A Prospective Study on Neural Biomarkers in Patients with Long-COVID Symptoms.

BACKGROUND: this prospective observational study aims to assess serum levels of glial fibrillary acidic protein (GFAP), s100b, and total Tau in long-COVID patients, exploring correlations with symptoms, cognitive decline, mental health, and quality of life. METHODS: Long-COVID patients visiting our outpatient clinic (February 2021-December 2022) were screened alongside age- and sex-matched controls. GFAP, s100b, and total Tau in serum were measured with ELISA. Cognitive function, depression, anxiety, post-traumatic stress disorder, and quality of life were evaluated using MoCA, HADS (depression and anxiety), IES-R, and SF-36, respectively. RESULTS: Sixty-five long-COVID patients and 20 controls were included. GFAP levels were significantly higher in long-COVID patients (p = 0.031), though not correlating with the presence of long-COVID symptoms. S100b and total Tau showed no significant differences between patients and controls. Nervous system-related symptoms were reported in 47% of patients. High rates of cognitive decline (65.9%), depression (32.2%), anxiety (47.5%), and post-traumatic stress disorder (44.1%) were observed. Over 80% of the study population scored below normative cutoffs for SF-36, indicating a significant impact on quality of life. CONCLUSIONS: in this long-COVID cohort with substantial psychological and cognitive symptoms, GFAP levels were elevated compared to controls, though not correlating with the presence of long-COVID symptoms.

Persistent Endothelial Lung Damage and Impaired Diffusion Capacity in Long COVID.

Since the beginning of the pandemic, both COVID-19-associated coagulopathy biomarkers and a plethora of endothelial biomarkers have been proposed and tested as prognostic tools of severity and mortality prediction. As the pandemic is gradually being controlled, attention is now focusing on the long-term sequelae of COVID-19. In the present study, we investigated the role of endothelial activation/dysfunction in long COVID syndrome. This observational study included 68 consecutive long COVID patients and a healthy age and sex-matched control group. In both groups, we measured 13 endothelial biomarkers. Moreover, in the long COVID patients, we evaluated fatigue and dyspnea severity, lung diffusion capacity (DLCO), and the 6-min walk (6MWT) test as measures of functional capacity. Our results showed that markers of endothelial activation/dysfunction were higher in long COVID patients, and that soluble intracellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1) negatively correlated with lung diffusion and functional capacity (sICAM-1 vs. DLCO, r = -0.306, p = 0.018; vs. 6MWT, r = -0.263, p = 0.044; and sVCAM-1 vs. DLCO, r= -0.346, p = 0.008; vs. 6MWT, r = -0.504, p < 0.0001). In conclusion, evaluating endothelial biomarkers alongside clinical tests might yield more specific insights into the pathophysiological mechanisms of long COVID manifestations.

Additive benefit of rehabilitation on physical status, symptoms and mental health after hospitalisation for severe COVID-19 pneumonia.

INTRODUCTION: The potential additive benefits of rehabilitation beyond spontaneous recovery post-COVID-19 currently remain unknown. METHODS: In this prospective, interventional, non-randomised parallel assignment two-arm study, we investigated the effects of an 8-week rehabilitation programme (Rehab, n=25) added to usual care (UC) versus UC (n=27) on respiratory symptoms, fatigue, functional capacity, mental health and health-related quality of life in patients with COVID-19 pneumonia, 6-8 weeks post-hospital discharge. The rehabilitation programme included exercise, education, dietary and psychological support. Patients with chronic obstructive pulmonary disease, respiratory and heart failure were excluded from the study. RESULTS: At baseline, groups were not different in mean age (56 years), gender (53% female), intensive care unit admission (61%), intubation (39%), days of hospitalisation (25), number of symptoms (9) and number of comorbidities (1.4). Baseline evaluation was conducted at median (IQR) 76 (27) days after symptoms onset. Groups were not different regarding baseline evaluation outcomes. At 8 weeks, Rehab showed significantly greater improvement in COPD Assessment Test by a mean±SEM (95% CI) 7.07±1.36 (4.29-9.84), p <0.001 and all three fatigue questionnaires: Chalder-Likert: 5.65±1.27 (3.04-8.25), p <0.001; bimodal: 3.04±0.86 (1.28-4.79), p=0.001; Functional Assessment of Chronic Illness Therapy: 6.37±2.09 (2.08-10.65), p=0.005 and Fatigue Severity Scale: 1.36±0.433 (0.47-2.25), p=0.004. At 8 weeks rehab also showed significantly greater improvment in Short Physical Performance Battery: 1.13±0.33 (0.46-1.79), p=0.002; Hospital Anxiety and Depression Scale (HADS) Anxiety: 2.93±1.01 (0.67-5.18), p=0.013; Beck Depression Inventory: 7.81±3.07 (1.52-14.09), p=0.017; Montreal Cognitive Assessment: 2.83±0.63 (1.5-4.14), p <0.001; EuroQol (EQ-5D-5L) Utility Index: 0.21±0.05 (0.1-0.32), p=0.001 and Visual Analogue Scale: 6.57±3.21 (0.2-13.16), p=0.043. Both groups significantly improved 6-min walking distance by approximately 60 m and pulmonary function measures, whereas post-traumatic stress disorder measurement IES-R (Impact of Event Scale, Revised) and HADS-Depression score were not different between groups at 8 weeks. A 16% attrition rate was observed in the rehabilitation group exhibiting a threefold increase in training workload. There were no adverse effects reported during exercise training. DISCUSSION: These findings highlight the added value of rehabilitation post-COVID-19 to amplify the natural course of physical and mental recovery that otherwise would remain incomplete with UC.

