Severe Stable Chronic Obstructive Pulmonary Disease Research Articles

Tai Chi as a complementary exercise for pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomised controlled trial

ObjectivesWith the characteristics of mindfulness and breathing techniques, Tai Chi has been recommended with therapeutic values in chronic obstructive pulmonary disease (COPD). However, its strengths as a complementary exercise for conventional pulmonary rehabilitation (PR) remain unclear. Design and settingThis single-blinded randomised controlled trial recruited patients with mild to severe stable COPD. Eligible participants were randomly assigned to the group with usual care (control), total body recumbent stepper (TBRS) exercise, Tai Chi (TC), or combined TBRS exercise and Tai Chi (TBRS-TC). Patients received a two-month hospital-based supervised exercise, followed by a ten-month community- or home-based rehabilitation program. ResultsA total of 120 participants were recruited, and 102 were included in the per-protocol analysis. The mean changes in St George’s Respiratory Questionnaire (SGRQ) total score from baseline to the post-hospital exercise in the control group, TBRS group, TC group, and TBRS-TC group was 2.62 (95 % CI −8.99 to 8.99), −9.28 (95 % CI −13.96 to −4.60), −10.19 (95 % CI −13.72 to −6.67), and −16.75 (95 % CI −20.25 to −13.24), respectively, with a statistically significant difference between groups in favor of the TBRS-TC exercise (P < 0.001). The remarkable effect of TBRS-TC exercise in improving the quality of life maintained until the end of the community- or home-based rehabilitation training (P < 0.001). Besides, a statistically better effect with the TBRS-TC exercise was also observed in the outcomes regarding exercise capacity, pulmonary function, symptom burden, and systemic inflammation after the whole process of 12-month integrative PR exercise programme. ConclusionsBased on the results, a novel integrated exercise modality combining Tai Chi and conventional pulmonary rehabilitation was developed. It might contribute to more positive effects in patients with stable COPD. RegistrationThe study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-15006874) prior to commencing recruitment.

Safety evaluation of revefenacin at the approved dose in patients with chronic obstructive pulmonary disease: A meta-analysis

BackgroundRevefenacin is the first once-daily long-acting muscarinic antagonist (LAMA) for nebulization use in maintenance therapy for patients with chronic obstructive pulmonary disease (COPD). ObjectiveTo investigate the safety and tolerability profile of revefenacin at the approved dose (175 μg), compared with placebo and a lower dose (88 μg), for the treatment of COPD. MethodsAvailable randomized controlled trials (RCTs), both published and unpublished, were identified via databases. Risk differences (RDs) and risk ratios (RRs), with their corresponding 95% confidence intervals (CIs) were calculated as effect sizes. ResultsOne unpublished RCT and four articles containing 5 RCTs were included. Combined results showed that there were no significant differences between COPD patients receiving 175 μg revefenacin and those receiving a placebo, concerning the risk of discontinuation due to adverse events (AEs), any all-grade AE, or any serious AE. 175 μg revefenacin also did not significantly increase the risk of antimuscarinic-related AEs, cardiovascular AEs, or 12 commonly reported AEs. Plus, a lower dose of 88 μg was shown to share a comparable safety profile with the 175 μg revefenacin. A non-significant trend towards a decrease in risks of AEs for 175 μg revefenacin was observed. The most frequently reported AE for each group was COPD worsening/exacerbation. ConclusionRevefenacin at the approved dose is generally well-tolerated and safe with minimal AEs, which supports its use as a once-daily nebulized LAMA for the treatment of moderate to severe stable COPD. Additional studies are needed to complete the safety and tolerability profile.

Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD)

BackgroundRefractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine.MethodsWe describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV1 < 50%, mMRC ≥ 3, on optimal standard therapy) will be included.DiscussionEvidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD.Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363.

