Are Predictors for Overall Mortality in COPD Patients Robust over Time?

(1) Background: Mortality is a major outcome in research on chronic obstructive pulmonary disease (COPD) with various predictors described. However, the dynamic courses of important predictors over time are disregarded. This study evaluates if longitudinal assessment of predictors provides additional information on the mortality risk in COPD when compared with a cross-sectional analysis.; (2) In a longitudinal, prospective, non-interventional cohort study including mild to very severe COPD patients, mortality and its various possible predictors were annually assessed up to seven years.; (3) Results: 297 patients were analysed. Mean (SD) age was 62.5 (7.6) years and 66% males. Mean (SD) FEV1 was 48.8 (21.4)%. A total of 105 events (35.4%) happened with a median (95% CI) survival time of 8.2 (7.2/NA) years. No evidence for a difference between the raw variable and the variable history on the predictive value for all tested variables over each visit was found. There was no evidence for changing effect estimates (coefficients) across the study visits due to the longitudinal assessment; (4) Conclusions: We found no evidence that predictors of mortality in COPD are time dependent. This implies that cross-sectional measured predictors show robust effect estimates over time and multiple assessments seem not to change the predictive value of the measure.

Prediction of Acute COPD Exacerbation in the Swiss Multicenter COPD Cohort Study (TOPDOCS) by Clinical Parameters, Medication Use, and Immunological Biomarkers.

BACKGROUND AND OBJECTIVE: Whether immunological biomarkers combined with clinical characteristics measured during an exacerbation-free period are predictive of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) frequency and severity is unknown. METHOD: We measured immunological biomarkers and clinical characteristics in 271 stable chronic obstructive pulmonary disease (COPD) patients (67% male, mean age 63 years) from "The Obstructive Pulmonary Disease Outcomes Cohort of Switzerland" cohort on a single occasion. One-year follow-up data were available for 178 patients. Variables independently associated with AECOPD frequency and severity were identified by multivariable regression analyses. Receiver operating characteristic analysis was used to obtain optimal cutoff levels and measure the area under the curve (AUC) in order to assess if baseline data can be used to predict future AECOPD. RESULTS: Higher number of COPD medications (adjusted incident rate ratio [aIRR] 1.17) and platelet count (aIRR 1.03), and lower FEV1% predicted (aIRR 0.84) and IgG2 (aIRR 0.84) were independently associated with AECOPD frequency in the year before baseline. Optimal cutoff levels for experiencing frequent (>1) AECOPD were ≥3 COPD medications (AUC = 0.72), FEV1 ≤40% predicted (AUC = 0.72), and IgG2 ≤2.6 g/L (AUC = 0.64). The performance of a model using clinical and biomarker parameters to predict future, frequent AECOPD events in the same patients was fair (AUC = 0.78) but not superior to a model using only clinical parameters (AUC = 0.79). The IFN-lambda rs8099917GG-genotype was more prevalent in patients who had severe AECOPD. CONCLUSIONS: Clinical and biomarker parameters assessed at a single point in time correlated with the frequency of AECOPD events during the year before and the year after assessment. However, only clinical parameters had fair discriminatory power in identifying patients likely to experience frequent AECOPD.

Compliance of Pharmacotherapy with GOLD Guidelines: A Longitudinal Study in Patients with COPD.

Objective: To evaluate the clinical implementation of pharmacotherapy recommendations for chronic obstructive pulmonary disease (COPD) based on the Global Initiative for chronic obstructive lung disease (GOLD) guidelines, in a longitudinal setting. Methods: This is a sub-analysis of a prospective, non-interventional cohort study including patients with confirmed mild-to-very-severe COPD from seven pulmonary outpatient clinics in Switzerland. Follow-up visits took place annually for up to 7 years, from October 2010 until December 2016. For each visit, we evaluated the compliance of the prescribed pharmacotherapy with the concurrently valid GOLD guideline. We investigated whether step-ups or step-downs in GOLD stage or risk-group were accompanied by concordant changes in prescribed medication. Groups were compared via ANOVA. Results: Data of 305 patients (62±7 years, 66% men) were analysed. In 59.1% of visits, the prescribed medication conformed to the respective valid GOLD-guideline. Patients with very severe COPD were most likely to receive pharmacotherapy in compliance with guidelines. Step-ups and step-downs in risk group, requiring escalation, or de-escalation of pharmacotherapy, were noticed in 24 and 43 follow-up visits, respectively. Step-ups were adequately implemented in 4 (16.7%) and step-downs in six cases (14.0%). Conclusion: The compliance of COPD-pharmacotherapy with GOLD-guidelines is suboptimal, especially in lower risk groups. The high rates of missed out treatment-adjustments suggest that the familiarity of physicians with guidelines leaves room for improvement.

