Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease

Rationale: The molecular mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorly understood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways.
Objectives: To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70^S6K glycogen synthase kinase-3ß (GSK-3ß), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, muscle ring finger (MuRF) protein 1, and FoxO-1 and -3 in the quadriceps of 12 patients with COPD with muscle atrophy and 10 healthy control subjects. Five patients with COPD with preserved muscle mass were subsequently recruited and were compared with six patients with low muscle mass.
Methods: Protein contents and mRNA expression were measured by Western blot and quantitative polymerase chain reaction, respectively.
Measurements and Main Results: The levels of atrogin-1 and MuRF1 mRNA, and of phosphorylated AKT and 4E-BP1 and FoxO-1 proteins, were increased in patients with COPD with muscle atrophy compared with healthy control subjects, whereas atrogin-1, p70^S6K, GSK-3ß, and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70^S6K, GSK-3ß, and 4E-BP1 compared with patients with COPD with preserved muscle mass.
Conclusions: An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was observed in the quadriceps of patients with COPD. The transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.

Factors affecting the offer of pulmonary rehabilitation to patients with chronic obstructive pulmonary disease by primary care professionals : a qualitative study

Aim: To explore health professionals’ experiences of barriers and facilitators to referring patients for pulmonary rehabilitation in a primary care setting.

Background: Pulmonary rehabilitation involves a multidisciplinary teamwork approach to improving
the quality of life for people with chronic obstructive pulmonary disease. This study aimed to find out about health care professionals’ experiences when referring patients. Reports suggest that a health care professional’s attitude towards a treatment affects the willingness of patients to accept advice.

Methods: Five focus group interviews were undertaken with 21 health professionals from North Midlands, UK. Data were analysed using a thematic analysis drawing on the techniques of grounded theory.

Findings: Chronic disease management has been delegated to Practice Nurses in many cases leaving some nurses feeling unsupported and some General Practitioners feeling deskilled. Problems with communication, a lack of adequate and timely local service provision, a difficult referral process, time pressures and lack of information were barriers to health care professionals making an offer of pulmonary rehabilitation. An explanatory model is proposed to describe how addressing barriers to referral may improve health care professionals views about pulmonary rehabilitation and therefore may mean that they present it in a more positive manner.

Early predictors of hospital admission in emergency department patients with chronic obstructive pulmonary disease

Background: Streamlining emergency department (ED) care of patients with chronic obstructive pulmonary disease (COPD) may be an important strategy in managing the increasing burden of this disease.

Study objectives: The aim of this study was to identify factors predictive of hospital admission in ED patients with COPD, specifically factors that can be used early in the ED episode of care.

Methods: Using retrospective regression analysis, case data from 321 randomly selected medical records from five Australian EDs were analysed. Patient characteristics, triage and ED system features, physiological status, and ED treatment during the first four hours of ED care were compared between discharged and admitted patients.

Results: Factors available on ED arrival associated with increased likelihood of admission were: age (OR = 1.04, p = 0.008) respiratory symptoms affecting activities of daily living (OR = 1.8, p = 0.043) and signs of respiratory dysfunction (OR = 2.5, p = 0.005). Factors available from the first four hours of ED care associated with increased likelihood of admission were: age (OR = 1.04, p = 0.021), oxygen use at four hours (OR = 3.5, p = 0.002) and IV antibiotic administration (OR = 2.6, p = 0.026). There were conflicting findings regarding the association between ambulance transport and admission.

Descriptive analysis of emergency department oxygen use in acute exacerbation of chronic obstructive pulmonary disease