Acute effects of noninvasive ventilation on sleep physiology in patients with moderate to severe stable chronic obstructive pulmonary disease: a pilot study

Objective/backgroundChanges in sleep architecture in patients with Chronic Obstructive Pulmonary Disease (COPD) can be explained by a combination of physiological changes in breathing during sleep, with impairment of respiratory mechanics and reduction of arterial oxygenation. This study aimed to evaluate the acute effects of noninvasive ventilation (NIV) – compared to spontaneous breathing – on sleep latency and stages, and on the occurrence of sleep-related respiratory events, nocturnal hypoxemia, and changes in heart rate (HR) in patients with moderate to severe stable COPD. Patients/methodsPatients completed two polysomnography (PSG) studies: one during spontaneous breathing and one while receiving NIV in bilevel mode and with backup respiratory rate (RR.) setting. Sleepware G3 software was used for the analysis of PSG and pressure, volume, and ventilator flow curves × time. ResultsParticipants were 10 female patients with a mean age of 68.1 ± 10.2 years. NIV during sleep decreased sleep onset latency (17 ± 18.8 min vs 46.8 ± 39.5 min; p = 0.02), increased REM sleep time (41.2 ± 24.7 min vs 19.7 ± 21.7 min; p = 0.03), and decreased the obstructive apnea index (OAI) (0 vs 8.7 ± 18.8; p = 0.01). Lower mean HR (66.6 ± 4.1 bpm vs 70.6 ± 5.9 bpm; p = 0.03) and lower maximum HR (84.1 ± 7.3 bpm vs 91.6 ± 7.8 bpm; p = 0.03) were observed in PSG with NIV. ConclusionsThe use of NIV in patients with moderate to severe stable COPD while they were sleeping increased REM sleep time and decreased sleep onset latency, the number of obstructive respiratory events, and the mean and maximum HR.

Exploration of n-6 and n-3 Polyunsaturated Fatty Acids Metabolites Associated with Nutritional Levels in Patients with Severe Stable Chronic Obstructive Pulmonary Disease.

Background and ObjectiveSevere chronic obstructive pulmonary disease (COPD) is the terminal stage of the disease characterized by declined lung function, malnutrition, and poor prognosis. Such patients cannot tolerate long-time sports rehabilitation owing to dyspnea and fail to achieve the desired therapeutic effect; therefore, increasing nutritional support will be an important strategy for them. The present study applied metabolomics technology to evaluate the correlation between serum concentrations of polyunsaturated fatty acid (PUFA) metabolites, nutritional status, and lung function in patients with COPD to provide a theoretical basis for accurate nutritional support.Materials and MethodsWe enrolled 82 patients with stable severe COPD in our hospital. The general characteristics including height, weight, and lung function were recorded. Metabolomics was used to detect the concentrations of serum metabolites of n-3 and n-6 at baseline and at 24 and 52 weeks after enrollment. The correlations between nutrition level and pulmonary function and clinical indicators were evaluated.ResultsThe concentrations of n-3 and n-6 increased over time along with the progression of COPD. Body mass index (BMI) and percent of ideal body weight (IBW%) decreased with disease development, and BMI was found to be significantly correlated with FEV1% predicted and FEV1/FVC. Serum levels of n-6 metabolites such as linoleic acid (LA), γ-linoleic acid (GLA), and arachidonic acid (ARA) (all P < 0.01) and the n-3 metabolites such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (all P < 0.05) showed significant correlations with BMI and were closely correlated with FEV1% predicted and FEV1/FVC of lung function (all P< 0.05).ConclusionThis study demonstrates that malnutrition in patients with severe COPD is progressive and is positively correlated with n-3 and n-6 polyunsaturated fatty acids and lung function.

Treatment of severe stable COPD: the multidimensional approach of treatable traits.

Now that additional treatment options for severe chronic obstructive pulmonary disease (COPD) have emerged in recent years, patients with severe COPD should not be left in the rather hopeless situation of “there is nothing to improve” any more. Inertia or fatalism is a disservice to our patients. Ranging from advanced care planning to quite intense and demanding therapies such as multidisciplinary pulmonary rehabilitation, (endoscopic) lung volume reduction, chronic noninvasive ventilation and lung transplantation, caregivers should try to provide a personalised treatment for every severe COPD patient. In this review, we aim to describe the multidimensional approach to these patients at our centre along the lines of treatable traits leading to specific additional treatment modalities on top of standard care.

