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Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study.
Cornelissen, MEB, Bloemsma, LD, Vaes, AW, Baalbaki, N, Deng, Q, Beijers, RJHCG, Noij, LCE, Houweling, L, Bazdar, S, Spruit, MA, et al
Journal of translational medicine. 2024;(1):191
Abstract
BACKGROUND In the Netherlands, the prevalence of post COVID-19 condition is estimated at 12.7% at 90-150 days after SARS-CoV-2 infection. This study aimed to determine the occurrence of fatigue and other symptoms, to assess how many patients meet the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) criteria, to identify symptom-based clusters within the P4O2 COVID-19 cohort and to compare these clusters with clusters in a ME/CFS cohort. METHODS In this multicentre, prospective, observational cohort in the Netherlands, 95 post COVID-19 patients aged 40-65 years were included. Data collection at 3-6 months after infection included demographics, medical history, questionnaires, and a medical examination. Follow-up assessments occurred 9-12 months later, where the same data were collected. Fatigue was determined with the Fatigue Severity Scale (FSS), a score of ≥ 4 means moderate to high fatigue. The frequency and severity of other symptoms and the percentage of patients that meet the ME/CFS criteria were assessed using the DePaul Symptom Questionnaire-2 (DSQ-2). A self-organizing map was used to visualize the clustering of patients based on severity and frequency of 79 symptoms. In a previous study, 337 Dutch ME/CFS patients were clustered based on their symptom scores. The symptom scores of post COVID-19 patients were applied to these clusters to examine whether the same or different clusters were found. RESULTS According to the FSS, fatigue was reported by 75.9% of the patients at 3-6 months after infection and by 57.1% of the patients 9-12 months later. Post-exertional malaise, sleep disturbances, pain, and neurocognitive symptoms were also frequently reported, according to the DSQ-2. Over half of the patients (52.7%) met the Fukuda criteria for ME/CFS, while fewer patients met other ME/CFS definitions. Clustering revealed specific symptom patterns and showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort, where 2 clusters had > 10 patients. CONCLUSIONS This study shows persistent fatigue and diverse symptomatology in post COVID-19 patients, up to 12-18 months after SARS-CoV-2 infection. Clustering showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort.
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Treatable traits in advanced emphysema patients eligible for bronchoscopic lung volume reduction with endobronchial valves.
Posthuma, R, van der Molen, MC, Hartman, JE, Spruit, MA, Slebos, DJ, Vanfleteren, LEGW, Vaes, AW
Respiratory medicine. 2024;:107558
Abstract
INTRODUCTION Patients with advanced emphysema eligible for bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBV) are characterized by severe static lung hyperinflation, which can be considered a treatable trait. Other treatable traits (TTs), which are assumed to be present in this highly selected patient group, have not been studied in detail nor how they may affect health-related quality of life (HRQL). AIMS We aimed to evaluate a spectrum of TTs in COPD patients eligible for EBV treatment and their association with HRQL. METHODS The SoLVE study (NCT03474471) was a prospective multicenter randomized controlled trial to examine the impact of pulmonary rehabilitation in COPD patients receiving EBV. The presence/absence of 16 TTs was based on pre-defined thresholds. HRQL was assessed with the St. George's Respiratory Questionnaire (SGRQ). Subjects were stratified into two groups, using the median split method, into higher or lower SGRQ total score. Logistic regression assessed the odds ratio (OR) of having a higher SGRQ total score per TT. RESULTS Ninety-seven subjects were included, the mean number of TTs per patient was 8.1 ± 2.5. Low physical activity (95%), poor exercise capacity (94%) and severe fatigue (75%) were the most prevalent TTs. The sum of TTs present in a subject was associated with the SGRQ total score (r = 0.53; p < 0.001). Severe fatigue, depression, and anxiety were predictors of having a higher SGRQ total score. CONCLUSIONS A high prevalence and co-occurrence of multiple TTs were identified in emphysema patients eligible for EBV. Patients with a higher number of TTs were more likely to have worse HRQL.
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Vitamin D Status and Longitudinal Changes in Body Composition in Patients with Chronic Obstructive Pulmonary Disease - A Prospective Observational Study.