Background: Inconsistencies in oxygen therapy recommendations in acute exacerbation of chronic obstructive pulmonary disease (COPD) may result in variability in emergency department (ED) oxygen management of patients with COPD. The aim of this study was to describe oxygen management in the first 4 h of ED care for patients with exacerbation of COPD.
Methods: A retrospective medical record audit was conducted at four public and one private ED in Melbourne, Australia. Participants were 273 adult ED patients with COPD presenting with a primary complaint of shortness of breath from July 2006 to July 2007. Outcome measures were physiological data, including oxygen saturation (SpO2), oxygen delivery devices and flow rates on ED arrival, 1 and 4 h.
Results: Oxygen was used in 82.0% of patients. Patients who required oxygen had higher incidence of ambulance transport (P < 0.001), triage category 2 (P = 0.006), home oxygen use (P < 0.001), and increased work of breathing on ED arrival (P < 0.001), and higher median respiratory rate (P < 0.001) and heart rate (P = 0.001). SpO2 > 90% occurred in the majority of patients (87.5%; 96.4%; 95.6%); however, a considerable number of patients with SpO2 < 90% were not given oxygen (61.8%; 30%; 45.5%).
Conclusions: A number of patients with documented hypoxaemia were not given oxygen and there may be variables other than oxygen saturation that may influence oxygen use. Future research should focus on increasing the evidence-based supporting
oxygen use and better understanding of clinicians’ oxygen decision-making in patients with COPD.

Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway

Background and objective: Natural killer (NK) and natural killer T (NKT)-like cells represent a small but important proportion of effector lymphocytes that we have previously shown to be major sources of pro-inflammatory cytokines and granzymes. We hypothesized that these cells would be increased in the airway in chronic obstructive pulmonary disease (COPD), accompanied by reduced expression of the inhibitory receptor CD94 (Kp43) and increased expression of cytotoxic mediators granzyme B and perforin.
Methods: We measured NK and NKT-like cells and their expression of CD94 in the blood of COPD patients (n = 71; 30 current and 41 ex-smokers), smokers (16) and healthy controls (25), and bronchoalveolar lavage fluid (BALF) from a cohort of subjects (19 controls, 12 smokers, 33 COPD). Activation was assessed by measuring CD69 in blood and the cytotoxic potential of NK cells by measuring granzymes A and B, and using a cytotoxicity assay in blood and BALF.
Results: In blood in COPD, there were no significant changes in the proportion of NK or NKT-like cells or expression of granzyme A or NK cytotoxic potential versus controls. There was, however, increased expression of granzyme B and decreased expression of CD94 by both cell types versus controls. The proportion of NK and NKT-like cells were increased in BALF in COPD, associated with increased NK cytotoxicity, increased expression of granzyme B and decreased expression of the inhibitory receptor CD94 by both cell types.
Conclusions: Treatment strategies that target NK and NKT-like cells, their cytotoxicity and production of inflammatory mediators in the airway may improve COPD morbidity.

Role of increased CD8/CD28null T cells and alternative co-stimulatory molecules in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease; it is a leading cause of death and existing treatments have no proven disease-modifying effect. The mechanisms underlying this resistance are largely unknown, but suggest the presence of some self-maintaining pathogenic process, possibly initiated by cigarette smoking, that prevents the normal resolution of inflammation. We have previously reported increased production of proinflammatory cytokines and granzyme b by CD8⁺ T cells in COPD; costimulatory receptor/ligand interactions required include CD80:86/CD28, B7-1/CTLA4, 4-1BB/1BBL and OX40/OX40L. We hypothesized that a dysregulated expression/function of these molecules may play a role in inflammatory/autoimmune components of COPD. We analysed T cell co-stimulatory molecules in blood from 34 controls, 15 smokers and 48 COPD subjects. We assessed the potential functional relevance of CD8/CD28^null cells in COPD by measuring their production of proinflammatory cytokines, co-stimulatory molecules, granzyme and perforin. A smoke-exposed murine model was applied to investigate the relative expression of CD8/CD28^null T cells in blood, lung tissue and airway. CD8/CD28^null cells were increased in both current- and ex-smoker COPD groups; these cells expressed significantly more interferon (IFN)-γ, OX40, 4-1BB, CTLA4, granzyme and perforin when stimulated than CD8/CD28⁺ T cells. There were no changes in CD4/CD28^null T cells. In mice exposed to cigarette smoke for 12 weeks, CD8/CD28^null T cells were significantly increased in the airway with a trend for an increase in lung tissue and blood. Increased production of proinflammatory cytokines and expression of alternative co-stimulatory molecules by CD8/CD28^null T cells may play a role in inflammatory or autoimmune responses in COPD and identify therapeutic targets.

Construct validity of the Dutch version of the 12-item Partners in Health scale: measuring patient self-management behaviour and knowledge in patients with Chronic Obstructive Pulmonary Disease

Objective The 12-item Partners in Health scale (PIH) was developed in Australia to measure self-management behaviour and knowledge in patients with chronic diseases, and has undergone several changes. Our aim was to assess the construct validity and reliability of the latest PIH version in Dutch COPD patients.