Handgrip Strength Seems Not to Be Affected by COPD Disease Progression: A Longitudinal Cohort Study.

Skeletal muscle dysfunction, functional exercise capacity impairment and reduced physical activity are characteristic features in patients with chronic obstructive pulmonary disease (COPD). Assessments addressing muscle strength of the upper limb, such as measurement of handgrip strength (HGS), are rarely performed and reported. We aimed to analyze the course of HGS and possible predictors of changes in HGS over time in COPD. Yearly assessments of various disease markers were performed for a follow-up of up to seven years in a cohort of COPD patients to assess the longitudinal disease process. Data of 194 patients with at least one follow-up measurement were analyzed. HGS decreased significantly by B = -0.86 (95% CI -1.09/-0.62, p < 0.001) over time. The multivariate mixed effects model showed an independent association between greater annual declines in HGS and lower numbers of steps per day by B = 0.11 (95% CI 0.03/0.18, p = 0.006) and an enhanced change in COPD Assessment Test scores by B = -0.01 (95% CI -0.01/-0.00, p = 0.034). No evidence for an independent association between annual decline in HGS and FEV1% pred. by B = -0.01 (95% CI -0.03/0.01, p = 0.297) was shown. Patients who died during follow-up did not exhibit greater declines in HGS compared to survivors (p = 0.884). Although HGS significantly decreased over time, no pathophysiological link with COPD disease progression could be demonstrated. Previous cross-sectional associations between HGS and mortality could not be confirmed in this longitudinal setting. Our data suggests that repeated monitoring of HGS in clinical settings seems not to be helpful to predict COPD specific disease progression.

"Can do, don't do" are not the lazy ones: a longitudinal study on physical functioning in patients with COPD.

BACKGROUND AND OBJECTIVE: Reduced physical capacity (PC) and physical activity (PA) are common in COPD patients and associated with poor outcome. However, they represent different aspects of physical functioning and interventions do not affect them in the same manner. To address this, a new PC-PA quadrant concept was recently generated to identify clinical characteristics of sub-groups of physical functioning. The objective of this study was to I) proof the new concept and to verify their differentiating clinical characteristics, II) evaluate the consistency of the concept over time, III) assess whether patients changed their quadrant affiliation over time, IV) and to test if changes in quadrant affiliations are associated with changes in clinical characteristics. METHODS: In a longitudinal, prospective, non-interventional cohort with mild to very severe COPD patients, PC and PA as well as respiratory variables, COPD-specific health status, comorbidities, survival, and exacerbations were yearly assessed. RESULTS: Data from 283 patients were analysed at baseline. Mean (min/max) follow-up time was 2.4 (0.5/6.8) years. The PC-PA quadrants could be characterized as follows: I) "can't do, don't do": most severe and symptomatic, several comorbidities II) "can do, don't do": severe but less symptomatic, several comorbidities III) "can't do, do do": few patients, severe and symptomatic, less comorbidities IV) "can do, do do": mildest and less symptomatic, less comorbidities, lowest exacerbation frequency. Of the 172 patients with at least one follow-up, 58% patients never changed their quadrant affiliation, while 17% declined either PC, PA or both, 11% improved their PC, PA or both, and 14% showed improvement and decline in PC, PA or both during study period. None of the clinical characteristics or their annual changes showed consistent significant and relevant differences between all individual sub-groups. CONCLUSION: Our findings suggest that there are no clinical characteristics allowing to distinguish between the PC-PA quadrants and the concept seems not able to illustrate disease process. However, the already low PA but preserved PC in the "can do, don't do" quadrant raises the question if regularly assessment of PA in clinical practice would be more sensitive to detect progressive deterioration of COPD compared to the commonly used PC. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01527773.

[Long-Term Non-Invasive Ventilation for Chronic Respiratory Failure]. / Respiratorische Heimdialyse.

Long-Term Non-Invasive Ventilation for Chronic Respiratory Failure Abstract. Non-invasive long-term ventilation (NIV) may be helpful for selected patients with severe COPD and chronic respiratory lailure (chronic hypercapnia and hypoxemia). The patient described in the case report became normocapnic under long-term NIV and both her sleep and quality of life improved significantly. She also suffered fewer COPD exacerbations and was better able to cope with them herself with the help of NIV.

No impact of exacerbation frequency and severity on the physical activity decline in COPD: a long-term observation.

INTRODUCTION: COPD exacerbations are associated with a concomitant profound reduction in daily physical activity (PA). Thereby, exacerbation frequency and severity may have an amplifying effect. Whether the reduced level of PA returns to the level prior to exacerbation or has a sustained negative impact on activity behavior over time is unclear. METHODS: The number of steps per day over 1 week, as a measure of daily PA, was assessed annually in a cohort of patients with COPD. Exacerbation frequency and severity were documented. Uni- and multivariate mixed effect models were used to investigate associations between change in number of steps per day (dependent variable) and exacerbations. Stratification by possible confounders was performed. RESULTS: One hundred and eighty one COPD patients (median [quartile] age 64 [59/69] years, 65% male, median [quartiles] FEV1 % pred. 46 [33/65]) suffered a total of 273 exacerbations during the observation period (median [quartiles] follow-up time of 2.1 [1.6/3.1] years). Neither the frequency nor the severity of exacerbations was significantly related to the overall decline in PA over time. Stratification by different possible confounders such as age, sex and disease severity did not yield a subgroup in which exacerbations enhance the decrease in PA over time. CONCLUSION: The drop in PA during the phase of an acute exacerbation seems not to be a lasting phenomenon leading to a fundamental change in activity behavior. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01527773.

Physical activity declines in COPD while exercise capacity remains stable: A longitudinal study over 5 years.

BACKGROUND AND OBJECTIVE: Daily physical activity (PA) and exercise capacity are reduced in patients with COPD. Whether the natural longitudinal course of both appears synchronically or one precedes the other is currently unclear. The aim was to assess the longitudinal relationship between exercise capacity and physical activity and their changes over time in patients with COPD. METHODS: In a longitudinal observation-study of heterogeneous COPD patients, recruited from pulmonary outpatient clinics or hospital settings, we annually investigated two exercise capacity tests (1-min sit to stand test (STS) and 6 min walking test (6MWT)) and daily physical activity assessed by number of steps per day for minimum one, up to seven years. Univariable and multivariable mixed effect models were used to investigate the annual change in STS, 6MWD and number of steps per day. RESULTS: 202 COPD patients (17% COPD risk group (considers symptoms and future exacerbation risk to grade disease severity) A, 49% B, 4% C and 34% D) with a mean (min/max) follow-up time of 2.4 (0.9/6.8) years were annually assessed. The number of steps per day decreased significantly over time (annual mean (95% CI) of -451.0 (-605.3/-296.6) steps, p < 0.001) while STS and 6MWD remained stable. CONCLUSION: Our findings suggest that COPD patients are increasingly impaired in their daily PA while exercise capacity remains stable during the study period. Thus, the longitudinal decline in PA seems not to be explained by a concomitant reduction in exercise tolerance. CLINICAL TRIAL REGISTRATION: www.Clinicaltrials.Gov, NCT01527773.

Accelerometer- versus questionnaire-based assessment of physical activity and their changes over time in patients with COPD.

BACKGROUND AND OBJECTIVE: Physical activity (PA) is an important outcome parameter in patients with COPD regarding hospitalizations and mortality. Both objective assessment by accelerometers and self-evaluation by questionnaires were used in studies investigating PA in COPD. Whether self-reported questionnaires can adequately reflect PA and its changes over time compared to objective assessments has not been thoroughly investigated in COPD. In this COPD cohort study, we evaluated whether PA measured by accelerometer and its annual changes can also be assessed by self-reported questionnaires. METHODS: In 178 COPD patients with at least two assessments of PA, the agreement between objectively measured and self-reported activity was analyzed by Bland-Altman plots. Daily PA was assessed by a triaxial activity monitor over 1 week and by the self-reported German PA questionnaire 50+. RESULTS: Comparison between the two methods of measurement revealed no convincing agreement with a mean difference and limits of agreement (±1.96 standard deviation [SD]) of time spent in at least moderate PA (>3 metabolic equivalent of task [MET]) of -77.6 (-340.3/185.2) min/day, indicating a self-reported overestimation of PA by the questionnaire. The mean difference and limits of agreement (±1.96SD) in the annual change of PA was 1.2 min/day (-208.2/282.6 min/day), showing also a poor agreement on an individual level. CONCLUSION: Evaluation of objectively measured and self-reported PA and their annual changes revealed no agreement in patients with COPD. Therefore, the evaluated questionnaire seems not helpful for measurement of PA and its changes over time.

