Introduction Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are the most critical events for patients with COPD that have a negative impact on patients’ quality of life, accelerate disease progression, and can result in hospital admissions and death. Although there is no distinct definition or detailed knowledge about AECOPD, it is commonly used as primary outcome in clinical studies. Furthermore, it may be difficult in clinical practice to differentiate the worsening of symptoms due to an AECOPD or to the development of heart failure. Therefore, it is of major clinical importance to investigate the underlying pathophysiology, and if possible, predictors of an AECOPD and thus to identify patients who are at high risk for developing an acute exacerbation.
Methods and analysis In total, 355 patients with COPD will be included prospectively to this study during a 3-week inpatient pulmonary rehabilitation programme at the Schoen Klinik Berchtesgadener Land, Schoenau am Koenigssee (Germany). All patients will be closely monitored from admission to discharge. Lung function, exercise tests, clinical parameters, quality of life, physical activity and symptoms will be recorded, and blood samples and exhaled air will be collected. If a patient develops an AECOPD, there will be additional comprehensive diagnostic assessments to differentiate between cardiac, pulmonary or cardiopulmonary causes of worsening. Follow-up measures will be performed at 6, 12 and 24 months.
Exploratory data analyses methods will be used for the primary research question (screening and identification of possible factors to predict an AECOPD). Regression analyses and a generalised linear model with a binomial outcome (AECOPD) will be applied to test if predictors are significant.
Ethics and dissemination This study has been approved by the Ethical Committee of the Philipps University Marburg, Germany (No. 61/19). The results will be presented in conferences and published in a peer-reviewed journal.
Trial registration number NCT04140097.
- thoracic medicine
- chronic airways disease
- rehabilitation medicine
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Strengths and limitations of this study
To the best of our knowledge, this is the largest chronic obstructive pulmonary disease (COPD) cohort with prospectively collected data to investigate the development of an acute exacerbation.
A large variety of assessments including basic science approaches will be used to detect potential early predictors for an acute exacerbation.
Acute exacerbation diagnosis will be based on clinical signs and judged by an experienced pulmonologist.
This is the first study to differentiate between COPD-related exacerbation and cardiac-related exacerbation.
This study is based on exploratory data analyses methods without a sample size or power computation.
Chronic obstructive pulmonary disease (COPD)1 is a lung disease characterised by respiratory problems and poor airflow with dyspnoea and cough being the main symptoms leading to impaired exercise performance and quality of life.2 COPD is a progressive disease that typically worsens over time.2 In this context, acute exacerbations of COPD (AECOPD) are the most critical events for patients with COPD, essential for the clinical course and the prognosis. The American Thoracic Society and the European Respiratory Society define AECOPD clinically as an episode of increased respiratory symptoms, particularly dyspnoea, cough, sputum production and increased sputum purulence.3 These issues are also reflected in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, which defines an exacerbation as ‘an acute worsening of respiratory symptoms that results in additional therapy’.2 It is assumed that the majority of AECOPD are triggered by infections mainly with respiratory viruses4 or pathogenic bacteria5 which increase local and systemic inflammation.6 Exacerbations have a negative impact on the quality of life of patients with COPD,7 accelerate disease progression, and can result in hospital admissions and death.8 9 Also within healthcare systems significant variability exists between physicians in both diagnostic practices and prescribing habits at exacerbations,10 and the utility of biomarkers to guide clinicians in exacerbation diagnosis and treatment is currently limited.11 12
Furthermore, physical comorbidities, such as cardiovascular disease, are also often prevalent in patients with COPD13 and are an additional challenge that impacts clinicians’ decision-making at COPD exacerbation.14 In patients with COPD with concomitant cardiovascular disease, exacerbations confer an increased risk of subsequent cardiovascular disease events, especially in hospitalised patients and within the first 30 days post-exacerbation.15
Until now, research in the field of AECOPD has gathered and analysed data usually after manifestation of AECOPD until recovery and most of them used a retrospective study design.16 17 A recent systematic review on the monitoring of physiological parameters (eg, oxygen saturation, heart rate or respiratory rate) to predict an AECOPD concluded that there is currently insufficient information on how physiological parameters vary prior to exacerbation to support routine domiciliary monitoring for the prediction of AECOPD.18 It would be of extreme clinical importance to determine early predictors of an AECOPD and to identify patients who are at high risk for developing an acute exacerbation and/or to detect the beginning of or prevent an acute exacerbation as early as possible. Early predictors of AECOPD could help to develop novel therapeutic treatment options and strategies, to prevent acute exacerbations in the future for patients with COPD.
Methods and analysis
Study design and registration
This study will be a monocentric, prospective observational study. Patients will be recruited during an inpatient pulmonary rehabilitation programme at the reference centre of the Philipps University Marburg: Schoen Klinik Berchtesgadener Land at Schoenau am Koenigssee (Germany). From an own former retrospective analysis in 401 patients with very severe COPD, we learnt that 15.2% of these patients develop an AECOPD during their stay in the clinic.19 Therefore, the setting of an inpatient pulmonary rehabilitation offers a unique model to study the phenomenon of an AECOPD prior to the first visible clinical sign and further on to have a follow-up of the underlying mechanisms. All patients with COPD who are referred to the reference centre for a rehabilitation programme will be included after providing written informed consent. Prospectively, a wide range of measurements will be collected (figure 1). If a patient develops an AECOPD, there will be an additional comprehensive diagnostic assessment to differentiate between pulmonary, cardiac or cardiopulmonary reasons for the acute exacerbation (table 1). The diagnosis of an AECOPD will be made clinically by an experienced pulmonologist within the first 24 hours according to the Anthonisen criteria with the occurrence of at least two symptoms among sputum volume, sputum purulence and breathlessness.20
To prospectively identify potential early, respiratory and or cardiac clinical predictors, laboratory parameters, breath print analyses and/or changes in lung function, symptoms and physical activity prior to an AECOPD in patients with COPD.
To identify potential mechanisms explaining the nature and composition of an acute exacerbation in patients with COPD.
To identify and differentiate patterns of acute COPD exacerbation versus cardiac failure in patients with COPD.
To investigate the potential role of exhaled breath volatile organic compound (VOC) profiles for the early detection of an AECOPD (‘COPD pre-exacerbation breath print’).
To use an electronic nose to capture exhaled breath metabolomic profiles for the early detection of an acute exacerbation in patients with COPD (‘COPD pre-exacerbation breath print’).
To identify parameters influencing mortality and other adverse events in the total study cohort at 6, 12 and 24 months’ follow-up.
The study started with the first-patient-in in February 2020 and is scheduled for last-patient-out by the end of 2023 (followed by the 6, 12 and 24 months’ follow-up measures).
Inclusion criteria: patients referred to an inpatient pulmonary rehabilitation programme at the Schoen Klinik Berchtesgadener Land (Germany) with a confirmed diagnosis of COPD according to GOLD stage II–IV,2 the ability to follow the rehabilitation protocol and a provided written informed consent.
Exclusion criteria: patients with an ongoing AECOPD or a current primary diagnosis of asthma will not be included in the study.
Study measures and outcomes
The following baseline characters will be recorded at study baseline concerning:
Age, gender, anthropometrics.
Regular drug treatment.
Social status (family, children), education (years of school and job training), employment status (full-time, half-time, pension).
Smoking status (active smoker, ex-smoker, never smoker).
Number of pack years (1 pack year=1 daily smoked pack of cigarettes for 1 year).
Long-term oxygen therapy (yes/no, daily usage duration and prescription since when).
Frailty status according to Fried Frailty Index.21
Comorbidities according to the criteria by Vanfleteren et al.13
Nocturnal non-invasive ventilation (yes/no, daily usage duration and prescription since when).
Nocturnal transcutaneous partial pressure of carbon dioxide measurement (Sentec Digitall Monitoring System) in case of hypercapnia to record CO2 max, SpO2 min).
Number of hospitalisations (with reason) and acute exacerbations within the last year and total so far.
Patient already attended a disease management programme like, for example, COBRA (yes/no).
Number of previous pulmonary rehabilitation programmes.
Frequency of regular physical exercise training (content, days per week and duration) and amount of physical activity (using Physical Activity Vital Sign questionnaire.
Bodyplethysmography and blood gas analysis
Initial measures of bodyplethysmography on day 1 will be performed after medication use. Blood gas analyses will be performed at rest under ambient conditions after at least 10 min of quiet sitting. Samples will be taken from the hyperaemic earlobe.
Bioelectrical impedance analysis
Body composition (fat-free mass) will be measured using bioelectrical impedance (NutriGuard-M, Data Input GmbH, Germany).22
Breath VOC analysis
Inflammatory phenotyping in patients with chronic airway disease can be made through blood or sputum analysis.23 These assessments do not provide results in real time because they require laboratory procedures. Hence, efforts are ongoing to bring biological assessment to the point of care. If properly validated, molecular profiling of exhaled air may provide a non-invasive and rapid alternative for blood and sputum.24 VOCs in exhaled air have been associated with inflammatory profiles in asthma25 26 and COPD.27 For VOC analysis 2, different approaches will be used:
Analysis by ion-mobility spectrometry (IMS) (BioScout IMS, B&S Analytik, Dortmund, Germany) will be performed. The IMS technology is fast and easy to use. Patients exhale directly into the IMS device where only low volumes of exhalation are needed for analysis. IMS has a great potential to proceed to become a point-of-care tool that produces characteristic disease-related breath profiles.28
Analysis by gas chromatography/mass spectrometry (GC/MS): we will collect breath samples on adsorption tubes for the analysis by GC/MS,29 30 using the novel ReCIVA sampler system (Owlstone medical, UK). The patients will inhale precleaned pressurised room air and the adsorption tubes will be loaded with 500 mL of exhaled breath. The tubes will then be shipped to Fraunhofer ITEM (Hannover, Germany) for GC/MS analysis.
It can be assumed that the clinical change from stable to exacerbated patients with COPD independent of the cause of the exacerbation will change the pattern of exhaled VOCs in patients with COPD.31 The early detection of these changes and a respective adjustment of treatment could potentially avoid the number of COPD exacerbations. Based on VOC pattern and clinical characteristics, COPD phenotypes could be defined.
Echocardiography will be performed to assess morphology and function of the left and right heart, including Doppler flow measurements. The intima-media diameter, the pulse wave transit time and the Ankle-Brachial Index will be assessed. In case of an AECOPD, a resting electrocardiography will be performed.
Nasopharyngeal swabs will be collected by means of nylon flocked swabs in combination with universal transport medium-RT (Copan Diagnostics, Murrieta, California, USA) and stored at −80°C. Viral RNA will be extracted with a QIAamp viral RNA purification kit (Qiagen, Valencia, California, USA) and tested by PCR for the determination of the most common respiratory viruses (including SARS-CoV-2, respiratory syncytial virus, influenza A, influenza B, rhinovirus, human metapneumovirus, adenovirus, human bocavirus). Moreover, whole genome sequencing of the same samples will be processed by next generation sequencing for analyses of the virome.
Venous blood samples
Basic inflammatory parameters will be analysed directly. Furthermore, blood samples will be frozen at −80°C and stored for further comprehensive analysis on, for example, virus-induced reasons for an AECOPD and a variety of clinically relevant serological parameters being able to modulate inflammatory processes (eg, interleukins, tumour necrosis factor-alpha).
Six-minute walk test (6MWT) including blood gas analyses pre/post-6MWT will be performed in accordance with international recommendations.32
Sit-to-stand tests (STSTs).
STSTs involve either the number of sit-to-stand repetitions from a standard chair within 1 min (1 min STST),33 or quantify the time that a patient needs to perform five repetitions in a row (5-repetition STST).
Peak quadriceps force.
Isometric peak quadriceps force will be measured at 90° knee angle using a fixed dynamometer on a knee-extension training device. At least three attempts will be performed with the best value in Newton and %pred. being recorded.34
Peak handgrip force.
Isometric peak handgrip force will be measured by handheld dynamometry (JAMAR hydraulic hand dynamometer) in a 90° elbow angle position. At least three attempts will be performed with the best value in kilogram and %pred.35 are recorded.
The 36-item Short Form Health Survey.
Generic health-related quality-of-life (HRQL) measure. The instrument is used widely to evaluate HRQL across various populations.36 There are two summary scales: an overall physical and a mental health component summary score.
COPD Assessment Test (CAT).
The CAT is a patient-completed questionnaire assessing the global impact of COPD on health status with scores <10 indicating low, 10–20 medium, 21–30 high and >30 very high influence on health status.37
COPD Angst Fragebogen (CAF).
The CAF questionnaire is a reliable and valid questionnaire to determine COPD-specific anxiety according to the following domains: social isolation, dyspnoea, physical activity, disease progression, partnership and long-term oxygen therapy.
Patient Health Questionnaire-9 (PHQ-9).
The PHQ-9 is a self-administered patient questionnaire that monitors the severity of depression and response to treatment (score: 0–27).
Modified Medical Research Council score (mMRC score).
The mMRC score is a simple grading system for patients with respiratory diseases, to assess degree of baseline functional disability due to dyspnoea.
Self-reported patient diary (EXAcerbations of Chronic pulmonary disease Tool-patient-reported outcome)
The EXAcerbations of Chronic pulmonary disease Tool is a 14-item patient-reported outcome daily diary used to quantify and measure exacerbations of COPD.1 It provides a simple, standardised approach for assessing the symptomatic manifestations of COPD exacerbations, with a development and validation history consistent with guidelines proposed by the Food and Drug Administration, and well-established measurement principles.
Physical activity monitoring
Physical activity will be measured using the GT3X+device from ActiGraph, a validated device in COPD.38 The device includes both a microelectromechanical system-based accelerometer and an ambient light sensor. Average steps per day as well as time spent in different physical activity levels during the day (low, moderate, vigorous) will be analysed.
Follow-up measures (at 6, 12, 24 months)
Following outcomes will be reassessed at the follow-up measures: number of hospitalisations, number of AECOPD, quality of life, amount of regular exercise training and physical activity monitoring (in a subgroup). Furthermore, if patients die during the follow-up period, date and cause of death will be recorded.
The clinic has an established protocol for managing patients if they develop an exacerbation during the programme. This protocol will be followed for the patients admitted to this study. In case of an AECOPD, patients are clinically diagnosed by a pulmonologist and treated according to international guidelines.3 In case of a life-threatening deterioration, patients are referred to an acute hospital. Otherwise, the AECOPD treatment is continued during the inpatient pulmonary rehabilitation (PR) programme or at an intermediate care room under close monitoring at the recruitment centre. Adverse events during the PR phase will be recorded in the electronic case report form (e-CRF).
Sample size estimation and recruitment target
In a previously presented analysis of pretransplant patients with COPD (n=401), 15% developed an AECOPD during the inpatient rehabilitation period.19 Therefore, we aim to include 355 patients with COPD in this study to end up with an adequate cohort of about 50 patients with AECOPD for further exploratory data analyses.
The recruiting reference centre (University of Marburg Teaching Hospital Schoen Klinik Berchtesgadener Land) represents a unique setting for this comprehensive observational study including diagnostic and scientific expertise. In 2018, a total of 300 patients with COPD have been referred to this centre. Due to staff and logistic reasons, only every second patient (according to the running patient ID) will be assessed for eligibility. It is very likely that the estimated sample size can be recruited within 36 months. A refusal rate of about 20% (95 out of 450 patients who will be assessed for eligibility) is in accordance to our own centre-based study experience with patients with COPD. Also, a dropout rate of about 20% must be expected (based on study centre experiences). Reasons for dropout will be recorded.
