Assessment and interpretation of aerobic exercise (dys)function in paediatric patients with cystic fibrosis

The purpose of this thesis was to extend our understanding of the assessment and interpretation of aerobic exercise function of paediatric patients with cystic fibrosis (CF). The first investigation sought to establish (1) the validity of traditional criteria to verify maximal oxygen (V ̇O2max) during a maximal cardiopulmonary exercise test (CPET); and (2) the utility of supramaximal verification (Smax) to confirm V ̇O2max. Traditional criteria significantly underreported V ̇O2max, whilst Smax was shown to provide a valid measurement in this patient group. The reproducibility of this CPET protocol, over the short- (48 h) and medium- (4-6 weeks) term, was then established in study two. V ̇O2max was repeatedly determined with no learning effect over 48 h (typical error (TE): ∆150 mL; ∆9.3%) and 4-6 weeks (TE: ∆160 mL; ∆13.3%). Supplementary maximal and submaximal CPET parameters should be incorporated for a comprehensive evaluation of a patient, however they are characterised by greater variability over time. The influence of mild-to-moderate CF on aerobic exercise function and the matching of muscle O2 delivery-to-O2 utilisation during ramp incremental exercise to exhaustion were then examined in study three. Aerobic function was impaired in CF, indicated by very likely reduced fat-free mass normalised V ̇O2max (mean difference, ±90% CI: -7.9 mL∙kg-1∙min-1, ±6.1), very likely lower V ̇O2 gain (-1.44 mL∙min-1∙W-1, ±1.12) and a likely slower V ̇O2 mean response time (MRT) (11 s, ±13). Arterial oxygen saturation was lower in CF, supporting the notion that centrally mediated O2 delivery may be impaired during ramp incremental exercise. Although a faster rate of fractional O2 extraction would be expected in the face of reduced O2 delivery, this was not observed, suggesting additional impairment in O2 extraction and utilisation at the periphery in CF. The fourth study then demonstrated the clinical utility of CPET to assess the response to 12 weeks treatment with Ivacaftor, using a case-based design. Whilst one patient with relatively mild disease demonstrated no meaningful change in V ̇O2max, the second demonstrated a 30% improvement in V ̇O2max, due to increased O2 delivery and extraction. Furthermore, changes in aerobic function were detected earlier than spirometric indices of pulmonary function. This study demonstrated that CPET represents an important and comprehensive clinical assessment tool and its use as an outcome measure in the functional assessment of patients is encouraged. Study five investigated the V ̇O2 kinetics in this patient group. During moderate intensity cycling, the phase II V ̇O2 time constant (τ) (p = 0.84, effect size (ES) = 0.11) and overall MRT (p = 0.52, ES=0.33) were not slower in CF. However, both were slowed during very heavy intensity cycling (p = 0.02, ES = 1.28 and p = 0.01, ES = 1.40, respectively) in CF. Cardiac output and muscle deoxygenation dynamics were unaltered in CF, however, the arterial-venous O2 content difference (C(a-v ̅)O2) was reduced (p=0.03) during VH and ∆C(a-v ̅)O2 correlated with the phase II τ (r= -0.85; p=0.02) and MRT (r = -0.79; p=0.03) in CF. This study showed that impaired oxidative muscle metabolism in this group is exercise intensity-dependent and mechanistically linked to an intrinsic intramuscular impairment, which limits O2 extraction and utilisation. In conclusion, this thesis has provided guidelines for a valid and reproducible CPET protocol for children and adolescents with mild-to-moderate CF, demonstrated the utility of CPET as clinical outcome measure and furthered our understanding of the factors responsible for impaired aerobic exercise function in this patient group.Royal Devon and Exeter NHS Foundation TrustUniversity of Exete

Revolutionizing care : unleashing the potential of Digital Health Technology in physiotherapy management for people with cystic fibrosis

This viewpoint paper explores the dynamic intersection of physiotherapy and digital health technologies (DHTs) in enhancing the care of people with cystic fibrosis (CF), in the context of advancements such as highly effective modulator therapies that are enhancing life expectancy and altering physiotherapy needs. The role of DHTs, including telehealth, surveillance, home monitoring, and activity promotion, has expanded, becoming crucial in overcoming geographical barriers and accelerated by the recent pandemic. Physiotherapy, integral to CF care since 1946, has shifted toward patient-centered approaches, emphasizing exercise training and a physically active lifestyle. The reduction in inpatient admissions due to highly effective modulator therapies has led to increased home care and online or electronic consultations, and DHTs have revolutionized service delivery, offering flexibility, self-management, and personalized care options; however, there is a need to comprehensively understand user experiences from both people with CF and physiotherapists. This paper highlights the essential exploration of user experiences to facilitate clinician adaptation to the digital requirements of modern clinical management, ensuring equitable care in the “future hospitals” arena. Identifying research gaps, this paper emphasizes the need for a thorough evaluation of DHT use in CF physiotherapy education, training, and self-monitoring, as well as the experiences of people with CF with online or electronic consultations, self-monitoring, and remote interventions. Online group exercise platforms address historical challenges relating to infection control but necessitate comprehensive evaluations of user experiences and preferences. Future-proofing DHTs within the physiotherapy management of CF demands a shift toward full integration, considering stakeholder opinions and addressing barriers. While DHTs have the potential to extend physiotherapy beyond the hospital, this paper stresses the importance of understanding user experiences, addressing digital poverty, and working toward more equitable health care access. A flexible approach in the “future hospital” is advocated, emphasizing the need for a nuanced understanding of user preferences and experiences to optimize the integration of DHTs in CF care