Risk of Sleepiness-Related Accidents in Switzerland: Results of an Online Sleep Apnea Risk Questionnaire and Awareness Campaigns.

OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with major morbidity and mortality but OSAS is frequently under recognized. To promote awareness of OSAS, the Swiss Lung League launched an online questionnaire combined with annual advertisements in mass media. Characteristics of participants, prevalence of sleep apnea, OSAS-related symptoms, and their association with accidents were investigated. METHODS: A questionnaire was created incorporating anthropometrics, the Epworth sleepiness scale (ESS), the OSAS domain of the sleep disorders questionnaire (SDQ), and a question on accidents related to sleepiness. RESULTS: A total of 198,422 persons participated, 63% were male, mean (±SD) age was 45 (±16) years, weight 80 (±18) kg, height 173 (±9) cm, and body mass index 26.7 (±5.4) kg/m2. Some male (19%) and female (17%) participants had both elevated ESS and SAS scores (SAS > 35 (m)/SAS > 31 (f) and ESS > 10) and were suspected of having sleep apnea. In all, 6,654 (3.4%) had suffered an accident related to sleepiness. In multivariate regression analysis, ESS item #8 (falling asleep on the wheel, while stopping for a few minutes in traffic) was closest related to suffering an accident (OR 2.8). CONCLUSION: The OSAS awareness campaign of the Swiss Lung League reached a large number of people of both genders and of a wide age range. Many participants suffered from excessive sleepiness and symptoms of sleep apnea were highly prevalent. The campaign raised awareness of OSAS and contributed to the diagnosis and treatment of sleep apnea, thereby possibly preventing related morbidity and mortality.

Determinants of annual change in physical activity in COPD.

BACKGROUND AND OBJECTIVE: Daily physical activity (PA) is reduced in patients with COPD. Previous cross-sectional analyses indicate various predictors for a low level of PA including airway obstruction, exacerbations and co-morbidities. However, information from longitudinal studies evaluating PA in the context of disease progression, survival and co-morbidities is scant. METHODS: In a heterogeneous cohort of COPD patients, we annually assessed the number of steps per day over 1 week and potential determinants including lung function, exacerbations and co-morbidities. Univariable and multivariable mixed effect models were used to investigate associations between the change in steps per day (dependent variable) and possible predictors and their annual changes. RESULTS: A total of 177 COPD patients (46% GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 1/2, 38% stage 3 and 16% stage 4) with a mean (min/max) follow-up time of 2.7 (1/5) years were annually assessed. The number of steps per day decreased significantly over time (P < 0.001) with a mean annual change of -508 steps. The decrease in activity was significantly associated with forced expiratory volume in 1 s (FEV1 ) % predicted (P = 0.020) but not with annual changes in FEV1 . Hyperinflation, exacerbations, co-morbidities and their annual changes, and survival did not significantly affect change in PA. CONCLUSION: COPD patients have a substantial decrease of PA over time. This decrease seems to be determined by the degree of airflow limitation. However, patients with a greater annual decline in lung function did not show a greater decrease in PA. The rate of decline in PA did not differ between survivors and non-survivors in this cohort.

Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

Impact of comorbidities on physical activity in COPD.