DIAGNOSTIC CRITERIA FOR THE PROGRESSION OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE UNDER A HIGH TECHNOGENIC LOAD

Introduction. The prevalence and gain in the incidence of chronic obstructive pulmonary disease (COPD) is a reason to search for new approaches to the diagnosis of its progression. Air pollution causes an additional burden on COPD patients, contributing to the progression of this pathology. The study of mechanisms of its impact on the inflammatory response in COPD is an urgent task. The aim is to establish the dynamics of expression of interleukin-4 (IL-4), IL-6 and their membrane receptors (IL-4R, IL-6R) in blood T-helpers during COPD progression in patients living in areas with the high technogenic load. Material and methods. Vladivostok was chosen as a region with significant technogenic air pollution - the amount of air pollutants is 59.9 thousand tons per year, with 80% related to vehicle emissions; the surface layer of air is characterized by a predominance of particles less than 10 µm, which are the most pathogenic for the respiratory system. Patients with stable mild (36), moderate (52 ) and severe COPD (24) patients living in Vladivostok for at least 5 years were examined. The control group consisted of healthy volunteers living in the same area (32cases). The levels of IL-4, IL-6 in plasma and the number of T-helper cells expressing IL-4R and IL-6R were determined by flow cytometry. Results. A decline in serum IL-4 concentration and an increase in serum IL-6 level in COPD patients living under constant air pollution has been found. A decrease in IL-4R expression in blood T-helpers at all COPD stages and the gain in IL-6R synthesis in blood T-helpers during the progression of COPD were established. Conclusion. Data on the expression of IL-6R and IL-4R on circulating T-helpers can be used to diagnose the progression of COPD in patients living in urbanized areas.

ДИАГНОСТИЧЕСКИЕ КРИТЕРИИ ПРОГРЕССИРОВАНИЯ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЁГКИХ В УСЛОВИЯХ ПОВЫШЕННОЙ ТЕХНОГЕННОЙ НАГРУЗКИ

Introduction. The prevalence and gain in the incidence of chronic obstructive pulmonary disease (COPD) is a reason to search for new approaches to the diagnosis of its progression. Air pollution causes an additional burden on COPD patients, contributing to the progression of this pathology. The study of mechanisms of its impact on the inflammatory response in COPD is an urgent task. The aim is to establish the dynamics of expression of interleukin-4 (IL-4), IL-6 and their membrane receptors (IL-4R, IL-6R) in blood T-helpers during COPD progression in patients living in areas with the high technogenic load. Material and methods. Vladivostok was chosen as a region with significant technogenic air pollution - the amount of air pollutants is 59.9 thousand tons per year, with 80% related to vehicle emissions; the surface layer of air is characterized by a predominance of particles less than 10 µm, which are the most pathogenic for the respiratory system. Patients with stable mild (36), moderate (52 ) and severe COPD (24) patients living in Vladivostok for at least 5 years were examined. The control group consisted of healthy volunteers living in the same area (32cases). The levels of IL-4, IL-6 in plasma and the number of T-helper cells expressing IL-4R and IL-6R were determined by flow cytometry. Results. A decline in serum IL-4 concentration and an increase in serum IL-6 level in COPD patients living under constant air pollution has been found. A decrease in IL-4R expression in blood T-helpers at all COPD stages and the gain in IL-6R synthesis in blood T-helpers during the progression of COPD were established. Conclusion. Data on the expression of IL-6R and IL-4R on circulating T-helpers can be used to diagnose the progression of COPD in patients living in urbanized areas.

Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease.

The role of noninvasive positive pressure ventilation (NIV) in severe chronic obstructive pulmonary disease (COPD) has been controversial. Over the past two decades, data primarily obtained from Europe have begun to define the clinical characteristics of patients likely to respond, the role of high-intensity NIV, and the potential best timing of initiating therapy. These approaches, however, have not been validated in the context of the U.S. healthcare delivery system. Use of NIV in severe COPD in the United States is limited by the practicalities of doing in-hospital titrations as well as a complex system of reimbursement. These systematic complexities, coupled with a still-emerging clinical trial database regarding the most effective means to deliver NIV, have led to persistent uncertainty regarding when in stable severe COPD treatment with NIV is actually appropriate. In this review, we propose an assessment algorithm and treatment plan that can be used in clinical practice in the United States, but we acknowledge that the absence of pivotal clinical trials largely precludes a robust evidence-based approach to this potentially valuable therapy.

