Cardiovascular Function in Long-Term Hematopoietic Cell Transplantation Survivors.

Peak oxygen consumption (VO2peak), as measured by cardiopulmonary exercise testing (CPET), is a powerful independent predictor of cardiovascular disease (CVD) and all-cause mortality in a broad range of populations. We assessed the safety and feasibility of CPET in aging long-term hematopoietic cell transplantation (HCT) survivors, a population at high risk for premature onset of CVD. Next, we examined how organ-specific impairments (eg, cardiac, pulmonary, hematologic) impact VO2peak after HCT. Twenty consecutive HCT survivors underwent a comprehensive assessment of cardiopulmonary health that included CPET, echocardiography with strain, pulmonary function testing, 6-minute walk test, and timed up and go. Median age at assessment was 67.4 years (range, 42 to 75), and median time from HCT was 9.8 years (range, 3 to 20). No adverse events were observed during CPET procedures, and 95% of studies were considered to be at "peak" effort (respiratory exchange ratio ≥ 1.10). VO2peak was on average 22% less than predicted, and allogeneic HCT survivors had markedly lower VO2peak when compared with autologous HCT survivors (18.2 mL/kg/min versus 22.2 mL/kg/min; P = .05). Six participants (30%) had VO2peak ≤ 16 mL/kg/min, a threshold associated with a 9-foldrisk of death in patients undergoing HCT. Despite the presence of normal (>50%) resting left ventricular ejection fraction in all participants, 25% had markedly abnormal left ventricular longitudinal strain, an advanced echocardiographic measure of myocardial dysfunction. These findings highlight the role of stress-based measures and advanced myocardial imaging to characterize CVD risk in HCT survivors, setting the stage for tailored interventions to prevent CVD with its attendant morbidity and mortality.

Rationale and design of the Children's Oncology Group (COG) study ALTE1621: a randomized, placebo-controlled trial to determine if low-dose carvedilol can prevent anthracycline-related left ventricular remodeling in childhood cancer survivors at high risk for developing heart failure.

BACKGROUND: Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. METHODS/DESIGN: The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m2) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability. DISCUSSION: When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02717507.

Pulmonary Rehabilitation for People With Persistent Symptoms After COVID-19.

TOPIC IMPORTANCE: COVID-19 can cause ongoing and persistent symptoms (such as breathlessness and fatigue) that lead to reduced functional capacity. There are parallels in symptoms and functional limitations in adults with post-COVID symptoms and adults with chronic respiratory diseases. Pulmonary rehabilitation is a key treatment for adults with chronic respiratory diseases, with the aims to improve symptom management and increase functional capacity. Given the similarities in presentation and aims, a pulmonary rehabilitation program may be optimal to meet the needs of those with ongoing symptoms after COVID-19. REVIEW FINDINGS: Aerobic and strength training has shown benefit for adults living with long COVID, although there is little evidence on structured education in this population. Breathing pattern disorder is common in adults with long COVID, and considerations on treatment before rehabilitation, or alongside rehabilitation, are necessary. Considerations on postexertional malaise are important in this population, and evidence from the chronic fatigue syndrome literature supports the need for individualization of exercise programs, and considerations for those who have an adverse reaction to activity and/or exercise. SUMMARY: This narrative review summarizes the current evidence on pulmonary rehabilitation programs in a long-COVID population. Where the evidence is lacking in long COVID the supporting evidence of these programs in chronic respiratory diseases has highlighted the importance of aerobic and strength training, considerations for fatigue, potential mechanisms for immunology improvement, and management of breathing pattern disorders in these programs.

Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation.

Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females [Odds Ratio (OR) = 2·9, P < 0·01], individuals with pre-HCT chest radiation (OR = 4·7, P = 0·05), hypertension (OR = 2·9, P = 0·01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR = 2·8, P < 0·01), HFE (rs1799945, 63C→G; OR = 2·5, P = 0·05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR = 4·3, P < 0·01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0·79] than the genetic (AUC = 0·67) or the clinical (AUC = 0·69) models alone.

Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation.

Advances in autologous hematopoietic cell transplantation (HCT) strategies have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing cardiovascular complications due to pre-HCT therapeutic exposures and conditioning and post-HCT comorbidities. We examined the incidence and predictors of congestive heart failure (CHF) in 1244 patients undergoing autologous HCT for a hematologic malignancy between 1988 and 2002. The cumulative incidence of CHF was 4.8% at 5 years and increased to 9.1% at 15 years after transplantation; the CI for female lymphoma survivors was 14.5% at 15 years. The cohort was at a 4.5-fold increased risk of CHF (standardized incidence ratio = 4.5), compared with the general population. The risk of CHF increased substantially for patients receiving ≥ 250 mg/m(2) of cumulative anthracycline exposure (odds ratio [OR]: 9.9, P < .01), creating a new and lower threshold for cardiac surveillance after HCT. The presence of hypertension among recipients of high-dose anthracycline (≥ 250 mg/m(2)) resulted in a 35-fold risk (OR: 35.3, P < .01) of CHF; the risk was nearly 27-fold (OR: 26.8, P < .01) for high-dose anthracycline recipients with diabetes, providing evidence that hypertension and diabetes may be critical modifiers of anthracycline-related myocardial injury after HCT and creating targeted populations for aggressive intervention.

Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS).

HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported ≥ 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life-threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population.

Public Use of the "Your COVID Recovery" Website Designed to Help Individuals Manage Their COVID-19 Recovery: Observational Study.

BACKGROUND: At the start of the COVID-19 pandemic, unprecedented pressure was placed on health care services globally. An opportunity to alleviate this pressure was to introduce a digital health platform that provided COVID-19-related advice and helped individuals understand and manage their COVID-19 symptoms. Therefore, in July 2020, the Your COVID Recovery website was launched by the National Health Service of England with the aim of creating a practical tool that provides advice and support to individuals recovering from COVID-19. The website includes information on many of the key COVID-19 symptoms. To date, public use of the Your COVID Recovery website and user behavior remain unknown. However, this information is likely to afford insight into the impact of the website and most commonly experienced COVID-19 symptoms. OBJECTIVE: This study aimed to evaluate public use of the Your COVID Recovery website, a digital health platform that provides support to individuals recovering from COVID-19, and determine user behavior during its first year of operation. METHODS: Google Analytics software that was integrated into the Your COVID Recovery website was used to assess website use and user behavior between July 31, 2020, and July 31, 2021. Variables that were tracked included the number of users, user country of residence, traffic source, number of page views, number of session views, and mean session duration. User data were compared to COVID-19 case data downloaded from the UK government's website. RESULTS: During the study period, 2,062,394 users accessed the Your COVID Recovery website. The majority of users were located in the United Kingdom (1,265,061/2,062,394, 61.30%) and accessed the website via a search engine (1,443,057/2,062,394, 69.97%). The number of daily website users (n=15,298) peaked on January 18, 2021, during the second wave of COVID-19 in the United Kingdom. The most frequently visited pages after the home page were for the following COVID-19 symptoms: Cough (n=550,190, 12.17%), Fatigue (n=432,421, 9.56%), Musculoskeletal pain (n=406,859, 9.00%), Taste and smell (n=270,599, 5.98%), and Breathlessness (n=203,136, 4.49%). The average session duration was 1 minute 13 seconds. CONCLUSIONS: A large cohort of individuals actively sought help with their COVID-19 recovery from the website, championing the potential of this tool to target an unmet health care need. User behavior demonstrated that individuals were primarily seeking advice on how to relieve and manage COVID-19 symptoms, especially symptoms of cough, fatigue, and musculoskeletal pain. COVID-19 rehabilitation programs should use the results of this study to ensure that the program content meets the needs of the post-COVID-19 population.

Resistance Training in Post-COVID Recovery: Rationale and Current Evidence.

During hospitalisation with COVID-19, individuals may experience prolonged periods of immobilisation. Combined with the inflammatory effects of the virus, this may lead to a significant reduction in both muscle mass and strength. Data from several long-term studies suggest that these symptoms may not fully resolve within one year. Owing to its effectiveness at inducing muscle fibre hypertrophy and improving neuromuscular efficiency, resistance training is of great interest in the rehabilitation of this population. This narrative review aims to identify the rationale and potential efficacy of resistance training for restoring physical function following infection with SARS-CoV-2, as well as evidence of its use in clinical practice. The studies included in this narrative review consisted mostly of multi-component rehabilitation trials. Of these, widespread improvements in muscle strength were reported using intensities of up to 80% of participants' 1-repetition-maximum. Evidence thus far indicates that resistance training may be safe and effective in patients following COVID-19, although its individual contribution is difficult to discern. Future exercise intervention studies investigating the efficacy of resistance training as a sole modality are needed.

The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium.

INTRODUCTION: Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group. METHODS AND ANALYSIS: This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care. ETHICS AND DISSEMINATION: Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority.

Effects of combining electrical stimulation of the calf and thigh muscles in patients with osteoarthritis of the knee: protocol for a double-blind, randomised, sham-controlled trial.

