In COPD with type 2 inflammation despite inhaled triple therapy, dupilumab safely reduced exacerbations.

SOURCE CITATION: Bhatt SP, Rabe KF, Hanania NA, et al; BOREAS Investigators. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389;205-214.37272521.

Bacterial Patterns and Empiric Antibiotic Use in COPD Patients With Community-Acquired Pneumonia.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. METHODS: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. RESULTS: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. CONCLUSIONS: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.

Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT.

Rationale: There is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear. Objectives: To examine the relationship between BMI and adverse outcomes in COPD. Methods: This post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m2], normal weight [BMI 20 to <25 kg/m2], overweight [BMI 25 to <30 kg/m2], obesity class I [BMI 30 to <35 kg/m2], obesity class II [BMI 35 to <40 kg/m2], and obesity class III [BMI ⩾ 40 kg/m2]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. Results: In TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62-2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16-1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR. Conclusions: These results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD.

Multicenter International Cohort Validation of a Modified Sequential Organ Failure Assessment Score Using the Richmond Agitation-sedation Scale.

OBJECTIVE: In a multicenter, international cohort, we aimed to validate a modified Sequential Organ Failure Assessment (mSOFA) using the Richmond Agitation-Sedation Scale, hypothesized as comparable to the Glasgow Coma Scale (GCS)-based Sequential Organ Failure Assessment (SOFA). SUMMARY BACKGROUND DATA: The SOFA score, whose neurologic component is based on the GCS, can predict intensive care unit (ICU) mortality. But, GCS is often missing in lieu of other assessments, such as the also reliable and validated Richmond Agitation Sedation Scale (RASS). Single-center data suggested an RASS-based SOFA (mSOFA) predicted ICU mortality. METHODS: Our nested cohort within the prospective 2016 Fourth International Study of Mechanical Ventilation contains 4120 ventilated patients with daily RASS and GCS assessments (20,023 patient-days, 32 countries). We estimated GCS from RASS via a proportional odds model without adjustment. ICU mortality logistic regression models and c-statistics were constructed using SOFA (measured GCS) and mSOFA (measured RASS-estimated GCS), adjusted for age, sex, body-mass index, region (Europe, USA-Canada, Latin America, Africa, Asia, Australia-New Zealand), and postoperative status (medical/surgical). RESULTS: Cohort-wide, the mean SOFA=9.4+/-2.8 and mean mSOFA = 10.0+/-2.3, with ICU mortality = 31%. Mean SOFA and mSOFA similarly predicted ICU mortality (SOFA: AUC = 0.784, 95% CI = 0.769-0.799; mSOFA: AUC = 0.778, 95% CI = 0.763-0.793, P = 0.139). Across models, other predictors of mortality included higher age, female sex, medical patient, and African region (all P < 0.001). CONCLUSIONS: We present the first SOFA modification with RASS in a "real-world" international cohort. Estimating GCS from RASS preserves predictive validity of SOFA to predict ICU mortality. Alternative neurologic measurements like RASS can be viably integrated into severity of illness scoring systems like SOFA.

International Analgesia, Sedation, and Delirium Practices: a prospective cohort study.

BACKGROUND: While understanding of critical illness and delirium continue to evolve, the impact on clinical practice is often unknown and delayed. Our purpose was to provide insight into practice changes by characterizing analgesia and sedation usage and occurrence of delirium in different years and international regions. METHODS: We performed a retrospective analysis of two multicenter, international, prospective cohort studies. Mechanically ventilated adults were followed for up to 28 days in 2010 and 2016. Proportion of days utilizing sedation, analgesia, and performance of a spontaneous awakening trial (SAT), and occurrence of delirium were described for each year and region and compared between years. RESULTS: A total of 14,281 patients from 6 international regions were analyzed. Proportion of days utilizing analgesia and sedation increased from 2010 to 2016 (p < 0.001 for each). Benzodiazepine use decreased in every region but remained the most common sedative in Africa, Asia, and Latin America. Performance of SATs increased overall, driven mostly by the US/Canada region (24 to 35% of days with sedation, p < 0.001). Any delirium during admission increased from 7 to 8% of patients overall and doubled in the US/Canada region (17 to 36%, p < 0.001). CONCLUSIONS: Analgesia and sedation practices varied widely across international regions and significantly changed over time. Opportunities for improvement in care include increasing delirium monitoring, performing SATs, and decreasing use of sedation, particularly benzodiazepines.

