Nicholas Locantore

Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease

BACKGROUND Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patients recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)

Determinants of Depression in the ECLIPSE Chronic Obstructive Pulmonary Disease Cohort

RATIONALE Depression is prevalent in patients with chronic obstructive pulmonary disease (COPD); however, its etiology and relationship to the clinical features of COPD are not well understood. OBJECTIVES Using data from a large cohort, we explored prevalence and determinants of depression in subjects with COPD. METHODS The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study is an observational 3-year multicenter study that enrolled smokers with and without COPD and nonsmoker controls. At baseline, several patient-reported outcomes were measured including the Center for Epidemiologic Studies of Depression Scale. For the purposes of this analysis, depression was defined as a score of 16 and higher on this scale, which reflects a high load of depressive symptoms and has a good correspondence with a clinical diagnosis of major depression. MEASUREMENTS AND MAIN RESULTS The study cohort consisted of 2,118 subjects with COPD; 335 smokers without COPD (smokers); and 243 nonsmokers without COPD (nonsmokers). A total of 26%, 12%, and 7% of COPD, smokers, and nonsmokers, respectively, suffered from depression. In subjects with COPD, higher depression prevalence was seen in females, current smokers, and those with severe disease (Global Initiative for Obstructive Lung Disease [GOLD]-defined). Multivariate modeling of depression determinants in subjects with COPD revealed that increased fatigue, higher St. Georges Respiratory Questionnaire for COPD patients score, younger age, female sex, history of cardiovascular disease, and current smoking status were all significantly associated with depression; physiologic and biologic measures were weak or nonsignificant descriptors. CONCLUSIONS Depression is more prevalent in subjects with COPD compared with smokers and nonsmokers without COPD. Clinical and biologic measures were less important determinants of depression in COPD than disease symptoms and quality-of-life. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St Georges Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.

Eosinophilic inflammation in COPD: prevalence and clinical characteristics

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with patients displaying varying clinical and pathophysiological features. The identification of COPD phenotypes with distinct characteristics may allow targeted treatment strategies directed towards specific biological pathways. Eosinophilic inflammation is thought to be a characteristic feature of asthma rather than COPD. However, studies have shown that a subset of COPD patients with eosinophilic airway inflammation exists, even after the careful exclusion of patients with any features of asthma, such as β-agonist reversibility, bronchial hyperresponsiveness, atopy or a childhood history of asthma [1–4]. Interestingly, these patients exhibit the greatest response to corticosteroid treatment [1–4]. Likewise, sputum eosinophil numbers are increased in a subset of COPD exacerbations [5, 6], and titrating corticosteroid therapy according to sputum eosinophil counts reduces exacerbation rates [7]. Furthermore, there are similar increases in sputum and blood eosinophil numbers during COPD exacerbations [5]; using blood eosinophils as a surrogate maker for airway eosinophils to direct oral corticosteroid therapy for the treatment of COPD exacerbations enhances clinical recovery [8]. Taken together, these observations suggest that eosinophilic airway inflammation in COPD is a predictive biomarker of corticosteroid responsiveness during clinical stability and exacerbations. The prevalence of eosinophilic inflammation in COPD patients is unknown. We do not know whether patients with sputum or blood eosinophilia represent a stable COPD phenotype over time and, apart from corticosteroid responsiveness, little is known about the other clinical characteristics of this subset of patients. We analysed samples from the ECLIPSE (Evaluation of COPD Longitudinally to Identify …

Efficacy and safety of an anti–IL-13 mAb in patients with severe asthma: A randomized trial

BACKGROUND Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti-IL-13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor α1 and α2. OBJECTIVES We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids. METHODS Patients who remained symptomatic (Asthma Control Questionnaire score ≥1.5) after uptitration to 1000 μg/d fluticasone propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n = 99) or placebo (n = 99). RESULTS Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586 = -0.31, placebo = -0.17, P = .058) and FEV₁ (GSK679586 = -0.01, placebo = 0.03, P = .276). Similar analyses in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most adverse events were nonserious and unrelated to treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles). CONCLUSIONS Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids.

Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort.

OBJECTIVE Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N = 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort. METHODS An analysis of time to first event of hospital admission was performed using Kaplan-Meier curves and Cox proportional hazard regression adjusting for possible confounders. RESULTS Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P < .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P < .001). CONCLUSIONS Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov.

Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease

RATIONALE There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. OBJECTIVES To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. METHODS PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. MEASUREMENTS AND MAIN RESULTS Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. CONCLUSIONS Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease

Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long‐acting &bgr;2‐agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. Objectives: We compared the effects of once‐daily triple therapy on lung function and health‐related quality of life with twice‐daily ICS/LABA therapy in patients with COPD. Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double‐blind, double‐dummy study comparing 24 weeks of once‐daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 &mgr;g/62.5 &mgr;g/25 &mgr;g; ELLIPTA inhaler) with twice‐daily ICS/LABA therapy (budesonide/formoterol 400 &mgr;g/12 &mgr;g; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co‐primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24. Measurements and Main Results: In the intent‐to‐treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and −29 ml (95% CI, −46 to −13), respectively, and mean changes from baseline in SGRQ scores were −6.6 units (95% CI, −7.4 to −5.7) and −4.3 units (95% CI, −5.2 to −3.4), respectively. For both endpoints, the between‐group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14‐51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. Conclusions: These results support the benefits of single‐inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10−6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

A phase 1, randomized, placebo‐controlled, dose‐escalation study of an anti‐IL‐13 monoclonal antibody in healthy subjects and mild asthmatics

AIMS IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586. METHODS In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo. RESULTS GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs. CONCLUSIONS GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.