Improvement in Resting Inspiratory Capacity and Hyperinflation with Tiotropium in COPD Patients with Increased Static Lung Volumes; B. Celli, R. Zu Wallack, S. Wang, S. Kesten (Chest 2003; 124:1743–1748).
Background: In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient‐focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once‐daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long‐term administration of tiotropium.
Methods: To evaluate the effect of tiotropium, 18 µg/d, on IC, a 4‐week, randomized, double blind, placebo‐controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV1, FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (− 60 and − 15 min) and after study drug (20, 50, 120, and 180 min).
Results: Mean age was 64 years; 62% were men. Mean baseline FEV1 was 1.12 L (43% predicted). The mean differences (tiotropium–placebo) in FEV1 trough (morning before drug), peak, and area under the curve over 3‐h values (adjusted for baseline and center differences) at week 4 were 0.16, 0.22, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22, 0.35, and 0.30 L (p < 0.01 for all). Differences in TGV were − 0.54, − 0.60, and − 0.70 L respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV1 and lung volumes (FEV1, 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%).
Conclusions: Observed improvements in IC and reductions in TGV with once‐daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h.
Comments: Tiotropium is a long‐acting anticholinergic agent that has recently been approved for use in the United States. It has a binding constant for the muscurinic 3, (M‐3), receptor that is approximately 100 times that of ipratropium bromide and hence remains active for 24 hours. It saturates the M‐3 receptors on smooth muscle and mucous glands such that there is no need for use of short‐acting anticholiniergics throughout the 24‐hour period. In this study Celli and colleagues demonstrate that tiotropium can provide superior bronchodilation compared to placebo reflected by improvements in inspiratory capacity (IC) over the 3 hours postdose and 1 hour predose. Similar or superior improvements were also noted in regard to standard measures including FEV1, FVC, and TGV. The tiotropium group had a higher baseline FEV1 at the start of the study and patients were not excluded if they had > 10% reversibility with bronchodilator. Patients with a clinical diagnosis of asthma were excluded. While the findings from this study might be regarded as somewhat predictable, it is encouraging to note that investigators are starting to assess efficacy in terms of IC as a primary outcome which appears to be more sensitive for detecting bronchodilator response in COPD patients. The FEV1 and FVC improved significantly as well in this cohort of patients and it would have been interesting to see if IC still correlated better with exercise capacity, but this was not examined in this study. The authors cite other studies that have shown that tiotropium reduces exacerbations, dyspnea and health‐related quality of life. The addition of tiotropium provides sustained bronchodilation that adds to our medical armamentarium available to achieve “pharmacological lung volume reduction.”
Longitudinal Changes in the Nature, Severity and Frequency of COPD Exacerbations; G.C. Donaldson, T.A.R. Seemungal, I.S. Patel, S.J. Lloyd‐Owen, T.M.A. Wilkinson, J.A. Wedzicha (Eur Respir J 2003; 22:931–936).
Exacerbations are an important feature and outcome measure in chronic obstructive pulmonary disease (COPD), but little is known about changes in their severity, recovery, symptom composition or frequency over time.
In this study 132 patients (91 male; median age 68.4 yrs and median forced expiratory volume in 1 second (FEV1) 38.4% predicted) recorded daily symptoms and morning peak expiratory flow.
Patients were monitored for a median of 918 days and 1,111 exacerbations were identified. Patients with severe COPD [Global Initiative For Chronic Obstructive Lung Disease (GOLD) category III, n = 38] had an annual exacerbation frequency of 3.43 yr− 1, 0.75 yr− 1 higher than those with moderate COPD (GOLD II, n = 94). Exacerbation frequency did not change significantly during the study. At exacerbation onset, symptom count increased to 2.23, relative to a baseline of 0.36 set 8–14 days previously, and this increase rose by 0.05 yr− 1. Recovery to baseline levels in symptoms and FEV1 took longer (0.32 and 0.55 days yr− 1) from an initial value of 17%.
The results of this study suggest that over time, individual patients have more symptoms during exacerbations, with an increased chance of sputum purulence and longer recovery times.
