Years After a Fire, Biocrust Microbial Communities are Similar to Unburned Communities in a Coastal Grassland.

Microbial communities are integral for ecosystem processes and their taxonomic composition and function may be altered by a disturbance such as fire. Biocrusts are composed of macroscopic and microscopic organisms and are important for a variety of ecosystem functions, such as nutrient cycling and erosion control. We sought to understand if biocrust community composition and function were altered 1 year after a prescribed fire and 6 years after a wildfire in a coastal California grassland on San Clemente Island. We used shotgun metagenomic sequencing and measurements of chlorophyll content, exopolysaccharide production related to soil stability, and nitrogen fixation. There were no differences in the community composition between unburned samples and the samples burned in the prescribed fire and wildfire. Chlorophyll content differed between the prescribed fire and the controls; however, there were no measured differences in exopolysaccharide production, and nitrogen fixation. However, the wildfire and their respective unburned samples had different functions based on the gene annotations. We compiled one Actinobacteria metagenome-assembled genome from the shotgun sequences which had genes for oxidative and heat stress tolerance. These results suggest that the biocrust community can reach a community composition and function similar to the unburned biocrusts within a year after a prescribed burn and 6 years after a wildfire. However, legacy effects of the wildfire may present themselves in the differences between functional gene sequences. Due to their ability to match the undisturbed community composition and function within years and without intervention, future restoration work should consider the biocrusts in their restoration plans as they may provide valuable ecosystem functions after a disturbance.

International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials.

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.

Effect of chronic mucus hypersecretion on treatment responses to inhaled therapies in patients with chronic obstructive pulmonary disease: Post hoc analysis of the IMPACT trial.

BACKGROUND AND OBJECTIVE: Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT. METHODS: Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg and designated CMH+ if they scored 1/2 in St George's Respiratory Questionnaire (SGRQ) questions 1 and 2. Endpoints assessed by baseline CMH status included on-treatment exacerbation rates, change from baseline in trough forced expiratory volume in 1 second, SGRQ total score, COPD Assessment Test (CAT) score, proportion of SGRQ and CAT responders at Week 52 and safety. RESULTS: Of 10,355 patients in the intent-to-treat population, 10,250 reported baseline SGRQ data (CMH+: 62% [n = 6383]). FF/UMEC/VI significantly (p < 0.001) reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in CMH+ (rate ratio: 0.87 and 0.72) and CMH- patients (0.82 and 0.80). FF/UMEC/VI significantly (p < 0.05) reduced on-treatment severe exacerbation rates versus UMEC/VI in CMH+ (0.62) and CMH- (0.74) subgroups. Similar improvements in health status and lung function with FF/UMEC/VI were observed, regardless of CMH status. In CMH+ patients, FF/VI significantly (p < 0.001) reduced on-treatment moderate/severe and severe exacerbation rates versus UMEC/VI (0.83 and 0.70). CONCLUSION: FF/UMEC/VI had a favourable benefit: risk profile versus dual therapies irrespective of CMH status. The presence of CMH did not influence treatment response or exacerbations, lung function and/or health status. However, CMH did generate differences when dual therapies were compared and the impact of CMH should be considered in future trial design.

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

BACKGROUND: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain. METHODS: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 µg, umeclidinium (a LAMA) at a dose of 62.5 µg, and vilanterol (a LABA) at a dose of 25 µg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 µg and 25 µg, respectively) and umeclidinium-vilanterol (at doses of 62.5 µg and 25 µg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). CONCLUSIONS: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

Organohalide-Respiring Bacteria at the Heart of Anaerobic Metabolism in Arctic Wet Tundra Soils.

