Publications by authors named "Malcolm Kohler"

249 Publications

Health Preference Measures in Patients with Obstructive Sleep Apnea Syndrome Undergoing Continuous Positive Airway Pressure Therapy: Data from a Randomized Trial.

Respiration 2021 Feb 4:1-11. Epub 2021 Feb 4.

Department of Respiratory Medicine, Sleep Disorders Center, University Hospital Zurich, Zurich, Switzerland,

Background: In patients with obstructive sleep apnea syndrome (OSAS), the preference-based, health-related quality of life in terms of utility has not been extensively studied.

Objective: To address this point, we compared the performance of different instruments assessing utility in patients with OSAS undergoing continuous positive airway pressure (CPAP) therapy.

Materials And Methods: Data of 208 patients with OSAS (28 women, mean ± SE age 54.4 ± 0.7 years, apnea-hypopnea index (AHI) 51.9 ± 1.8/h, Epworth sleepiness score 13.4 ± 0.2) participating in a randomized trial of different CPAP modalities over 2 years were analyzed. Evaluations included sleep studies, Epworth sleepiness scale, and several utility instruments that measure subjective health preference on a scale ranging from 1 (most preferred and perfect health) to 0 (least preferred and very poor health).

Results: After 2 years of CPAP therapy, the mean ± SE AHI was 6.7 ± 1.5/h and Epworth score 7.9 ± 0.4, both p < 0.001 versus baseline. Baseline utilities and changes (95% confidence interval) after 2 years of CPAP therapy were EuroQol 5-dimensions 0.79 ± 0.01, 0.02 (0.00-0.05, p = 0.064); short-form 6-dimension medical outcome questionnaire 0.72 ± 0.01, 0.06 (0.04-0.08, p < 0.001); Euro-thermometer visual analog scale 0.70 ± 0.01, 0.09 (0.07-0.12, p < 0.001); time trade-off 0.82 ± 0.01, 0.03 (0.01-0.06, p = 0.002); and standard gamble 0.82 ± 0.01, -0.01 (-0.03 to 0.02, p = 0.712).

Conclusion: The short-form 6-dimensions questionnaire, the Euro-thermometer, and the time trade-off instruments reflected the major clinical improvements in OSAS, while the EuroQoL 5-dimensions and standard gamble tests were not sensitive to CPAP effects. These results indicate that the evaluation of utility of a treatment for OSAS depends critically on the instrument used, which is important from an individual and societal perspective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000513306DOI Listing
February 2021

[CME/Antworten: Nacht-zu-Nacht-Variabilität der obstruktiven Schlafapnoe].

Praxis (Bern 1994) 2021 Jan;110(1):16-18

Pulmonary Division, University Hospital Zurich, Switzerland.

According to current recommendations, the diagnosis of obstructive sleep apnea (OSA) is established by a single-night sleep study. However, recent reports suggest a remarkable night-to-night variability of OSA severity. We report on a 76-year-old man with suspected OSA who underwent six sleep studies within 13 months. Sleep studies demonstrated a remarkable variability of respiratory events based on an apnea-hypopnea index (AHI) varying between 1.1 and 43.1/h. There were no changes in body weight, alcohol intake, medication or comorbidities during the evaluation period. Due to diagnostic uncertainty and missing subjective benefit, the initially implemented CPAP therapy was stopped after one year of therapy. Considering night-to-night variability of OSA severity, single-night sleep studies might not be accurate enough in order to reliably diagnose or exclude OSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1661-8157/a003600DOI Listing
January 2021

Evaluation of cytokines in the tumor microenvironment of lung cancer using bronchoalveolar lavage fluid analysis.

Cancer Immunol Immunother 2021 Jan 4. Epub 2021 Jan 4.

Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Introduction: Lung cancer is the leading cause of death by cancer. In recent years, immunotherapy with checkpoint inhibitors (ICI) emerged as a promising new therapeutic approach. However, a deeper understanding of the immunologic responses adjacent to the tumor known as tumor microenvironment (TME) is needed. Our study investigated TME of lung cancer by analyzing cytokines in bronchoalveolar lavage fluid (BALF).

Materials And Methods: Between January 2018 and June 2019, 119 patients were prospectively enrolled in this study. For each cancer patient, levels of 16 cytokines (fractalkine, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukins (IL): IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, and IL-23) were measured in BALF and serum and compared to healthy individuals and patients with other lung diseases.

Results: There were several significant differences of cytokine levels of patients with lung cancer compared to healthy individuals. However, none of them remained in the multivariate analysis compared to other lung diseases in either BALF or serum. Furthermore, there were no significant differences between the groups in cell differentiation of either BALF or serum. Cytokine levels in BALF were generally near the lower detection limit and showed almost no correlation with their respective levels measured in serum of the same individual.

