioma , Aprendizado de MáquinaRESUMO
BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13 signaling, key drivers of type 2 inflammation. In the phase 3 study (NCT02414854), add-on dupilumab 200 mg/300 mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in those with a high baseline type 2 phenotype. OBJECTIVE: To assess the efficacy and safety of dupilumab in patients with uncontrolled, moderate-to-severe asthma with or without self-reported comorbid chronic rhinosinusitis (CRS or non-CRS). METHODS: Comorbid CRS was self-reported by patients using an e-diary. Annualized severe exacerbation rates, changes from baseline in pre- and post-bronchodilator FEV1, patient-reported outcomes, type 2 biomarkers, and safety were assessed. RESULTS: CRS was self-reported by 382 of 1902 (20.1%) patients. Dupilumab 200 mg/300 mg reduced annualized severe exacerbation rates by 63%/61%, respectively, in patients with CRS, and by 42%/40% in patients without CRS (all P < .001 vs placebo). Dupilumab also improved lung function and patient-reported asthma control and quality of life, and suppressed type 2 biomarkers versus placebo in both subgroups. Clinical responses were rapid, with near-maximal responses observed at the earliest measured time points and sustained at week 52. Improvements observed in the CRS subgroup were similar to or numerically greater than those in the non-CRS subgroup. CONCLUSION: Dupilumab showed efficacy and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma with or without CRS.