Recent work revealed an active biological chlorine cycle in coastal Arctic tundra of northern Alaska. This raised the question of whether chlorine cycling was restricted to coastal areas or if these processes extended to inland tundra. The anaerobic process of organohalide respiration, carried out by specialized bacteria like Dehalococcoides, consumes hydrogen gas and acetate using halogenated organic compounds as terminal electron acceptors, potentially competing with methanogens that produce the greenhouse gas methane. We measured microbial community composition and soil chemistry along an ∼262-km coastal-inland transect to test for the potential of organohalide respiration across the Arctic Coastal Plain and studied the microbial community associated with Dehalococcoides to explore the ecology of this group and its potential to impact C cycling in the Arctic. Concentrations of brominated organic compounds declined sharply with distance from the coast, but the decrease in organic chlorine pools was more subtle. The relative abundances of Dehalococcoides were similar across the transect, except for being lower at the most inland site. Dehalococcoides correlated with other strictly anaerobic genera, plus some facultative ones, that had the genetic potential to provide essential resources (hydrogen, acetate, corrinoids, or organic chlorine). This community included iron reducers, sulfate reducers, syntrophic bacteria, acetogens, and methanogens, some of which might also compete with Dehalococcoides for hydrogen and acetate. Throughout the Arctic Coastal Plain, Dehalococcoides is associated with the dominant anaerobes that control fluxes of hydrogen, acetate, methane, and carbon dioxide. Depending on seasonal electron acceptor availability, organohalide-respiring bacteria could impact carbon cycling in Arctic wet tundra soils.IMPORTANCE Once considered relevant only in contaminated sites, it is now recognized that biological chlorine cycling is widespread in natural environments. However, linkages between chlorine cycling and other ecosystem processes are not well established. Species in the genus Dehalococcoides are highly specialized, using hydrogen, acetate, vitamin B12-like compounds, and organic chlorine produced by the surrounding community. We studied which neighbors might produce these essential resources for Dehalococcoides species. We found that Dehalococcoides species are ubiquitous across the Arctic Coastal Plain and are closely associated with a network of microbes that produce or consume hydrogen or acetate, including the most abundant anaerobic bacteria and methanogenic archaea. We also found organic chlorine and microbes that can produce these compounds throughout the study area. Therefore, Dehalococcoides could control the balance between carbon dioxide and methane (a more potent greenhouse gas) when suitable organic chlorine compounds are available to drive hydrogen and acetate uptake.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. METHODS: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range. RESULTS: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. CONCLUSIONS: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

InforMing the PAthway of COPD Treatment (IMPACT) trial: fibrinogen levels predict risk of moderate or severe exacerbations.

BACKGROUND: Fibrinogen is the first qualified prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This analysis used IMPACT trial data to examine the relationship between fibrinogen levels and exacerbation outcomes in patients with COPD. METHODS: 8094 patients with a fibrinogen assessment at Week 16 were included, baseline fibrinogen data were not measured. Post hoc analyses were performed by fibrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs). RESULTS: Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels < 3.5 g/L were 1.03 (0.95, 1.11) for moderate exacerbations, 1.08 (1.00, 1.15) for moderate/severe exacerbations, and 1.30 (1.10, 1.54) for severe exacerbations. There was an increased risk of moderate/severe exacerbation (hazard ratio [95% CI]: highest vs lowest quartile 1.16 [1.04, 1.228]; ≥ 3.5 g/L vs < 3.5 g/L: 1.09 [1.00, 1.16]) and severe exacerbation (1.35 [1.09, 1.69]; 1.27 [1.08, 1.47], respectively) with increasing fibrinogen level. Cardiovascular AESIs were highest in patients in the highest fibrinogen quartile. CONCLUSIONS: Rate and risk of exacerbations was higher in patients with higher fibrinogen levels. This supports the validity of fibrinogen as a predictive biomarker for COPD exacerbations, and highlights the potential use of fibrinogen as an enrichment strategy in trials examining exacerbation outcomes. TRIAL REGISTRATION: NCT02164513.

Trichotorquatus gen. nov. - a new genus of soil cyanobacteria discovered from American drylands1.