The Greek Collaborative Long COVID Study: Non-Hospitalized and Hospitalized Patients Share Similar Symptom Patterns.

Long COVID-19 syndrome refers to persisting symptoms (>12 weeks) after the initial coronavirus infection and is estimated to affect 3% to 12% of people diagnosed with the disease globally. Aim: We conducted a collaborative study with the Long COVID patient organization in Greece, in order to estimate the characteristics, symptoms, and challenges these patients confront. Methods: Data were collected from 208 patients using unstructured qualitative free-text entries in an anonymized online questionnaire. Results: The majority of respondents (68.8%) were not hospitalized and reported lingering symptoms (66.8%) for more than six months. Eighteen different symptoms (fatigue, palpitations, shortness of breath, parosmia, etc.) were mentioned in both hospitalized and community patients. Awareness of Long COVID sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still not included inthe management plan of Long COVID patients. Conclusions: Patients infected with coronavirus with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Long COVID syndrome appears to be a multi-systemic entity and a multidisciplinary medical approach should be adopted in order to correctly diagnose and successfully manage these patients.

Greater exercise tolerance in COPD during acute interval, compared to equivalent constant-load, cycle exercise: physiological mechanisms.

KEY POINTS: Exercise intolerance is common in chronic obstructive pulmonary disease (COPD) patients. In patients with COPD, we compared an interval exercise (IE) protocol (alternating 30 s at 100% peak work rate (WRpeak ) with 30 s at 50% WRpeak ) with moderate-intensity constant-load exercise (CLE) at 75% WRpeak , which yielded the same work rate. Exercise endurance time and total work output were almost twice as high for IE than CLE. At exercise isotime (when work completed was the same between IE and CLE), IE was associated with less dynamic hyperinflation, lower blood lactate concentration, and greater respiratory and locomotor muscle oxygenation, but there were no differences in ventilation or cardiac output. However, at the limit of tolerance for each modality, dynamic hyperinflation was not different between IE and CLE, while blood lactate remained lower and muscle oxygenation higher with IE. Taken together, these findings suggest that dynamic hyperinflation and not muscle-based factors dictate the limits of tolerance in these COPD patients. ABSTRACT: The relative importance of ventilatory, circulatory and peripheral muscle factors in determining tolerance to exercise in patients with chronic obstructive pulmonary disease (COPD) is not known. In 12 COPD patients (forced expiratory volume in one second: 58 ± 17%pred.) we measured ventilation, cardiac output, dynamic hyperinflation, local muscle oxygenation, blood lactate and time to exhaustion during (a) interval exercise (IE) consisting of 30 s at 100% peak work rate alternating with 30 s at 50%, and (b) constant-load exercise (CLE) at 75% peak work rate, designed to produce the same average work rate. Exercise time was substantially longer during IE than CLE (19.5 ± 4.8 versus 11.4 ± 2.1 min, p = 0.0001). Total work output was therefore greater during IE than CLE (81.3 ± 27.7 versus 48.9 ± 23.8 kJ, p = 0.0001). Dynamic hyperinflation (assessed by changes from baseline in inspiratory capacity, ΔIC) was less during IE than CLE at CLE exhaustion time (isotime, p = 0.009), but was similar at exhaustion (ΔICCLE : -0.38 ± 0.10 versus ΔICIE : -0.33 ± 0.12 l, p = 0.102). In contrast, at isotime, minute ventilation, cardiac output and systemic oxygen delivery did not differ between protocols (P > 0.05). At exhaustion in both protocols, the vastus lateralis and intercostal muscle oxygen saturation were higher in IE than CLE (p = 0.014 and p = 0.0002, respectively) and blood lactate concentrations were lower (4.9 ± 2.4 mmol l-1 versus 6.4 ± 2.2 mmol l-1 , p = 0.039). These results suggest that (1) exercise tolerance with COPD is limited by dynamic hyperinflation; and (2) cyclically lower (50%) effort intervals in IE help to preserve muscle oxygenation and reduce metabolic acidosis compared with CLE at the same average work rate; but these factors do not appear to determine time to exhaustion.

