Sputum neutrophils as a biomarker in COPD: findings from the ECLIPSE study

<p>Abstract</p> <p>Introduction</p> <p>The percentage of neutrophils in sputum are increased in COPD patients, and may therefore be a biomarker of airway inflammation. We studied the relationships between sputum neutrophils and FEV₁, health status, exacerbation rates, systemic inflammation and emphysema, and long term variability at 1 year.</p> <p>Methods</p> <p>Sputum samples were obtained from 488 COPD patients within the ECLIPSE cohort. 359 samples were obtained at baseline, and 297 after 1 year. 168 subjects provided samples at both visits. Serum interleukin-6 (IL-6), IL-8, surfactant protein D and C-reactive protein levels were measured by immunoassays. Low-dose CT scans evaluated emphysema.</p> <p>Results</p> <p>Sputum neutrophil % increased with GOLD stage. There was a weak association between % sputum neutrophils and FEV₁% predicted (univariate r²= 0.025 and 0.094 at baseline and year 1 respectively, p < 0.05 after multivariate regression). Similar weak but significant associations were observed between neutrophil % and health status measured using the St Georges Respiratory Questionairre. There were no associations between neutrophils and exacerbation rates or emphysema. Associations between sputum neutrophils and systemic biomarkers were non-significant or similarly weak. The mean change over 1 year in neutrophil % was an increase of 3.5%.</p> <p>Conclusions</p> <p>Sputum neutrophil measurements in COPD are associated weakly with FEV₁% predicted and health status. Sputum neutrophil measurements were dissociated from exacerbation rates, emphysema and systemic inflammation.</p

The Effect of a Short Duration, High Intensity Exercise Intervention on Gait Biomechanics in Patients With COPD: Findings From a Pilot Study

Previous work has shown that patients with chronic obstructive pulmonary disease (COPD) demonstrate changes in their gait biomechanics as compared to controls. This pilot study was designed to explore the possibility that biomechanical alterations present in COPD patients might be amenable to treatment by exercise training of skeletal muscle. This study investigated the effect of a 6-week exercise intervention on gait biomechanics in patients with COPD under both a rest and a non-rested condition. Seven patients with COPD underwent a supervised cardio-respiratory and strength training protocol 2-3 times per week for 6-weeks for a total of 16-sessions. Spatiotemporal, kinematic and kinetic gait variables were collected prior to and post intervention. All patients demonstrated significant improvements in strength following the intervention. The knee joint biomechanics demonstrated a significant main effect for intervention and for condition. Step width demonstrated a significant interaction as it decreased from pre- to post-intervention under the rest condition and increased under the non-rested condition. It does appear that being pushed (non-rested) has a strong influence at the knee joint. The quadriceps muscles, the primary knee extensors, have been shown to demonstrate muscular abnormalities in patients with COPD and the intervention may have influenced gait patterns through an effect on this skeletal muscle structure and function. Additionally, the intervention influenced step width closer to a more healthy value. Patients with COPD are more likely to fall and step width is a risk factor for falling suggesting the intervention may address fall risk. Whether a longer duration intervention would have more profound effects remains to be tested

Platelets stimulate fibroblast-mediated contraction of collagen gels

BACKGROUND: Platelets are thought to play a role in a variety of inflammatory conditions in the lung, some of which may lead to fibrosis. In the current study we tested the hypothesis that whole platelets and platelet lysate can mediate remodelling of extracellular matrix in vitro by affecting fibroblast-mediated contraction of a collagen gel. We also sought to determine to what extent platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) contribute to this effect. METHODS: Washed platelets, isolated from healthy blood donors, and platelet lysate (freezing and thawing), were cast together with human lung fibroblasts in three-dimensional collagen gels. The gels were then released and cultured for four days. PDGF and TGF-β(1 )concentrations were measured in culture supernatants by ELISA. RESULTS: Both platelets and platelet lysate augmented fibroblast-mediated gel contraction in a time and concentration dependent manner (19.9% ± 0.1 (mean ± SEM) of initial area vs. 48.0% ± 0.4 at 48 hours; P < 0.001 and 41.5% ± 0.6 vs. 60.6% ± 0.3 at 48 hours; P < 0.001, respectively). Fixed platelets had no effect in the system. Both TGF-β(1 )and PDGF-AA/AB were released in co-culture. PDGF-AA/AB had a maximum release at 24 hours whereas TGF-β(1 )release increased with longer culture periods. Neutralising antibodies to these mediators partially inhibited platelet-induced gel contraction. CONCLUSION: We conclude that platelets may promote remodelling of extracellular matrix in vitro and that PDGF and TGF-β partially mediate this effect, also indicating a role for other mediators. The findings may be an important mechanism in regulating repair processes after injury