Cyanobacteria are crucial ecosystem components in dryland soils. Advances in describing α-level taxonomy are needed to understand what drives their abundance and distribution. We describe Trichotorquatus gen. nov. (Oculatellaceae, Synechococcales, Cyanobacteria) based on four new species isolated from dryland soils including the coastal sage scrub near San Diego, California (USA), the Mojave and Colorado Deserts with sites at Joshua Tree National Park and Mojave National Preserve, California (USA), and the Atacama Desert (Chile). The genus is morphologically characterized by having thin trichomes (<4.5 µm wide), cells both shorter and longer than wide, rarely occurring single and double false branching, necridia appearing singly or in rows, and sheaths with a distinctive collar-like fraying and widening mid-filament, the feature for which the genus is named. The genus is morphologically nearly identical with Leptolyngbya sensu stricto but is phylogenetically quite distant from that genus. It is consequently a cryptic genus that will likely be differentiated in future studies based on 16S rRNA sequence data. The type species, T. maritimus sp. nov. is morphologically distinct from the other three species, T. coquimbo sp. nov., T. andrei sp. nov. and T. ladouxae sp. nov. However, these latter three species are morphologically very close and are considered by the authors to be cryptic species. All species are separated phylogenetically based on sequence of the 16S-23S ITS region. Three distinct ribosomal operons were recovered from the genus, lending difficulty to recognizing further diversity in this morphologically cryptic genus.

The Effect of Inhaled Corticosteroid Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study. A Randomized, Double-Blind, Multicenter Clinical Trial.

Rationale: In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.Objectives: To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.Methods: Exacerbations and change from baseline in trough FEV1 and St. George's Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days.Measurements and Main Results: FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction; P < 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction; P = 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%; P < 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction; P < 0.001; non-ICS users, 35% reduction; P = 0.018), and overall when excluding the first 30 days (29%; P < 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV1 and St. George's Respiratory Questionnaire, regardless of prior ICS use.Conclusions: These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.Clinical trial registered with www.clinicaltrials.gov (NCT02164513).

Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

Rationale: The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc.Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.

Phosphorus alleviation of nitrogen-suppressed methane sink in global grasslands.

Grassland ecosystems account for more than 10% of the global CH4 sink in soils. A 4-year field experiment found that addition of P alone did not affect CH4 uptake and experimental addition of N alone significantly suppressed CH4 uptake, whereas concurrent N and P additions suppressed CH4 uptake to a lesser degree. A meta-analysis including 382 data points in global grasslands corroborated these findings. Global extrapolation with an empirical modelling approach estimated that contemporary N addition suppresses CH4 sink in global grassland by 11.4% and concurrent N and P deposition alleviates this suppression to 5.8%. The P alleviation of N-suppressed CH4 sink is primarily attributed to substrate competition, defined as the competition between ammonium and CH4 for the methane mono-oxygenase enzyme. The N and P impacts on CH4 uptake indicate that projected increases in N and P depositions might substantially affect CH4 uptake and alter the global CH4 cycle.

The effect of exacerbation history on outcomes in the IMPACT trial.

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI versus FF/VI or UMEC/VI and UMEC/VI versus FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group versus FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and versus UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group versus UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status versus both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function versus FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.

Snow melt stimulates ecosystem respiration in Arctic ecosystems.