Conclusions: Cytokines in BALF and serum of lung cancer patients may indicate unspecific inflammation. BAL is not recommendable as a tool to investigate TME of lung cancer. Therefore, cytokines measured in BALF are probably not appropriate as predictors in patients treated with ICIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02798-zDOI Listing
January 2021

Which are the Central Aspects of Infant Sleep? The Dynamics of Sleep Composites across Infancy.

Sensors (Basel) 2020 Dec 15;20(24). Epub 2020 Dec 15.

Department of Pulmonology, University Hospital Zurich, 8091 Zurich, Switzerland.

Sleep during infancy is important for the well-being of both infant and parent. Therefore, there is large interest in characterizing infant sleep with reliable tools, for example by combining actigraphy with 24-h-diaries. However, it is critical to select the right variables to characterize sleep. In a longitudinal investigation, we collected sleep data of 152 infants at ages 3, 6, and 12 months. Using principal component analysis, we identified five underlying sleep composites from 48 commonly-used sleep variables: , , , , . These composites accurately reflect known sleep dynamics throughout infancy as (representing naps), (representing sleep efficiency and consolidation), and (representing day-to-day stability) decrease across infancy, while (representing nighttime sleep) slightly increases, and becomes earlier as one ages. We uncover interesting dynamics between the sleep composites and demonstrate that infant sleep is not only highly variable between infants but also dynamic within infants across time. Interestingly, is associated with behavioral development and therefore a potential marker for maturation. We recommend either the use of sleep composites or the core representative variables within each sleep composite for more reliable research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s20247188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765288PMC
December 2020

[CME: Nacht-zu-Nacht-Variabilität der obstruktiven Schlafapnoe].

Praxis (Bern 1994) 2020 ;109(16):1225-1230

Pulmonary Division, University Hospital Zurich, Switzerland.

Die aktuellen Leitlinien empfehlen, unkomplizierte Patientinnen und Patienten mit Verdacht auf obstruktive Schlafapnoe (OSA) mittels einer einzigen Schlafuntersuchung zu diagnostizieren. Eine kürzlich veröffentlichte Meta-Analyse konnte hingegen eine ausgeprägte intra-individuelle Variabilität respiratorischer Parameter von Nacht zu Nacht zeigen. Wir präsentieren den Fall eines 76-jährigen Patienten mit Verdacht auf OSA, der innerhalb von 13 Wochen sechs Schlafuntersuchungen unterzogen wurde. Hierbei präsentierte sich eine relevante Variabilität des AHI zwischen 1,1 und 43,1/h. Es konnten keine relevanten Unterschiede betreffend Gewicht, Alkoholkonsum, Medikation und Begleiterkrankungen zwischen den Schlafuntersuchungen festgestellt werden. Aufgrund fehlender subjektiver Wirksamkeit wurde die CPAP-Therapie nach einem Jahr gestoppt. Die ausgeprägte Nacht-zu-Nacht-Variabilität respiratorischer Parameter stellt eine akkurate OSA-Diagnostik mittels einer einzelnen Schlafuntersuchung in Frage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1661-8157/a003599DOI Listing
December 2020

A few more steps lead to improvements in endothelial function in severe and very severe COPD.

Respir Med 2021 Jan 20;176:106246. Epub 2020 Nov 20.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Introduction: Cardiovascular disease is among the most prevalent concomitant chronic diseases in COPD. Physical activity (PA) modifies endothelial function and is commonly impaired in COPD. However, studies directly investigating the effects of increased PA on endothelial function in COPD are lacking. We investigated the effect of changes in PA on endothelial function in patients with severe to very severe COPD. Furthermore, we determined which variables modify this effect.

Materials And Methods: This is a secondary outcome analysis from a randomised controlled trial investigating the effects of combined PA counselling and pedometer-based feedback in COPD. We analysed the change in PA based on three visits during one year. We measured PA using a validated triaxial accelerometer, and endothelial function using flow-mediated dilation.

Results: Data was analysed from 54 patients, which provided 101 change scores. Multiple regression modelling, including adjustment for baseline step count, showed strong evidence for an association between changes in flow-mediated dilation and changes in PA (p < 0.001). The analysis of several effect modificators showed no evidence of any influence on the interaction between PA and endothelial function: smoking status (p = 0.766), severity of airflow obstruction (p = 0.838), exacerbation frequency (p = 0.227), lung diffusion capacity of carbon monoxide % pred. (p = 0.735).

Conclusion: We found strong evidence that increasing steps per day ameliorates the heavily impaired endothelial function in patients with severe and very severe COPD. Further studies should examine which factors influence this relationship in a positive or negative manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2020.106246DOI Listing
January 2021

Absenteeism and presenteeism in healthcare workers due to respiratory illness.

