Nicola A Hanania

Abstract: PURPOSE OF REVIEW: Asthma is a common disease in the older population that is frequently undiagnosed and undertreated. We will review the current knowledge of asthma in the elderly (AIE) and shed light on the diagnostic and management challenges outlining needs for future research. RECENT FINDINGS: There has been very little original research in the field of AIE published in the last few years, and current literature focuses primarily on a series of review articles. AIE often presents with multiple comorbidities, which complicates its course and management. There is renewed interest in nonallergic (intrinsic) asthma. T helper cell 1 inflammation triggered by respiratory infection, superantigens, proteases and interleukin 17 are possible mechanisms. An association between systemic inflammation in frailty and asthma may also be important. SUMMARY: The diagnosis and treatment of AIE requires that the individual patient and his or her specific triggers and the likely pathophysiology be understood. Understanding the mechanisms of inflammation in this population is key to improved therapeutic interventions.

Abstract: PURPOSE OF REVIEW: beta2-Adrenoceptor (AR) agonists are the most effective bronchodilators known, and play important roles in every step of asthma therapy. Intrinsic efficacy is an important pharmacological property that differentiates the clinical effects and safety profile of beta2-AR agonists. We review the role of beta2-AR agonist intrinsic efficacy in asthma treatment focusing on recent literature. RECENT FINDINGS: In acute asthma, a full agonist (high intrinsic efficacy) offers a clinical advantage over a partial agonist (low intrinsic efficacy) but with the potential of inducing dose-dependent adverse effects. The chronic use of beta2-AR agonists may be associated with several adverse outcomes including loss of asthma control and even increased mortality. Recently, the role of beta-AR inverse agonists (beta-blockers) which have a negative intrinsic efficacy was studied. Whereas contraindicated in acute asthma, preliminary data suggest that the chronic use of these agents may be associated with attenuation of airway hyper-responsiveness in patients with mild asthma. Studies in a murine model of asthma suggest that such effects may be related to decreased airway inflammation and mucous metaplasia. SUMMARY: Rational choice among beta2-AR agonists in acute and chronic asthma should be influenced by differences in intrinsic efficacy among these agents. In acute severe asthma, a full agonist offers a clinical advantage over a partial agonist. Whereas the use of inverse agonists in the treatment of asthma is still experimental and needs further exploration in future trials, preliminary studies suggest that their chronic use is well tolerated and is associated with decreased airway hyper-responsiveness.

Abstract: INTRODUCTION: The use of one or more long-acting bronchodilators is key in the maintenance therapy of chronic obstructive pulmonary disease (COPD). This analysis pooled the results of two double-blind studies evaluating the efficacy and safety of adding nebulized formoterol fumarate inhalation solution (FFIS) to maintenance tiotropium (TIO) treatment. METHODS: Following a run-in period of 7-14 days with once-daily TIO 18 microg, COPD subjects (> or =25% to <65% predicted forced expiratory volume in 1 second [FEV(1)]) were randomized to twice-daily FFIS 20 microg (n=145) or nebulized placebo (PLA, n=140) while continuing on maintenance TIO for 6 weeks. Efficacy was measured using serial spirometry, transition dyspnea index (TDI), rescue albuterol use, and St. George's Respiratory Questionnaire (SGRQ). RESULTS: The mean standardized area under the curve for FEV(1) over 3 hours (FEV(1)AUC(0-3)), the primary efficacy variable, was significantly higher in the FFIS/TIO group than the PLA/TIO group on day 1 (140 mL difference, P<0.0001) and week 6 (192 mL difference, P<0.0001). Mean TDI scores in the FFIS/TIO and PLA/TIO groups were 1.97 and 0.67, respectively (P=0.0001). Mean albuterol use declined in the FFIS/TIO group from 2.6 to 1.5 puffs/day compared with little change in the PLA/TIO group (P<0.0001). SGRQ scores were similar between treatment groups with the exception of the symptoms score, which improved in the FFIS/TIO group (-5.8) compared with PLA/TIO (-1.0), and more FFIS/TIO-treated subjects experienced a clinically significant improvement in total SGRQ score. More PLA/TIO-treated subjects than FFIS/TIO-treated subjects experienced adverse events (AEs) (45.7% vs. 31.0%) and COPD exacerbations (7.9% vs. 3.4%). CONCLUSIONS: The addition of FFIS to maintenance TIO treatment for moderate to severe COPD results in significantly improved FEV(1) and dyspnea, decreased rescue medication use, and a lower incidence of AEs and COPD exacerbations. The addition of FFIS to TIO yields clinically and statistically significant benefits for COPD patients and might be of long-term benefit.

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Abstract: AIMS: To develop a practical patient-completed chronic obstructive pulmonary disease assessment questionnaire (COPD-AQ) to improve COPD assessment and management in primary care, based on the concept of COPD stability. METHODS: An Expert Working Group defined parameters of COPD stability and a 10-item Physician's Global Assessment was established. A 21-item COPD-AQ was developed and validated in a cross-sectional, non-randomised study of patients with COPD (n=395). Items most discriminative of stability status (stable/unstable) were selected to produce a 5-item COPD-AQ, which was then validated. RESULTS: In the development sample, internal consistency reliability of the 5-item COPD-AQ was 0.74 (n=296). The COPD-AQ discriminated between stability groups based on physician assessment (F=44.26; p<0.0001) and post-bronchodilator spirometry measures (F=2.92; p<0.05). A questionnaire score >20 (range: 5.0-25.0) had a specificity of 82.9% and sensitivity of 64.7%. CONCLUSIONS: The 5-item COPD-AQ proved a practical tool for assessing COPD status and was sufficiently simple for routine clinical use. However, overall validation was limited by small numbers of patients in the validation sample. Difficulties also existed over using the term 'stability' to define COPD status. COPD-AQ was not progressed further, but this work will prove valuable in the future development of a global questionnaire to improve COPD management in primary care.

Abstract: Chronic regular use of beta(2)-adrenoceptor (beta(2)-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of beta(2)-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonist-induced signaling and reducing signaling by empty receptors, beta-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the beta-AR inverse agonists, we compared the asthma phenotype in beta(2)-AR-null and wild-type mice. Antigen challenge of beta(2)-AR-null mice produced results similar to what was observed with chronic beta(2)-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of beta(2)-AR inverse agonists are caused by inhibition of beta(2)-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a beta-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced beta(2)-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, beta(2)-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.

Abstract: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs that usually manifests late in life. Physiologic and immunologic changes that occur in COPD often mimic changes seen in the aging lung. This has led some to characterize COPD as an "accelerated aging phenotype." At the molecular level, COPD and aging share common mechanisms and are associated with significant dysregulation of the immune systems. Aging and COPD are characterized by increases in proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, which are implicated in aging-related inflammatory diseases and correlate with degree of obstruction in COPD. There is an age-dependent decline in naïve T cells with oligoclonal expansion of CD8(+) CD28(null) T cells from chronic antigenic stimulation. The increase in CD8(+) CD28 (null) T regulatory cells inhibits antigen-specific CD4(+) T cell responses, leading to a decline in adaptive immune response. To compensate for the decline in the adaptive immune function there is a paradoxical up-regulation of innate immune system resulting in a proinflammatory state. The dysregulated adaptive immune system with activated innate immune responses seen with aging results in recruitment and retention of neutrophils, macrophages, and CD4(+) and CD8(+) T cells in the lungs of smokers with COPD. Once the inflammation is triggered, there is a self-perpetuating cascade of inflammation and lung parenchymal damage. This review will focus on how the aging immune system may contribute to COPD development later in life in susceptible individuals.