Effects of home-based neuromuscular electrical stimulation in severe chronic obstructive pulmonary disease patients: a randomized controlled clinical trial.

Chronic obstructive pulmonary disease (COPD) patients experience a sustained deterioration of several capacities. Those with severe COPD undergo a considerable decline in their physical and functional capacities, but pulmonary rehabilitation (PR) is used to reduce the weakness of such patients. To date, neuromuscular electrical stimulation (NMES) has been used in acute COPD patients but NMES superimposed onto voluntary muscular contraction has not been tested in COPD patients. The aim of this study was to evaluate the effects of superimposed NMES on the cardiorespiratory performance and functionality of severe COPD patients undergoing a home-based rehabilitation program. This was a randomized controlled clinical trial. A total of 36 stable severe COPD patients were included in this study and were randomly divided into two groups: an intervention group and a control group. The study was conducted as a home-based program. The control group received standard medical treatment. The intervention group additionally underwent an individualized physical therapy program. The intervention consisted of a pulmonary rehabilitation (PR) protocol for 8 weeks (2 h/week). The protocol was carried out as follows: 10 minutes of controlled breathing training; 30 minutes of NMES superimposed onto voluntary muscular contraction; and 5 minutes of relaxation/cool-down. The outcome measures were cardiorespiratory performance measured using the 6-Minute Walk Test in the treadmill and functionality assessed with the functional independence measure. In the intervention group, significant improvements were observed after the treatment in cardiorespiratory performance and functionality (P<0.05), while the control group did not show any significant changes (P>0.05). The between-group analysis showed significant differences in cardiorespiratory performance and functionality (P<0.05). An 8-week individualized home-based PR program including controlled breathing training, aerobic exercise with elastic bands, and NMES superimposed onto voluntary muscle contraction significantly improves cardiorespiratory performance and functionality in stable COPD patients. A home-based pulmonary rehabilitation program including controlled breathing training, and NMES superimposed onto voluntary muscle contraction significantly improves cardiorespiratory performance and functionality in stable COPD patients.

Effect of home noninvasive positive pressure ventilation on patients with severe stable chronic obstructive pulmonary disease: a meta-analysis

Objective: To evaluate the effect of home noninvasive positive pressure ventilation (NPPV) on patients with severe stable chronic obstructive pulmonary disease(COPD) by meta-analysis. Methods: The data of this meta-analysis was retrieved from the PubMed, EMBASE, Cochrane library, Wanfang, Weipu and CNKI databases from January 1980 to January 2016. Randomized controlled trials (RCTs) on comparison of the effect of home NPPV in patients with severe stable COPD were enrolled. The enrolled data were divided into different subgroups in terms of the levels of inspiratory positive airway pressure(IPAP), different duration of ventilation per day, and different levels of baseline hypercapnia on change in PaCO(2). Meta-analysis was performed to compare the effect of different subgroups by RevMan 5.3. Results: Ten studies with a total of 789 patients were included. Home NPPV improved 6-minute walk distance (WMD: -45.12, 95%CI: -85.39--4.85, P=0.03) and forced expiratory volume in the first second [standard mean difference(SMD): -0.26, 95%CI: -0.51--0.02, P=0.03]after 1 year of ventilation, but did not improve the mortality, PaCO(2,)PaO(2,)pH, FVC, maximal inspiratory pressure (MIP), FEV(1)/FVC, maximal voluntary ventilation(MVV) total sleep time, sleep efficiency and the proportion of rapid eye movement (REM) sleep. Subgroup analysis showed that home NPPV can significantly reduce the PaCO(2) in patients ventilated with 18 cmH(2)O(1 cmH(2)O=0.098 kPa) and higher IPAP levels than those with lower IPAP levels (SMD: -0.6, 95%CI: -1.09--0.12, P=0.01), and in patients with NPPV for at least 5 h per day and those with lower duration (SMD: -0.45, 95%CI: -0.87--0.02, P=0.04), and in patients with baseline PaCO(2) of at least 55 mmHg (1 mmHg=0.133 kPa) (SMD: -0.69, 95%CI: -1.07--0.31, P=0.00) than those with lower levels. Conclusions: Home NPPV can improve 6MWD and FEV(1) in severe stable COPD patients but does not improve the mortality, gas exchange and sleep efficiency. Patients may gain more benefits when using higher IPAP levels, longer ventilation per day and in those with higher baseline PaCO(2).

Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression.

Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4+ and CD8+ cells and airflow obstruction. NOD1 expression correlated with CD8+ cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.

Erectile dysfunction in male patients with severe chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary disease (COPD) is a common chronic disease, which diminishes the patient’s functional capacity and quality of life. Only few studies have been published on the occurrence of erectile dysfunction (ED) in COPD patients. Objective The aim of this work was to study the prevalence of ED in COPD patients and its relation with other clinical and laboratory parameters. Patients and methods The study included 30 patients with severe chronic stable COPD (diagnosed and staged according to the American Thoracic Society guidelines) and 30 healthy volunteers. Assessment of erectile function was carried out for all participants using the International Index of Erectile Function (IIEF-5) Questionnaire. Results Both COPD patients and controls were age matched. On comparing the 6 min walk test results between the two groups, there was a highly significant decrease in the distance×weight parameter in COPD patients (19.687±3.104 kg/km) than in normal controls (35.24±4.35 kg/2 km). Evaluation of erectile function was carried out using the questionnaire of IIEF. The mean score of erectile function was significantly decreased in COPD patients than in the normal control group (P Conclusion ED is a frequent problem in patients with COPD. The limitations of physical activity in the pathophysiology of COPD seem to interfere with the sexual function of these patients.

Efficacy of non-invasive ventilation as a rescue therapy for relieving dyspnea in patients with stable severe COPD

Exertional Dyspnea is a troublesome symptom in chronic obstructive pulmonary disease (COPD) even after optimal therapy, which is a physiological and perceptional burden to limit their activities. Non-invasive ventilation (NIV) might provide rescue therapy for this population to relieve exertional dyspnea.This was a randomized crossover study in 18 patients with stable severe COPD. Exertional dyspnea was induced with maximal symptom-limited incremental cycle exercise. Then the patients would randomly receive oxygen or NIV plus oxygen therapy. Patients were crossed to another therapy in the second day. During the whole process, breathing pattern were monitored continuously until complete recovery. At every 30s interval, inspiratory capacity (IC) and Borg scale were assessed. Changes were compared between two interventions.Compared with oxygen therapy, NIV plus oxygen therapy resulted in increase of tidal volume and minute ventilation, decrease in dyspnea intensity at isotime (reduction of 1.0 ± 2.0 Borg units, p < 0.05) and a tendency but not statistically significant shortening in total dyspnea recovery time (326.2 ± 132.0s vs 356.5 ± 156.9s, p = 0.225). These improvements were negatively correlated with baseline FEV1 (r = −0.617, p < 0.01). Subjects were divided into responders (n = 9) with dyspnea recovery time shortening > 30s or non-responders. Responder subgroup had significantly poorer pulmonary function in FEV1, FEV1%, IC than non-responder subgroup, indicating that NIV is effective as rescue therapy for exertional dyspnea in stable COPD with poorer pulmonary function.NIV as rescue therapy could help relieve dyspnea after exercise in patients with stable severe COPD with a poor pulmonary function.

Efficiency and safety of roflumilast combined with long-acting bronchodilators on moderate-to-severe stable chronic obstructive pulmonary disease patients: a meta-analysis.

Roflumilast, a phosphodiesterase-4 inhibitor recommended by clinical guideline, is always being used in combination with at least one long-acting bronchodilator in patients with stable chronic obstructive pulmonary disease (COPD). However, there are few evidences about whether the combination of roflumilast and long-acting bronchodilators is safer and more effective in patients with moderate-to-very severe stable COPD. In our study, we investigate the effect and safety of roflumilast combined with long-acting bronchodilators on moderate-to-severe stable COPD patients. Several databases were adopted in February 5th 2016, so as to identify relevant randomized controlled trial (RCT). Studies indicated that the patients in the experimental group had to receive roflumilast and concomitant treatment with long-acting bronchodilators, and the patients in the control group had to receive placebo and concomitant treatment with long-acting bronchodilators. The primary outcome was COPD exacerbations and the secondary outcome was adverse events. The relative risks (RRs) and 95% confidence intervals (CIs) were calculated. Total 5,746 patients were involved in all six trials. Roflumilast combined with long-acting bronchodilators could lead to significant reduction in exacerbations of COPD (RR, 0.77; 95% CI, 0.69 to 0.86; P<0.00001; I2=0%), and cause some adverse events such as: back pains, headache, diarrhea, nausea, weight loss, insomnia and decreased appetite. According to the subgroup analysis, the test for finding subgroup difference between roflumilast combined with long-acting bronchodilators and roflumilast combined with ICS and long-acting bronchodilators showed no significance in reducing exacerbations. Roflumilast combined with long-acting bronchodilators is a better option for moderate-to-severe COPD patients than exclusive use of long-acting bronchodilators in reducing exacerbations. However, it can cause some side effects. Further study needs consider well enough of the benefits and adverse events caused by roflumilast combined with long-acting bronchodilators.