Infect Control Hosp Epidemiol 2020 Nov 26:1-6. Epub 2020 Nov 26.

Institute of Medical Virology, University of Zurich, Zurich, Switzerland.

Objective: To assess influenza symptoms, adherence to mask use recommendations, absenteesm and presenteeism in acute care healthcare workers (HCWs) during influenza epidemics.

Methods: The TransFLUas influenza transmission study in acute healthcare prospectively followed HCWs prospectively over 2 consecutive influenza seasons. Symptom diaries asking for respiratory symptoms and adherence with mask use recommendations were recorded on a daily basis, and study participants provided midturbinate nasal swabs for influenza testing.

Results: In total, 152 HCWs (65.8% nurses and 13.2% physicians) were included: 89.1% of study participants reported at least 1 influenza symptom during their study season and 77.8% suffered from respiratory symptoms. Also, 28.3% of HCW missed at least 1 working day during the study period: 82.6% of these days were missed because of symptoms of influenza illness. Of all participating HCWs, 67.9% worked with symptoms of influenza infection on 8.8% of study days. On 0.3% of study days, symptomatic HCWs were shedding influenza virus while at work. Among HCWs with respiratory symptoms, 74.1% adhered to the policy to wear a mask at work on 59.1% of days with respiratory symptoms.

Conclusions: Respiratory disease is frequent among HCWs and imposes a significant economic burden on hospitals due to the number of working days lost. Presenteesm with respiratory illness, including influenza, is also frequent and poses a risk for patients and staff.

Trial Registration: NCT02478905 (clinicaltrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2020.444DOI Listing
November 2020

Nocturnal heart rate variability in obstructive sleep apnoea: a cross-sectional analysis of the Sleep Heart Health Study.

J Thorac Dis 2020 Oct;12(Suppl 2):S129-S138

Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland.

Background: Obstructive sleep apnoea (OSA) results in sympathetic overdrive. Increased nocturnal heart rate variability (HRV) is a surrogate marker of autonomic disturbance. The aim was to study the association of the apnoea-hypopnea index (AHI), nocturnal hypoxaemia, and sleep fragmentation with nocturnal HRV to address the pathophysiological mechanisms underlying autonomic disturbance in OSA.

Methods: Participants of the Sleep Hearth Health Study with available data on nocturnal HRV and an AHI ≥10/h have been included in this cross-sectional analysis. The main outcome of interest was the association of sleep fragmentation, nocturnal hypoxaemia, and the AHI with nocturnal HRV. Multivariate regression modelling with the mean of the standard deviations of normal-sinus-to-normal-sinus-interbeat intervals in all 5-minute segments (SDNNIDX) and with low to high frequency power-ratio (LF/HF) as dependent variables controlling for prespecified confounders (age, sex, cups of coffee, beta blocker, nocturnal heart rate) was used to assess the contribution of the arousal index, total sleep time with an oxygen saturation <90% (TST90) and the AHI not due to arousals to HRV. The significance level was set at P<0.01.

Results: In 258 patients with OSA (mean ± SD age 62±10 years, BMI 29±4 kg/m, median (IQR) AHI 18.6/h (14.0-25.6), the arousal index (coef =0.42, P=0.002) was independently positively associated with SDNNIDX also after having controlled for potential confounders, whereas the AHI (coef =0.22, P=0.030) and TST90 (coef =0.36, P=0.054) were not. The arousal index-but not TST and AHI-was also independently associated with LF/HF.

Conclusions: In OSA, pronounced sleep fragmentation is associated with higher nocturnal HRV and a sympatho-vagal imbalance with sympathetic dominance. OSA severity and nocturnal hypoxaemia did not independently predict nocturnal HRV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-cus-2020-005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642633PMC
October 2020

Obstructive sleep apnea and the progression of thoracic aortic aneurysm: a prospective cohort study.

Eur Respir J 2020 Nov 19. Epub 2020 Nov 19.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland

Background: Obstructive sleep apnea (OSA) is associated with an increased prevalence of aortic aneurysms, and it has also been suggested that severe OSA furthers aneurysm expansion in the abdomen. We evaluated whether OSA is a risk factor for the progression of ascending thoracic aortic aneurysms (TAA).

Methods: Patients with TAA underwent yearly standardised echocardiographic measurements of the ascending aorta over 3 years, and two level-III sleep studies. The primary outcome was the expansion rate of TAA in relation to the apnea-hypopnea-index (AHI). Secondary outcomes included surveillance for aortic events (composite endpoints of rupture, dissection, elective surgery, and death).

