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.

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.

Multimodal predictions of treatment outcome in major depression: A comparison of data-driven predictors with importance ratings by clinicians.

BACKGROUND: Reliable prediction models of treatment outcome in Major Depressive Disorder (MDD) are currently lacking in clinical practice. Data-driven outcome definitions, combining data from multiple modalities and incorporating clinician expertise might improve predictions. METHODS: We used unsupervised machine learning to identify treatment outcome classes in 1060 MDD inpatients. Subsequently, classification models were created on clinical and biological baseline information to predict treatment outcome classes and compared to the performance of two widely used classical outcome definitions. We also related the findings to results from an online survey that assessed which information clinicians use for outcome prognosis. RESULTS: Three and four outcome classes were identified by unsupervised learning. However, data-driven outcome classes did not result in more accurate prediction models. The best prediction model was targeting treatment response in its standard definition and reached accuracies of 63.9 % in the test sample, and 59.5 % and 56.9 % in the validation samples. Top predictors included sociodemographic and clinical characteristics, while biological parameters did not improve prediction accuracies. Treatment history, personality factors, prior course of the disorder, and patient attitude towards treatment were ranked as most important indicators by clinicians. LIMITATIONS: Missing data limited the power to identify biological predictors of treatment outcome from certain modalities. CONCLUSIONS: So far, the inclusion of available biological measures in addition to psychometric and clinical information did not improve predictive value of the models, which was overall low. Optimized biomarkers, stratified predictions and the inclusion of clinical expertise may improve future prediction models.

Biomarker-based clustering of patients with chronic obstructive pulmonary disease.

Rationale: COPD has been associated repeatedly with single biomarkers of systemic inflammation, ignoring the complexity of inflammatory pathways. This study aimed to cluster patients with COPD based on systemic markers of inflammatory processes and to evaluate differences in their clinical characterisation and examine how these differences may relate to altered biological pathways. Methods: 213 patients with moderate-to-severe COPD in a clinically stable state were recruited and clinically characterised, which included a venous blood sample for analysis of serum biomarkers. Patients were clustered based on the overall similarity in systemic levels of 57 different biomarkers. To determine interactions among the regulated biomarkers, protein networks and biological pathways were examined for each patient cluster. Results: Four clusters were identified: two clusters with lower biomarker levels (I and II) and two clusters with higher biomarker levels (III and IV), with only a small number of biomarkers with similar trends in expression. Pathway analysis indicated that three of the four clusters were enriched in Rage (receptor for advanced glycation end-products) and Oncostatin M pathway components. Although the degree of airflow limitation was similar, the clinical characterisation of clusters ranged from 1) better functional capacity and health status and fewer comorbidities; 2) more underweight, osteoporosis and static hyperinflation; 3) more metabolically deranged; and 4) older subjects with worse functional capacity and higher comorbidity load. Conclusions: These new insights may help to understand the functionally relevant inflammatory interactions in the pathophysiology of COPD as a heterogeneous disease.

Differential Outcomes Following 4 Weeks of Aclidinium/Formoterol in Patients with COPD: A Reanalysis of the ACTIVATE Study.

Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD. Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups. Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients. Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy. Clinical Trial Registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344.

Multidimensional outcome assessment of pulmonary rehabilitation in traits-based clusters of COPD patients.