Cardiac output measurement during exercise in COPD: A comparison of dye dilution and impedance cardiography.

INTRODUCTION: Impedance cardiography (IC) derived from morphological analysis of the thoracic impedance signal is now commonly used for noninvasive assessment of cardiac output (CO) at rest and during exercise. However, in Chronic Obstructive Pulmonary Disease (COPD), conflicting findings put its accuracy into question. OBJECTIVES: We therefore compared concurrent CO measurements captured by IC (PhysioFlow: COIC ) and by the indocyanine green dye dilution method (CODD ) in patients with COPD. METHODS: Fifty paired CO measurements were concurrently obtained using the two methods from 10 patients (FEV1 : 50.5 ± 17.5% predicted) at rest and during cycling at 25%, 50%, 75% and 100% peak work rate. RESULTS: From rest to peak exercise COIC and CODD were strongly correlated (r = 0.986, P < 0.001). The mean absolute and percentage differences between COIC and CODD were 1.08 L/min (limits of agreement (LoA): 0.05-2.11 L/min) and 18 ± 2%, respectively, with IC yielding systematically higher values. Bland-Altman analysis indicated that during exercise only 7 of the 50 paired measurements differed by more than 20%. When data were expressed as changes from rest, correlations and agreement between the two methods remained strong over the entire exercise range (r = 0.974, P < 0.001, with no significant difference: 0.19 L/min; LoA: -0.76 to 1.15 L/min). Oxygen uptake (VO2 ) and CODD were linearly related: r = 0.893 (P < 0.001), CODD = 5.94 × VO2 + 2.27 L/min. Similar results were obtained for VO2 and COIC (r = 0.885, P < 0.001, COIC = 6.00 × VO2 + 3.30 L/min). CONCLUSIONS: These findings suggest that IC provides an acceptable CO measurement from rest to peak cycling exercise in patients with COPD.

Home-based maintenance tele-rehabilitation reduces the risk for acute exacerbations of COPD, hospitalisations and emergency department visits.

Pulmonary rehabilitation (PR) remains grossly underutilised by suitable patients worldwide. We investigated whether home-based maintenance tele-rehabilitation will be as effective as hospital-based maintenance rehabilitation and superior to usual care in reducing the risk for acute chronic obstructive pulmonary disease (COPD) exacerbations, hospitalisations and emergency department (ED) visits.Following completion of an initial 2-month PR programme this prospective, randomised controlled trial (between December 2013 and July 2015) compared 12 months of home-based maintenance tele-rehabilitation (n=47) with 12 months of hospital-based, outpatient, maintenance rehabilitation (n=50) and also to 12 months of usual care treatment (n=50) without initial PR.In a multivariate analysis during the 12-month follow-up, both home-based tele-rehabilitation and hospital-based PR remained independent predictors of a lower risk for 1) acute COPD exacerbation (incidence rate ratio (IRR) 0.517, 95% CI 0.389-0.687, and IRR 0.635, 95% CI 0.473-0.853), respectively, and 2) hospitalisations for acute COPD exacerbation (IRR 0.189, 95% CI 0.100-0.358, and IRR 0.375, 95% CI 0.207-0.681), respectively. However, only home-based maintenance tele-rehabilitation and not hospital-based, outpatient, maintenance PR was an independent predictor of ED visits (IRR 0.116, 95% CI 0.072-0.185).Home-based maintenance tele-rehabilitation is equally effective as hospital-based, outpatient, maintenance PR in reducing the risk for acute COPD exacerbation and hospitalisations. In addition, it encounters a lower risk for ED visits, thereby constituting a potentially effective alternative strategy to hospital-based, outpatient, maintenance PR.