Mental health, serum biomarkers and survival in severe COPD: a pilot study

Background: Chronic obstructive pulmonary disease (COPD) impairs physical status and impacts on mental health. This prospective study was designed to assess associations between mental health and systemic biomarkers, and their combined relationship with long-term survival in stable severe COPD.&#x0D; Methods: Forty-five patients with severe but stable COPD (forced expiratory volume in 1 s of 29.8 (quartiles: 22.6; 41.4) %predicted) were assessed using the Hospital Anxiety and Depression Scale (HADS), the Patient Health Questionnaire (PHQ), St. George’s Respiratory Questionnaire and the State-Trait Anxiety Inventory (STAI). The following serum biomarkers were measured: 25-OH-cholecalciferol, C-reactive protein, erythrocyte sedimentation rate, leucocyte number, serum amyloid-A (SA-A), N-terminal pro-brain natriuretic peptide, troponin I, glycosylated haemoglobin, haemoglobin (Hb), haematocrit (Hc), creatinine and thyroid-stimulating hormone. Patients were followed-up for 36 months. Associations between aspects of mental health and biomarkers, and their utility as predictors of 3-year survival were evaluated by regression analyses.&#x0D; Results: The prevalence of anxiety (HADS-A: 89.9 %), depression (HADS-D: 58.8 %; PHQ: 60.6 %), somatisation (PHQ-15: 81.8 %) and psychosocial stress (PHQ-stress: 60.6 %) was high. There was a significant positive association between the leucocyte count and SA-A level with STAI-trait anxiety (p = 0.03 and p = 0.005, respectively), and between leucocytes and PHQ-stress (p = 0.043). Hb and Hc were significantly negatively associated with HADS-depression (p = 0.041 and p = 0.031, respectively). Univariate Cox regression analyses revealed that leucocyte count (hazard ratio (HR) 2.976, 95 % CI 1.059-8.358; p = 0.038), and stress (HR 4.922, 95 % CI 1.06–22.848; p = 0.042) were linked to long-term survival. In multivariate Cox regression analyses, including known risk factors for survival in COPD, PHQ-stress (HR 45.63, 95 % CI 1.72–1,208.48; p = 0.022) remained significantly associated with survival.&#x0D; Conclusion: In this pilot study different dimensions of mental health were correlated to serum biomarkers, probably reflecting systemic effects of COPD. While leucocyte number and PHQ-stress were associated with long-term survival in univariate analyses, PHQ-stress remained in multivariate analyses as independent prognostic factor.

Inflammatory markers and circulating extracellular matrix proteins in patients with chronic obstructive pulmonary disease and left ventricular diastolic dysfunction.