BACKGROUND: Clusters of COPD patients have been reported in order to individualize the treatment program. Neither co-morbidity clusters, nor integrated respiratory physiomics clusters contributed to a better prediction of outcomes. Based on a thoroughly assessed set of pulmonary and extra-pulmonary traits at the start of a pulmonary rehabilitation (PR) program, we recently described seven clusters of COPD patients. The aims of this study are to confirm multidimensional differential response and to assess the potential of pulmonary and extra-pulmonary traits-based clusters to predict this multidimensional response to PR pulmonary in COPD patients. METHODS: Outcomes of a 40-session PR program for COPD patients, referred by a chest physician, were evaluated based on the minimal clinically important difference (MCID) for 6-minute walk distance (6MWD), cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression scores, MRC dyspnea grade and St George's Respiratory Questionnaire. The aforementioned response indicators were used to calculate the overall multidimensional response and patients were grouped in very good, good, moderate and poor responders. In the same way, responses to pulmonary rehabilitation were compared based on seven previously identified pulmonary and extra-pulmonary traits-based clusters. RESULTS: Of the whole sample, drop out was 19% and 419 patients (55.4% males, age: 64.3 ± 8.8, FEV1% of predicted: 48.9 ± 20) completed the pulmonary rehabilitation program. Very good responders had significantly worse baseline characteristics with a higher burden of disease, a higher proportion of rollator-users, higher body mass index (BMI), more limitations of activities in daily life, emotional dysfunction, higher symptoms of dyspnea and worse quality of life. Of the seven pre-identified clusters, 'the overall best functioning cluster' and 'the low disease burden cluster' both including the best 6MWD, the lowest dyspnea score and the overall best health status, demonstrated attenuated outcomes, while in 'the cluster of disabled patients', 76% of the patients improved health status with at least 2 times MCID. This 'cluster of disabled patients' as well as 'the multimorbid cluster', 'the emotionally dysfunctioning cluster', 'the overall worst-functioning cluster' and 'the physically dysfunctioning cluster' all demonstrated improvements in performance and satisfaction for occupational activities (more than 65% of patients improved with > 1MCID), emotional functioning (more than 50% of patients improved with > 1 MCID) and overall health status (more than 58%). CONCLUSION: The current study confirms the differential response to pulmonary rehabilitation based on multidimensional response profiling. Cluster analysis of baseline traits illustrates that non-linear, clinically important differences can be achieved in the most functionally and emotionally impaired clusters and that 'the overall best functional cluster' as well as 'the low disease burden cluster' had an attenuated outcome.

Clustering based on comorbidities in patients with chronic heart failure: an illustration of clinical diversity.

AIMS: It is increasingly recognized that the presence of comorbidities substantially contributes to the disease burden in patients with heart failure (HF). Several reports have suggested that clustering of comorbidities can lead to improved characterization of the disease phenotypes, which may influence management of the individual patient. Therefore, we aimed to cluster patients with HF based on medical comorbidities and their treatment and, subsequently, compare the clinical characteristics between these clusters. METHODS AND RESULTS: A total of 603 patients with HF entering an outpatient HF rehabilitation programme were included [median age 65 years (interquartile range 56-71), 57% ischaemic origin of cardiomyopathy, and left ventricular ejection fraction 35% (26-45)]. Exercise performance, daily life activities, disease-specific health status, coping styles, and personality traits were assessed. In addition, the presence of 12 clinically relevant comorbidities was recorded, based on targeted diagnostics combined with applicable pharmacotherapies. Self-organizing maps (SOMs; www.viscovery.net) were used to visualize clusters, generated by using a hybrid algorithm that applies the classical hierarchical cluster method of Ward on top of the SOM topology. Five clusters were identified: (1) a least comorbidities cluster; (2) a cachectic/implosive cluster; (3) a metabolic diabetes cluster; (4) a metabolic renal cluster; and (5) a psychologic cluster. Exercise performance, daily life activities, disease-specific health status, coping styles, personality traits, and number of comorbidities were significantly different between these clusters. CONCLUSIONS: Distinct combinations of comorbidities could be identified in patients with HF. Therapy may be tailored based on these clusters as next step towards precision medicine. The effect of such an approach needs to be prospectively tested.

Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members.

BACKGROUND: It remains unknown whether and to what extent members of online "long COVID" peer support groups remain symptomatic and limited over time. Therefore, we aimed to evaluate symptoms in members of online long COVID peer support groups up to 6 months after the onset of coronavirus disease 2019 (COVID-19)-related symptoms. METHODS: Demographics, symptoms, health status, work productivity, functional status and health-related quality of life were assessed about 3 and 6 months after the onset of COVID-19-related symptoms in members of online long COVID peer support groups. RESULTS: Data from 239 patients with a confirmed COVID-19 diagnosis (83% women; median (interquartile range) age 50 (39-56) years) were analysed. During the infection, a median (interquartile range) of 15 (11-18) symptoms was reported, which was significantly lower 3 and 6 months later: 6 (4-9) and 6 (3-8), respectively (p<0.05). From 3 to 6 months follow-up, the proportion of patients without symptoms increased from 1.3% to only 5.4% (p<0.001). Patients also reported a significantly improved work productivity (work absenteeism and presenteeism: 73% versus 52% and 66% versus 60%, respectively), self-reported good health (9.2% versus 16.7%), functional status (mean±sd Post-COVID-19 Functional Status scale: 2.4±0.9 versus 2.2±1.0) and health-related quality of life (all p<0.05). CONCLUSION: Although patients with confirmed COVID-19, who were all members of online long COVID peer support groups, reported significant improvements in work productivity, functional status and quality of life between 3 and 6 months follow-up, these data clearly highlight the long-term impact of COVID-19, as approximately 6 months after the onset of COVID-19-related symptoms a large proportion still experienced persistent symptoms, a moderate-to-poor health, moderate-to-severe functional limitations, considerable loss in work productivity, and/or an impaired quality of life. Action is needed to improve the management and healthcare of these patients.