Results: Between July 2014 and March 2020, 230 patients (median age 70 years, 78% male) participated in the cohort. At baseline, 34.8% of patients had an AHI of ≥15 events·h. There was no association between TAA diameters and the AHI at baseline. After 3 years mean expansion rates were 0.55±1.25 mm at the aortic sinus and 0.60±1.12 mm at the ascending aorta. In the regression analysis, after controlling for baseline diameter and cardiovascular risk factors, there was strong evidence for a positive association of TAA expansion with AHI (aortic sinus estimate 0.025 mm [95%CI 0.009 to 0.040], p<0.001; ascending aorta estimate 0.026 mm [95%CI 0.011 to 0.041], p=0.001). Twenty participants (8%) experienced an aortic event, however, there was no association with OSA severity.

Conclusion: OSA may be a modest but independent risk factor for faster TAA expansion and thus potentially contributes to life-threatening complications in aortic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.03322-2020DOI Listing
November 2020

Long-Term Effects of Pedometer-Based Physical Activity Coaching in Severe COPD: A Randomized Controlled Trial.

Int J Chron Obstruct Pulmon Dis 2020 6;15:2837-2846. Epub 2020 Nov 6.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland.

Background And Objective: Limited evidence on long-term effects of physical activity programs in COPD is available. The aim of the study was to investigate the effects of a three-month program combining physical activity counselling and pedometer-based feedback in addition to usual care, followed by a nine-month unsupervised observation period as compared to usual care in participants with severe to very severe COPD.

Methods: Participants were randomized to either a control group receiving usual care or an intervention group receiving motivational support, an activity diary with an individual step count goal (ie, an increase of ≥15% from baseline) and a pedometer in addition to usual care. The intervention ended after three months and an unsupervised observational period followed until twelve months. Primary outcome was daily step count after one year.

Results: Seventy-four participants were included, 61 (82%) completed the study. Linear regression modelling, adjusted for baseline step count, showed no significant difference in change in step count after 12 months between the groups (Β = 547.33, 95% CI = -243.55/1338.20).

Conclusion: A three-month program combining physical activity counselling and pedometer-based feedback in addition to usual care does not attenuate the declining course of physical activity in participants with severe and very severe COPD during a long term follow-up of one year as compared to usual care. This result was primarily determined by the low intervention response rates to the combined program.

Clinical Trial Registration: www.ClinicalTrials.gov, NCT03114241.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S279293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655791PMC
November 2020

The Swiss Prison Study (SWIPS): Protocol for Establishing a Public Health Registry of Prisoners in Switzerland.

JMIR Res Protoc 2020 Dec 8;9(12):e23973. Epub 2020 Dec 8.

Global Health and Population, Harvard T H Chan School of Public Health, Boston, MA, United States.

Background: The health aspects, disease frequencies, and specific health interests of prisoners and refugees are poorly understood. Importantly, access to the health care system is limited for this vulnerable population. There has been no systematic investigation to understand the health issues of inmates in Switzerland. Furthermore, little is known on how recent migration flows in Europe may have affected the health conditions of inmates.

Objective: The Swiss Prison Study (SWIPS) is a large-scale observational study with the aim of establishing a public health registry in northern-central Switzerland. The primary objective is to establish a central database to assess disease prevalence (ie, International Classification of Diseases-10 codes [German modification]) among prisoners. The secondary objectives include the following: (1) to compare the 2015 versus 2020 disease prevalence among inmates against a representative sample from the local resident population, (2) to assess longitudinal changes in disease prevalence from 2015 to 2020 by using cross-sectional medical records from all inmates at the Police Prison Zurich, Switzerland, and (3) to identify unrecognized health problems to prepare successful public health strategies.

Methods: Demographic and health-related data such as age, sex, country of origin, duration of imprisonment, medication (including the drug name, brand, dosage, and release), and medical history (including the International Classification of Diseases-10 codes [German modification] for all diagnoses and external results that are part of the medical history in the prison) have been deposited in a central register over a span of 5 years (January 2015 to August 2020). The final cohort is expected to comprise approximately 50,000 to 60,000 prisoners from the Police Prison Zurich, Switzerland.

Results: This study was approved on August 5, 2019 by the ethical committee of the Canton of Zurich with the registration code KEK-ZH No. 2019-01055 and funded in August 2020 by the "Walter and Gertrud Siegenthaler" foundation and the "Theodor and Ida Herzog-Egli" foundation. This study is registered with the International Standard Randomized Controlled Trial Number registry. Data collection started in August 2019 and results are expected to be published in 2021. Findings will be disseminated through scientific papers as well as presentations and public events.

Conclusions: This study will construct a valuable database of information regarding the health of inmates and refugees in Swiss prisons and will act as groundwork for future interventions in this vulnerable population.

Trial Registration: ISRCTN registry ISRCTN11714665; http://www.isrctn.com/ISRCTN11714665.