Cardiovascular effects of high-intensity interval aerobic training combined with strength exercise in patients with chronic heart failure. A randomized phase III clinical trial.

BACKGROUND: The aim of this work was to evaluate the effect of high-intensity interval exercise (i.e., 30s at 100% of max workload, followed by 30s at rest, 45 min 3 days/week working-out schedule for 12 weeks) on left ventricular function and aortic elastic properties among chronic heart failure (CHF) patients. METHODS: This study is a phase III clinical trial. Of the 100 consecutive CHF patients (NYHA classes II-IV, ejection fraction<50%) that were randomly allocated, 72 completed the study (exercise training group, n=33, 63 ± 9 years, 88% men, and control group, n=39, 56 ± 11 years, 82% men). All patients underwent cardiopulmonary stress test, non-invasive high-fidelity tonometry of the radial artery, pulse wave velocity measurement using a SphygmoCor device and echocardiography before and after the completion of the training program. RESULTS: Both groups reported similar medical characteristics and physical activity status. General mixed effects models revealed that the intervention group reduced pulse wave velocity by 9% (p=0.05); Emv/Vp by 14% (p=0.06); E to A ratio by 24% (p=0.004), E to Emv ratio by 8% (p=0.05), MLHFQ score by 66% (p=0.003) and the depression score by 19% (p=0.5); increased augmentation index by 29%; VTI by 4% (p=0.05), 6-minute-walk distance up to 13% (p=0.05), peak oxygen uptake by 28% (p=0.001) and peak power by 25% (p=0.005). There were no significant changes in the control group. CONCLUSION: Interval high-intensity aerobic training, combined with strength exercise, seems to benefit aortic dilatation capacity and augmented systolic pressure in parallel with improvement in left ventricular diastolic function and quality of life.

Intensity of daily physical activity is associated with central hemodynamic and leg muscle oxygen availability in COPD.

In chronic obstructive pulmonary disease (COPD), daily physical activity is reported to be adversely associated with the magnitude of exercise-induced dynamic hyperinflation and peripheral muscle weakness. There is limited evidence whether central hemodynamic, oxygen transport, and peripheral muscle oxygenation capacities also contribute to reduced daily physical activity. Nineteen patients with COPD (FEV1, 48 ± 14% predicted) underwent a treadmill walking test at a speed corresponding to the individual patient's mean walking intensity, captured by a triaxial accelerometer during a preceding 7-day period. During the indoor treadmill test, the individual patient mean walking intensity (range, 1.5 to 2.3 m/s2) was significantly correlated with changes from baseline in cardiac output recorded by impedance cardiography (range, 1.2 to 4.2 L/min; r = 0.73), systemic vascular conductance (range, 7.9 to 33.7 ml·min(-1)·mmHg(-1); r = 0.77), systemic oxygen delivery estimated from cardiac output and arterial pulse-oxymetry saturation (range, 0.15 to 0.99 L/min; r = 0.70), arterio-venous oxygen content difference calculated from oxygen uptake and cardiac output (range, 3.7 to 11.8 mlO2/100 ml; r = -0.73), and quadriceps muscle fractional oxygen saturation assessed by near-infrared spectrometry (range, -6 to 23%; r = 0.77). In addition, mean walking intensity significantly correlated with the quadriceps muscle force adjusted for body weight (range, 0.28 to 0.60; r = 0.74) and the ratio of minute ventilation over maximal voluntary ventilation (range, 38 to 89%, r = -0.58). In COPD, in addition to ventilatory limitations and peripheral muscle weakness, intensity of daily physical activity is associated with both central hemodynamic and peripheral muscle oxygenation capacities regulating the adequacy of matching peripheral muscle oxygen availability by systemic oxygen transport.