Minter, M, van Odijk, J, Augustin, H, Machado, FVC, Franssen, FME, Spruit, MA, Vanfleteren, LEGW
International journal of chronic obstructive pulmonary disease. 2024;:1291-1302
Abstract
BACKGROUND Alterations in body weight and composition are common in patients with chronic obstructive pulmonary disease (COPD) and are independent predictors for morbidity and mortality. Low vitamin D status is also more prevalent in patients with COPD compared to controls and has been related to lower lung function, muscle atrophy and impaired musculoskeletal function. This study aimed to evaluate the association between vitamin D levels and status with body composition (BC), as well as with its changes over time. PATIENTS AND METHODS Patients with COPD and controls without COPD, participating in the Individualized COPD Evaluation in relation to Ageing (ICE-Age) study, a prospective observational study, were included. Plasma 25-hydroxyvitamin D (25(OH)D) was measured at baseline and BC was measured by dual-energy X-ray absorptiometry scan, at baseline and after two years of follow-up. Multiple linear regression analyses were performed to assess the relationships between 25(OH)D (nmol/l) and longitudinal changes in BMI, fat-free mass index (FFMI), fat mas index (FMI) and bone mineral density (BMD). RESULTS A total of 192 patients with COPD (57% males, mean ± SD age, 62 ± 7, FEV1, 49 ± 16% predicted) and 199 controls (45% males, mean ± SD age 61 ± 7) were included in this study. Vitamin D levels were significantly lower in patients with COPD (64 ± 26 nmol/L, 95% CI 60-68 nmol/L versus 75 ± 25 nmol/L, 95% CI 72-79 nmol/L) compared to controls. Both patients and controls presented a significant decline in FFMI and T-score hip, but vitamin D level or status did not determine differences in BC or changes in BC over time in either COPD or controls. CONCLUSION Vitamin D status was not associated with BC or longitudinal changes in BC. However, vitamin D insufficiency and low BMD were more prevalent in patients with COPD compared to controls.
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Impact and timing of pulmonary rehabilitation in patients undergoing bronchoscopic lung volume reduction with endobronchial valves: A multicentre randomized controlled trial in patients with severe emphysema.
van der Molen, MC, Posthuma, R, Hartman, JE, van der Vaart, H, Bij de Vaate, E, Vaes, AW, van den Borst, B, van Ranst, D, Spruit, MA, Vanfleteren, LEGW, et al
Respirology (Carlton, Vic.). 2024;(8):694-703
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Abstract
BACKGROUND AND OBJECTIVE Both bronchoscopic lung volume reduction with endobronchial valves (BLVR-EBV) and pulmonary rehabilitation (PR) are effective treatments for improving exercise capacity and patient-reported outcomes in patients with severe Chronic Obstructive Pulmonary Disease (COPD). According to current recommendations, all BLVR-EBV patients should have undergone PR first. Our aim was to study the effects of PR both before and after BLVR-EBV compared to BLVR-EBV alone. METHODS We included patients with severe COPD who were eligible for BLVR-EBV and PR. Participants were randomized into three groups: PR before BLVR-EBV, PR after BLVR-EBV or BLVR-EBV without PR. The primary outcome was change in constant work rate cycle test (CWRT) endurance time at 6-month follow-up of the PR groups compared to BLVR-EBV alone. Secondary endpoints included changes in 6-minute walking test, daily step count, dyspnoea and health-related quality of life. RESULTS Ninety-seven participants were included. At 6-month follow-up, there was no difference in change in CWRT endurance time between the PR before BLVR-EBV and BLVR-EBV alone groups (median: 421 [IQR: 44; 1304] vs. 787 [123; 1024] seconds, p = 0.82) or in any of the secondary endpoints, but the PR after BLVR-EBV group exhibited a smaller improvement in CWRT endurance time (median: 107 [IQR: 2; 573], p = 0.04) and health-related quality of life compared to BLVR-EBV alone. CONCLUSION The addition of PR to BLVR-EBV did not result in increased exercise capacity, daily step count or improved patient-reported outcomes compared to BLVR-EBV alone, neither when PR was administered before BLVR-EBV nor when PR was administered after BLVR-EBV.
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Unravelling the complex interplay of factors behind exercise limitations and physical inactivity in COPD.
