The 'ABC' of respiratory disorders among adult Indigenous people: asthma, bronchiectasis and COPD among Aboriginal Australians - a systematic review.

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.

Acceptability, adaptability and adherence to CPAP therapy among Aboriginal Australians with OSA - "The A5 study".

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.

Joint association between ambient air pollutant mixture and pediatric asthma exacerbations.

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.

COPD disease knowledge, self-awareness and reasons for hospital presentations among a predominately Indigenous Australian cohort: a study to explore preventable hospitalisation.

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.

Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose.

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.

Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study.

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.

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma.

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.).

Effect of exacerbation history on clinical response to dupilumab in moderate-to-severe uncontrolled asthma.

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 300 mg every 2 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 1 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 ≥300 cells·µL-1 or baseline exhaled nitric oxide fraction ≥25 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, 0.15-0.25 L; ≥2 exacerbations, 0.12-0.32 L; ≥3 exacerbations, 0.09-0.38 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.

Classification of visual comprehension based on EEG data using sparse optimal scoring.

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.

Efficacy of dupilumab on clinical outcomes in patients with asthma and perennial allergic rhinitis.

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.

Corrigendum: The Extended Specimen Network: A Strategy to Enhance US Biodiversity Collections, Promote Research and Education.

[This corrects the article DOI: 10.1093/biosci/biz140.].

Dupilumab Efficacy in Uncontrolled, Moderate-to-Severe Asthma with Self-Reported Chronic Rhinosinusitis.

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.

Temperature-related changes in airborne allergenic pollen abundance and seasonality across the northern hemisphere: a retrospective data analysis.

BACKGROUND: Ongoing climate change might, through rising temperatures, alter allergenic pollen biology across the northern hemisphere. We aimed to analyse trends in pollen seasonality and pollen load and to establish whether there are specific climate-related links to any observed changes. METHODS: For this retrospective data analysis, we did an extensive search for global datasets with 20 years or more of airborne pollen data that consistently recorded pollen season indices (eg, duration and intensity). 17 locations across three continents with long-term (approximately 26 years on average) quantitative records of seasonal concentrations of multiple pollen (aeroallergen) taxa met the selection criteria. These datasets were analysed in the context of recent annual changes in maximum temperature (Tmax) and minimum temperature (Tmin) associated with anthropogenic climate change. Seasonal regressions (slopes) of variation in pollen load and pollen season duration over time were compared to Tmax, cumulative degree day Tmax, Tmin, cumulative degree day Tmin, and frost-free days among all 17 locations to ascertain significant correlations. FINDINGS: 12 (71%) of the 17 locations showed significant increases in seasonal cumulative pollen or annual pollen load. Similarly, 11 (65%) of the 17 locations showed a significant increase in pollen season duration over time, increasing, on average, 0·9 days per year. Across the northern hemisphere locations analysed, annual cumulative increases in Tmax over time were significantly associated with percentage increases in seasonal pollen load (r=0·52, p=0·034) as were annual cumulative increases in Tmin (r=0·61, p=0·010). Similar results were observed for pollen season duration, but only for cumulative degree days (higher than the freezing point [0°C or 32°F]) for Tmax (r=0·53, p=0·030) and Tmin (r=0·48, p=0·05). Additionally, temporal increases in frost-free days per year were significantly correlated with increases in both pollen load (r=0·62, p=0·008) and pollen season duration (r=0·68, p=0·003) when averaged for all 17 locations. INTERPRETATION: Our findings reveal that the ongoing increase in temperature extremes (Tmin and Tmax) might already be contributing to extended seasonal duration and increased pollen load for multiple aeroallergenic pollen taxa in diverse locations across the northern hemisphere. This study, done across multiple continents, highlights an important link between ongoing global warming and public health-one that could be exacerbated as temperatures continue to increase. FUNDING: None.

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.

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 .).

Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma.

INTRODUCTION: Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. METHODS: Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. CONCLUSION: Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc. CLINICAL TRIALS. GOV IDENTIFIER: NCT02414854.

A comparison of fluticasone propionate nasal spray and cetirizine in ragweed fall seasonal allergic rhinitis.

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, www.clinicaltrials.gov.