Rachel C. Tennant

A prospective study of decline in fat free mass and skeletal muscle strength in chronic obstructive pulmonary disease

BackgroundSkeletal muscle depletion is an important complication of chronic obstructive pulmonary disease (COPD) but little prospective data exists about the rate at which it occurs and the factors that promote its development. We therefore prospectively investigated the impact of disease severity, exacerbation frequency and treatment with corticosteroids on change in body composition and maximum isometric quadriceps strength (QMVC) over one year.Methods64 patients with stable COPD (FEV1 mean (SD) 35.8(18.4) %predicted) were recruited from clinic and studied on two occasions one year apart. Fat free mass was determined using bioelectrical impedance analysis and a disease specific regression equation.ResultsQMVC fell from 34.8(1.5) kg to 33.3(1.5) kg (p = 0.04). The decline in quadriceps strength was greatest in those with the highest strength at baseline (R -0.28 p = 0.02) and was not correlated with lung function, exacerbation frequency or steroid treatment. Decline in fat free mass was similarly higher in those with largest FFM at baseline (R = -0.31 p = 0.01) but was more strongly correlated with greater gas trapping (R = -0.4 p = 0.001). Patients with frequent exacerbations (>1 per year) (n = 36) experienced a greater decline in fat free mass compared to infrequent exacerbators (n = 28) -1.3(3.7)kg vs. +1.2(3.1)kg (p = 0.005), as did patients on maintenance oral steroids (n = 8) -2.8(3.3) kg vs. +0.2(3.5) kg (p = 0.024) whereas in those who stopped smoking (n = 7) fat free mass increased; +2.7(3.1) kg vs. -0.51(3.5) kg (p = 0.026).ConclusionDecline in fat free mass in COPD is associated with worse lung function, continued cigarette consumption and frequent exacerbations. Factors predicting progression of quadriceps weakness could not be identified from the present cohort.

Long-acting β2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?

Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.

Non-specific interstitial pneumonia in cigarette smokers: a CT study

The goal of this study was to seek indirect evidence that smoking is an aetiological factor in some patients with non-specific interstitial pneumonia (NSIP). Ten current and eight ex-smokers with NSIP were compared to controls including 137 current smokers with no known interstitial lung disease and 11 non-smokers with NSIP. Prevalence and extent of emphysema in 18 smokers with NSIP were compared with subjects meeting GOLD criteria for chronic obstructive pulmonary disease (COPD; group A; n = 34) and healthy smokers (normal FEV1; group B; n = 103), respectively. Emphysema was present in 14/18 (77.8%) smokers with NSIP. Emphysema did not differ in prevalence between NSIP patients and group A controls (25/34, 73.5%), but was strikingly more prevalent in NSIP patients than in group B controls (18/103, 17.5%, P < 0.0005). On multiple logistic regression, the likelihood of emphysema increased when NSIP was present (OR = 18.8; 95% CI = 5.3–66.3; P < 0.0005) and with increasing age (OR = 1.04; 95% CI = 0.99–1.11; P = 0.08). Emphysema is as prevalent in smokers with NSIP as in smokers with COPD, and is strikingly more prevalent in these two groups than in healthy smoking controls. The association between NSIP and emphysema provides indirect support for a smoking pathogenesis hypothesis in some NSIP patients.

Smoking‐related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung

A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis‐interstitial lung disease (RA‐ILD)), and to compare the morphological features of lung fibrosis between smokers and non‐smokers.

Smoking Cessation in COPD Causes a Transient Improvement in Spirometry and Decreases Micronodules on High-Resolution CT Imaging