Abstract: Current guidelines for the treatment of chronic obstructive pulmonary disease (COPD) recommend the use of long-acting bronchodilators in the maintenance management of COPD. Combining bronchodilators that work through different mechanisms is recommended in patients with continuous symptoms. We conducted this study to confirm and further investigate the efficacy and safety of nebulized formoterol as an add-on therapy to maintenance tiotropium in patients with COPD. This randomized, double-blind, placebo-controlled, parallel-group study (NCT00507234) was conducted at 24 US sites from March to October 2007 in 155 patients aged > or =40 years with post-bronchodilator forced expiratory volume in 1 second (FEV(1)) > or =25% to <65% predicted normal. COPD patients receiving open-label tiotropium bromide 18 microg once daily during a 1- to 2-week run-in period were randomized to receive either formoterol fumarate inhalation solution 20 microg or placebo by nebulization twice daily for 6 weeks while continuing treatment with tiotropium. Outcomes included serial spirometry, inspiratory capacity (IC), baseline dyspnoea index/transition dyspnoea index (BDI/TDI), daily symptom scores, salbutamol (albuterol) use and health status measured by the St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was standardized absolute FEV(1) area under the curve over 3 hours (AUC(0-3)) at week 6. Treatment groups (formoterol plus tiotropium, n = 78; placebo plus tiotropium, n = 77) were comparable at baseline. At 6 weeks, FEV(1) AUC(0-3) was significantly greater in the formoterol group compared with the placebo group (1.57 vs 1.38 L [p < 0.0001]). Similarly, formoterol plus tiotropium improved other lung function measures, including FEV(1), forced vital capacity and post-dose IC at day 1, and maintained efficacy through week 6. Formoterol plus tiotropium decreased rescue albuterol use throughout the study (p < 0.05). Mean TDI, SGRQ and most symptom scores did not differ between the two treatment groups. Overall, 37% of formoterol plus tiotropium recipients experienced adverse events versus 51% of those receiving placebo plus tiotropium. The addition of nebulized formoterol to tiotropium in maintenance treatment of COPD provided clinically meaningful, statistically significant and sustained improvements in pulmonary function without additional adverse effects.

Abstract: Chronic obstructive pulmonary disease (COPD) is an under-recognized cause of morbidity and mortality worldwide that imposes an ever increasing burden on the patient and society alike. The disease encompasses multiple structural and functional components of which inflammation is at the core of the disease, affecting the lungs and other organs. Consequently, current treatment strategies are aimed at treating both the symptoms and the pulmonary inflammation underlying the complex pathophysiology of COPD. Smoking cessation is the only intervention currently shown to slow disease progression in COPD and decrease all-cause mortality, aside from lung transplant, lung-volume reduction surgery and oxygen therapy in selective patients. However, this intervention is difficult to achieve and sustain because of the addictive and chronic relapsing nature of cigarette smoking. Pharmacotherapy with bronchodilating agents, including the beta 2-agonists, anticholinergics and methylxanthines, is central to the symptomatic management of all stages of COPD. While inhaled corticosteroids (ICS) are employed to reduce inflammation in more severe patients, their role as stand alone medication in COPD is not well defined. However, increasing evidence suggests that long-acting beta 2-agonists (LABAs) and ICS have complementary and synergistic effects, when delivered as combination therapy from a single inhaler. In this respect, two preparations comprising combinations of salmeterol+fluticasone propionate (SFC) and formoterol+budesonide (FBC) are currently available and employed for treatment of more severe disease. Several large-scale studies in patients with moderate-to-severe COPD have demonstrated that treatment with SFC and FBC leads to significantly greater improvements in lung function, exacerbations, health status and breathlessness, compared with placebo or monotherapy with the component drugs. In the recently published landmark study, Towards a Revolution in COPD Health (TORCH), regular treatment with SFC narrowly missed demonstrating a statistically significant benefit on the reduction in all-cause mortality over 3 years (17.5% reduction in risk, P=0.052), further emphasizing the clinical usefulness of LABA+ICS therapy in COPD. In view of this increasing evidence for the additional effectiveness of LABA+ICS combinations compared with the individual components, and the potential benefits of LABA+ICS on lung function, disease progression and potentially on all-cause mortality, initiation of LABA+ICS combination treatment early in the COPD disease process may be warranted. SEARCH STRATEGY: The studies discussed in this review were identified from systematic searches of Medline and the Cochrane Database, up to October 2007, for articles in English or with English abstracts describing randomized, double-blind, parallel-group/crossover trials of at least 24 weeks' duration. All searches were performed using the terms: chronic obstructive pulmonary disease, COPD, chronic obstructive airway disease, or COAD AND either salmeterol, formoterol, long-acting beta 2-adrenoceptor agonist, fluticasone propionate, budesonide, inhaled corticosteroids, or inhaled glucocorticosteroids. Additional relevant references were identified from the reference lists of selected papers. Only studies that compared a combined LABA+ICS therapy with its monotherapy components were selected for inclusion in this manuscript.

Abstract: Asthma is a chronic inflammatory disease of the airway that requires long-term antiinflammatory therapy. Inhaled corticosteroids (ICSs) are recommended for first-line treatment of persistent disease, but not all patients achieve asthma control even when these agents are used in high doses and in combination with other medications, including a long-acting beta(2)-agonist or a leukotriene modifier. Such patients may require additional therapy. As information about asthma pathophysiology and inflammatory phenotypes continues to increase, and additional antiinflammatory options become available, it may be possible to target antiinflammatory therapy to various aspects of the disease and consequently to improve the treatment of patients with inadequate responses to standard ICS-based therapy. Several novel antiinflammatory therapies are in different stages of clinical development. The most clinically advanced of these is omalizumab, a recombinant humanized monoclonal antibody that specifically targets IgE and is indicated for patients with moderate-to-severe asthma caused by allergies. Omalizumab has demonstrated efficacy in patients with moderate-to-severe asthma and documented evidence of allergen sensitivity. Other key therapy options in clinical development either target proinflammatory cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) or inflammatory cells (eg, T-helper type 2 cells and eosinophils). This review provides an overview of the current and future approaches targeting airway inflammation in patients with asthma.

Abstract: RATIONALE: Arformoterol, a single isomer long-acting beta(2)-agonist, was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD. METHODS: The pulmonary function efficacy of nebulized arformoterol (15 micro g BID, 25 micro g BID, 50 micro g QD) and salmeterol MDI (42 micro g BID) versus placebo was assessed in 1456 subjects (mean FEV(1) 1.2L, mean predicted 41%). Data were pooled from 2 identical, 12-week, double-blind, randomized trials. The percent change in trough FEV(1), percent change in FEV(1) average AUC((0 - 12 hrs)) and peak percent change FEV(1) from predose were analyzed. RESULTS: Improvement in trough FEV(1) averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo (mean differences from placebo [95% CI] arformoterol-15 micro g BID: 11.4% [8.4, 14.3]; 25 micro g BID: 15.4% [12.2, 18.6]; 50 micro g QD: 10.9% [7.9, 13.9]); salmeterol: (11.6% [8.8, 14.4]). Greater improvements versus placebo occurred after the first dose (mean differences between arformoterol and placebo for trough FEV(1): 13-19%; FEV(1) AUC((0 - 12 hrs)): 19-24%; peak percent change: 20-25%) and at week 12 (trough FEV(1): 10-13%; FEV(1) AUC((0 - 12 hrs)): 6-13%; peak percent change: 7-14%); all 95% CIs excluded zero. Increases in FEV(1) AUC((0 - 12 hrs)) and peak percent change were greater for arformoterol than for salmeterol (95% CIs excluded zero). After 12 weeks, 78-87% of arformoterol subjects had > or = 10% increases in FEV(1) from pre-dose (56% salmeterol, 44% placebo); the median time to response was 3-13 minutes (142 minutes salmeterol). CONCLUSIONS: In these trials, COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks.

Abstract: Beta-blockers are currently contraindicated in asthma because their acute administration may be associated with worsening bronchospasm. However, their effects and safety with their chronic administration are not well evaluated. The rationale for this pilot study was based on the paradigm shift that was observed with the use of beta-blockers in congestive heart failure, which once contraindicated because of their acute detrimental effects, have now been shown to reduce mortality with their chronic use. We hypothesized that certain beta-blockers may also be safe and useful in chronic asthma therapy. In this prospective, open-label, pilot study, we evaluated the safety and effects of escalating doses of the beta-blocker, nadolol, administered over 9 weeks to 10 subjects with mild asthma. Dose escalation was performed on a weekly basis based on pre-determined safety, lung function, asthma control and hemodynamic parameters. The primary objective was to evaluate safety and secondary objectives were to evaluate effects on airway hyperresponsiveness, and indices of respiratory function. The escalating administration of nadolol was well tolerated. In 8 out of the 10 subjects, 9 weeks of nadolol treatment produced a significant, dose-dependent increase in PC20 that reached 2.1 doubling doses at 40 mg (P<0.0042). However, there was also a dose-independent 5% reduction in mean FEV1 over the study period (P<0.01). We conclude that in most patients with mild asthma, the dose-escalating administration of the beta-blocker, nadolol, is well tolerated and may have beneficial effects on airway hyperresponsiveness. Our findings warrant further testing in future larger trials.