BACKGROUND AND OBJECTIVE: Both comorbidities and physical inactivity have been shown to impair quality of life and contribute to hospital admissions and mortality in chronic obstructive pulmonary disease (COPD) patients. We hypothesized that the comorbid status predicts the level of daily physical activity (PA) in COPD. METHODS: In 228 patients with COPD (76% men; median (quartiles) age: 64 (59/69) years; percentage of predicted forced expiratory volume in 1 s (FEV1 % pred): 44 (31/63)), comorbidities were assessed by medical history, clinical interviews, examination and blood analysis. PA level (PAL) was measured by an activity monitor (SenseWear Pro, Bodymedia Inc., Pittsburgh, PA, USA). The association between PAL and comorbidities was investigated by univariate and multivariate regression analysis. RESULTS: Seventy-nine percent of the COPD patients had at least one additional chronic comorbidity, 56% had two or more comorbidities and 35% had three or more comorbidities. In univariate analysis body mass index, the number of pack years and having at least one additional comorbidity was negatively associated with PAL while there was a positive nonlinear association between FEV1 and PAL. The presence of at least one additional comorbidity was independently associated with PAL irrespective of airflow limitation. CONCLUSIONS: In this cohort, almost 80% of COPD patients had at least one additional chronic comorbidity. The level of daily PA seems to be significantly impaired by the presence of comorbidities irrespective of the type of comorbidity and independent of the degree of airflow limitation. CLINICAL TRIAL REGISTRATION: NCT01527773 at http://www.clinicalTrials.gov.

Accuracy of the Hospital Anxiety and Depression Scale for identifying depression in chronic obstructive pulmonary disease patients.

Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I-IV, 40-75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601-0.719), and HADS-Total, AUC 0.681 (95%CI 0.620-0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression.

Cheyne-Stokes respiration in patients with heart failure: prevalence, causes, consequences and treatments.

Cheyne-Stokes respiration (CSR) is characterized by a pattern of cyclic oscillations of tidal volume and respiratory rate with periods of hyperpnea alternating with hypopnea or apnea in patients with heart failure. CSR harms the failing heart through intermittent hypoxia brought about by apnea and hypopnea and recurrent sympathetic surges. CSR impairs the quality of life and increases cardiac mortality in patients with heart failure. Thus, CSR should actively be pursued in patients with severe heart failure. When CSR persists despite optimal therapy of heart failure, noninvasive adaptive servoventilation is currently the most promising treatment.

Daytime Cheyne-Stokes respiration in ambulatory patients with severe congestive heart failure is associated with increased mortality.

BACKGROUND: Cheyne-Stokes respiration (CSR) frequently occurs in patients with severe heart failure during sleep and may increase mortality. Daytime CSR supposedly poses an even greater risk, but its prevalence and prognostic importance remain elusive. Therefore, we investigated the circadian prevalence of CSR and its influence on survival in patients with heart failure. METHODS: In 60 consecutive ambulatory patients (mean age+/-SE, 58.0+/-1.5 years; 6 women) with stable severe heart failure (left ventricular ejection fraction, 26+/-1%; New York Heart Association [NYHA] class, 2.6+/-0.1), the breathing pattern was unobtrusively monitored during 24 h of usual activities with a portable respiratory inductive plethysmograph. RESULTS: During nights, 62% of patients had >or=15 periodic breathing cycles per hour; during days, the corresponding prevalence was 16%. CSR prevailed in 32+/-3% of the night and in 10+/-2% of the day, with peaks at 4:00 am, 2:00 pm, and 6:00 pm. Eighteen patients with CSR during >or=10% of the daytime lived shorter without heart transplantation than 42 patients with <10% of daytime CSR (p<0.05) during 836+/-27 days of follow-up. CSR during >or=10% of the daytime was an independent predictor of mortality (hazard ratio, 3.8; 95% confidence interval, 1.1 to 12.7; p<0.05) when controlling for age, sex, brain natriuretic peptide, left ventricular ejection fraction, and NYHA class. CONCLUSIONS: CSR occurs in 62% of patients with severe heart failure at night and in 16% during the day. Since daytime CSR is associated with reduced survival, solely performing sleep studies may not allow to adequately assess prognosis and tailor treatment in patients with severe heart failure.

Cheyne-Stokes respiration in patients with heart failure: ominous sign or innocent bystander?

Cheyne-Stokes respiration (CSR) during the day and at night is common in patients with severe heart failure. CSR harms the failing heart through recurrent sympathetic overstimulation caused by sleep disturbances and intermittent hypoxia brought about by apnoea and hypopnoea. CSR impairs patients' quality of life and wakefulness, and probably also increases cardiac mortality in patients with heart failure. Thus, CSR should be actively sought in patients with a left ventricular ejection fraction <40%. When CSR persists despite optimal drug therapy for heart failure, non-invasive ventilation, particularly as adaptive servoventilation, and cardiac resynchronisation therapy are currently the most promising treatment options.