BACKGROUND Smoking cessation is of major importance for all smokers; however, in patients with COPD, little information exists on how smoking cessation influences lung function and high-resolution CT (HRCT) scan appearances. METHODS In this single-center study, we performed screening spirometry in a group of heavy smokers aged 40 to 80 years (N = 358). We then studied the effects of smoking cessation in two groups of selected subjects: smokers with COPD (n = 38) and smokers with normal spirometry (n = 55). In parallel to subjects undergoing smoking cessation, we studied a control group of nonsmokers (n = 19). RESULTS Subjects with COPD who quit smoking had a marked, but transient improvement in FEV1 at 6 weeks (184 mL, n = 17, P < .01) that was still present at 12 weeks (81 mL, n = 17, P < .05) and only partially maintained at 1 year. In contrast, we saw improvement in the transfer factor of lung for carbon monoxide at 6 weeks in both subjects with COPD who quit smoking (0.47 mmol/min/kPa, n = 17, P < .01) and subjects who quit smoking with normal spirometry (0.40 mmol/min/kPa, n = 35, P < .01). An upper-zone single HRCT image slice reliably identified emphysema at baseline in 74% of smokers with COPD (28 of 38) and 29% of healthy smokers (16 of 55). Smoking cessation had no significant effect on the appearances of emphysema but decreased the presence of micronodules on HRCT imaging. CONCLUSIONS Cigarette smoking causes extensive lung function and HRCT image abnormalities, even in patients with normal spirometry. Smoking cessation has differential effects on lung function (FEV1 and gas transfer) and features on HRCT images (emphysema and micronodules). Cessation of smoking in patients with COPD causes a transient improvement in FEV1 and decreases the presence of micronodules, offering an opportunity for concomitant therapy during smoking cessation to augment these effects. Smoking cessation at the earliest possible opportunity is vital to minimize permanent damage to the lungs.

New drugs for COPD based on advances in pathophysiology

There is a pressing need to develop new treatments for chronic obstructive pulmonary disease (COPD), as no currently available drug has been shown to reduce the relentless progression of this disease. Furthermore, recognition of the global importance and rising prevalence of COPD and the absence of effective therapies has now led to a concerted effort to develop new drugs for this disease [1, 2]. However, there have been disappointingly few therapeutic advances in the drug therapy of COPD, in contrast to the enormous advances made in asthma management that reflect a much better understanding of the underlying disease [3, 4].

Computed tomography (CT) scans in COPD

Structural information about the lungs has been obtainable for over one hundred years through imaging techniques. Cross-sectional computed tomography (CT) provides a great advance over conventional radiography, since it avoids the inevitable superimposition of structures that occurs with a projectional image, and CT allows resolution of structures as small as 200 Ettm. The digital nature of CT data also permits objective assessment of respiratory diseases including COPD. Sophisticated computer software has allowed the development of image processing techniques that may improve detection and quantification of COPD Fig. 1. The development, over the past decade, of volumetric acquisition with spiral CT and 3D image reconstruction is an exciting development, the full value of which is only just being exploited. It is becoming apparent that CT can also be used to provide functional data, for example, looking at changes in airway calibre in response to drugs. An exciting development is that CT has been demonstrated to show very early smoking-related lung damage, and may be of use in monitoring resolution of such changes in response to treatment.

Evaluation of New Drugs for Asthma and COPD: Endpoints, Biomarkers and Clinical Trial Designs

The incidence of both asthma and chronic obstructive pulmonary disease (COPD) is increasing throughout the world, and acts as a major incentive for the development of new and improved drug therapy. For the large range of bronchodilator and anti-inflammatory agents in current clinical development, reliable decision-making is imperative in phase II, before entering large-scale phase III clinical studies. With anti-inflammatory therapies for asthma, many studies have been performed utilising the inhaled allergen challenge as a proof of concept study, effects on airway hyper-reactivity (AHR) can be assessed, and it is also possible to directly study limited numbers of symptomatic asthma patients. Additional clinical trial designs in asthma include studies to assess bronchodilation, bronchoprotection against a variety of inhaled constrictor agents, exercise tolerance, add-on and titration studies with inhaled and oral corticosteroids, and prevention and treatment of exacerbations. In contrast, it is a major issue for the development of new anti-inflammatory drugs for COPD that large-scale phase II studies are generally required in this disease in order to detect clinical efficacy. In COPD, clinical trial designs range from studies on lung function, symptoms and exercise performance, inflammatory biomarkers, natural history of chronic stable disease, prevention and treatment of exacerbations, and effects on cachexia and muscle function. Compared with asthma, inclusion criteria, monitoring parameters, comparator therapies and trial design are less well established for COPD. The large variety of potential clinical endpoints includes lung function, symptoms, walking tests, hyperinflation, health-related quality of life (HR-QOL), airway reactivity, and frequency and severity of exacerbations. In addition, surrogate biomarkers may be assessed in blood, exhaled breath, induced sputum, bronchial mucosal biopsy and bronchoalveolar lavage (BAL), and advanced radiographic imaging employed. Of particular utility is ex vivo whole blood stimulation to enable pharmacokinetic/pharmacodynamic modelling in establishing an optimal dosage regimen relatively early in human clinical studies. There have been considerable recent advances in the development of non-invasive biomarkers and novel clinical trial designs, as well as clarification of regulatory requirements, that will facilitate the development of new therapies for patients with asthma and COPD.