The physiological and clinical importance of cardiorespiratory fitness in people with abdominal aortic aneurysm

NEW FINDINGS: What is the topic of this review? This review focuses on the physiological impact of abdominal aortic aneurysm (AAA) on cardiorespiratory fitness and the negative consequences of low fitness on clinical outcomes in AAA. We also discuss the efficacy of exercise training for improving cardiorespiratory fitness in AAA. What advances does it highlight? We demonstrate the negative impact of low fitness on disease progression and clinical outcomes in AAA. We highlight potential mechanistic determinants of low fitness in AAA and present evidence that exercise training can be an effective treatment strategy for improving cardiorespiratory fitness, postoperative mortality and disease progression. ABSTRACT: An abdominal aortic aneurysm (AAA) is an abnormal enlargement of the aorta, below the level of the renal arteries, where the aorta diameter increases by >50%. As an aneurysm increases in size, there is a progressive increase in the risk of rupture, which ranges from 25 to 40% for aneurysms >5.5 cm in diameter. People with AAA are also at a heightened risk of cardiovascular events and associated mortality. Cardiorespiratory fitness is impaired in people with AAA and is associated with poor (postoperative) clinical outcomes, including increased length of hospital stay and postoperative mortality after open surgical or endovascular AAA repair. Although cardiorespiratory fitness is a well‐recognized prognostic marker of cardiovascular health and mortality, it is not assessed routinely, nor is it included in current clinical practice guidelines for the management of people with AAA. In this review, we discuss the physiological impact of AAA on cardiorespiratory fitness, in addition to the consequences of low cardiorespiratory fitness on clinical outcomes in people with AAA. Finally, we summarize current evidence for the effect of exercise training interventions on cardiorespiratory fitness in people with AAA, including the associated improvements in postoperative mortality, AAA growth and cardiovascular risk. Based on this review, we propose that cardiorespiratory fitness should be considered as part of the routine risk assessment and monitoring of people with AAA and that targeting improvements in cardiorespiratory fitness with exercise training might represent a viable adjunct treatment strategy for reducing postoperative mortality and disease progression

Practical considerations for assessing pulmonary gas exchange and ventilation during flume swimming using the MetaSwim metabolic cart

The MetaSwim (MS) metabolic cart can assess pulmonary gas exchange and ventilation in aquatic environments. The aims of this study were: 1) to determine the agreement between minute ventilation (V̇E), pulmonary oxygen uptake (V̇O2) and carbon dioxide output (V̇CO2) using the MS and Douglas Bag (DB) methods during flume swimming; 2) to assess the repeatability of these and other MS derived parameters. Sixteen trained swimmers completed a combined incremental and supramaximal verification cardiopulmonary swimming test to determine maximal V̇O2, two progressive intensity swimming tests during which MS and DB measurements were made (agreement protocol), and/or three-four constant velocity submaximal swimming tests during which only the MS was used (repeatability protocol). Agreement was determined using limits of agreement (LoA), bias, random error and 95% confidence intervals with systematic bias assessed using paired samples t-tests. Within-trial and between trial repeatability were determined using the coefficient of variation (CV) and the repeatability coefficient (CR). Where data were heteroscedastic, LoA and CR were log-transformed, anti-logged and displayed as ratios. MS underestimated peak V̇O2 and V̇CO2 (<0.39 L.min-1) and V̇E (9.08 L.min-1), while submaximal values varied between 2-5% for CV and ±1.09-1.22 for ratio CR. The test re-test CV during constant velocity swimming for V̇E, tidal volume, breathing frequency, V̇O2, V̇CO2, and end-tidal pressures of O2 and CO2 was < 9% (ratio CR of ±1.09-1.34). Thus, the MS and DB cannot be used interchangeably. Whether the MS is suitable for evaluating ventilatory and pulmonary responses in swimming will depend upon the size of effect required

Personalised Health Behaviour Support Programme in Adults With Post-COVID Syndrome: A Randomised, Controlled Pilot Feasibility Trial