International Registered Report Identifier (irrid): DERR1-10.2196/23973.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/23973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755536PMC
December 2020

The Accuracy of Repeated Sleep Studies in OSA: A Longitudinal Observational Study With 14 Nights of Oxygen Saturation Monitoring.

Chest 2020 Sep 25. Epub 2020 Sep 25.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; Centre for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland. Electronic address:

Background: Strong evidence exists for clinically relevant night-to-night variability of respiratory events in patients with suspected OSA.

Research Question: How many sleep study nights are required to diagnose OSA accurately?

Study Design And Methods: Patients with suspected OSA underwent up to 14 nights of pulse oximetry (PO) at home and one night of in-hospital respiratory polygraphy (RP). The accuracy of each of the 13 sleep study nights was analyzed using the mean oxygen desaturation index 3% (ODI) of all 14 nights as a reference. Multiple regression analyses assessed possible predictors for night-to-night variability.

Results: One hundred three patients underwent in-hospital RP. Using only the results of the RP, 19.7% were misdiagnosed using an ODI cutoff of 15/h. One hundred eight patients underwent properly performed PO studies at home with a coefficient of variation (CV) of 31.5% (SD, 14.7%) across all nights. The first PO night demonstrated a sensitivity of 71.4% (95% CI, 55.4%-84.3%) and a specificity of 89.4% (95% CI, 79.4%-95.6%) to diagnose moderate OSA. Using only the first PO night, the negative predictive value was 83.1%. Adding a second recording night increased sensitivity up to 88.1% (95% CI, 74.4%-96.0%) with a slightly lower specificity of 85.9% (95% CI, 74.9%-93.4%). The ODI of the in-hospital RP showed an independent negative association to the log-transformed CV (exponentiated coefficient, 0.989; 95% CI, 0.984-0.995).

Interpretation: One single night of in-hospital RP may miss relevant OSA. Multiple study nights, for example, using ambulatory oxygen saturation monitoring, increase accuracy for diagnosing moderate OSA.

Trial Registry: ClinicalTrials.gov; No.: NCT03819361; URL: www.clinicaltrials.gov.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.09.098DOI Listing
September 2020

Increased augmentation index in patients with Ehlers-Danlos syndrome.

BMC Cardiovasc Disord 2020 09 15;20(1):417. Epub 2020 Sep 15.

Department of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.

Background: Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascular disease progression (e.g. arterial aneurysms, dissections, and ruptures) in EDS patients are still missing. Recently, applanation tonometry derived augmentation index (AIx), an indirect marker of arterial stiffness, has shown to be positively associated with progression of aortic disease in Marfan syndrome. In this study, we assessed aortic AIx in patients with EDS and matched healthy controls.

Methods: We performed noninvasive applanation tonometry in 61 adults with EDS (43 women and 18 men aged 39.3 ± 14.6 years) and 61 age-, gender-, height-, and weight-matched healthy controls. Radial artery pulse waveforms were recorded and analyzed using the SphygmoCor System (AtCor Medical, Sydney, NSW, Australia). Calculated AIx was adjusted to a heart rate of 75/min. Groups were compared and association between AIx and EDS was determined by univariate and multivariate regression analysis.

Results: EDS patients were categorized in classical type EDS (34%), hypermobile type EDS (43%), vascular type EDS (5%), or remained unassignable (18%) due to overlapping features. EDS patients showed a significantly increased aortic AIx compared to healthy controls (22.8% ± 10.1 vs 14.8% ± 14.0, p < 0.001). EDS showed a positive association with AIx; independent of age, sex, height, blood pressure, medication, and pack years of smoking.

Conclusions: Patients with EDS showed elevated AIx, indicating increased arterial stiffness when compared to healthy controls. Further investigations are needed in order to assess the prognostic value of increased AIx for cardiovascular outcomes in patients with EDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12872-020-01684-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493396PMC
September 2020

Effect of CPAP on cardiovascular events in minimally symptomatic OSA: long-term follow-up of the MOSAIC randomised controlled trial.

BMJ Open Respir Res 2020 09;7(1)

NIHR Biomedical Research Centre Oxford, University of Oxford, Oxford, Oxfordshire, UK.

The effect of continuous positive airway pressure (CPAP) on cardiovascular events is uncertain in minimally symptomatic obstructive sleep apnoea. Previous 2-year follow-up data from the Multicentre Obstructive Sleep Apnoea Intervention Cardiovascular (MOSAIC) trial showed a marginal reduction in cardiovascular events with CPAP therapy. We now present long-term MOSAIC study follow-up data. Median (first quartile, third quartile) follow-up was 5.0 (2.2, 5.0) and 3.7 (1.5, 5.0) years for CPAP and standard care, respectively. Compared to standard care, CPAP had no statistically significant effect on the risk of cardiovascular events (HR=0.83, p=0.54, 95% CI 0.46-1.51).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjresp-2020-000742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490925PMC
September 2020

Patterns of nightly CPAP usage in OSA patients with suboptimal treatment adherence.