Cold seasons in Arctic ecosystems are increasingly important to the annual carbon balance of these vulnerable ecosystems. Arctic winters are largely harsh and inaccessible leading historic data gaps during that time. Until recently, cold seasons have been assumed to have negligible impacts on the annual carbon balance but as data coverage increases and the Arctic warms, the cold season has been shown to account for over half of annual methane (CH4 ) emissions and can offset summer photosynthetic carbon dioxide (CO2 ) uptake. Freeze-thaw cycle dynamics play a critical role in controlling cold season CO2 and CH4 loss, but the relationship has not been extensively studied. Here, we analyze freeze-thaw processes through in situ CO2 and CH4 fluxes in conjunction with soil cores for physical structure and porewater samples for redox biogeochemistry. We find a movement of water toward freezing fronts in soil cores, leaving air spaces in soils, which allows for rapid infiltration of oxygen-rich snow melt in spring as shown by oxidized iron in porewater. The snow melt period coincides with rising ecosystem respiration and can offset up to 41% of the summer CO2 uptake. Our study highlights this important seasonal process and shows spring greenhouse gas emissions are largely due to production from respiration instead of only bursts of stored gases. Further warming is projected to result in increases of snowpack and deeper thaws, which could increase this ecosystem respiration dominate snow melt period causing larger greenhouse gas losses during spring.

Measuring disease activity in COPD: is clinically important deterioration the answer?

Given the heterogeneity of chronic obstructive pulmonary disease (COPD), personalized clinical management is key to optimizing patient outcomes. Important treatment goals include minimizing disease activity and preventing disease progression; however, quantification of these components remains a challenge. Growing evidence suggests that decline over time in forced expiratory volume in 1 s (FEV1), traditionally the key marker of disease progression, may not be sufficient to fully determine deterioration across COPD populations. In addition, there is a lack of evidence showing that currently available multidimensional COPD indexes improve clinical decision-making, treatment, or patient outcomes. The composite clinically important deterioration (CID) endpoint was developed to assess disease worsening by detecting early deteriorations in lung function (measured by FEV1), health status (assessed by the St George's Respiratory Questionnaire), and the presence of exacerbations. Post hoc and prospective analyses of clinical trial data have confirmed that the multidimensional composite CID endpoint better predicts poorer medium-term outcomes compared with any single CID component alone, and that it can demonstrate differences in treatment efficacy in short-term trials. Given the widely acknowledged need for an individualized holistic approach to COPD management, monitoring short-term CID has the potential to facilitate early identification of suboptimal treatment responses and patients at risk of increased disease progression. CID monitoring may lead to better-informed clinical management decisions and potentially improved prognosis.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol and umeclidinium/vilanterol in patients with COPD: results on cardiovascular safety from the IMPACT trial.

BACKGROUND: This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. METHODS: IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. RESULTS: Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments. CONCLUSIONS: In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. TRIAL REGISTRATION: NCT02164513 (GSK study number CTT116855).

Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials.

BACKGROUND: The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS: 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 µg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) < 50% predicted, or FEV1 < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS: The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [- 13, 43]; Study 207609: 11 mL [- 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS: FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION: GSK (207608/207609; NCT03478683/NCT03478696).

Impact of prior and concurrent medication on exacerbation risk with long-acting bronchodilators in chronic obstructive pulmonary disease: a post hoc analysis.