Abstract: BACKGROUND: The National Heart, Lung, and Blood Institute guideline recommends that dosing racemic albuterol be administered every 1 to 4 hours for treating patients with asthma or chronic obstructive pulmonary disease (COPD) in the hospital. Previously published preliminary and retrospective studies suggested that levalbuterol can be administered every 8 hours for the treatment of bronchoconstriction in hospitalized patients. However, it is unclear how the different dosing regimens affect the total number of nebulizations (scheduled plus as-needed treatments) and the costs of treatment of bronchoconstriction in a hospital setting. Moreover, it is not clear how the different dosing regimens affect symptom outcomes and health status in hospitalized patients with asthma or COPD. OBJECTIVE: The aim of this study was to evaluate these issues in hospitalized patients with acute asthma or COPD. METHODS: In this prospective, multicenter, randomized, open-label study, hospitalized patients aged > or = 18 years were randomly assigned to receive 14-day treatment with levalbuterol 1.25 mg q6-8h or racemic albuterol 2.5 mg q1-4h, administered per routine hospital practice at each institution. The primary efficacy end point was total number of nebulizations during hospitalization. Pulmonary function, symptom evaluation (subject general well-being score [SGWB], disease symptom assessment [DSA], and beta-mediated adverse effect scores), hospital costs (excluding medication costs) and hospital length of stay (LOS) were also evaluated. RESULTS: In the intent-to-treat population (n = 479; levalbuterol, 241;racemic albuterol, 238), the mean (SE) age was 55.3 (16.9) years, the majority of patients were white (57.8%), and the mean (SE) weight was 80.9 (24.5) kg. Demographic characteristics were similar between the 2 treatment groups, except that there were more females with COPD in the levalbuterol treatment group (63.88%) compared with the racemic albuterol treatment group (45.5%) (P = 0.005). Patients treated with levalbuterol required significantly fewer median total nebulizations (10 vs 12; P = 0.031) and scheduled nebulizations (9 vs 11; P = 0.009) compared with those in the racemic albuterol group. The 2 treatment groups required 0 rescue nebulizations. Mean (SD) forced expiratory volume in 1 second improved from baseline with both levalbuterol and racemic albuterol (0.06 [0.43] and 0.10 [0.37] L, respectively); these improvements were maintained throughout the hospital stay (0.11 [0.48] and 0.16 [0.52] L). DSA and SGWB scores improved significantly from baseline in both treatment groups, and beta-mediated adverse effects mean scores were significantly greater with levalbuterol versus racemic albuterol (P < 0.001). In the levalbuterol and racemic albuterol treatment groups, hospital LOS (70.6 and 65.7 hours, respectively), time to discharge (66.0 and 62.8 hours), and total hospital costs (least squares mean [SE], US $4869.30 [$343.58] and $4899.41 [$343.20]) were similar. CONCLUSIONS: In these hospitalized patients with acute asthma or COPD treated with levalbuterol every 6 to 8 hours or racemic albuterol every 1 to 4 hours, significantly fewer total nebulizations were required with levalbuterol, without an increased need for rescue nebulizations during 14 days of hospitalization. Both treatments were associated with improvements from baseline in symptoms and health status. The costs of treating bronchoconstriction in hospitalized patients were similar between the levalbuterol and racemic albuterol groups.

Abstract: Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.

Abstract: As optimal treatment and prognosis differ between asthma and COPD, a new diagnostic approach to differentiating between the two disorders would be clinically desirable. We evaluated the utility of vibration response imaging in differentiating between asthma and COPD. Sixty-six subjects with asthma or COPD were recorded, before and after the administration of a short-acting bronchodilator, using a computerized lung sound analysis device. Gray-scale images of breath sound distribution in the lungs, quantitative data in breath sound graphs (timing, amplitude) and automatic crackle and wheeze detection programs were used to differentiate between asthma and COPD subjects. Imaging data were compared with the clinical diagnosis, made by the standard methods (medical history, physical examination, and spirometric indices). Blinded evaluation of images demonstrated a significantly higher rate of improvement in image dynamics, shape and overall improvement following bronchodilator in subjects with asthma compared with those with COPD. Quantitative data showed distinct patterns in timing and amplitude for these two pathologies. Combined analyses based on qualitative image evaluation and quantitative data demonstrated an overall 85% accuracy (84% for asthma, 86% for COPD) in differentiating between asthma and COPD. Combined qualitative and quantitative evaluations of lung sounds are quite sensitive in distinguishing between lung sound recordings of COPD and asthma individuals. Lung sound features of synchronization in timing and intensity provide objective data that may further differentiate these two airway disorders.

Abstract: Formoterol fumarate is a long-acting beta2-agonist that is an effective bronchodilator for the maintenance management of patients with chronic obstructive pulmonary disease. The safety profile of the newly developed nebulized formoterol was evaluated over a twelve-month period in an open-label, active-control study. After completing a twelve-week double-blind double-dummy period, 569 subjects with chronic obstructive pulmonary disease entered an open-label extension study and received twice-daily 20 microg formoterol fumarate inhalation solution for nebulization (FFIS) or 12 microg formoterol fumarate dry powder inhalation (FA) for 52 weeks. Most of the FFIS-treated subjects (86%) completed at least six months of open-label treatment with over 90% compliance, comparable to the FA group (88%). RESULTS: of safety monitoring for adverse events, laboratory values, and cardiac changes were similar between treatment groups. Three hundred forty (73%) of FFIS-treated subjects and 83 (78%) of FA-treated subjects experienced an adverse event over the course of the study, the majority of which were mild to moderate and considered unrelated to treatment. COPD exacerbation occurred in 15.8% of FFIS-treated and 17.9% of FA-treated subjects. Deaths, serious adverse events, and discontinuations for adverse events occurred in 1.3, 16.2, and 5.4% of the nebulized group versus 1.9, 17.9, and 7.5% of the inhaled group, respectively. There were no clinically important changes from baseline in laboratory tests, including serum potassium and glucose, or vital signs and no treatment-related increases in cardiac arrhythmias, heart rate, or QTc prolongation. We conclude that nebulized formoterol fumarate twice daily is well tolerated over long-term treatment in moderate-to-severe COPD subjects and has a similar safety profile to the DPI formulation.

Abstract: BACKGROUND: Approximately 60 million people in the United States live with one of four chronic conditions: heart disease, diabetes, chronic respiratory disease, and major depression. Anxiety and depression are very common comorbidities in COPD and have significant impact on patients, their families, society, and the course of the disease. METHODS: We report the proceedings of a multidisciplinary workshop on anxiety and depression in COPD that aimed to shed light on the current understanding of these comorbidities, and outline unanswered questions and areas of future research needs. RESULTS: Estimates of prevalence of anxiety and depression in COPD vary widely but are generally higher than those reported in some other advanced chronic diseases. Untreated and undetected anxiety and depressive symptoms may increase physical disability, morbidity, and health-care utilization. Several patient, physician, and system barriers contribute to the underdiagnosis of these disorders in patients with COPD. While few published studies demonstrate that these disorders associated with COPD respond well to appropriate pharmacologic and nonpharmacologic therapy, only a small proportion of COPD patients with these disorders receive effective treatment. CONCLUSION: Future research is needed to address the impact, early detection, and management of anxiety and depression in COPD.

Abstract: The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

Abstract: INTRODUCTION: Concerns have been raised regarding the safety of extended use of long-acting beta2-agonists (LABAs). The safety of arformoterol (50 microg QD), and salmeterol (42 microg BID), was assessed over 12 months in subjects with COPD. The study also examined the occurrence of tolerance with these agents, i.e. whether improvement in airway function diminished or frequency of exacerbations increased with 12-months of use. METHODS: Subjects with COPD (mean FEV1 1.2 L, ~41% predicted) were enrolled in the study and randomized to receive nebulized arformoterol 50 microg QD (n = 528) or salmeterol 42 microg BID (MDI; n = 265) in a prospective, multicenter, open-label, 12-month trial. The frequency of adverse events, COPD exacerbations, and use of short-acting bronchodilator agents were assessed throughout the study period. Pulmonary function was also examined. RESULTS: Among treated subjects, the frequency of adverse events was similar for those taking arformoterol (90.5%) and salmeterol (88.3%). Tremor was more frequent among subjects treated with arformoterol (13.4%) than those treated with salmeterol (1.1%). The frequency of COPD exacerbations did not increase over 12 months for arformoterol and salmeterol (weeks 0-13: 15.7% and 11.7%, respectively; weeks 39-52: 10.0% and 9.4%, respectively). Supplemental ipratropium bromide and rescue racemic albuterol use decreased for both groups by 0.8 to 1.5 actuations/day, decreases that remained stable throughout the 52-week study. Mean predose (trough) FEV1 improved for arformoterol and salmeterol at week 13 (7.1% +/- 17.0 and 7.6% +/- 17.8, respectively) and the improvement continued at week 52 (5.9% and 6.2%, respectively). Mean peak percent predicted postdose FEV1 over the course of the 52-week study declined by about 2% for both treatments, but throughout was higher for arformoterol than for salmeterol. CONCLUSION: In this trial, both arformoterol 50 microg QD and salmeterol 42 microg BID were well tolerated in patients with COPD. Both LABAs produced effective bronchodilation and their use was not associated with the development of clinically meaningful tolerance over a 1-year treatment period.