Patients with Chronic Obstructive Pulmonary Disease Walk with Altered Step Time and Step Width Variability as Compared with Healthy Control Subjects

Rationale: Compared with control subjects, patients with chronic obstructive pulmonary disease (COPD) have an increased incidence of falls and demonstrate balance deficits and alterations in mediolateral trunk acceleration while walking. Measures of gait variability have been implicated as indicators of fall risk, fear of falling, and future falls. Objectives: To investigate whether alterations in gait variability are found in patients with COPD as compared with healthy control subjects. Methods: Twenty patients with COPD (16 males; mean age, 63.6 ± 9.7 yr; FEV1/FVC, 0.52 ± 0.12) and 20 control subjects (9 males; mean age, 62.5 ± 8.2 yr) walked for 3 minutes on a treadmill while their gait was recorded. The amount (SD and coefficient of variation) and structure of variability (sample entropy, a measure of regularity) were quantified for step length, time, and width at three walking speeds (self-selected and ±20% of self-selected speed). Generalized linear mixed models were used to compare dependent variables. Results: Patients with COPD demonstrated increased mean and SD step time across all speed conditions as compared with control subjects. They also walked with a narrower step width that increased with increasing speed, whereas the healthy control subjects walked with a wider step width that decreased as speed increased. Further, patients with COPD demonstrated less variability in step width, with decreased SD, compared with control subjects at all three speed conditions. No differences in regularity of gait patterns were found between groups. Conclusions: Patients with COPD walk with increased duration of time between steps, and this timing is more variable than that of control subjects. They also walk with a narrower step width in which the variability of the step widths from step to step is decreased. Changes in these parameters have been related to increased risk of falling in aging research. This provides a mechanism that could explain the increased prevalence of falls in patients with COPD

Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation.</p> <p>Methods</p> <p>Serum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay.</p> <p>Results</p> <p>Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile.</p> <p>Conclusions</p> <p>A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov, <it>No</it>.: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00056264">NCT00056264</a>.</p

Updated Perspectives on the Role of Biomechanics in COPD: Considerations for the Clinician

Patients with chronic obstructive pulmonary disease (COPD) demonstrate extra-pulmonary functional decline such as an increased prevalence of falls. Biomechanics offers insight into functional decline by examining mechanics of abnormal movement patterns. This review discusses biomechanics of functional outcomes, muscle mechanics, and breathing mechanics in patients with COPD as well as future directions and clinical perspectives. Patients with COPD demonstrate changes in their postural sway during quiet standing compared to controls, and these deficits are exacerbated when sensory information (eg, eyes closed) is manipulated. If standing balance is disrupted with a perturbation, patients with COPD are slower to return to baseline and their muscle activity is differential from controls. When walking, patients with COPD appear to adopt a gait pattern that may increase stability (eg, shorter and wider steps, decreased gait speed) in addition to altered gait variability. Biomechanical muscle mechanics (ie, tension, extensibility, elasticity, and irritability) alterations with COPD are not well documented, with relatively few articles investigating these properties. On the other hand, dyssynchronous motion of the abdomen and rib cage while breathing is well documented in patients with COPD. Newer biomechanical technologies have allowed for estimation of regional, compartmental, lung volumes during activity such as exercise, as well as respiratory muscle activation during breathing. Future directions of biomechanical analyses in COPD are trending toward wearable sensors, big data, and cloud computing. Each of these offers unique opportunities as well as challenges. Advanced analytics of sensor data can offer insight into the health of a system by quantifying complexity or fluctuations in patterns of movement, as healthy systems demonstrate flexibility and are thus adaptable to changing conditions. Biomechanics may offer clinical utility in prediction of 30-day readmissions, identifying disease severity, and patient monitoring. Biomechanics is complementary to other assessments, capturing what patients do, as well as their capability

Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD

<p>Abstract</p> <p>Background</p> <p>As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.</p> <p>Methods</p> <p>The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.</p> <p>Results</p> <p>The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).</p> <p>Conclusions</p> <p>This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.</p> <p>Trials registration</p> <p>ClinicalTrials.gov identifiers: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00076089">NCT00076089</a> and <a href="http://www.clinicaltrials.gov/ct2/show/NCT00430729">NCT00430729</a>.</p

Long-term safety study of infliximab in moderate-to-severe chronic obstructive pulmonary disease

SummaryRationaleThere was an increased number of malignancies in infliximab-treated (5.7%) over placebo-treated (1.3%) patients in a 44-week, phase 2 clinical study of 234 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).ObjectivesTo collect malignancy and mortality data from completed clinical studies of infliximab in COPD treatment.MethodsThe multicenter, observational Remicade Safety Under Long-Term Study in COPD (RESULTS COPD) collected malignancy and mortality data every six months for five years from patients who received ≥1 study-agent dose in a phase 2 study. Co-primary endpoints were the number of patients with malignancy and the number of deaths. Secondary endpoints included the number of patients with a malignancy according to malignancy type.ResultsThere was a gap period between the end of the phase 2 study and the initiation of RESULTS COPD, during which six malignancies and 14 deaths were reported spontaneously for the 107 (45.7%) of 234 patients with long-term safety information. Twenty-eight patients (overall 12.0%; placebo 10.4%, infliximab 12.7%) reported malignancies, including 12 patients during RESULTS COPD. Twenty-six patients (overall 11.1%; placebo 9.1%, infliximab 12.1%) died, including nine during RESULTS COPD. Lung cancer was the most common malignancy type (placebo n = 2; infliximab n = 10).ConclusionsThe greater proportion of malignancies observed with infliximab versus placebo in a phase 2 study diminished over the long-term follow-up. Due to the observational nature, limited patient participation, potential reporting bias from the interim spontaneous reporting period, and unblinding of all patients, more definitive conclusions cannot be drawn.Trial Registration Number: NCT00056264

Walking abnormalities are associated with COPD: An investigation of the NHANES III dataset

Research on the peripheral effects of COPD has focused on physiological and structural changes. However, different from muscular weakness or decreased physical activity, mechanical abnormalities of the muscular system, e.g. walking, have yet to be investigated. Our purpose was to utilize the National Health and Nutritional Examination Survey (NHANES) dataset to determine whether walking abnormalities are associated with COPD severity. To determine if walking abnormalities were independently associated with COPD severity, our analysis aimed to investigate the association of physical activity levels with COPD severity and with walking abnormalities. The NHANES III dataset that contains data for 31,000 persons that were collected from 1988 to 1994, was used to explore the association of COPD severity on gross walking abnormalities, i.e. limp, shuffle, etc. Logistic regression models were created using FEV1/FVC ratio, age, gender, BMI, and smoking status as predictors of walking abnormalities and physical activity in persons aged 40 to 90 years old. Results demonstrated a significant correlation between the presence of walking abnormalities and severe COPD (odds ratio: 1.97; 95% CI: 1.1 to 3.5). This suggests that disease severity can contribute to mechanical outcomes of patients with COPD. In addition, decreased physical activity levels were significantly associated with all COPD severity levels with the exception of mild COPD. The association between altered gait and COPD status may be due to the presence of physical inactivity that is present in patients with COPD. Future research directions should include investigating more closely the mechanical outcomes of persons with COPD