Tang, CY, Bernstein, B, Blackstock, F, Blondeel, A, Gershon, A, Gimeno-Santos, E, Gloeckl, R, Marques, A, Spruit, MA, Garvey, C, et al
Breathe (Sheffield, England). 2024;(2):230180
Abstract
Exercise limitation and physical inactivity are known treatable traits for people with COPD. Maximising exercise capacity and keeping people physically active improves health status and survival rates among people with COPD. However, managing these two treatable traits can be extremely challenging for clinicians due to the complex intersectionality of factors influencing an individual's capacity, opportunity and motivation to engage in physical activity. This review presents the complex factors influencing exercise capacity ("can do"), levels of physical activity ("do do") and sedentary behaviours amongst people with COPD and provides practical recommendations on how clinicians can address some of these factors in practice. Most importantly, it highlights the importance of referring to pulmonary rehabilitation as a way to improve exercise capacity among people with COPD.
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Early diagnostic BioMARKers in exacerbations of chronic obstructive pulmonary disease: protocol of the exploratory, prospective, longitudinal, single-centre, observational MARKED study.
Waeijen-Smit, K, DiGiandomenico, A, Bonnell, J, Ostridge, K, Gehrmann, U, Sellman, BR, Kenny, T, van Kuijk, S, Peerlings, D, Spruit, MA, et al
BMJ open. 2023;(3):e068787
Abstract
INTRODUCTION Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) play a pivotal role in the burden and progressive course of chronic obstructive pulmonary disease (COPD). As such, disease management is predominantly based on the prevention of these episodes of acute worsening of respiratory symptoms. However, to date, personalised prediction and early and accurate diagnosis of AECOPD remain unsuccessful. Therefore, the current study was designed to explore which frequently measured biomarkers can predict an AECOPD and/or respiratory infection in patients with COPD. Moreover, the study aims to increase our understanding of the heterogeneity of AECOPD as well as the role of microbial composition and hostmicrobiome interactions to elucidate new disease biology in COPD. METHODS AND ANALYSIS The 'Early diagnostic BioMARKers in Exacerbations of COPD' study is an exploratory, prospective, longitudinal, single-centre, observational study with 8-week follow-up enrolling up to 150 patients with COPD admitted to inpatient pulmonary rehabilitation at Ciro (Horn, the Netherlands). Respiratory symptoms, vitals, spirometry and nasopharyngeal, venous blood, spontaneous sputum and stool samples will be frequently collected for exploratory biomarker analysis, longitudinal characterisation of AECOPD (ie, clinical, functional and microbial) and to identify host-microbiome interactions. Genomic sequencing will be performed to identify mutations associated with increased risk of AECOPD and microbial infections. Predictors of time-to-first AECOPD will be modelled using Cox proportional hazards' regression. Multiomic analyses will provide a novel integration tool to generate predictive models and testable hypotheses about disease causation and predictors of disease progression. ETHICS AND DISSEMINATION This protocol was approved by the Medical Research Ethics Committees United (MEC-U), Nieuwegein, the Netherlands (NL71364.100.19). TRIAL REGISTRATION NUMBER NCT05315674.
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Differential Response to 12 Weeks of Once-Daily Tiotropium/Olodaterol Fixed Dose Combination in Patients with COPD: A Multidimensional Response Profiling in the TORRACTO Study.
Posthuma, R, Vanfleteren, LEGW, Gaffron, S, Vaes, AW, Franssen, FME, Spruit, MA
International journal of chronic obstructive pulmonary disease. 2023;:1091-1102
Abstract
PURPOSE Long-acting bronchodilators (LABD), in general, reduce respiratory symptoms, improve exercise endurance time and pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, there might be heterogeneity in improvement for several outcomes on an individual level. Therefore, we aimed to profile the multidimensional response in patients receiving tiotropium/olodaterol (T/O) using self-organizing maps (SOM). MATERIALS AND METHODS This is a secondary analysis of the TORRACTO study: a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effects of T/O (2.5/5 and 5/5 μg) compared with placebo after 6 and 12 weeks of treatment in patients with COPD. In the current study, we used endurance time, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), inspiratory capacity (IC) at rest and IC at isotime (ICiso) to identify clusters by means of SOM in patients treated with T/O. RESULTS Six clusters with distinct response profiles were generated at week 12 in COPD patients receiving T/O (n = 268). Patients in cluster 1 improved significantly on all outcomes, whilst cluster 5 showed strong improvement in endurance time (357s); contrarily, FEV1, FVC, ICrest and ICiso decreased when compared to baseline. CONCLUSION Individual responses on endurance time and pulmonary function after 12 weeks of T/O are heterogeneous. This study identified clusters in COPD patients with markedly different multidimensional response on LABD.
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Physical activity measurements in individuals with interstitial lung disease: a systematic review and meta-analysis.