INTRODUCTION: Knee osteoarthritis (KOA) is a leading cause of disability and is characterised by degenerative changes causing pain and loss of function. Neuromuscular electrical stimulation (NMES) has been shown to influence muscle size and strength in healthy subjects. A novel self-administered NMES device has been developed to help manage the symptoms of KOA. This study aims to investigate the effects of combining NMES of the calf and quadriceps on individuals with KOA. METHODS AND ANALYSIS: 193 individuals with KOA will be recruited to a single-centre, double-blind, randomised, sham-controlled trial at the Respiratory Biomedical Research Centre, Leicester, UK. Participants will be randomised (1:1) to follow an 8-week home-based intervention using a NMES device or sham device. The NMES device consists of footplate electrodes and two quadriceps electrodes. Footplate stimulation will be completed daily for 30 min and quadriceps stimulation for 20 min, five times a week (compliance is recorded in a self-reported participant diary). The primary outcome is the Western Ontario and McMaster Universities Arthritis Index pain domain, taken at 8 weeks follow-up. Secondary outcomes will explore quadriceps muscle strength, swelling, health-related quality of life, exercise capacity, anxiety and depression, sleep, physical activity and self-reported compliance. A powered subgroup analysis for compliance to the active device will be complete for the primary outcome. Participant focus groups will be completed following recruitment of half of the participants and after all participants have been recruited. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North-West Preston ethics committee (17/NW/0081). Participants are required to provide informed consent following review of the participant information sheet and discussion regarding study procedures with a member of the research team. The study results will be disseminated to the appropriate stakeholders through presentations, conferences and peer-reviewed journals. Results will be presented to participants following study completion at the Biomedical Research Centre-Respiratory, Glenfield Hospital, Leicester. TRIAL REGISTRATION NUMBER: ISRCTN registry, ISRCTN12112819 (date registered 1 May 2019). IRAS registry 219 693. University Hospitals of Leicester registry 91 017. Protocol Version 8.

Early experiences of the Your COVID Recovery® digital programme for individuals with long COVID.

OBJECTIVES: To describe the early data from the Your COVID Recovery® digital programme and to explore the data collected from two embedded outcome measures. DESIGN: Observational. SETTING: Primary and secondary care (England-Online). PARTICIPANTS: 110 individuals completed the programme (68.1% female, 88.1% White British, age: 46.3 (10.8) years, weight: 86.5 (21.1) kg, height: 169.3 (10.0) cm). 47.2% of patients reported comorbidities. INTERVENTION: Following an assessment by a healthcare professional, individuals with long COVID were offered access to the Your COVID Recovery® digital programme. The programme comprises of four stages for the participants to progress through. Participants are encouraged to record severity of their symptoms and amount of activity they are doing on a symptom and an activity tracker. Resources and interactive material on managing symptoms of long COVID are available throughout each stage. PRIMARY OUTCOME MEASURES: Questionnaire (EuroQ0l 5-Dimension 5-Level (EQ-5D-5L) and the chronic obstructive pulmonary disease assessment test (CAT)) data were extracted from the site from 11 March 2021 until 9 November 2021. RESULTS: Participants were on the programme for 8.6 (4.3) weeks. There was a statistically significant increase in EQ-5D-5L visual analogue scale (VAS) score (pre=48.8 (19.5); post=59.9 (22.1); p<0.01). The EQ-5D-5L Index Value preintervention to postintervention did improve but not significantly (pre=0.5 (0.3); post=0.6 (0.3); p=0.09). CAT total score improved significantly preintervention to postintervention (pre=19.8 (7.2); post=15.6 (7.6); p<0.01). All CAT item scores significantly improved preintervention to postintervention (p<0.005), except the phlegm item score (p=0.168). DISCUSSION: This early data describes the impact of the Your COVID Recovery® digital programme on the first cohort of patients to complete the digital recovery programme. The outcome data are promising and should encourage uptake.

Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation.

Long-term survival after hematopoietic cell transplantation (HCT) is now an expected outcome. The growing population of survivors is at risk of developing treatment-related complications, including cardiovascular disease (CVD). A nested case-controlled design was used to identify clinical and treatment-related risk factors for development of late (1+ years after HCT) CVD. Cases were identified from a cohort of 1+-year survivors who underwent transplantation at City of Hope between 1977 and 2006. Controls (HCT survivors without CVD) were matched on age, year of HCT, type of HCT, and duration of follow-up. Sixty-three patients with late CVD were identified, 44 (69.8%) with a coronary artery event and 19 (30.2%) with a cerebrovascular event. Median age at HCT was 49.0 years. Median age at onset of late CVD was 54.0 years; 66.7% of the affected patients had undergone autologous HCT. Multivariate logistic regression analysis showed that the presence of multiple cardiovascular risk factors (2 or more of the following: obesity, dyslipidemia, hypertension, and diabetes) after HCT was associated with a 5.2-fold increased risk of late CVD (P < .01), and that pre-HCT chest radiation exposure was associated with a 9.5-fold greater risk of coronary artery disease (P = .03). Pre-HCT exposure to chest radiation and the presence of comorbidities were primarily responsible for the risk associated with late CVD after HCT. These data form the basis for developing predictive models for identifying high-risk individuals for targeted surveillance and aggressive management of comorbidities.