Abstract: Chronic obstructive pulmonary disease (COPD) is an increasing health problem and one of the leading causes of morbidity and mortality worldwide, but knowledge about its pathogenesis has increased substantially in recent years. The disease results from interaction between individual risk factors (like enzymatic deficiencies) and environmental exposures to noxious agents, like cigarette smoking, occupational dusts, air pollution and infections in childhood. The main mechanisms that may contribute to airflow limitation in COPD are fixed narrowing of small airways, emphysema and luminal obstruction with mucus secretions. COPD is characterised by a chronic inflammatory process in the pulmonary tissue, with a pattern different from bronchial asthma, associated with extrapulmonary effects and is considered now a complex, systemic disease. Optimal therapeutic targeting of COPD depends on a clear understanding of the precise mechanisms of these complex processes and on early and correct evaluation of disease severity. A combination of pharmacological and non-pharmacological approaches is used to treat COPD. Bronchodilators are the mainstay of COPD treatment and can be combined with inhaled corticosteroids for greater efficacy and fewer side effects. The use of LTOT for hypoxemic patients has resulted in increased survival, and expanded drug therapy options have effectively improved dyspnoea and quality of life. Recent studies have documented the benefits of pulmonary rehabilitation. In addition, non-invasive mechanical ventilation offers new alternatives for patients with acute or chronic failure.

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Abstract: BACKGROUND: Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial beta(2)-agonist. METHODS: We conducted a randomized, double-blind, proof-of-concept study to investigate whether a full beta(2)-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV(1)<50%) who fail to respond to an initial treatment of the partial beta(2)-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV(1)=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV(1)=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected. RESULTS: Subjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV(1) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (-0.52 vs. -0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group. CONCLUSIONS: Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms.

Abstract: Salmeterol is a long-acting beta(2)-adrenergic receptor (beta(2)AR) agonist commonly used in the treatment of asthma and chronic obstructive pulmonary disease. It differs from other beta-agonists in that it has a very low intrinisic efficacy, especially when compared with the other available long-acting beta-agonist, formoterol. Receptor desensitization and down-regulation has been described with the chronic use of beta-agonists. This effect may not be the same with all beta-agonists and may be related to their stabilization of altered receptor states. The extreme hydrophobicity and high-affinity quasi-irreversible binding of salmeterol have rendered studies examining the mechanisms by which it mediates receptor desensitization, down-regulation, and internalization difficult. We determined the capacity of salmeterol to induce beta(2)AR endocytosis, G protein-coupled receptor kinase (GRK)-site phosphorylation, degradation, and beta-arrestin2 translocation in HEK293 cells as compared with other agonists of varying intrinsic efficacies. Despite stimulating GRK-mediated phosphorylation of Ser355,356 after 30 min and 18 h to an extent similar to that observed with agonists of high intrinsic efficacy, such as epinephrine and formoterol, salmeterol did not induce significant beta(2)AR internalization or degradation and was incapable of stimulating the translocation of enhanced green fluorescent protein-beta-arrestin2 chimera (EGFP-beta-arrestin2) to the cell surface. Salmeterol-induced receptor endocytosis was rescued, at least in part, by the overexpression of EGFP-beta-arrestin2. Our data indicate that salmeterol binding induces an active receptor state that is unable to recruit beta-arrestin or undergo significant endocytosis or degradation despite stimulating considerable GRK-site phosphorylation. Defects in these components of salmeterol-induced receptor desensitization may be important determinants of its sustained bronchodilation with chronic use.

Abstract: OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P <or= 0.001); all doses of arformoterol were statistically different from salmeterol for this end point (P <or= 0.024). At week 12, TDI focal scores were significantly greater with all arformoterol doses compared with placebo (mean [95% CI]: 15 microg BID, 0.97 [0.25-1.69]; 25 microg BID, 1.08 [0.3-1.86]; 50 microg QD, 1.04 [0.32-1.771), suggesting treatment-associated improvement in dyspnea, however, the difference between salmeterol and placebo was not statistically significant (0.36 [-0.40 to 1.12]). Improvements in health status, as measured using SGRQ total scores, were -2.6 to -3.6 U in the arformoterol groups, -4.4 U for salmeterol, and -1.2 U for placebo; 95% CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups. There was a similar frequency of AEs and COPD exacerbations across all groups, including placebo. CONCLUSIONS: In this trial, patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo. The results also suggest that all doses of arformoterol, including the lowest dose (15 microg BID), were effective. Overall, nebulized arformoterol was well tolerated.

Abstract: RATIONALE: Improvement in FEV(1) is a main endpoint in clinical trials assessing the efficacy of bronchodilators. However, the effect of bronchodilators on maximal expiratory flow may be confounded by thoracic gas compression (TGC). OBJECTIVE: To determine whether TGC confounds effect of albuterol on FEV(1). METHODS: We evaluated the response to albuterol inhalation in 10 healthy subjects, 9 subjects with asthma, and 15 subjects with chronic obstructive pulmonary disease (COPD) with mean (SD) age in years of 38 (SD, 11), 45 (SD, 11), and 64 (SD, 8), respectively. Lung mechanics were measured at baseline and 20 minutes after inhalation of 180 micro g of albuterol. We then applied a novel method to calculate FEV(1) corrected for the effect of TGC (NFEV(1)). RESULTS: Prior to albuterol administration, NFEV(1) was significantly higher than FEV(1). However, post-albuterol inhalation, FEV(1) increased more than NFEV(1) because of reduced TGC. In multiple regression analysis, the changes in TGC, inspiratory lung resistance, and ratio of residual volume to total lung capacity postalbuterol predicted more than 75% of FEV(1) improvement in patients with COPD. CONCLUSION: Improvements in FEV(1) after albuterol in patients with COPD are due to reduction of lung resistance, hyperinflation, and TGC. The latter is negligible during tidal breathing. Thus, although reduction of lung resistance and hyperinflation may result in improved dyspnea with a bronchodilator, the contribution of TGC reduction to improvement of FEV(1) may not exert any meaningful clinical effect during tidal breathing. This fact has to be taken into consideration when assessing the efficacy of new bronchodilators.

Abstract: Chronic obstructive pulmonary disease (COPD) is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression, improvement of symptoms, exercise tolerance, health status, and decrease in exacerbations and in mortality are the main goals of the management of COPD. Bronchodilators play a pivotal role in the treatment of symptomatic patients with COPD. Inhaled short-acting bronchodilators are currently recommended for rescue of symptoms in patients with mild disease, whereas inhaled long-acting bronchodilators are recommended as first-line agents for maintenance therapy in patients with moderate and severe disease and those with daily symptoms. Long-acting bronchodilators improve symptoms, exercise tolerance, and health status, and reduce exacerbations in patients COPD. However, their effects on long-term decline in lung function and mortality are currently under investigation. When symptoms are not sufficiently controlled by the use of one bronchodilator, combining bronchodilators of different classes may be a more effective approach. In fact, recent evidence supports the regular use of a combination of a long-acting beta2-adrenoceptor agonist and a long-acting anticholinergic agent in patients with severe COPD. Combining a long-acting beta2-adrenoceptor agonist with an inhaled corticosteroid has also been shown to be more effective than the use of either agent alone. The use of theophylline has declined in recent years because of its narrow therapeutic index, and should be reserved as a third-line option in patients with very severe disease. Several novel bronchodilators are now in different stages of development for use alone or in combination with other agents.

Abstract: Management guidelines for asthma emphasize a stepwise approach in treating this disease based on daytime symptoms, nighttime symptoms, and lung function assessed by peak expiratory flow or forced expiratory volume at 1s (FEV(1)). Although improvement of lung function is a key goal in managing asthma, clinicians often see patients who may have achieved a normal FEV(1) with guideline-recommended treatment but continue to experience limitations in their daily activities. In such situations, focusing the assessment solely on pulmonary function (e.g. FEV(1)) is often inadequate and may lead to undertreatment. Alternate assessment measures are therefore often needed to assess asthma control and achieve a successful treatment outcome. This review will provide practical guidance relevant to the clinical assessment of asthma control.