BackgroundWe investigated whether a novel 8-week personalised health behaviour support programme, focusing on the stability of symptoms and strategies to improve activities of daily living, was feasible and acceptable in adults with post-COVID syndrome.MethodsIn this randomised, controlled, pilot feasibility trial, 32 adults with post-COVID syndrome (continued symptoms for ≥ 12 weeks) were randomised 1:1 to receive personalised health behaviour support (self-reported physical activity and symptom diaries, plus seven one-to-one remotely delivered personalised self-management support sessions), once weekly for 8-weeks, or usual care (referral to online ‘your COVID-19 recovery’ programme). The primary outcome was the feasibility of recruiting and randomising adults with post-COVID syndrome. The secondary outcomes were to assess the acceptability and safety of the intervention and various outcome measures.ResultsOf the 48 adults who expressed interest in the study, 32 (67%) were eligible and completed the baseline assessment. All 32 adults were willing to be randomised to either the personalised health behaviour support programme (n = 17) or usual care (n = 15) and 27 (age: 45 ± 12 years) adults completed follow-up at 9 weeks. The intervention was deemed feasible, with high adherence (92% and 94% completion rates for the physical activity and symptom diaries, respectively) and excellent acceptability rates (94% ‘liked the intervention a lot’). The intervention was deemed safe, with no symptom exacerbations reported.ConclusionAn 8-week personalised health behaviour support programme was feasible for adults with post-COVID syndrome, with good adherence and acceptability rates. Early pilot data from this small sample also suggests meaningful improvements in physical activity, fatigue and respiratory symptoms.Patient or Public ContributionPeople living with post-COVID syndrome were involved from the outset with the study design, review of study documentation and interpretation of the data following completion. Furthermore, several participants have supported the local dissemination of findings following the completion of the study

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in human lung microvascular endothelial cells controls oxidative stress, reactive oxygen-mediated cell signaling and inflammatory responses

Background: Perturbation of endothelial function in people with cystic fibrosis (CF) has been reported, which may be associated with endothelial cell expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Previous reports indicate that CFTR activity upregulates endothelial barrier function, endothelial nitric oxide synthase (eNOS) expression and NO release, while limiting interleukin-8 (IL-8) release, in human umbilical vein endothelial cells (HUVECs) in cell culture. In view of reported microvascular dysfunction in people with CF we investigated the role of CFTR expression and activity in the regulation of oxidative stress, cell signaling and inflammation in human lung microvascular endothelial cells (HLMVECs) in cell culture.Methods: HLMVECs were cultured in the absence and presence of the CFTR inhibitor GlyH-101 and CFTR siRNA. CFTR expression was analyzed using qRT-PCR, immunocytochemistry (IHC) and western blot, and function by membrane potential assay. IL-8 expression was analyzed using qRT-PCR and ELISA. Nrf2 expression, and NF-κB and AP-1 activation were determined using IHC and western blot. The role of the epidermal growth factor receptor (EGFR) in CFTR signaling was investigated using the EGFR tyrosine kinase inhibitor AG1478. Oxidative stress was measured as intracellular ROS and hydrogen peroxide (H2O2) concentration. VEGF and SOD-2 were measured in culture supernatants by ELISA.Results: HLMVECs express low levels of CFTR that increase following inhibition of CFTR activity. Inhibition of CFTR, significantly increased intracellular ROS and H2O2 levels over 30 min and significantly decreased Nrf2 expression by 70% while increasing SOD-2 expression over 24 h. CFTR siRNA significantly increased constitutive expression of IL-8 by HLMVECs. CFTR inhibition activated the AP-1 pathway and increased IL-8 expression, without effect on NF-κB activity. Conversely, TNF-α activated the NF-κB pathway and increased IL-8 expression. The effects of TNF-α and GlyH-101 on IL-8 expression were additive and inhibited by AG1478. Inhibition of both CFTR and EGFR in HLMVECs significantly increased VEGF expression. The antioxidant N-acetyl cysteine significantly reduced ROS production and the increase in IL-8 and VEGF expression following CFTR inhibition.Conclusion: Functional endothelial CFTR limits oxidative stress and contributes to the normal anti-inflammatory state of HLMVECs. Therapeutic strategies to restore endothelial CFTR function in CF are warranted.<br/

The effects of aerobic and resistance exercise on markers of large joint health in stable rheumatoid arthritis patients:a pilot study