Sleep Med 2020 10 11;74:109-115. Epub 2020 Jun 11.

Department of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Centre for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland. Electronic address:

Background And Objectives: Low adherence impairs the effectiveness of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA), but knowledge on CPAP usage micro-patterns is mostly lacking. Thus, the aim of this study was to analyse usage micro-patterns among patients with suboptimal CPAP adherence.

Methods: We analysed CPAP usage datasets comprising the initial 31 nights of therapy. By employing a threshold of 4 h usage in at least 70% of nights, we subdivided the patients into suboptimal and optimal users. We investigated single CPAP start- and stop-points, and introduced the parameter "interruption-rate", by dividing the amount of therapy interruptions per night by the usage duration per night. This parameter represents the amount of interruptions per 1 h of CPAP usage. Group comparison analysis was performed via t-test, Wilcoxon rank sum-test, and via Chi-test.

Results: We included datasets of 48 suboptimal and 48 optimal users (55.9 ± 11.3 years, 83.3% men) in the analysis. Interruption-rate was significantly higher among suboptimal users, when compared with optimal users (median (quartiles) 0.24 (0.14/0.45) versus 0.15 (0.05/0.28), p < 0.001∗). Suboptimal users were more likely to report that CPAP reduced their sleep quality, waked them up at night, and that CPAP side effects or problems with the device impaired their adherence.

Conclusions: CPAP usage micro-patterns are more fragmented among OSA patients with lower overall adherence. These patterns might result from impaired sleep quality, due to CPAP side effects, and device-associated problems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2020.05.042DOI Listing
October 2020

Night-to-night variability of respiratory events in obstructive sleep apnoea: a systematic review and meta-analysis.

Thorax 2020 12 13;75(12):1095-1102. Epub 2020 Aug 13.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland

Background: It is current practice to use a single diagnostic sleep study in the diagnostic workup of obstructive sleep apnoea (OSA). However, a relevant night-to-night variability (NtNV) of respiratory events has been reported.

Methods: We evaluated the NtNV of respiratory events in adults with suspected or already diagnosed OSA who underwent more than one diagnostic sleep study. Data sources were PubMed, Cochrane and Embase up to 23 January 2019. Random-effects models were used for evidence synthesis. For moderator analysis, mixed-effects regression analysis was performed. The study was registered with PROSPERO (CRD42019135277).

Results: Of 2143 identified papers, 24 studies, comprising 3250 participants, were included. The mean Apnoea-Hypopnoea Index (AHI) difference between the first and second night was -1.70/hour (95% CI -3.61 to 0.02). REM time differences (first to second night) were significantly positive associated with differences in mean AHI (β coefficient 0.262 (95% CI 0.096 to 0.428). On average, 41% (95% CI 27% to 57%) of all participants showed changes of respiratory events >10/hour from night to night. Furthermore, 49% (95% CI 32% to 65%) of participants changed OSA severity class (severity thresholds at 5/hour, 15/hour and 30/hour) at least once in sequential sleep studies. Depending on the diagnostic threshold (5/hour, 10/hour or 15/hour), on average 12% (95% CI 9% to 15%), 12% (95% CI 8% to 19%) and 10% (95% CI 8% to 13%) of patients would have been missed during the first night due to single night testing.

Conclusion: While there was no significant difference between mean AHI in two sequential study nights on a group level, there was a remarkable intraindividual NtNV of respiratory events, leading to misdiagnosis and misclassification of patients with suspected OSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2020-214544DOI Listing
December 2020

It's Time for Multiple Sleep Night Testing in OSA.

Chest 2020 Jul 2;158(1):33-34. Epub 2020 Jul 2.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; Centre for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.02.024DOI Listing
July 2020

Advanced nursing practice in COPD exacerbations: the solution for a gap in Switzerland?

ERJ Open Res 2020 Apr 15;6(2). Epub 2020 Jun 15.

Centre of Clinical Nursing Science, University Hospital Zürich, Zürich, Switzerland.

Aim: This study aimed to address the need for adaptation of the current model of chronic obstructive pulmonary disease (COPD) care in Switzerland, particularly in regard to acute exacerbations, and how far an integrated approach involving advanced nursing practice can meet those needs.

Methods: A state analysis guided by the PEPPA framework was initiated by the Pulmonology Clinic of University Hospital Zürich. Literature describing the current provision of COPD care regarding exacerbations in Switzerland and international qualitative studies describing the patient perspective were systematically searched and summarised. The health providers' perspective was investigated in three focus-group interviews.