Abstract: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity and mortality. Published practice guidelines and treatment algorithms for COPD are designed to increase awareness of the problem and improve patient care; however, <40% of subjects diagnosed with COPD are receiving appropriate maintenance therapy. OBJECTIVE: This paper reviews the use of maintenance therapy in COPD and examines the optimal timing for initiating such therapy based on the available literature. METHODS: Relevant publications were identified through a search of MEDLINE (1995-May 2007) using the terms COPD, guidelines, treatment, maintenance therapy, bronchodilator, ipratropium, tiotropium, beta-agonist, salmeterol, and inhaled corticosteroid. English-language publications discussing pharmacologic maintenance therapy for COPD, including practice statements/guidelines, randomized controlled clinical trials, systematic reviews, and meta-analyses, with a focus on agents currently approved for use in the United States, were selected for inclusion. RESULTS: Although guidelines and algorithms agree on the importance of regularly scheduled maintenance therapy to reduce symptoms of COPD, minimize activity limitations, and improve health status, the timing of the initiation of such therapy is debatable. In most instances, maintenance medications, which include long-acting beta(2)-agonists, long-acting anticholinergics, and combination products, are prescribed late in the disease process and mainly for patients with severe disease. However, there is increasing evidence that the use of maintenance therapy early in the disease process may be associated with improvements in such outcomes as lung function, symptoms, exercise tolerance, exacerbations of COPD, and quality of life. CONCLUSION: The high burden associated with COPD highlights the need to initiate maintenance therapy before a substantial decline in lung function has occurred.

Abstract: Asthma is underdiagnosed and undertreated in older adults. The classic symptoms, including episodic wheezing, shortness of breath, and chest tightness, are nonspecific in this age group. Older patients may underrate symptoms, and other diseases, such as chronic obstructive pulmonary disease, congestive heart failure, and angina, may have similar presentations. Objective measurements of lung function always should complement the history taking and physical examination. Management of asthma in older adults should include careful monitoring, controlling triggers, optimizing and monitoring pharmacotherapy, and providing appropriate asthma education. Adverse effects to commonly used asthma medications are more common in older adults, and careful monitoring of their use and adverse effects is important.

Abstract: Chronic obstructive pulmonary disease is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression; improvement of symptoms, exercise tolerance, and health status; and decrease in exacerbations and mortality are the goals of management. Inhaled short-acting bronchodilators are recommended for symptoms in mild disease, whereas inhaled long-acting bronchodilators are recommended for maintenance therapy of daily symptoms. When symptoms are not controlled using one bronchodilator, combining bronchodilators may be more effective. Combining a long-acting beta-agonist with an inhaled corticosteroid is more effective than either agent alone. Several novel therapies are in different stages of development.

Abstract: Influenza virus continues to be a major cause of respiratory infection and is an important contributor to morbidity and mortality in at-risk populations, including those with underlying pulmonary conditions such as asthma. Vaccination with inactivated influenza vaccine remains the most popular method in controlling influenza through prevention. Current guidelines recommend the administration of the influenza vaccine to all patients with asthma. However, a third or fewer of those patients with asthma are currently receiving this vaccine. In this review, the risk-versus-benefit of influenza vaccination in children and adults with asthma is evaluated, based on the current evidence.

Abstract: This multicenter, randomized, double-blind trial compared nebulized levalbuterol (Lev) and racemic albuterol (Rac) in the treatment of acute asthma. METHODS: Adults with acute asthma exacerbations (FEV(1) 20%-55% predicted) received prednisone and either Lev (1.25 mg, n = 315) or Rac (2.5 mg, n = 312). Nebulized treatments were administered every 20 minutes in the first hour, then every 40 minutes for 3 additional doses, then as necessary for up to 24 hours. The primary end point was time to meet discharge criteria. Secondary end points included changes in lung function and hospitalization rates. A subset of 160 patients had plasma (S)-albuterol concentrations determined at study entry. RESULTS: Time to meet discharge criteria did not differ between the 2 treatments. FEV(1) improvement was greater following Lev compared with Rac, both after dose 1 and cumulatively over the entire treatment period (dose 1 in intent to treat [ITT] group: Lev 0.50 +/- 0.43 L, Rac 0.43 +/- 0.37 L; P = .02), particularly among the 60% of patients not on recent steroid therapy (dose 1: Lev 0.58 +/- 0.47 L, Rac 0.44 +/- 0.37 L; P < .01), and patients whose entry (S)-albuterol concentrations were in the highest quartile of those measured. A small and similar proportion of Lev-treated (7.0%) and Rac-treated (9.3%) patients required hospitalization (P = .28). Among patients not on steroids, fewer Lev- than Rac-treated patients required admission (3.8% vs 9.3%, P = .03), as was also the case for patients with high plasma (S)-albuterol concentrations. Asthma relapses (5% in 30 days) were lower than in previous reports and did not differ between groups. CONCLUSIONS: This study suggests that early, regular nebulized beta(2)-agonist and systemic corticosteroid therapy may reduce hospitalization and relapse rates in patients with acute severe asthma. Lev was well tolerated and compared favorably with Rac in improving airway function, particularly in those who were not on inhaled or oral corticosteroids and in those who had high plasma (S)-albuterol concentrations at presentation.

Abstract: BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.

Abstract: Acute exacerbations of COPD can complicate the course of the disease in patients with severe airway obstruction. Reduction of exacerbations is an important clinical outcome in evaluating new therapies in COPD. Combination therapies with long-acting beta-agonists and inhaled corticosteroids have now been approved for use. Three 1-year randomized clinical trials, which studied the effect of combining a long-acting beta2-agonist with an inhaled corticosteroid in COPD, documented that exacerbation frequency was lower with therapy than placebo. Combination therapy had a similar effect to its monocomponents in the trial evaluating salmeterol/fluticasone combination. However, when patients with more severe COPD were studied using a combination of budesonide and formoterol, a clear improvement was seen in the overall exacerbation rates compared with the use of a long-acting beta2-agonist alone.

Abstract: Long-acting beta(2)-agonists (LABAs) are recommended in the management of patients with chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated that the LABA, salmeterol, improves lung function, symptoms and quality of life in patients with COPD. In this study, we have performed additional analyses of the combined data from two previous double-blind, placebo-controlled, parallel studies of salmeterol (50 microg, b.i.d) in patients with COPD. The new analyses reveal that the significant improvements seen in pre-dose and 2-h post-dose forced expiratory volume in 1 s (FEV(1)) compared to placebo, occur early in the treatment period, and are sustained for at least 24 weeks. Moreover, improvements in peak expiratory flow rate occur as early as Day 1, and are sustained throughout the 24-week period. Additional analyses of 12-h FEV(1) data also show that salmeterol is associated with an increase in the area under the curve at Week 12 compared with Day 1, adding further support to evidence that it results in a sustained bronchodilator response, with no evidence of tolerance.

Abstract: BACKGROUND: The pathology of chronic obstructive pulmonary disease (COPD) includes both obstructive and inflammatory components. OBJECTIVE: The aim of this study was to confirm the findings of a previous study that compared the efficacy of a combination of 2 short-acting bronchodilators with the use of an inhaled corticosteroid and a long-acting beta-agonist in the treatment of COPD. METHODS: We conducted an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group study of subjects with moderate to severe COPD to compare fluticasone propionate/salmeterol 250/50 microg BID (FSC) with ipratropium/albuterol 36/206 microg QID (IB/ALB). The primary efficacy measure was morning preadministration forced expiratory volume in 1 second (FEV(1)). Secondary measures were morning peak expiratory flow (PEF), 6-hour FEV(1) AUC, percentage of symptom-free nights, Transition Dyspnea Index (TDI) score, and overall daytime symptom score. Additional measures included sleep symptoms, supplemental albuterol use, and nighttime awakenings due to respiratory symptoms. Safety evaluations were based on clinical adverse events and COPD exacerbations. RESULTS: Baseline characteristics were similar between the FSC (n = 180) and IB/ALB (n = 181) groups, including mean age (63.7 and 65.4 years, respectively), mean body weight (81 and 79 kg, respectively), screening pulmonary function (mean [SD], 43.7% [14.2%] and 41.6% [13.4%] of predicted FEV(1)), race (82% and 91% white), and sex (64% and 62% male). FSC resulted in greater improvements in morning preadministration FEV(1), morning PEF, and 6-hour FEV(1) AUC (all, P < 0.001), TDI score (P = 0.026), overall daytime symptom score (P = 0.024), percentage of symptom-free nights (P = 0.010), nighttime awakenings due to respiratory symptoms (P = 0.002), sleep symptom score (P = 0.003), and percentage of days and nights without rescue albuterol use compared with IB/ALB (P = 0.021 and P < 0.001, respectively). Compared with day 1, the FEV(1) AUC at week 8 increased by 0.38 L-h with FSC and decreased by 0.18 L-h with IB/ALB (P < 0.001 between groups). The type and incidence of adverse events were similar between the 2 groups. One or more adverse event was reported for 81 (45%) and 85 (47%) subjects in the FSC and IB/ALB groups, respectively. CONCLUSION: In this 8-week study, subjects with moderate to severe COPD experienced greater improvements in lung function and symptom measures with FSC than with IB/ALB.

Abstract: PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. RECENT FINDINGS: Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. SUMMARY: Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.

Abstract: OBJECTIVES: To provide an overview on the interrelationship between asthma and pregnancy, focusing on management of pregnant women presenting with an acute severe exacerbation. DESIGN: A review of the current English-language published clinical trials was performed based on MEDLINE search using the Medical Subject Headings pregnancy and asthma. Current reviews on the topic and practice guidelines were also reviewed. RESULTS: Asthma is the most common medical condition to complicate pregnancy, and episodes of acute asthma requiring emergency department visits or hospitalization have been reported in 9-11% of pregnant women managed by asthma specialists. Pregnancy can affect the course of asthma, and the risk of asthma exacerbations requiring intervention in pregnant women is higher than in nonpregnant women. Similarly, asthma can affect pregnancy outcomes. Maternal inflammatory pathways may contribute to the poor pregnancy outcomes, especially in women with uncontrolled asthma. Although data on the effects of maternal asthma on pregnancy have been conflicting, mainly because many published studies have not corrected for asthma severity, it has generally been observed that poorly managed asthma during pregnancy is associated with a higher risk of preterm delivery, low birth weight, and complications such as preeclampsia. Optimal therapy of asthma has been shown to contribute to improved maternal and fetal outcomes. CONCLUSIONS: Asthma can complicate the course of pregnancy, and pregnancy can worsen asthma control in some women. Optimal management of asthma during pregnancy is key in ensuring the safety of the mother and the fetus.

Abstract: The multicomponent nature of chronic obstructive pulmonary disease (COPD) has provided a challenging environment in which to develop successful treatments. A combination of pharmacological and non-pharmacological approaches is used to combat this problem, and an overview of these approaches and their possible future direction is given. Bronchodilators are the mainstay of COPD treatment and can be combined with inhaled corticosteroids for greater efficacy and fewer side effects. A new generation of pharmacotherapeutic agents, most notably phosphodiesterase-4 inhibitors, which are already in the advanced stages of clinical development, and leukotriene B4 inhibitors (in early clinical development), may shape future treatment as further insight is gained into the pathological mechanisms underlying COPD. Non-pharmacologic treatments for COPD include long-term oxygen therapy (LTOT), nasal positive pressure ventilation (nPPV), pulmonary rehabilitation and lung-volume-reduction surgery (LVRS). Apart from smoking cessation, LTOT is the only treatment to date which has been shown to modify survival rates in severe cases; thus its role in COPD is well defined. The roles of nPPV and LVRS are less clear, though recent progress is reported here. In the future, it will be important to establish the precise value of the different treatments available for COPD--evaluating both clinical and physiological endpoints and using the data to more accurately define candidate patients accordingly. The challenge will be to develop this base of knowledge in order to shape future research and allow clinicians to deliver tailored COPD management programmes for the growing number of patients afflicted with this disease.

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Abstract: BACKGROUND: Annual influenza vaccination is currently recommended as a preventative measure for all patients with asthma. However, the effect of maintenance corticosteroid therapy on the immune response to influenza vaccine has received limited evaluation. OBJECTIVE: In this study, we evaluated the effect of corticosteroid therapy on the immune response to influenza vaccine in children and adults with asthma. METHODS: This was a substudy of a larger multicenter, randomized, double-masked, placebo-controlled, crossover study investigating the safety of trivalent influenza vaccine in patients with asthma. At baseline, 294 subjects were randomized to receive either placebo first (n=139) or inactivated trivalent split-virus influenza vaccine first (n=155). Study subjects were categorized into 2 groups: subjects in group 1 (n=148) were receiving medium-dose or high-dose inhaled corticosteroids (ICSs) or oral corticosteroids, whereas subjects in group 2 (n=146) were not receiving corticosteroids or were receiving low-dose ICSs. Serum hemagglutination inhibition antibody titers for the vaccine antigens were measured before and 4 weeks after the administration of placebo or vaccine. RESULTS: Serologic responses to each influenza vaccine antigen were significantly higher in vaccine than in placebo recipients and were similar among influenza vaccine recipients in groups 1 and 2 for the following endpoints: rise in antibody titer, percent of participants who developed a serological response, and percent of subjects who developed a serum hemagglutination inhibition antibody titer > or =1:32. Post hoc subgroup analyses demonstrated an attenuated response to influenza B antigen in subjects receiving high-dose ICS compared with subjects who were steroid-naïve (P<.05). CONCLUSION: The immune response to the A antigens of the inactivated influenza vaccine in subjects with asthma is not adversely affected by ICS therapy. High-dose ICS therapy may diminish the response to the B antigen of the vaccine, an observation that needs further investigation.

Abstract: Asthma is one of the most common medical conditions that can complicate pregnancy. Although most pregnant women with asthma have controlled disease, some women may experience exacerbation of their disease, necessitating immediate intervention. This article discusses the interrelations between asthma and pregnancy and presents an overview on the management of pregnant women presenting to the hospital with acute severe asthma. Treating physicians must overcome the common belief that pregnant women should not take any medications during pregnancy, and they should keep asthma in pregnant women under control to minimize the risk for maternal and fetal hypoxia.

Abstract: Beta2-adrenergic agonists (beta2-agonists) play a pivotal role in the acute and chronic management of asthma. Their major action on the airways is the relaxation of smooth muscle cells. In addition to their bronchodilator properties, beta2-agonists may have other effects through their activation of beta2-receptors expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils. These non-bronchodilator activities of beta2-agonists may enhance their efficacy in the management of asthma. In pre-clinical studies, the anti-inflammatory effects of beta2-agonists are demonstrated through their stabilizing effect on mast cells and their inhibition of mediator release from eosinophils, macrophages T-lymphocytes, and neutrophils. In addition, beta2-agonists may inhibit plasma exudation in the airway, the release of neuropeptides from sensory nerves, and mediator release from epithelial cells. These in vitro observations are not as clearly demonstrated in clinical trials, which may be explained by the rapid desensitization of beta2-adrenergic receptors on airway inflammatory cells. The regular use of short-acting beta2-agonists alone has been shown to have deleterious effects on asthma control. Therefore, short-acting agents should only be used when needed for rescue of acute symptoms. Monotherapy with long-acting beta2-agonists has also been associated with poor asthma control. However, when given concomitantly with inhaled corticosteroids, beta2-agonists may potentiate the anti-inflammatory effect of corticosteroids, improve asthma control and prevent exacerbations.

Abstract: STUDY OBJECTIVES: To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting beta(2)-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD. DESIGN: Randomized, double-blind, multicenter, placebo-controlled study. SETTING: Seventy-six investigative sites in the United States. PATIENTS: Seven hundred twenty-three patients > or =40 years of age with COPD and a mean baseline FEV(1) of 42% predicted. INTERVENTIONS: FP (250 microg), SM (50 microg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks. MEASUREMENTS: Primary efficacy measures were morning predose (ie, trough FEV(1)) for FSC compared with SM and 2-h postdose FEV(1) for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures. RESULTS: At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p < or = 0.012) increased the morning predose FEV(1) (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p < or = 0.001) increased the 2-h postdose FEV(1) (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p < or = 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups. CONCLUSIONS: Treatment with FSC (FP, 250 microg, and SM, 50 microg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components.

Abstract: We describe an HIV-infected 44-year-old man who presented 1 month after discontinuation of HAART therapy with a large mass extending from the mediastinum, enclosing the heart and extending through the diaphragm to the epigastric region. Biopsies subsequently revealed a highly aggressive non-Hodgkin's lymphoma (NHL) producing sheets of cells with an organoid distribution. The cells had abundant basophilic cytoplasm and a plasmacytic appearance. Although immunohistochemistry failed to show either B- or T-cell markers, antigens consistent with plasma cells were found. An immunoglobulin heavy chain clonal rearrangement was identified by PCR analysis. These studies were supportive of a diagnosis of a plasmablastic lymphoma. While awaiting the results of these tests, the patient was reinitiated on his HAART regimen. He was found on follow-up a month later to have complete resolution of his bulky mediastinal mass. He remained free of disease for 3 months with subsequent rectal and abdominal recurrence. Treatment with CHOP chemotherapy with filgrastim support was begun which resulted in another remission. Plasmablastic lymphoma is now reported in some studies to account for 2.6% of all HIV-related NHL. Originally described in 1997 in a series of 16 patients, this entity is highly associated with HIV infection in its later stages. Often, patients present with oral or jaw lesions with a rapidly progressive course. The tumors have the morphologic appearance of a plasmacytoid tumor with high proliferative index. Markers are positive mainly for LCA, CD79a, VS38C, and CD138. Co-infection with HHV-8 and EBV has not been consistently reported. Therapy with standard regimens has variable response. One case has been reported with a 3.5 year disease free survival. The regression of disease after resumption of HAART therapy alone in this patient suggests that HAART has an important role in the treatment of lymphoma in the HIV infected patient.

Abstract:

Abstract: Individuals at extremes of age and those who have certain underlying medical conditions are at greatest risk for hypothermia. Hypothermia may occur during any season of the year and in any climate. Prompt recognition of hypothermia and early institution of the rewarming techniques are imperative for a successful outcome with minimal complications. Several rewarming techniques are available and the decision to use any of them depends on the degree of hypothermia, the condition of the patient, and the rewarming rate possible with the technique chosen.

Abstract: STUDY OBJECTIVES: In a previous study published by our group, six out of nine subjects with mild allergic asthma were shown to have an enhanced response to allergen challenge following a 1-h exposure in an 0.8-m3 exposure chamber (modified from a body plethysmograph) to an average of 120 parts per billion (ppb) ozone at rest. Other studies failed to confirm this effect. In the present study, using a similar design, we reexamined this effect using a larger group of asthmatics and a larger chamber allowing minimal fluctuations in ozone levels during exposures. DESIGN: Prospective, randomized single-blinded crossover study. SETTING: Pulmonary function laboratory equipped with an exposure chamber. SUBJECTS: Fifteen subjects had mild allergic asthma; 9 men and 6 women; the mean (SD) age was 32.5 (10) years; FEV1 was 3.4 (0.8) L; baseline methacholine provocation concentration causing a 20% fall in FEV1 was (PC20) 3.28 (4.1) mg/mL. INTERVENTIONS: Each participant was exposed, at rest, on 1 day to filtered air and on another day to ozone (mean level=120 ppb) in a larger exposure chamber than the one used in our first study with less variability in ozone level (110 to 130 vs 85 to 175 ppb) using a random, single-blinded design. After each exposure, the subject was challenged with allergen (nine with grass pollen extract and six with ragweed extract) and allergen PC15 was measured. RESULTS: Ozone preexposure did not affect allergen PC15 when compared with clean air preexposure (allergen PC15 dilution 1/114 vs 1/119, respectively). Ozone vs air preexposure resulted in an allergen PC15 that was lower in five subjects, higher in six, and unchanged (within one doubling dose) in four. CONCLUSIONS: At this low level with less variability and lower peaks than our previous study, ozone had no significant effect on airway allergen responsiveness.

Abstract: There is enough evidence to support the short-term beneficial effects and safety of administering inhaled NO to ARDS patients. This effect may be potentiated when inhaled NO is administered in conjunction with other therapies. The full spectrum of effects of inhaled NO remains to be elucidated. Long-term benefit in terms of mortality and duration of mechanical ventilation has not been demonstrated; more randomized trials probing these effects are needed.

Abstract: Vasodilators that affect the pulmonary vasculature are appealing adjuncts in many cardiopulmonary conditions that require mechanical ventilation such as ARDS, COPD, PPHN, and cardiothoracic surgery. The adverse systemic effects of parenteral PGE1 and parenteral prostacyclin limit their usefulness in critically ill patients. Liposomal PGE1 has few systemic effects, but thus far has not resulted in a significant clinical benefit in patients with ARDS. Inhaled NO and aerosolized prostacyclin offer the advantage of selective pulmonary vasodilation with minimal systemic effects. Both agents decrease PAP and in many clinical situations improve oxygenation; however, the physiologic effects of inhaled NO and aerosolized prostacyclin have not convincingly led to improved clinical outcomes. Currently, use of vasodilators in mechanically ventilated patients remains investigational.

Abstract: Mechanical ventilation in a patient with obstructive airway disease may be a lifesaving measure; however, it may also be associated with significant morbidity and mortality. It is important for a physician to be familiar with the potential complications of mechanical ventilation in this group of patients and to know how to avoid them by carefully applying safe ventilator strategies. The cornerstone of such strategies is to minimize minute ventilation, maximize time for expiration, and avoid hyperinflation of the lung. Several bedside parameters (iPEEP, VEI, Pplat) that reflect presence of gas trapping and potential hyperinflation may be measured. In addition to mechanical ventilation, management should include inhaled bronchodilators and systemic corticosteroid therapies. In the event controlled hypoventilation is necessary, sedation with or without the use of muscle relaxants may be required. Unconventional therapies such as the use of Heliox, magnesium sulfate, ketamine, and inhalational anesthetics may be attempted in severe cases that do not respond to conventional management. With appropriate use of ventilator strategies, a reduction in the mortality and morbidity of patients with obstructive airway disease requiring mechanical ventilation has recently been noted.

Abstract: BACKGROUND: Dependence on crisis-oriented care rather than continuous ambulatory care for asthma is thought to contribute to asthma morbidity and mortality. We contrasted the characteristics of patients who depend on emergency department (ED) care for the management of their asthma exacerbations to the characteristics of patients employing self-management plans in an ambulatory setting. METHODS: In prospective fashion, we used a structured interview and charted information to survey two cohorts of patients suffering from an acute exacerbation of asthma; those seen in a hospital ED (n = 80) and those seen in an ambulatory asthma care facility (Asthma Center [AC]) (n = 40) at the same hospital. We looked for differences in socioeconomic characteristics, asthma severity, asthma knowledge, and asthma self-management skills between groups. RESULTS: There were no significant differences in mean age (SD) (ED vs AC: 36.65 [13.8] vs 40 [13.8] years) or female to male ratio (ED vs AC: 2/1 vs 2.5/1) between the two groups. There were no major differences in ethnic origin, educational status, marital status, smoking history, employment status, number of children in the household, possession of an extended health insurance plan, sick leave benefits, and child care availability between the two groups. Patients seeking ED care were more likely to have resided in the city for < 5 years (34% vs 8%; p < 0.05), and more likely to be living alone (35% vs 15%; p < 0.05). Significantly more patients from the ED group had a below average gross annual income (55% vs 3%; p < 0.05). There were several significant differences between groups in their knowledge of asthma and its therapy. Most striking, 79% of AC patients reported having a predetermined crisis plan vs just 23% of ED patients (p < 0.001). Although measurements of airflow (percent predicted FEV1) were significantly lower in the ED group than the AC group (mean, 50% vs 78.4%; p < 0.001), other indexes reflecting the degree of asthma severity over the long term such as past use of oral steroids, history of hospitalization, or ICU admission for asthma and the mean total days of disability within the preceding year were not significantly different between the two groups. Most of the ED patients had more than one previous visit to the ED for asthma exacerbation within the preceding year while most exacerbations of AC patients had been treated in the ambulatory care setting. Only 17% of ED patients initiated or increased inhaled or oral steroids before seeking medical care vs 89% of AC patients (p < 0.001). CONCLUSION: We conclude that a subgroup of asthmatics depends primarily on crisis-oriented care for the management of asthma. These patients are more likely to have lower income, to live alone, and to have resided at their current address for less time than patients seeking less urgent ambulatory care. Moreover, such patients are less knowledgeable about asthma and its management and are less likely to have a predetermined crisis plan.