Methods The 12 items of the PIH, scored on a self-rated 9-point Likert scale, are used to calculate total and subscale scores (knowledge; coping; recognition and management of symptoms; and adherence to treatment). We used forward-backward translation of the latest version of the Australian PIH to define a Dutch PIH (PIH(Du)). Mokken Scale Analysis and common Factor Analysis were performed on data from a Dutch COPD sample to investigate the psychometric properties of the Dutch PIH; and to determine whether the four-subscale solution previously found for the original Australian PIH could be replicated for the Dutch PIH.

Results Two subscales were found for the Dutch PIH data (n = 118); 1) knowledge and coping; 2) recognition and management of symptoms, adherence to treatment. The correlation between the two Dutch subscales was 0.43. The lower-bound of the reliability of the total scale equalled 0.84. Factor analysis indicated that the first two factors explained a larger percentage of common variance (39.4% and 19.9%) than could be expected when using random data (17.5% and 15.1%).

Conclusion We recommend using two PIH subscale scores when assessing self-management in Dutch COPD patients. Our results did not support the four-subscale structure as previously reported for the original Australian PIH.

Automated attention flags in chronic disease care planning

Objectives: To assess the value of computerised decision support in the management of chronic respiratory disease by comparing agreement between three respiratory specialists, general practitioners (care coordinators), and decision support software.
Methods: Care guidelines for two chronic obstructive pulmonary disease projects of the SA HealthPlus Coordinated Care Trial were formulated. Decision support software, Care Plan On-Line (CPOL), was created to represent the intent of these guidelines via automated attention flags to appear in patients' electronic medical records. For a random sample of 20 patients with care plans, decisions about the use of nine additional services (eg,.smoking cessation, pneumococcal vaccination) were compared between the respiratory specialists, the patients' GPs and the CPOL attention flags.
Results: Agreement among the specialists was at the lower end of moderate (intraclass correlation coefficient [ICC], 0.48; 95% CI, 0.39-0.56), with a 20% rate of contradictory decisions. Agreement with recommendations of specialists was moderate to poor for GPs (le, 0.49; 95% CI, 0.33-0.66) and moderate to good for CPOL (K, 0.72; 95% CI, 0.55-0.90). CPOL agreement with GPs was moderate to poor (le, 0.41; 95% CI, 0.24-0.58). GPs were less likely than specialists or CPOL to decide in favour of an additional service (P< 0.001). CPOL was 87% accurate as an indicator of specialist decisions. It gave a 16% false-positive rate according to specialist decisions, and flagged 61% of decisions where GPs said No and specialists said Yes.
Conclusions: Automated decision support may provide GPs with improved access to the intent of guidelines; however, further investigation is required.

Improving the uptake of pulmonary rehabilitation in patients with COPD : qualitative study of experiences and attitudes

Background
Pulmonary rehabilitation can improve the quality of life and ability to function of patients with chronic obstructive pulmonary disease (COPD). It may also reduce hospital admission and inpatient stay with exacerbations of COPD. Some patients who are eligible for pulmonary rehabilitation may not accept an offer of it, thereby missing an opportunity to improve their health status.

Aim
To identify a strategy for improving the uptake of pulmonary rehabilitation.

Design of study
Qualitative interviews with patients.

Setting
Patients with COPD were recruited from a suburban general practice in north-east Derbyshire, UK.

Method
In-depth interviews were conducted on a purposive sample of 16 patients with COPD to assess their concerns about accepting an offer of pulmonary rehabilitation. Interviews were analysed using grounded theory.

Results
Fear of breathlessness and exercise, and the effect of pulmonary rehabilitation on coexisting medical problems were the most common concerns patients had about taking part in the rehabilitation. The possibility of reducing the sensation of breathlessness and regaining the ability to do things, such as play with their grandchildren, were motivators to participating.

Conclusion
A model is proposed where patients who feel a loss of control as their disease advances may find that pulmonary rehabilitation offers them the opportunity to regain control. Acknowledging patients' fears and framing pulmonary rehabilitation as a way of ‘regaining control’ may improve patient uptake.