Results: A lack of systematic and state-of-the-art support for patient self-management in Switzerland was described in literature and confirmed by the health providers interviewed. While care was assessed as being comprehensive and of good quality in each individual sector, such as inpatient, outpatient, rehabilitation and home settings, it was identified as being highly fragmented across sectors. The interview participants described day-to-day examples in which a lack of support in COPD self-management and fragmentation of care negatively affected the patients' disease management.

Conclusion: The necessity of coordinating the transition between healthcare sectors and self-management support and that these organisational boundaries should be addressed by a multi-professional team were identified. Initial evaluation indicates that advanced practice nurses potentially have the skill set to coordinate the team and address patients' self-management needs in complex patient situations. However, the legal foundation and a reimbursement system to ensure long-term implementation is not yet available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/23120541.00354-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293988PMC
April 2020

Predictors of changes in subjective daytime sleepiness in response to CPAP therapy withdrawal in OSA: A post-hoc analysis.

J Sleep Res 2020 May 22:e13078. Epub 2020 May 22.

Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland.

Subjective sleepiness is the hallmark symptom of untreated obstructive sleep apnea (OSA) and leads to an increased risk of motor vehicle accidents and impaired quality of life. Continuous positive airway pressure (CPAP) is the standard therapy for OSA and improves sleepiness. The aim was to identify factors that might predict recurrence of sleepiness in times off CPAP and to define OSA patient types with a likely effect of CPAP on sleepiness. A post-hoc analysis of six clinical trials, including 132 patients with OSA effectively treated with CPAP prior to study inclusion, who were allocated to 2 weeks of CPAP withdrawal, was conducted to assess predictors of a change in subjective sleepiness. A multivariate regression model was used to assess predictors of a change in the Epworth Sleepiness Scale (ESS) score. In response to CPAP withdrawal, the median apnea-hypopnea index (AHI) and the ESS score significantly increased compared to baseline on CPAP by 32.6/hr (95% CI, 28.8, 36.4)/hr and 2.5 (95% CI, 1.8,3.2), respectively (p < .001), in the included 132 patients. There was an independent positive association of AHI (Coef. [95% CI] 0.04 [0.01, 0.08]) with an increase in ESS score upon CPAP withdrawal, and an independent negative association of age (coef. [95% CI], -0.10 [-0.18, -0.2]), ESS on CPAP (coef. [95% CI], -0.21 [-0.40, -0.015]) and active smoking status (coef. [95% CI], -1.22 [-2.26, -0.17]). These findings suggest that younger patients with a low residual sleepiness on CPAP and a recurrence of more severe OSA during CPAP withdrawal are at highest risk of suffering from a clinically relevant return of daytime sleepiness in times off CPAP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jsr.13078DOI Listing
May 2020

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

Int J Chron Obstruct Pulmon Dis 2020 26;15:627-635. Epub 2020 Mar 26.

Pulmonary Division, University Hospital Zurich, Zurich, Switzerland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S240444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105357PMC
March 2020

Arterial Stiffness Increases Over Time in Relation to Lung Diffusion Capacity: A Longitudinal Observation Study in COPD.

Int J Chron Obstruct Pulmon Dis 2020 23;15:177-187. Epub 2020 Jan 23.

Pulmonary Division, University Hospital of Zurich, Zurich, Switzerland.

Background: Cardiovascular events are, after cancer, the most common cause of death in COPD patients. Arterial stiffness is an independent predictor of all-cause mortality and cardiovascular events. Several cross-sectional studies have confirmed increased arterial stiffness in patients with COPD. Various mechanisms in the development of arterial stiffness in COPD such as reduced lung function or systemic inflammation have been proposed. However, clinical predictors of arterial stiffness that had been reported in cross-sectional studies have not yet been confirmed in a longitudinal setting. We have assessed the course of augmentation index (AIx) - a measure of systemic arterial stiffness - and possible predictors in a cohort of COPD patients over a period of up to 7 years.

Methods: COPD patients underwent annual AIx measurement by applanation tonometry for a maximum duration of 7 years. Additionally, we performed annual assessments of lung function, blood gases, systemic inflammation, serum lipids and blood pressure. Associations between the course of AIx and potential predictors were investigated through a mixed effect model.

Results: Seventy-six patients (mean (SD) age 62.4 (7.1), male 67%) were included. The AIx showed a significant annual increase of 0.91% (95% CI 0.21/1.60) adjusted for baseline. The change in diffusion capacity (DLco), low-density lipoprotein (LDL), and high-sensitivity c-reactive protein (hsCRP) was independently associated with the increasing evolution of AIx (Coef. - 0.10, p<0.001, Coef. 1.37, p=0.003, and Coef. 0.07, p=0.033, respectively).