Quadriceps muscle blood flow and oxygen availability during repetitive bouts of isometric exercise in simulated sailing.

In this study, we wished to determine whether the observed reduction in quadriceps muscle oxygen availability, reported during repetitive bouts of isometric exercise in simulated sailing efforts (i.e. hiking), is because of restricted muscle blood flow. Six national-squad Laser sailors initially performed three successive 3-min hiking bouts followed by three successive 3-min cycling tests sustained at constant intensities reproducing the cardiac output recorded during each of the three hiking bouts. The blood flow index (BFI) was determined from assessment of the vastus lateralis using near-infrared spectroscopy in association with the light-absorbing tracer indocyanine green dye, while cardiac output was determined from impedance cardiography. At equivalent cardiac outputs (ranging from 10.3±0.5 to 14.8±0.86 L · min(-1)), the increase from baseline in vastus lateralis BFI across the three hiking bouts (from 1.1±0.2 to 3.1±0.6 nM · s(-1)) was lower (P = 0.036) than that seen during the three cycling bouts (from 1.1±0.2 to 7.2±1.4 nM · s(-1)) (Cohen's d: 3.80 nM · s(-1)), whereas the increase from baseline in deoxygenated haemoglobin (by ∼17.0±2.9 µM) (an index of tissue oxygen extraction) was greater (P = 0.006) during hiking than cycling (by ∼5.3±2.7 µM) (Cohen's d: 4.17 µM). The results suggest that reduced vastus lateralis muscle oxygen availability during hiking arises from restricted muscle blood flow in the isometrically acting quadriceps muscles.

Effectiveness of Interval Exercise Training in Patients with COPD.

Physical training is beneficial and should be included in the comprehensive management of all patients with COPD independently of disease severity. Different rehabilitative strategies and training modalities have been proposed to optimize exercise tolerance. Interval exercise training has been used as an effective alternative modality to continuous exercise in patients with moderate and severe COPD.Although in healthy elderly individuals and patients with chronic heart failure there is evidence that this training modality is superior to continuous exercise in terms of physiological training effects, in patients with COPD, there is not such evidence. Nevertheless, in patients with COPD application of interval training has been shown to be equally effective to continuous exercise as it induces equivalent physiological training effects but with less symptoms of dyspnea and leg discomfort during training.The main purpose of this review is to summarize previous studies of the effectiveness of interval training in COPD and also to provide arguments in support of the application of interval training to overcome the respiratory and peripheral muscle limiting factors of exercise capacity. To this end we make recommendations on how best to implement interval training in the COPD population in the rehabilitation setting so as to maximize training effects.

Effects of interval-load versus constant-load training on the BODE index in COPD patients.

The BODE index is frequently used to assess functional capacity in patients with COPD. The aim of this study was to investigate the effectiveness of interval-load training (ILT) to improve the BODE index in comparison to the commonly implemented constant-load training (CLT). Forty-two patients with COPD [FEV(1): (mean+/-SEM) 42+/-3% predicted] were randomly allocated to either ILT (n=21) or CLT (n=21). The training program consisted of cycling exercise 3 days/week for 10 weeks. Patients assigned to ILT exercised at a mean intensity of 126+/-4% of baseline peak work rate (Wpeak) with 30-s work periods alternated with 30-s rest periods for 45 min per day, whereas patients allocated to CLT exercised at a mean intensity of 76+/-5% of baseline Wpeak for 30 min per day. The BODE index and its components: body mass index, FEV(1), MMRC dyspnea score and the 6-min walk test (6-MWT) as well as cycling Wpeak were assessed before and after both exercise training regimes. Both ILT and CLT significantly (p<0.001) decreased the BODE index (from 4.8+/-0.5 to 4.0+/-0.5 units and from 4.4+/-0.5 to 3.8+/-0.5 units, respectively). In addition, both ILT and CLT significantly decreased the MMRC dyspnea score by 0.4+/-0.1 units and increased the 6-MWT (by 52+/-16 and 44+/-12 m, respectively) as well as cycling Wpeak (by 14+/-2 and 10+/-2W, respectively). The magnitude of these changes was not significantly different between ILT and CLT. Consequently, ILT is equally effective to CLT in terms of improving the BODE index in patients with COPD and as such it may constitute an alternative rehabilitative modality in COPD.