Comments: This is the first study to prospectively follow the history of exacerbations over 6 years duration in a cohort of 177 COPD subjects with moderate to very severe disease (GOLD class II–IV, new GOLD classification). There were 19 deaths over that time and patients were excluded from analysis if they did not have diary card data for a minimum of 365 days. Data on 132 subjects were analyzed, 32 of these patients had very severe disease (FEV1 < 30% predicted). Daily inhaled corticosteroids were used in 119 patients (90%) and 12 patients (9%) received oral prednisolone daily. There were 41 patients who were current smokers. Exacerbations were defined as an increase in two or more major symptoms (sputum purulence or volume, dyspnea), or any major symptom plus a minor symptom (colds nasal discharge/congestion, wheeze, sore throat and cough). There were 65 hospitalisations for acute exacerbations representing 5.9% of the 1,111 exacerbations. The study showed that exacerbation frequency was higher in the very severe group [GOLD Group IV (new classification scheme)] compared to those who had moderate or severe disease (new GOLD groups II and III). The other major findings were that symptoms, particularly sputum purulence, were more frequent and that recovery time was longer in subsequent years. The authors did not find that exacerbation frequency increased over time and this may be a result of the vast majority of subjects being on inhaled steroids but this was not specifically analyzed in the paper. With use of diary card data and peak flows the authors showed that about half of all exacerbations go unreported and hence their average exacerbation rate for moderate to very severe patients (2.52 events/patient/year) was higher than that found in other studies. Considering the increased interest in monitoring exacerbation rate to assess the efficacy of various interventions, one should clearly give pause when considering studies that rely on health care utilization or reports to health care professionals to document exacerbations.
Systemic Inflammation in Chronic Obstructive Pulmonary Disease; E‐J.D. Oudijk, J‐W.J. Lammers, L. Koenderman (Eur Respir J 2003; 22:Suppl 46, 5s–13s).
Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammation in the pulmonary tissue. The disease is associated with a switch from a self‐limiting inflammatory response, mainly initiated by smoke inhalation, to a chronic persistent inflammatory response after prolonged interaction with cigarette smoke. The extent of the inflammatory reaction is correlated with the severity of the disease.
Chronic inflammation in the pulmonary tissue is also associated with systemic effects. These effects range from cytokine‐induced priming of peripheral leukocytes, to muscle wasting induced by cytokines such as tumor necrosis factor‐α. Despite a general consensus that chronic inflammation is a characteristic phenomenon of the disease, surprisingly little is known regarding the underlying pathogenetic mechanism.
Clear communication is present between the disease mechanisms in the pulmonary compartment and peripheral tissues, leading to the concept of COPD as a systemic inflammatory disease. This communication can be mediated by: 1) leakage of reactive oxygen species and stress‐induced cytokines directly into the peripheral blood, 2) preactivation of peripheral blood leukocytes that can result in aberrant homing and activation of inflammatory cells in distant tissues, and 3) the liberation of proinflammatory mediators by leukocytes and/or stromal cells present in the pulmonary tissues during progression of the disease.
The authors hypothesize that the occurrence of a chronic inflammatory response after prolonged interaction of pulmonary tissue with cigarette smoke causes aberrant homing of leukocytes to the tissue and delayed apoptosis. This leads to the characteristic inflammatory response in patients with chronic obstructive pulmonary disease.
Comments: The authors provide a concise but highly informative review of the potential systemic inflammatory effects of COPD. They discuss the current understanding of the effects of cigarette smoke in inducing oxidative stress, protease/antiprotease imbalances and acute and chronic inflammation in the lungs. These local inflammatory responses lead to systemic inflammation either by direct leakage and/or induction of stress or tissue injury related cytokines into the systemic circulation. The activation of peripheral leukocytes such as neutrophils and monocytes and the release of cytokines in the systemic circulation helps explain observations of muscle wasting, weight loss and other systemic manifestations of COPD. They also discuss the fact that the systemic and pulmonary inflammation persists even after smoking has ceased. The authors propose that the various cytokine signals alter the normal homing of these inflammatory cells to the lungs such that they end up in other peripheral tissues such as the cardiovascular system. There has been an increased interest in the role of systemic inflammation contributing to coronary artery disease. Recent studies have reported reduced hospital readmission and reduced all cause mortality for patients treated with inhaled corticosteroids following hospital admission for acute exacerbations of COPD. The pathogenetic mechanisms for these relationships require extensive further study; however, the notion that anti‐inflammatory treatment for COPD may reduce cardiovascular risk and mortality makes it critical that cardiovascular outcomes be specifically assessed in clinical studies that are evaluating long‐term use of inhaled corticosteroids or other novel antiinflammatory therapies for COPD.
Ron Balkissoon M.D., M.Sc., F.R.C.P.C.
National Jewish Medical and Research Center
1400 Jackson Street
Denver, CO 80206