Patient and public involvement
Prior to the study, we have interviewed several patients with frequent AECOPD in our clinic asking for early signs of AECOPD. We could not elaborate individual predictors for AECOPD. Asking for the importance, patients generally described AECOPD as the most frightening event markedly influencing their quality of life.
The public was not involved in planning this study.
Data will be stored and managed in a password-secured e-CRF (MACRO database) managed by the Coordinating Centre for Clinical Trials of the Philipps University Marburg. Professional data management will also be provided by this institution. Data consistency will be checked and data will be screened for outliers, normality, gamma or lognormal distributions by using quantile plots. Continuous variables will be tested for the above-mentioned distributions by using Kolmogrov-Smirnov test. Cross-tabulation tables will be analysed using Fisher’s exact test or Pearson’s Χ2 test. Exploratory data analyses methods will be used for the primary research question (screening and identification of possible factors to predict an AECOPD). Univariate correlation (Pearson or Spearman) and regression analyses will be used to restrict the large number of possible predictors in the first step; and then in the second step, this restricted set will be offered to a forward variable selection algorithm to end up with an even smaller set. Finally, this smaller set will be analysed by a generalised linear model with a binomial outcome (AECOPD) which will test if predictors are significant. Secondary research questions will be analysed by using mixed models or generalised estimation equation models which offer modelling of normal, gamma or lognormal distributions. In case of deviations of these distributions, Friedman analysis of variance, Wilcoxon matched pairs test as non-parametric alternatives will be used. It will be clearly stated in the Discussion section of the final manuscript as a limitation of the study that the analysis is based on exploratory data analyses methods without a sample size or power computation. All reported tests will be done two-sided, and p values of <0.05 will be considered as statistically significant. All statistical analyses will be done by the use of NCSS (NCSS V.10, NCSS, Kaysville, Utah, USA), STATISTICA V.13 (Hill, T & Lewicki, P. Statistics: Methods and Applications. StatSoft, Tulsa, Oklahoma, USA).
Ethics and dissemination
This study has been approved by the Ethical Committee of the Philipps University Marburg, Germany (no. 61/19). There are no safety considerations.
The results of this study will be disseminated by different complimentary strategies:
Publication of study results in high-quality international peer-reviewed journals.
Presentation and discussion of study results during national and international conferences and congresses.
Sharing results with national and international clinical networks and medical societies.
Contributors KK, RG, TS, IJ, CFV, PWJ and ARK contributed to the conception and design of the study. WH developed the statistical analysis plan. DL, RG, TS, IJ, SW, MB and BS were planning clinical study measures and will be involved in collecting data and performing study measures. PA planned all cardiovascular aspects of this study. OH planned all assessments on collecting breath volatile organic compounds and will perform all analyses. CS-B contributed to the study logistic and the creation of the electronic case report form. CS designed all aspects concerning virus analyses. RG drafted the manuscript. All authors revised the content and approved the final manuscript before publication.
Funding This study will be partly funded by GlaxoSmithKline GmbH & Co (Munich, Germany). For CS: supported by the Universities Giessen and Marburg Lung Centre (UGMLC), the German Centre for Lung Research (DZL), University Hospital Giessen and Marburg (UKGM) research funding according to article 2, section 3 cooperation agreement, and the Deutsche Forschungsgemeinschaft (DFG)-funded SFB 1021 (C04), KFO 309 (P10), and SK 317/1-1 (project number 428518790) as well as by the Foundation for Pathobiochemistry and Molecular Diagnostics.
Disclaimer The funding body was not involved in developing the study design nor will it be involved in data collection, analyses/interpretation of data or writing the manuscript.
Competing interests For CS: consultancy and research funding, Hycor Biomedical, Bencard Allergie and Thermo Fisher Scientific; research funding, Mead Johnson Nutrition (MJN).
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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