Iwakura, M, Kawagoshi, A, Tamaki, A, Oki, Y, Oshima, Y, Spruit, MA
European respiratory review : an official journal of the European Respiratory Society. 2023;(169)
Abstract
BACKGROUND Physical activity (PA) measurements are becoming common in interstitial lung disease (ILD); however, standardisation has not been achieved. We aimed to systematically review PA measurement methods, present PA levels and provide practical recommendations on PA measurement in ILD. METHODS We searched four databases up to November 2022 for studies assessing PA in ILD. We collected information about the studies and participants, the methods used to measure PA, and the PA metrics. Studies were scored using 12 items regarding PA measurements to evaluate the reporting quality of activity monitor use. RESULTS In 40 of the included studies, PA was measured using various devices or questionnaires with numerous metrics. Of the 33 studies that utilised activity monitors, a median of five out of 12 items were not reported, with the definition of nonwear time being the most frequently omitted. The meta-analyses showed that the pooled means (95% CI) of steps, time spent in moderate to vigorous PA, total energy expenditure and sedentary time were 5215 (4640-5791) steps·day-1, 82 (58-106) min·day-1, 2130 (1847-2412) kcal·day-1 and 605 (323-887) min·day-1, respectively, with considerable heterogeneity. CONCLUSION The use of activity monitors and questionnaires in ILD lacks consistency. Improvement is required in the reporting quality of PA measurement methods using activity monitors.
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Post-Pulmonary Embolism Syndrome and Functional Outcomes after Acute Pulmonary Embolism.
Luijten, D, de Jong, CMM, Ninaber, MK, Spruit, MA, Huisman, MV, Klok, FA
Seminars in thrombosis and hemostasis. 2023;(8):848-860
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Abstract
Survivors of acute pulmonary embolism (PE) are at risk of developing persistent, sometimes disabling symptoms of dyspnea and/or functional limitations despite adequate anticoagulant treatment, fulfilling the criteria of the post-PE syndrome (PPES). PPES includes chronic thromboembolic pulmonary hypertension (CTEPH), chronic thromboembolic pulmonary disease, post-PE cardiac impairment (characterized as persistent right ventricle impairment after PE), and post-PE functional impairment. To improve the overall health outcomes of patients with acute PE, adequate measures to diagnose PPES and strategies to prevent and treat PPES are essential. Patient-reported outcome measures are very helpful to identify patients with persistent symptoms and functional impairment. The primary concern is to identify and adequately treat patients with CTEPH as early as possible. After CTEPH is ruled out, additional diagnostic tests including cardiopulmonary exercise tests, echocardiography, and imaging of the pulmonary vasculature may be helpful to rule out non-PE-related comorbidities and confirm the ultimate diagnosis. Most PPES patients will show signs of physical deconditioning as main explanation for their clinical presentation. Therefore, cardiopulmonary rehabilitation provides a good potential treatment option for this patient category, which warrants testing in adequately designed and executed randomized trials. In this review, we describe the definition and characteristics of PPES and its diagnosis and management.
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Endothelial function in patients with COPD: an updated systematic review of studies using flow-mediated dilatation.
Vaes, AW, De Boever, P, Franssen, FME, Uszko-Lencer, NHMK, Vanfleteren, LEGW, Spruit, MA
Expert review of respiratory medicine. 2023;(1):53-69
Abstract
INTRODUCTION Cardiovascular disease is a significant cause of morbidity and mortality in COPD. Endothelial dysfunction is suggested to be involved in cardiovascular disease pathogenesis, and multiple studies report endothelial dysfunction in COPD. This article summarized the current knowledge on endothelial function in COPD patients. AREAS COVERED Databases were screened until November 2022 for studies using ultrasound-based flow-mediated dilation in patients with stable COPD. Pooled effect sizes were calculated using random effects model. Meta-regression analyses assessed the effects of demographic and clinical variables. EXPERT OPINION 34 studies were identified (1365 COPD patients; 617 controls). Pooled analysis demonstrated an impaired endothelial-dependent (-2.33%; 95%CI -3.30/-1.35; p < 0.001) and endothelial-independent dilation (-3.11%; 95%CI -5.14/-1.08; p = 0.003) in COPD patients when compared to non-COPD controls. Meta-regression identified that higher age, worse severity of airflow obstruction, and current smoking were significantly associated with impaired endothelial function. Studies evaluating the effects of pharmacological and non-pharmacological interventions on endothelial function in COPD patients demonstrated conflicting results.