Objective: exercise is beneficial for people with rheumatoid arthritis (RA). However, patients and health professionals have expressed concern about the possible detrimental effects of exercise on joint health. The present study investigated the acute and chronic effects of high-intensity, low-impact aerobic and resistance exercise on markers of large joint health in RA.Methods: eight RA patients and eight healthy, matched control (CTL) participants performed 30 minutes’ high-intensity, low-impact aerobic and lower-body resistance exercise, one week apart. Primary outcome measures assessing joint health were serum cartilage oligomeric matrix protein (sCOMP) and knee joint synovial inflammation (Doppler ultrasound colour fraction; CF). These measures were taken at baseline, immediately after and 0.5, one, two, six and 24 hours post-exercise. In a separate study, nine RA patients completed eight weeks of progressive exercise training. The same outcome measures were reassessed at baseline, and at one hour post-exercise of training weeks 0, 1, 4 and 8.Results: RA patients showed higher overall sCOMP [RA: 1,347 ± 421, CTL: 1,189 ± 562 ng/mL; p &lt; 0.05; effect size (ES) = 0.32] and CF when scanned longitudinally (RA: 0.489 ± 0.30 × 10–3, CTL: 0.101 ± 0.13 × 10–3; p &lt; 0.01; ES = 1.73) and transversely (RA: 0.938 ± 0.69 × 10–3, CTL: 0.199 ± 0.36 × 10–3; p &lt; 0.01; ES = 1.33) than CTL. However, no acute effects on joint health were observed post-exercise. Similarly, no chronic effects were observed over eight weeks of combined aerobic and resistance training in RA, with positive effects on physical fitness and function.Conclusions: RA patients on stable treatment with low disease activity were able to perform an individually prescribed high-intensity, low-impact aerobic and resistance exercise without changes in markers of large joint health

Guidance and standard operating procedures for functional exercise testing in cystic fibrosis

Regular exercise testing is recommended for all people with cystic fibrosis (PwCF). A range of validated tests, which integrate both strength and aerobic function, are available and increasingly being used. Together, these tests offer the ability for comprehensive exercise evaluation. Extensive research and expert consensus over recent years has enabled the adaptation and standardisation of a range of exercise tests to aid the understanding of the pathophysiology related to exercise limitation in PwCF and has led to the development of novel exercise tests which may be applied to PwCF. This article provides expert, opinion-based clinical practice guidance, along with test instructions, for a selection of commonly used valid tests which have documented clinimetric properties for PwCF. Importantly, this document also highlights previously used tests that are no longer suggested for PwCF and areas where research is mandated. This collaboration, on behalf of the European Cystic Fibrosis Society Exercise Working Group, represents expert consensus by a multidisciplinary panel of physiotherapists, exercise scientists and clinicians and aims to improve global standardisation of functional exercise testing of PwCF. In short, the standardised use of a small selection of tests performed to a high standard is advocated

Exercise as an Airway Clearance Technique in people with Cystic Fibrosis (ExACT-CF):rationale and study protocol for a randomised pilot trial

BACKGROUND: Chest physiotherapy is an established cornerstone of care for people with cystic fibrosis (pwCF), but is often burdensome. Guidelines recommend at least one chest physiotherapy session daily, using various airway clearance techniques (ACTs). Exercise (with huffs and coughs) may offer an alternative ACT, however the willingness of pwCF to be randomised into a trial needs testing. The 'ExACT-CF: Exercise as an Airway Clearance Technique in people with Cystic Fibrosis' trial will test the feasibility of recruiting pwCF to be randomised to continue usual care (chest physiotherapy) or replace it with exercise ACT (ExACT) for 28-days. Secondary aims include determining the short-term clinical impact (and safety) of stopping routine chest physiotherapy and replacing it with ExACT, and effects on physical activity, sleep, mood, quality of life and treatment burden, alongside preliminary health economic measures and acceptability.METHODS: Multi-centre, two-arm, randomised (1:1 allocation using minimisation), pilot trial at two sites. Fifty pwCF (≥10 years, FEV 1 &gt;40% predicted, stable on Elexacaftor/Tezacaftor/Ivacaftor (ETI)) will be randomised to an individually-customised ExACT programme (≥once daily aerobic exercise of ≥20-minutes duration at an intensity that elicits deep breathing, with huffs and coughs), or usual care. After baseline assessments, secondary outcomes will be assessed after 28-days, with additional home lung function and exacerbation questionnaires at 7, 14 and 21-days, physical activity and sleep monitoring throughout, and embedded qualitative and health-economic components. Feasibility measures include recruitment, retention, measurement completion, adverse events, interviews exploring the acceptability of trial procedures, and a trial satisfaction questionnaire. DISCUSSION: Co-designed with the UK CF community, the ExACT-CF pilot trial is the first multi-centre RCT to test the feasibility of recruiting pwCF stable on ETI into a trial investigating ExACT. This pilot trial will inform the feasibility, design, management, likely external validity for progression to a main phase randomised controlled trial.REGISTRATION: Clinicaltrials.gov ( NCT05482048).</p