Left ventricular diastolic dysfunction (LVDD) is a frequent condition in chronic obstructive pulmonary disease (COPD). Tenascin-C (Tn-C) and matrix metalloproteinase-9 (MMP-9) are extracellular matrix proteins associated with myocardial fibrosis and wall remodeling because of inflammation. To determine whether the circulating levels of inflammatory markers, Tn-C and MMP-9 are associated with LVDD in COPD patients. Forty-two severe stable COPD patients (64 ± 8 years, 88% male, FEV1% 38 ± 5.7) and a control group (n = 11) were included. Pulmonary function tests and a Doppler echocardiography were performed on COPD patients. Baseline serum levels of C-reactive protein (CRP), leukocytes, fibrinogen, interleukins (IL) 6 and 8, Tn-C and MMP-9 were analyzed in all participants. COPD patients were classified in two groups: LVDD (n = 35) and non-LVDD (n = 7). Serum levels of IL-6 and CRP were higher in the LVDD group compared to the non-LVDD group [median(IQR)] [3.46 pg/mL (2.36-4.74) vs 1.87 pg/mL (1.10-3.28), P = 0.045] and [6.0 mg/L (3.0-13.0) vs 1.0 mg/L (1.0-2.3), P = 0.001], respectively. The same trend was observed in the analysis adjusted by age and BMI, being significant for CRP (P = 0.04). Circulating IL-6 was associated with the type of LVDD, being higher in the type-II (P = 0.046). Obese patients with COPD-LVDD showed a higher level of inflammatory markers (P = 0.021). Tn-C were significantly higher in patients with LVDD type-II compared to type-I [1422 ng/mL (826-1948) vs 781 ng/mL (640-1139), P = 0.015], without differences in MMP-9. Severe COPD patients with LVDD showed a different inflammatory pattern, suggesting a link between low-grade inflammation and the presence of LVDD. In COPD, high levels of Tn-C are related to LVDD type-II.

Long-Term NIV in COPD – Who and When?

Dr Wijkstra opened this symposium on long-term non-invasive ventilation (NIV) in the treatment of chronic obstructive pulmonary disease (COPD). Dr Köhnlein presented data from a recent randomised controlled trial (RCT) of NIV for the treatment of severe stable COPD.1 Dr Cheval discussed the use of telemonitoring in French patients with COPD. The meeting concluded with a round-table discussion on the international practice of home mechanical ventilation (HMV) for COPD, moderated by Dr Wijkstra and Prof Windisch with contributions from Dr Köhnlein, Dr Nava, Dr Hart, and Prof Pépin.

Faster reduction in hyperinflation and improvement in lung ventilation inhomogeneity promoted by aclidinium compared to glycopyrronium in severe stable COPD patients. A randomized crossover study

Standard spyrometric assessment in chronic obstructive pulmonary disease (COPD) only evaluates bronchial obstruction. However, airflow limitation and hyperinflation are the main pathophysiological factors responsible for dyspnoea and reduced exercise tolerance in patients with COPD. This study evaluated the effects of aclidinium bromide 400 μg and glycopyrronium bromide 50 μg on these parameters.Patients with stable severe/very severe COPD were randomized in this double-blind, double-dummy, crossover, Phase IV study. Patients received single doses of each drug on separate days. Primary endpoints were changes in residual volume (RV) and intra-thoracic gas volume (ITGV), assessed by full-body plethysmography. Other endpoints included changes variations in lung ventilation inhomogeneity (Phase III slope of single-breath nitrogen washout test, SBN2), dyspnoea visual analogue scale, and pulmonary specific total airway resistances. Assessments were performed at baseline and 5, 15, 30, 60, and 180 min post-administration.Thirty-seven patients were randomized (31 male; mean age 71 years). Aclidinium and glycopyrronium significantly improved ITGV versus baseline at all-time points (p < 0.05). Significant improvements in RV were observed after 5 min with aclidinium and after 60 min with glycopyrronium. RV improvements were significantly greater with aclidinium than glycopyrronium from 5 to 60 min post-administration (p < 0.05). Both treatments improved dyspnoea versus baseline at all-time points (p < 0.05). Aclidinium significantly improved ventilation inhomogeneity versus baseline at all-time points; no significant changes were observed for glycopyrronium.For the first time two long-acting muscarinic antagonists have been compared in acute conditions with body plethysmography and SBN2 test. We demonstrated that both aclidinium and glycopyrronium significantly reduce hyperinflation and dyspnoea in severe and very severe COPD patients. Aclidinium however promoted a faster reduction in RV and was the only able to reduce lung ventilation inhomogeneity.Trial Registration numbers available on Clinicaltrials.gov: NCT02181023.

Phospho-p38 MAPK Expression in COPD Patients and Asthmatics and in Challenged Bronchial Epithelium

Background: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. Objectives: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. Methods: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. Results: No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H₂O₂), cytomix (tumour necrosis factor-α + IL-1β + interferon-γ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H₂O₂ and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H₂O₂, cytomix or LPS treatments. Conclusion: p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations.