Zab Mosenifar

The minimal important difference of exercise tests in severe COPD

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4–6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St Georges Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohens effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1–20.1 m), 24.2 m (95% CI 23.4–25.4 m), 24.6 m (95% CI 23.4–25.7 m) and 26.4 m (95% CI 25.4–27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0–2.4 W), 3.2 W (95% CI 3.0–3.4 W), 3.2 W (95% CI 3.0–3.4 W) and 3.3 W (95% CI 3.0–3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26±2 m for 6MWD and 4±1 W for MCEC for patients with severe COPD.

Longitudinal change in the BODE index predicts mortality in severe emphysema.

RATIONALE The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. OBJECTIVES To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. METHODS Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. MEASUREMENTS AND MAIN RESULTS The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components. CONCLUSIONS The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

Inhaled and Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease

Systemic and local inflammation is central to the pathophysiology of chronic obstructive pulmonary disease (COPD). Increased levels of inflammation have been linked to a more progressive course in COPD and have been shown to be present during an exacerbation. Decreases in inflammatory cytokines, C-reactive protein, and inflammatory cells have been observed with corticosteroid use, suggesting a possible mechanism for a therapeutic benefit of steroids. No available data support the routine use of systemic corticosteroids in stable COPD; however, short courses during exacerbations are likely to improve length of hospitalization, lung function, and relapse rate. Inhaled corticosteroids (ICS) decrease the rate of exacerbation and may improve the response to bronchodilators and decrease dyspnea in stable COPD. No study shows that ICS reduce the loss of lung function; however, recent data suggest a possible survival benefit when combined with long-acting beta agonists. There are limited data on the use of ICS in the treatment of acute exacerbations of COPD, and its role in this setting must be more clearly defined. The empiric use of systemic corticosteroids perioperatively represents another area of uncertainty. The role of pharmacogenetics in the metabolism of corticosteroids in COPD is evolving but may be partially responsible for the observed variability in patient responsiveness. The potential benefits of systemic or inhaled corticosteroid use must be weighed against the risk of known toxicities.

Exercise Testing in Severe Emphysema: Association with Quality of Life and Lung Function

Six-minute walk testing (6MWT) and cardiopulmonary exercise testing (CPX) are used to evaluate impairment in emphysema. However, the extent of impairment in these tests as well as the correlation of these tests with each other and lung function in advanced emphysema is not well characterized. During screening for the National Emphysema Treatment Trial, maximum ergometer CPX and 6MWT were performed in 1,218 individuals with severe COPD with an average FEV1 of 26.9 ± 7.1 % predicted. Predicted values for 6MWT and CPX were calculated from reference equations. Correlation coefficients and multivariable regression models were used to determine the association between lung function, quality of life (QOL) scores, and exercise measures. The two forms of exercise testing were correlated with each other (r = 0.57, p < 0.0001). However, the impairment of performance on CPX was greater than on the 6MWT (27.6 ± 16.8 vs. 67.9 ± 18.9 % predicted). Both exercise tests had similar correlation with measures of QOL, but maximum exercise capacity was better correlated with lung function measures than 6-minute walk distance. After adjustment, 6MWD had a slightly greater association with total SGRQ score than maximal exercise (effect size 0.37 ± 0.04 vs. 0.25 ± 0.03 %predicted/unit). Despite advanced emphysema, patients are able to maintain 6MWD to a greater degree than maximum exercise capacity. Moreover, the 6MWT may be a better test of functional capacity given its greater association with QOL measures whereas CPX is a better test of physiologic impairment.