Incorporating Comprehensive Assessment Parameters to Better Characterize and Plan Rehabilitation for Persons with Chronic Obstructive Pulmonary Disease.

OBJECTIVES: The current management of chronic obstructive pulmonary disease (COPD) largely ignores its heterogeneous pulmonary and extrapulmonary manifestations in the individual patient. This study aimed to identify clusters of patients with COPD based on a thorough traits assessment. DESIGN: An observational, prospective, single-center study. SETTING AND PARTICIPANTS: Patients with COPD referred by chest physicians for a comprehensive pulmonary rehabilitation program to CIRO (Horn, the Netherlands) were eligible to participate. CIRO is a specialized pulmonary rehabilitation center in the southern part of the Netherlands for patients with complex underlying respiratory diseases. METHODS: Clinically stable patients with COPD underwent a comprehensive assessment, including pulmonary traits (airflow limitation, static hyperinflation, gas transfer, respiratory pressures, and arterial blood gases), extrapulmonary functional traits, and health status (quadriceps muscle strength, physical functioning, body composition, comorbidities, symptoms perception, and social and emotional functioning). Clusters were generated using the SOM-Ward Cluster algorithm, a hybrid algorithm that applies the classical hierarchical method of Ward on top of the self-organizing map topology. RESULTS: Based on the abovementioned attributes of 518 patients with mild to very severe COPD (44% women, age 64.1 ± 9.1 years, forced expiratory volume in the first second 48.6% ± 20.0% of predicted), 7 clusters were identified. Clusters had unique patterns differing in demographics, pulmonary, extrapulmonary functional, and behavioral traits and/or health status. CONCLUSION AND IMPLICATIONS: The tremendous heterogeneity in pulmonary, extrapulmonary functional and behavioral traits, and health status in patients with COPD supports the need for an individual comprehensive assessment and a goal-directed personalized management strategy.

Disease-Specific Comorbidity Clusters in COPD and Accelerated Aging.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often suffer from multiple morbidities, which occur in clusters and are sometimes related to accelerated aging. This study aimed to assess the disease specificity of comorbidity clusters in COPD and their association with a biomarker of accelerated aging as a potential mechanistic factor. METHODS: Body composition, metabolic, cardiovascular, musculoskeletal, and psychological morbidities were objectively evaluated in 208 COPD patients (age 62 ± 7 years, 58% males, FEV1 50 ± 16% predicted) and 200 non-COPD controls (age 61 ± 7 years, 45% males). Based on their presence and severity, the morbidities were clustered to generate distinct clusters in COPD and controls. Telomere length in circulating leukocytes was compared across the clusters. RESULTS: (co)morbidities were more prevalent in COPD patients compared to controls (3.9 ± 1.7 vs. 2.4 ± 1.5, p < 0.05). A "Psychologic" and "Cachectic" cluster were only present in the COPD population. "Less (co)morbidity", "Cardiovascular", and "Metabolic" clusters were also observed in controls, although with less complexity. Telomere length was reduced in COPD patients, but did not differ between the (co)morbidity clusters in both populations. CONCLUSIONS: Two COPD-specific comorbidity clusters, a "Cachectic" and "Psychologic" cluster, were identified and warrant further studies regarding their development. Accelerated aging was present across various multimorbidity clusters in COPD.

Comprehensive Lung Function Assessment Does not Allow to Infer Response to Pulmonary Rehabilitation in Patients with COPD.