BACKGROUND: Symptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk still have disease instability, which can be improved with better bronchodilation. We evaluated two long-acting bronchodilators individually and in combination on reducing exacerbation risk and the potential impact of concurrent medication in these patients. METHODS: Integrated post hoc intent-to-treat (ITT) analysis of data from two large 24-week, randomized placebo (PBO)-controlled trials (NCT01313637, NCT01313650). Symptomatic patients with moderate-to-very-severe COPD with/without an exacerbation history were randomized (2:3:3:3) to once-daily: PBO, umeclidinium/vilanterol (UMEC/VI 62.5/25 µg [NCT01313650] or 125/25 µg [NCT01313637]), UMEC (62.5 [NCT01313650] or 125 µg [NCT01313637]) or VI (25 µg) via the ELLIPTA inhaler. Medication subgroups were segmented by treatment status at screening: a) maintenance-naïve or on maintenance medications, b) inhaled corticosteroid [ICS]-free or ICS-treated, c) low or high albuterol use based on median run-in use (< 3.6 or ≥ 3.6 puffs/day). Time to first moderate/severe exacerbation (Cox proportional hazard model) and change from baseline in trough forced expiratory volume in 1 s (FEV1; mixed model repeated measures) were analyzed. Safety was also assessed. RESULTS: Of 3021 patients (ITT population; UMEC/VI: n = 816; UMEC: n = 825; VI: n = 825; PBO: n = 555), 36% had a recent exacerbation history, 33% were maintenance-naïve, 51% were ICS-free. Mean baseline albuterol use was 5.1 puffs/day. In the ITT population, UMEC/VI, UMEC, and VI reduced the risk of a first exacerbation versus PBO by 58, 44, and 39%, respectively (all p < 0.05). UMEC/VI provided significant risk reductions versus PBO in all subgroups. VI had no benefit versus PBO in maintenance-naïve, ICS-free, and low rescue use patients and was significantly less effective than UMEC/VI in these subgroups. UMEC had no significant benefit versus PBO in maintenance-naïve and ICS-free patients. All bronchodilators improved FEV1 versus PBO, and UMEC/VI significantly improved FEV1 versus both monotherapies across all populations studied (p < 0.05). All bronchodilators were similarly well tolerated. CONCLUSIONS: Results suggest that UMEC/VI reduces exacerbation risk versus PBO more consistently across medication subgroups than UMEC or VI, particularly in patients with no/low concurrent medication use. Confirmed prospectively, these findings may support first-line use of dual bronchodilation therapy in symptomatic low-risk patients.

Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial.

BACKGROUND: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. METHODS: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 µg once-daily, umeclidinium 62.5 µg once-daily or salmeterol 50 µg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. RESULTS: Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments. CONCLUSIONS: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Efficacy and safety of the dual bronchodilator combination umeclidinium/vilanterol in COPD by age and airflow limitation severity: A pooled post hoc analysis of seven clinical trials.

BACKGROUND: Elderly patients with chronic obstructive pulmonary disease (COPD) and those with more severe airway limitation are perceived to experience reduced efficacy from inhaled bronchodilators, especially those administered in a dry powder inhaler. This study compared the efficacy and safety of a long-acting muscarinic antagonist/long-acting ß2-agonist dry powder combination in elderly patients with COPD and patients with moderate-to-very severe airflow limitation. METHODS: This post hoc pooled analysis of seven randomized studies of ≥12 weeks' duration investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg versus tiotropium (TIO) 18 µg or fluticasone propionate/salmeterol (FP/SAL) 250/50 µg. Change from baseline in trough forced expiratory volume in 1 s (FEV1), a common efficacy measure in all trials, proportion of FEV1 responders (≥100 mL increase from baseline) and safety outcomes were analyzed at Day 28, 56, and 84 in patients classified by age (<65, ≥65, and ≥75 years of age) and severity of baseline airflow limitation (Global initiative for chronic Obstructive Lung Disease [GOLD] stage 2 [moderate] and stage 3/4 [severe/very severe]). A 24-week analysis was also conducted for the UMEC/VI versus TIO comparison. RESULTS: The pooled intent-to-treat population comprised 3821 patients (≥65 years: 44-45%; ≥75 years: 9-10%; GOLD stage 3/4: 50-55%); 2246, 874, and 701 patients received UMEC/VI, TIO, or FP/SAL, respectively. Significant improvements in trough FEV1 at Day 84 were observed with UMEC/VI versus TIO or FP/SAL irrespective of age (all p ≤ 0.029) or GOLD stage (all p < 0.001). The proportion of FEV1 responders at Day 84 was significantly greater with UMEC/VI versus TIO or FP/SAL across all age groups (all p ≤ 0.016) and GOLD stages (all p < 0.001). Safety profiles were similar between treatment groups. CONCLUSION: UMEC/VI consistently demonstrated improved lung function versus TIO and FP/SAL across age and airflow limitation severity subgroups, with no safety concerns, indicating that UMEC/VI provides no loss in efficacy or additional safety concerns for both elderly patients with COPD and patients with severe/very severe airway limitation.