Differentiating COPD From Asthma in Clinical Practice

It has been recognized that features of chronic obstructive pulmonary disease (COPD) and asthma overlap, often rendering a firm diagnosis difficult to achieve for the clinical practitioner. There are hypotheses suggesting that both asthma and COPD may indeed share common origins with differences in phenotypic presentation being related to disease evolution or interaction between endogenous and exogenous factors. Others suggest that the two conditions are clinically and pathophysiologically distinct. Studies of the underlying inflammation demonstrate a difference in the preponderance of inflammatory cells and mediators in each disease, yet many shared characteristics in the inflammatory process can be found when examining the two conditions. Generally, later age of presentation favors a diagnosis of COPD; fully reversible airflow limitation on pulmonary function testing suggests a diagnosis of asthma; hyperinflation at rest makes a diagnosis of COPD likely; impaired diffusing capacity is associated with COPD whereas these measurements in patients suffering from asthma are usually normal or even elevated; reduced elastic recoil is the hallmark of COPD, particularly those who pathophysiologically demonstrate abnormal enlargement of air spaces with wall destruction seen in emphysema; and finally history of atopy favors a diagnosis of asthma, particularly if presenting at a younger age. This review reflects discussion of the differences and similarities in diagnosis and treatment.

Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease

SummaryBackground. Fabry disease is an X-linked genetic disorder resulting in the accumulation of glycosphingolipids in various organs, leading to exercise intolerance and early mortality. Enzyme replacement therapy (ERT) has recently been approved for use in Fabry patients. Goals of study. To assess baseline cardiopulmonary exercise characteristics in both invasive and noninvasive tests and to study the impact of ERT on exercise. Methods. A total of 15 patients with Fabry disease underwent baseline cardiopulmonary exercise tests. Six patients were randomized 2:1 to receive either ERT or placebo. We performed serial cardiopulmonary exercise tests at baseline and every 3 months over a period of at least 18 months. The baseline test was compared to the last two exercise tests for each patient. Results. Mean age was 32 years. Mean VO2 max was 1.680 ± 0.67 L/min and increased by 0.459 ± 0.64 L/min in the patients receiving ERT. Mean VO2 max was 1.462 ± 0.25 L/min and decreased by 0.116 ± 0.44 L/min in patients on placebo. Mean oxygen pulse (VO2/HR) increased by 1.71 with enzyme, but increased only 0.025 in patients taking placebo. Estimated stroke volume (SV) increased by 10 ml in patients on ERT. Conclusions. In this small cohort, exercise tolerance increased in patients receiving enzyme replacement therapy. Cardiopulmonary exercise testing is a useful test in measuring the response to therapy in Fabry disease patients.

Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts

Background Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists. Objective To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV1 to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible. Design Individual subject data analysis of 10 European and American cohorts (n=13 914). Setting Population-based, primary, secondary and tertiary care. Patients COPD GOLD stages I–IV. Measurements We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses. Results 1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV1 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV1 alone. Interpretation The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions.

Multivariate models of determinants of health-related quality of life in severe chronic obstructive pulmonary disease

Persons with severe chronic obstructive pulmonary disease (COPD) and similar levels of forced expiratory volume in 1 second (FEV(1)), exercise capacity, and dyspnea have a wide range of health-related quality of life (HRQL). We identified the independent determinants of HRQL in persons with COPD. Comprehensive assessments of physiological, psychosocial, and clinical variables from the National Emphysema Treatment Trial were used. HRQL was assessed by the Medical Outcomes Study 36-Item Short Form Physical Component Summary (PCS) and Mental Component Summary (MCS) scores and the St. Georges Respiratory Questionnaire total score (SGRQ-TS). In multivariate linear regression models, exercise capacity, dyspnea, age, single-breath diffusing capacity of the lung for carbon monoxide percent predicted, and self-report of being disabled were significant determinants of PCS score. Dyspnea, depression, antidepressant use, daytime sleepiness, and education were significant determinants of MCS score. Prior participation in pulmonary rehabilitation, supplemental oxygen use, and oral corticosteroid use were significant determinants of SGRQ-TS. Although FEV(1), 6-minute walk test distance, and dyspnea significantly correlated with HRQL, their effects on HRQL were reduced when other variables were considered. Greater exercise capacity, prior participation in pulmonary rehabilitation, and use of supplemental oxygen were significantly associated with better HRQL. Self-perception of being disabled, (Abstract continued) depression, dyspnea, oral corticosteroid use, and daytime sleepiness were associated with worse HRQL. To optimize HRQL, clinicians should pay attention to a number of clinical and physiological factors.