Abstract: BACKGROUND: Objective measurement of lung function is considered essential in the management of patients with asthma and COPD. Many primary care practitioners lack the means necessary to obtain these measurements conveniently. To meet this need, electronic spirometers, offering portability, ease of operation, and timesaving readout options have been introduced. We compared the accuracy of a typical pneumotachograph-based device with a conventional volume displacement spirometer. METHODS: We compared indexes of pulmonary function (FVC, FEV1, mean forced expiratory flow during the middle half of FVC, [FEF25-75%], and peak expiratory flow rate [PEFR]) measured by the handheld device with those measured by a conventional spirometer in 75 white subjects (33 men, 42 women) with a median age of 43 years (22 to 77 years) who were either healthy or were referred to the pulmonary function laboratory of a large tertiary care teaching hospital. The order of the instrument tested first was randomized and the patients were blinded to which instrument was being studied. RESULTS: There was a linear relationship between instruments for all indexes measured (r = 0.97, 0.98, 0.94, 0.94 for FVC, FEV1, FEF25-75%, and PEFR, respectively, for all p < 0.001). The random error (precision) was within 5% only for FEV1. The mean of the differences between the values obtained using both instruments (the bias) +/- limits of agreement (+/- 2 SD) were 0.06 +/- 0.56 L for FVC (p = NS), 0.2 +/- 0.44 L for FEV1 (p < 0.05), 0.61 +/- 1.26 L/s for FEF25-75% (p < 0.05), and 0.44 +/- 1.9 L/s for PEFR (p < 0.05). CONCLUSION: Our data suggest that measurements obtained using the pneumotachograph device are closely related to those obtained by volume displacement spirometry and that the handheld device may be useful in clinical practice. However, because the limits of agreement are wide and the difference between the two instrument measurements are significant for FEV1, FEF25-75%, and PEFR, the bias between them is not consistent nor is it insignificant. Therefore, the measurements made with the two types of machine cannot be used interchangeably.

Abstract: Inhaled corticosteroids are considered by many to be the anti-inflammatory therapy of choice in adult asthma, given their remarkable efficacy and apparent safety. They are presently being prescribed to more patients, at larger doses, and for longer periods of time than ever before. Oropharyngeal candidiasis and dysphonia are the most commonly recognized adverse effects of therapy, but these topical phenomena cause no significant morbidity and are easily managed. By contrast, there is now increasing concern about the potential systemic effects of inhaled corticosteroids. These putative effects may include adrenal suppression, bone loss, skin thinning, increased cataract formation, decreased linear growth in children, metabolic changes, and behavioral abnormalities. Changes in adrenal function have been noted in patients using medications such as beclomethasone dipropionate and budesonide in doses exceeding 1,500 micrograms/day. The clinical relevance of these changes has yet to be clarified. Several short-term and cross-sectional studies have also revealed changes in biochemical markers of bone turnover and retrospective studies have found reduced bone density in asthmatics treated regularly with inhaled steroids. Long-term prospective studies assessing bone density changes remain to be done. Although much controversy exists, there is no unequivocal evidence that conventional doses of inhaled steroids significantly retard bone growth in children. Reports on skin changes, increased cataract formation, and behavioral changes are difficult to interpret because of several confounding factors. Although inhaled steroids should, at the present time, continue to be a recommended therapeutic option to all patients with symptomatic asthma, they should always be used in the lowest dosage compatible with disease control.

Abstract: Near-fatal asthma has been repeatedly associated with an increased risk of premature death. Despite a higher risk, death after near-fatal asthma remains infrequent. Few studies have examined the long-term outcome of those who experience a near-fatal event but do not succumb to asthma. We therefore contacted patients who had an episode of near-fatal asthma 5 to 10 years earlier and documented their use of health-care services for asthma. Each index case was compared with two age-matched controls who had been hospitalized for severe but not near-fatal asthma within 2 years of the index case admission. Thirty-seven index cases and 74 control subjects were assessed. Demographics did not distinguish the two groups. Availability of primary care physicians and asthma specialists were similar. There was no difference in the frequency of hospitalizations, emergency room visits, or visits to physicians for asthma between the two groups. ICU admissions were extremely infrequent. Although the mean number of ICU admissions per subject were similar in the year preceding our contact (0.03 +/- 0.16 in each group), there was a trend toward ICU admissions occurring more often in the near-fatal group (0.62 +/- 1.67 vs 0.31 +/- 0.91 admissions/subject). Days away from work were more frequent in the control group (3.5 +/- 5.5 vs 1.6 +/- 3.3 d/yr) including days away from work in the year preceding our contact (8.9 +/- 43 vs 1.8 +/- 6.1 d). The data suggests that with regards to characteristics and health-care utilization, it may not be possible to distinguish people with near-fatal asthma from those who are hospitalized without a near-fatal event.

Abstract: BACKGROUND: Inhaled corticosteroids are being prescribed more commonly and in higher doses than previously in the management of asthma. Although these topically active compounds have less potential for systemic impact than oral steroids, biochemical markers suggest that they are not devoid of systemic side effects. We conducted this study to investigate the effect of commonly prescribed doses of inhaled steroids on bone density. METHODS: We studied 36 patients with asthma. Those in group A (n = 18) had been taking inhaled beclomethasone dipropionate or budesonide in a dosage of 800 micrograms or more per day for at least 1 year. Those in group B (n = 18) had used only bronchodilator therapy. Adrenal function was assessed by morning serum cortisol level and by short adrenocorticotropic hormone stimulation test. Bone turnover was assessed by measurement of serum osteocalcin, alkaline phosphatase, and urinary pyridinium cross-links. Bone mineral density was measured by dual-energy x-ray absorptiometry with a Hologic QDR-1000 densitometer (Hologic Inc., Waltham, Mass.). RESULTS: Group A, mean age (SD) = 36.6 (8.4) years, had used inhaled corticosteroids at a mean dose of 1323 micrograms/day (range, 800 to 2000 micrograms/day) for a median duration of 24 months. Group B, mean age (SD) = 33.4 (8.1) years, had not been taking any form of steroid. Four patients from group A had suppressed morning serum cortisol; three of these had abnormal adrenocorticotropic hormone stimulation test results. All patients in group B had normal baseline adrenal function and an appropriate response to adrenocorticotropic hormone. Mean serum osteocalcin level in group A was significantly lower than that in group B (8.8 vs 14.2 ng/ml, p = 0.0003). Bone density measurements showed parallel changes: in group A the mean Z score (SD) of the femoral neck was -0.78 (1.02), significantly below predicted normal values (p = 0.0025). Mean Z scores of the lumbar spine and of femoral Ward's triangle were not significantly reduced. In group B the mean Z scores of the lumbar spine, femoral neck, and femoral Ward's triangle were all within normal limits. In group A the dose duration of inhaled corticosteroid therapy corrected for body mass index correlated negatively with bone density and adrenal function measurements. CONCLUSION: We conclude that the regular use of conventional doses of inhaled corticosteroids by patients with asthma can suppress adrenal function and decrease bone density in a dose-related fashion.

Abstract: BACKGROUND: Current treatment strategies for asthma and chronic obstructive pulmonary disease (COPD) emphasize the inhalation route, yet patients often misuse metered-dose inhalers (MDI). To address this problem, patient education by medical personnel has been recommended and a variety of alternate inhaler devices have been developed. METHODS: We surveyed medical personnel to assess their knowledge of and ability to use three widely used inhaler devices; MDI, MDI with a spacing chamber (Aerochamber, Trudell Medical, Canada), and a breath-actuated multidose dry powder inhaler (Turbuhaler, Astra Pharmacy, Inc., Conada). Thirty respiratory therapists (RT), 30 registered nurses (RN), and 30 medical house staff physicians (MD) were asked to demonstrate the use of each device using placebo inhalers and to answer 11 clinically relevant questions related to the use and maintenance of the tested devices. RESULTS: The RT's percent mean knowledge score (67 +/- 5 percent) was significantly higher than those achieved by either the RNs (39 +/- 7 percent) or the MDs (48 +/- 7 percent) (for all p < 0.0001). Similarly, percent mean demonstration scores for each device were significantly higher for RTs than either RN or MD groups; for MDI, 97 +/- 3 percent versus 82 +/- 13 percent and 69 +/- 24 percent, respectively (p < 0.0001); for the Aerochamber, 98 +/- 2 percent versus 78 +/- 20 percent and 57 +/- 31 percent (p < 0.0001); and for the Turbuhaler, 60 +/- 30 percent versus 12 +/- 23 percent and 21 +/- 30 percent (p < 0.0001). Knowledge of and practical skills with the devices were roughly proportional to the length of time the device had been in clinical use, Turbuhaler demonstration scores being lower than either MDI or Aerochamber scores (p = 0.05 and p = 0.09, respectively). More RTs (77 percent) had received formal instruction on the use of devices at school than either RNs (30 percent) or MDS (43 percent) (p < 0.05). CONCLUSION: We conclude that (1) many medical personnel responsible for monitoring and instructing patients in optimal inhaler use lack rudimentary skills with these devices, (2) nurses and physicians seldom receive formal training in the use of inhaling devices, and (3) newer inhaling devices designed to obviate problems of technique are at present less likely to be used well by medical personnel soon after their introduction.