Indacaterol/glycopyrronium versus salmeterol/fluticasone in the prevention of clinically important deterioration in COPD: results from the FLAME study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disease and a composite endpoint could be an indicator of treatment effect on disease worsening. This post-hoc analysis assessed whether indacaterol/glycopyrronium (IND/GLY) 110/50 µg once daily reduced the risk of clinically important deterioration (CID) versus salmeterol/fluticasone (SFC) 50/500 µg twice daily in moderate-to-very severe COPD patients from the FLAME study. METHODS: CID was defined as ≥100 mL decrease in forced expiratory volume in 1 s (FEV1) or ≥ 4-unit increase in St. George's Respiratory Questionnaire (SGRQ) total score or a moderate-to-severe COPD exacerbation. Changes from baseline in the rate of moderate and severe exacerbations, time to first moderate-to-severe exacerbation, and change from baseline in the SGRQ score, measured after Week 12 up to Week 52, were assessed by presence of early CID (CID+) or absence of CID (CID-) at Week 12. RESULTS: IND/GLY significantly delayed the time to CID (hazard ratio [HR] (95% confidence interval [CI]), 0.72 [0.67-0.78]; P < 0.0001), and reduced the incidences of CID versus SFC. Additionally, IND/GLY delayed the time to CID in all patient subgroups. After 12 weeks until 52 weeks, CID+ patients had a significantly higher rate of moderate-to-severe exacerbations versus CID- patients (P < 0.0001); moreover, CID+ patients experienced moderate-to-severe exacerbations significantly earlier versus CID- patients (P < 0.0001). CID+ patients had a comparable change in the SGRQ total score versus CID- patients. CONCLUSIONS: IND/GLY reduced the risk of CID versus SFC. CID had a significant impact on long-term exacerbation outcomes in patients with moderate-to-very severe COPD and a history of ≥1 exacerbations in the previous year. TRIAL REGISTRATION: Clinicaltrials.gov NCT01782326 .

Treatment of exacerbations as a predictor of subsequent outcomes in patients with COPD.

RATIONALE: Exacerbations of COPD are managed differently, but whether treatment of one exacerbation predicts the likelihood of subsequent events is unknown. OBJECTIVE: We examined whether the treatment given for exacerbations predicted subsequent outcomes. METHODS: This was a post-hoc analysis of 17,135 patients with COPD from TIOtropium Safety and Performance In Respimat® (TIOSPIR®). Patients treated with tiotropium with one or more moderate to severe exacerbations on study were analyzed using descriptive statistics, logistic and Cox regression analysis, and Kaplan-Meier plots. RESULTS: Of 8,061 patients with moderate to severe exacerbation(s), demographics were similar across patients with exacerbations treated with antibiotics and/or steroids or hospitalization. Exacerbations treated with systemic corticosteroids alone or in combination with antibiotics had the highest risk of subsequent exacerbation (HR: 1.21, P=0.0004 and HR: 1.33, P<0.0001, respectively), and a greater risk of having a hospitalized (severe) exacerbation (HR: 1.59 and 1.63, P<0.0001, respectively) or death (HR: 1.50, P=0.0059 and HR: 1.47, P=0.0002, respectively) compared with exacerbations treated with antibiotics alone. Initial hospitalization led to the highest risk of subsequent hospitalization (all-cause or COPD related [severe exacerbation], HR: 3.35 and 4.31, P<0.0001, respectively) or death (all-cause or COPD related, HR: 3.53 and 5.54, P<0.0001, respectively) versus antibiotics alone. CONCLUSION: These data indicate that the way exacerbations are treated initially is a useful guide to the patient's subsequent clinical course. Factors that clinicians consider when making treatment choices require further clarification.

Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial.

BACKGROUND: Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. METHODS: This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 µg-5 µg or tiotropium 5 µg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. FINDINGS: Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium-olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium-olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85-1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments. INTERPRETATION: Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. FUNDING: Boehringer Ingelheim International GmbH.

The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials.

BACKGROUND: When discontinuation in COPD randomized controlled trials (RCTs) is unevenly distributed between treatments (differential dropout), the capacity to demonstrate treatment effects may be reduced. We investigated the impact of the time of differential dropout on exacerbation outcomes in RCTs, in relation to study duration and COPD severity. METHODS: A post hoc analysis of 2,345 patients from three RCTs of 6- and 12-month duration was performed to compare budesonide/formoterol and formoterol in moderate, severe, and very severe COPD. Outcomes were exacerbation rate, time-to-first exacerbation, or discontinuation; patients were stratified by disease severity. Outcomes were studied by censoring data monthly from 1 to 12 months. RESULTS: In patients treated with budesonide/formoterol, annualized exacerbation rates (AERs) were comparable for each study duration (rate ratio [RR] =0.6). With formoterol, the AER decreased with study duration (RR =1.20 at 1 month to RR =0.86 at 12 months). There was a treatment-related difference in exacerbation rates of 45%-48% for shorter study durations (≤4 months) and 27% for 12-month duration. This treatment-related difference in exacerbation rates was comparable for the three disease severities in studies ≤4 months (range: 39%-51%), but this difference decreased with longer study durations, especially in more severe groups (22% and 29% at 12 months). There were fewer discontinuations with budesonide/formoterol; the treatment-related difference in time-to-first discontinuation decreased by study duration (35%, 30%, 26%, and 22% at 3, 6, 9, and 12 months, respectively). Numbers of differential dropouts increased with increasing disease severity, being greatest during second, third, and fourth months. CONCLUSIONS: COPD severity and study duration impact exacerbation as an outcome in double-blind RCTs. This effect is most obvious in patients with severe/very severe COPD and in studies that are longer than 4 months. Early differential dropout particularly impacts study outcome, producing a "healthy survivor effect," which reduces estimations of treatment impact on exacerbations.

The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD.

BACKGROUND: Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients. METHODS: Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George's Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1. RESULTS: Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001). With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036). CONCLUSION: These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD. Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting ß2-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population.

Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis.

BACKGROUND: Currently available antifibrotic treatments may slow down disease progression in idiopathic pulmonary fibrosis (IPF), but are associated with potentially significant side effects and are costly. Mycophenolate mofetil (MMF) is well known for its potent immunosuppressive properties and possesses important antiproliferative and antifibrotic effects. The safety and effectiveness of MMF in IPF is unknown. METHODS: We performed a retrospective multicohort analysis of IPF patients treated with MMF compared to those treated with either ineffective/harmful treatments or no treatment. Longitudinal change in forced vital capacity (FVC) between the groups was analyzed using a mixed model with random intercept and slope allowing for repeated measures within subjects. Categorical change in FVC, median overall survival, and adverse events were also assessed. RESULTS: Forty-one IPF patients were included: 11 treated with MMF, 20 treated with ineffective/harmful agents (such as prednisone, azathioprine, and/or NAC), and 10 did not receive any specific treatment for their IPF. After one year, there was a trend towards reduced FVC decline in the MMF-treated group (-76.3 mL, -2.4% of predicted) compared to the non-MMF-treated (-165 mL, -8.9% of predicted) and the no-treatment (-239 mL, -11.5% of predicted) groups, respectively. By categorical change, there was a trend towards greater FVC stability in the MMF-treated group (87.5%) compared to the non-MMF-treated (57%) and the no-treatment groups (50%), respectively. MMF-treated IPF patients had a trend towards improved median overall survival (40.3 months) compared to the non-MMF-treated (25.5 months) and the no-treatment (29.3 months) groups, respectively. Treatment-related adverse events were not different between groups; however, very few adverse events were reported overall. CONCLUSIONS: MMF treatment was associated with potentially clinically important trends toward reduced annual FVC decline (similar to approved antifibrotics), greater FVC stability and improved overall survival in IPF patients. MMF was generally safe, well tolerated, and relatively inexpensive. Future prospective studies of MMF in combination with antifibrotic therapy in IPF are needed.