Conclusion: This study demonstrated a meaningful increase in arterial stiffness in COPD over time. A greater annual increase in arterial stiffness was associated with the severity of emphysema (measured by DLco), systemic inflammation, and dyslipidaemia.

Clinical Trial Registration: www.ClinicalTrials.gov, NCT01527773.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S234882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986246PMC
February 2021

Protocol for the EARCO Registry: a pan-European observational study in patients with α-antitrypsin deficiency.

ERJ Open Res 2020 Jan 2;6(1). Epub 2020 Mar 2.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

Rationale And Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD.

Study Design And Population: The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager.

Summary: The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/23120541.00181-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049712PMC
January 2020

[CME: Obstructive Sleep Apnea: A Common Disease].

Praxis (Bern 1994) 2020 ;109(3):207-213

Klinik für Pneumologie, Universitätsspital Zürich, Zürich.

CME: Obstructive Sleep Apnea: A Common Disease Obstructive sleep apnea is a common sleep related breathing disorder with a collapse of the upper respiratory tract, leading to repetitive oxygen desaturations and 'micro arousals'. If the physiological sleep architecture is impaired, patients are at risk for an increased daytime sleepiness and an increased blood pressure. Main risk factors are central obesity, age, male sex, (and snoring). By means of weight loss, alcohol restriction, and continuous nocturnal positive pressure ventilation (CPAP), the obstructive sleep apnea syndrome can be treated, with mandibular advancement devices representing a second-choice therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1661-8157/a003385DOI Listing
July 2020

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

COPD 2020 04 19;17(2):150-155. Epub 2020 Feb 19.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland.

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 = -0.86 (95% CI -1.09/-0.62,  < 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  = 0.11 (95% CI 0.03/0.18,  = 0.006) and an enhanced change in COPD Assessment Test scores by = -0.01 (95% CI -0.01/-0.00,  = 0.034). No evidence for an independent association between annual decline in HGS and FEV% pred. by = -0.01 (95% CI -0.03/0.01,  = 0.297) was shown. Patients who died during follow-up did not exhibit greater declines in HGS compared to survivors ( = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15412555.2020.1727428DOI Listing
April 2020

Low repeatability of Epworth Sleepiness Scale after short intervals in a sleep clinic population.

J Clin Sleep Med 2020 05 10;16(5):757-764. Epub 2020 Feb 10.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland.

Study Objectives: The purpose of this study was to evaluate the short-term repeatability of the Epworth Sleepiness Scale (ESS) in patients with suspected obstructive sleep apnea and to determine whether transitory sleepiness of the patient influenced ESS results.

Methods: Adult participants with suspected obstructive sleep apnea taking part in a study on the diagnostic accuracy of repeated sleep studies were eligible. For assessment of repeatability, the agreement between 2 sequential ESS scores obtained within 1 day (same-day group) or on different days within 1 week (same-week group) was evaluated. By analyzing the within-day repeatability, a possible influence of situational sleepiness on ESS results was assessed. By comparing correlations of sequential scores between both groups, a potential influence of test day-specific sleepiness on ESS results was evaluated. Data were analyzed using Bland-Altman plots, intraclass correlation coefficients, standard error of measurement analysis, and relative amounts of ESS discrepancies beyond 2, 3, 5, and 7 points.

Results: Forty participants (mean age, 47.7 ± 15.4 years; 67.5% men) were included in this study, with 20 in each group. Bland-Altman analysis demonstrated considerable variability of repeated scores (mean ± 1.96 × SD = 1.93 [-3.81 to 7.66]). Discrepancies of at least 3 points between sequential ESS scores were found in 48% of all participants. Comparison of ESS repeatability between both groups showed no evidence for a difference.

Conclusions: A clinically relevant variability in ESS scores was found, even when repeated on the same day, possibly because of situational sleepiness influencing ESS results. Changes in ESS in response to interventions should be interpreted with caution because of its low test-retest reliability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5664/jcsm.8350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849809PMC
May 2020

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

Respir Res 2020 Jan 20;21(1):27. Epub 2020 Jan 20.

Pulmonary Division, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-020-1290-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972031PMC
January 2020

Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial.

Eur Respir J 2020 03 20;55(3). Epub 2020 Mar 20.

Dept of Pulmonology, University Hospital Zurich, Zurich, Switzerland

Introduction: Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA.

Material And Methods: In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score >10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3-4 h). Patients were allocated through minimisation to either subtherapeutic CPAP ("sham CPAP") or continuation of CPAP ("therapeutic CPAP"). A Bayesian analysis with historical priors calculated the posterior probability of superiority.

Results: Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6-4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure.

Conclusions: Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01526-2019DOI Listing
March 2020