The degree of lung function is frequently used as referral criterion for pulmonary rehabilitation. The efficacy of pulmonary rehabilitation was assessed in 518 chronic obstructive pulmonary disease (COPD) patients, after clustering based on a comprehensive pre-rehabilitation lung function assessment. Mean improvements in dyspnea, exercise performance, health status, mood status and problematic activities of daily life after pulmonary rehabilitation were mostly comparable between the seven clusters, despite significant differences in the degree of lung function. The current study demonstrates no significant relationship between the seven lung-function-based clusters and response to pulmonary rehabilitation. Therefore, baseline lung function cannot be used to identify those who will respond well to pulmonary rehabilitation, and moreover, cannot be used as a criterion for referral to pulmonary rehabilitation in patients with COPD.

The respiratory physiome: Clustering based on a comprehensive lung function assessment in patients with COPD.

BACKGROUND: While spirometry and particularly airflow limitation is still considered as an important tool in therapeutic decision making, it poorly reflects the heterogeneity of respiratory impairment in chronic obstructive pulmonary disease (COPD). The aims of this study were to identify pathophysiological clusters in COPD based on an integrated set of standard lung function attributes and to investigate whether these clusters can predict patient-related outcomes and differ in clinical characteristics. METHODS: Clinically stable COPD patients referred for pulmonary rehabilitation underwent an integrated assessment including clinical characteristics, dyspnea score, exercise performance, mood and health status, and lung function measurements (post-bronchodilator spirometry, body plethysmography, diffusing capacity, mouth pressures and arterial blood gases). Self-organizing maps were used to generate lung function based clusters. RESULTS: Clustering of lung function attributes of 518 patients with mild to very severe COPD identified seven different lung function clusters. Cluster 1 includes patients with better lung function attributes compared to the other clusters. Airflow limitation is attenuated in clusters 1 to 4 but more pronounced in clusters 5 to 7. Static hyperinflation is more dominant in clusters 5 to 7. A different pattern occurs for carbon monoxide diffusing capacity, mouth pressures and for arterial blood gases. Related to the different lung function profiles, clusters 1 and 4 demonstrate the best functional performance and health status while this is worst for clusters 6 and 7. All clusters show differences in dyspnea score, proportion of men/women, age, number of exacerbations and hospitalizations, proportion of patients using long-term oxygen and number of comorbidities. CONCLUSION: Based on an integrated assessment of lung function variables, seven pathophysiological clusters can be identified in COPD patients. These clusters poorly predict functional performance and health status.

Differential response to pulmonary rehabilitation in COPD: multidimensional profiling.

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; "very good responder"), n=742 (35.9%; "good responder"), n=731 (35.4%; "moderate responder"), and n=217 (10.5%; "poor responder"). Patients in the "very good responder" cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters.A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD.

Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease.

RATIONALE: Comorbidities contribute to disease severity and mortality in patients with chronic obstructive pulmonary disease (COPD). Comorbidities have been studied individually and were mostly based on self-reports. The coexistence of objectively identified comorbidities and the role of low-grade systemic inflammation in the pathophysiology of COPD remain to be elucidated. OBJECTIVES: To cluster 13 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical outcomes and systemic inflammation. METHODS: A total of 213 patients with COPD (FEV1, 51 ± 17% predicted; men, 59%; age, 64 ± 7 yr) were included prospectively. Comorbidities were based on well-known cut-offs identified in the peer-reviewed English literature. Systemic inflammatory biomarkers were determined in all patients. Self-organizing maps were used to generate comorbidity clusters. MEASUREMENTS AND MAIN RESULTS: A total of 97.7% of all patients had one or more comorbidities and 53.5% had four or more comorbidities. Five comorbidity clusters were identified: (1) less comorbidity, (2) cardiovascular, (3) cachectic, (4) metabolic, and (5) psychological. Comorbidity clusters differed in health status but were comparable with respect to disease severity. An increased inflammatory state was observed only for tumor necrosis factor (TNF) receptors in the metabolic cluster (geometric mean [lower and upper limit]; TNF-R1, 2,377 [1,850, 3,055] pg/ml, confidence, 98.5%; TNF-R2, 4,080 [3,115, 5,344] pg/ml, confidence, 98.8%) and only for IL-6 in the cardiovascular cluster (IL-6, 3.4 [1.8, 6.6] pg/ml; confidence, 99.8%). CONCLUSIONS: Multimorbidity is common in patients with COPD, and different comorbidity clusters can be identified. Low-grade systemic inflammation is mostly comparable among comorbidity clusters. Increasing knowledge on the interactions between comorbidities increases the understanding of their development and contributes to strategies for prevention or improved treatment.