Prevalence and clinical correlates of bronchoreversibility in severe emphysema

Chronic obstructive pulmonary disease (COPD) exhibits airflow obstruction that is not fully reversible. The importance of bronchoreversibility remains controversial. We hypothesised that an emphysematous phenotype of COPD would be associated with decreased bronchoreversibility. 544 patients randomised to the medical arm of the National Emphysema Treatment Trial formed the study group. Participants underwent multiple measurements of bronchoreversibility on a mean of four sessions over 1.91 yrs. They were also characterised by measures of symptoms, quality of life and quantitative measures of emphysema by computed tomography. Mean baseline forced expiratory volume in 1 s (FEV1) in this patient population is 24% predicted. 22.2% of patients demonstrated bronchoreversibility on one or more occasions using American Thoracic Society/European Respiratory Society criteria. Few patients (0.37%) had bronchoreversibility on all completed tests. Patients who demonstrated bronchoreversibility were more likely to be male, and have better lung function and less emphysema. 64% of patients demonstrated large (≥400 mL) changes in forced vital capacity (FVC). In a severe emphysema population, bronchoreversibility as defined by change in FEV1 is infrequent, varies over time, and is more common in males and those with less severe emphysema. Improvements in FVC, however, were demonstrated in the majority of patients.

Effects of Lung Volume Reduction Surgery on Gas Exchange and Breathing Pattern During Maximum Exercise

BACKGROUND The National Emphysema Treatment Trial studied lung volume reduction surgery (LVRS) for its effects on gas exchange, breathing pattern, and dyspnea during exercise in severe emphysema. METHODS Exercise testing was performed at baseline, and 6, 12, and 24 months. Minute ventilation (Ve), tidal volume (Vt), carbon dioxide output (Vco(2)), dyspnea rating, and workload were recorded at rest, 3 min of unloaded pedaling, and maximum exercise. Pao(2), Paco(2), pH, fraction of expired carbon dioxide, and bicarbonate were also collected in some subjects at these time points and each minute of testing. There were 1,218 patients enrolled in the study (mean [+/- SD] age, 66.6 +/- 6.1 years; mean, 61%; mean FEV(1), 0.77 +/- 0.24 L), with 238 patients participating in this substudy (mean age, 66.1 +/- 6.8 years; mean, 67%; mean FEV(1), 0.78 +/- 0.25 L). RESULTS At 6 months, LVRS patients had higher maximum Ve (32.8 vs 29.6 L/min, respectively; p = 0.001), Vco(2), (0.923 vs 0.820 L/min, respectively; p = 0.0003), Vt (1.18 vs 1.07 L, respectively; p = 0.001), heart rate (124 vs 121 beats/min, respectively; p = 0.02), and workload (49.3 vs 45.1 W, respectively; p = 0.04), but less breathlessness (as measured by Borg dyspnea scale score) [4.4 vs 5.2, respectively; p = 0.0001] and exercise ventilatory limitation (49.5% vs 71.9%, respectively; p = 0.001) than medical patients. LVRS patients with upper-lobe emphysema showed a downward shift in Paco(2) vs Vco(2) (p = 0.001). During exercise, LVRS patients breathed slower and deeper at 6 months (p = 0.01) and 12 months (p = 0.006), with reduced dead space at 6 months (p = 0.007) and 24 months (p = 0.006). Twelve months after patients underwent LVRS, dyspnea was less in patients with upper-lobe emphysema (p = 0.001) and non-upper-lobe emphysema (p = 0.007). CONCLUSION During exercise following LVRS, patients with severe emphysema improve carbon dioxide elimination and dead space, breathe slower and deeper, and report less dyspnea.