Early efficacy of budesonide/formoterol in patients with moderate-to-very-severe COPD.

BACKGROUND AND OBJECTIVE: Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting ß2-agonist combinations in patients with chronic obstructive pulmonary disease (COPD). It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity. METHODS: Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very-severe COPD. Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 µg or placebo, twice daily; in one study, tiotropium 18 µg once daily was also given. RESULTS: Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with ≥1 exacerbation, respectively). This was true in each COPD severity group. Compared with placebo, B/F treatment led to significantly lower 3-month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD. Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity. B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo. CONCLUSION: Treatment with B/F decreased exacerbations in patients with moderate-to-very-severe COPD within 3 months of commencing treatment. This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity.

Early response to inhaled bronchodilators and corticosteroids as a predictor of 12-month treatment responder status and COPD exacerbations.

BACKGROUND: Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates. METHODS: This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2-12. Responders were defined by ≥100 mL improvement in prebronchodilator FEV1 and ≥4-point decrease in SGRQ total score. RESULTS: Overall, 2,331 and 1,799 patients were included in the 0-2- and 0-12-month responder analyses, respectively, and 2,360 patients in the 2-12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2-month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14-7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83-5.31). Two-month response in FEV1 (P<0.001), but not SGRQ (P=0.11), was associated with greater reductions in exacerbation risk. CONCLUSION: Early FEV1 and SGRQ treatment responses relate to their changes at 12 months. FEV1 response, but not SGRQ response, at 2 months predicts the risk of a future COPD exacerbation in some, but not all patients. This is potentially useful in clinical practice, although more sensitive and specific markers of favorable treatment response are required.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Guiding Principles for the Use of Nebulized Long-Acting Beta2-Agonists in Patients with COPD: An Expert Panel Consensus.

Determining which patients with COPD may benefit from a nebulized long-acting beta2-agonist (LABA) is a challenge in current practice. In the absence of strong clinical guidelines addressing this issue, an expert panel convened to develop guiding principles for the use of nebulized LABA therapy in patients with COPD. This article summarizes these guiding principles and other practical issues discussed during a roundtable meeting.

Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease.

BACKGROUND: Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations. We hypothesized that short-acting ß2-agonist (SABA) reliever use would predict short- and long-term exacerbation risk in COPD patients. METHODS: We performed a retrospective analysis of data from a study (ClinicalTrials.gov registration: NCT00419744) comparing budesonide/formoterol 320/9 µg with formoterol 9 µg (both twice daily) in patients with moderate-to-very-severe COPD; reliever salbutamol 90 µg was provided. First occurrence of reliever use >4 (low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term (3-week) exacerbation risk. Mean daily reliever use in the week preceding the 2-month visit was investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2-5, 6-9, and ≥10 inhalations/day. RESULTS: Overall, 810 patients were included (61 % male; mean age 63.2 years; post-bronchodilator forced expiratory volume in 1 s 37.7 % of predicted). First occurrence of low, medium, or high reliever use was predictive of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with increasing reliever use. Mean reliever use over 1 week was predictive of long-term exacerbation risk. Patients with mean use of 2-5, 6-9, and ≥10 inhalations/day exhibited 21 %, 67 %, and 135 % higher exacerbation rates, respectively, in the following 10 months, compared with <2 inhalations/day. Budesonide/formoterol was associated with lower short- and long-term exacerbation risk than formoterol in all reliever-use groups. CONCLUSIONS: SABA reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol.

Assessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.

The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).

Non-invasive mechanical ventilation and mortality in elderly immunocompromised patients hospitalized with pneumonia: a retrospective cohort study.

BACKGROUND: Mortality after pneumonia in immunocompromised patients is higher than for immunocompetent patients. The use of non-invasive mechanical ventilation for patients with severe pneumonia may provide beneficial outcomes while circumventing potential complications associated with invasive mechanical ventilation. The aim of our study was to determine if the use of non-invasive mechanical ventilation in elderly immunocompromised patients with pneumonia is associated with higher all-cause mortality. METHODS: In this retrospective cohort study, data were obtained from the Department of Veterans Affairs administrative databases. We included veterans age ≥65 years who were immunocompromised and hospitalized due to pneumonia. Multilevel logistic regression analysis was used to determine the relationship between the use of invasive versus non-invasive mechanical ventilation and 30-day and 90-day mortality. RESULTS: Of 1,946 patients in our cohort, 717 received non-invasive mechanical ventilation and 1,229 received invasive mechanical ventilation. There was no significant association between all-cause 30-day mortality and non-invasive versus invasive mechanical ventilation in our adjusted model (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.66-1.10). However, those patients who received non-invasive mechanical ventilation had decreased 90-day mortality (OR 0.66, 95% CI 0.52-0.84). Additionally, receipt of guideline-concordant antibiotics in our immunocompromised cohort was significantly associated with decreased odds of 30-day mortality (OR 0.31, 95% CI 0.24-0.39) and 90-day mortality (OR 0.41, 95% CI 0.31-0.53). CONCLUSIONS: Our findings suggest that physicians should consider the use of non-invasive mechanical ventilation, when appropriate, for elderly immunocompromised patients hospitalized with pneumonia.

Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans.

BACKGROUND: COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD. METHODS: We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW). RESULTS: Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms). CONCLUSIONS: Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.

Factor analysis in predominantly severe COPD: identification of disease heterogeneity by easily measurable characteristics.

BACKGROUND: The clinical and demographic variables defining the heterogeneity of chronic obstructive pulmonary disease (COPD) are unclear. A post-hoc analysis of five randomised studies in patients with a history of previous exacerbations examined the clinical and demographic characteristics describing moderate-to-very-severe COPD. METHODS: Factor analysis was performed on all continuous baseline demographic and clinical data, without variable selection. Analyses were based on the full cohort and on stratifications by pack-years smoked, smoking status, gender, and comorbidities; patient exacerbation history was analysed in two of the five studies. FINDINGS: 6162 COPD patients were evaluated (70% male; 40% current smokers; mean pre-bronchodilator forced expiratory volume in 1 s [FEV1] 35.2% predicted). Baseline clinical and demographic variables loaded differentially on six factors with minimal overlap, explaining 60.4% of the heterogeneity: 1) symptoms (cough, dyspnoea, sleep disturbance), health status, reliever use; 2) pre-bronchodilator FEV1, FEV1/forced vital capacity, morning peak expiratory flow (PEF), body mass index (BMI); 3) blood pressure; 4) age, months since first COPD symptoms; 5) PEF variability; 6) pulse, FEV1 reversibility. Most factors loaded similarly in stratified and exacerbation analyses. BMI loaded with reversibility in females, and with age and months since first COPD symptoms in ex-smokers. Exacerbations loaded to factor 6. INTERPRETATION: Readily available data can explain ≈ 60% of COPD heterogeneity in a large dataset of predominantly severe COPD patients. Factors were robust over determinants of disease outcome; gender, smoking status, pack-years smoked, and comorbidities. The main factors were largely unchanged by adding exacerbations. Only BMI loaded to other factors.