Clinical characterization of new-onset chronic musculoskeletal pain in Long COVID: a cross-sectional study (preprint)

Purpose: New-onset chronic musculoskeletal (MSK) pain is one of the common persistent symptoms in Long COVID (LC). This study investigated its clinical characteristics, underlying mechanisms, and impact on function, psychological health, and quality of life. Patients and methods: 30 adults (19 female, 11 male) with LC and new-onset chronic MSK pain underwent clinical examination, Quantitative Sensory Testing (QST), and blood tests for inflammatory markers, and completed the following outcome measures: Timed Up and Go test (TUG), handgrip strength test, COVID-19 Yorkshire Rehabilitation Scale (C19-YRS), Brief Pain Inventory (BPI), Pain Self-Efficacy Questionnaire (PSEQ), Pain Catastrophizing Scale (PCS), International Physical Activity Questionnaire - short form (IPAQ-sf), Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-9), and EuroQol Five Dimensions health-related quality of life (EQ-5D-5L). Results: New-onset chronic MSK pain was widespread and continuous in nature, and worse in the joints. When compared to normative values reported in the literature: a) QST revealed mechanical hyperalgesia, heightened temporal summation of pain, and hypoesthesia to vibration stimuli, which is strongly suggestive of central sensitization; b) Plasma cytokine assays indicated distinct pro- inflammatory profiles; c) TUG time indicated reduced balance and mobility; d) handgrip strength revealed general weakness; e) physical activity was lower ; and f) there were moderate levels of depression and anxiety with lower self-efficacy scores and lower levels of pain catastrophizing. LC symptoms were of moderate severity (44.8/100), moderate functional disability (22.8/50) and severely compromised overall health (2.6/10) when compared to pre-COVID scores. Conclusion: New-onset chronic MSK pain in LC tends to be widespread, constant, and associated with weakness, reduced function, depression, anxiety, and reduced quality of life. There is associated central sensitization and proinflammatory state in the condition. Further research is essential to explore the longitudinal progression and natural evolution of the new-onset chronic MSK pain in LC.

Psychometric analysis of the modified Covid-19 Yorkshire Rehabilitation Scale (C19-YRSm) in a prospective multicentre study (preprint)

BckgroundLong COVID is a novel multisystem clinical syndrome affecting millions of individuals worldwide. The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) is a condition-specific patient-reported outcome measure designed for assessment and monitoring of people with Long COVID (LC). ObjectivesTo evaluate the psychometric properties of the C19-YRSm in a prospective sample of people with Long COVID. Methods1314 patients attending UK specialist Long COVID clinics completed C19-YRSm and EQ-5D-5L longitudinally. Scale characteristics were derived for C19-YRSm subscales (Symptom Severity, SS; Functional Disability, FD; and Overall Health, OH) and internal consistency (Cronbachs alpha). Convergent validity was assessed using the FACIT-Fatigue scale. Known groups validity was assessed for the Other Symptoms (OS) subscale as tertiles, hospitalisation and intensive care admission. Responsiveness and test-retest reliability was evaluated for C19-YRSm subscales and EQ-5D-5L. The minimal important difference (MID) and minimal clinically important difference (MCID) were estimated. Confirmatory factor analysis was applied to determine the instruments two-factor structure. ResultsC19-YRSm demonstrated good scale characteristic properties. Item-total correlations were between 0.37 to 0.65 (for SS and FD), with good internal reliability (Cronbachs alphas >0.8). Item correlations between subscales ranged between 0.46 to 0.72. Convergent validity with FACIT was good (-0.46 to -0.62). The three subscales discriminated between different levels of symptom burden (p<0.001), and between patients admitted to hospital and intensive care. There was moderate responsiveness for the three subscales ranging from 0.22 (OH) to 0.50 (SS) and was greater than the EQ-5D-5L. Test-retest reliability was good for both SS 0.86 and FD 0.78. MID was 2 for SS, 2 for FD, and 1 for OH; MCID was 4 for both the SS and FD. The factor analysis supported the two-factor SS and FD structure. ConclusionsThe C19-YRSm is a condition-specific, reliable, valid, and responsive patient-reported outcome measure for Long COVID. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSLong Covid or Post-COVID-19 syndrome is a multisystem, fluctuating condition. C19-YRSm is literatures first condition-specific patient reported outcome measure which needed validation in a large population sample. What this study addsC19-YRSm is a valid, reliable, responsive and easy to administer measure which is able to show clinically meaningful change in the status of the condition in people living with Long Covid. How this study might affect research, practice or policyC19-YRSm can be used in clinical and research settings to reliably capture the condition trajectory and the effect of interventions and also help inform clinical policy.

Prevalence of orthostatic intolerance in Long Covid clinic patients - A multicentre observational study (preprint)

PurposeOrthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with symptoms and comorbidities. MethodsParticipants were recruited from 8 UK long covid clinics, and healthy volunteers from general population. All undertook standardised National Aeronautics and Space Administration Lean Test (NLT). Participants history of typical OI symptoms (e.g. dizziness, palpitations) prior to and during the NLT were recorded. Results277 long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or PoTS, 10% had asymptomatic OH. 130 (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. 41 (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive to one reading, resulted in 11% of long covid participants meeting criteria for PoTS, but not in healthy volunteers. ConclusionMore than half of long covid patients experienced OI symptoms during NLT and more than one in ten patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced. Trial registration numbers NCT05057260, ISRCTN15022307

A systematic review of quantitative EEG findings in Long COVID, Fibromyalgia and Chronic Fatigue Syndrome (preprint)

Long COVID (LC) is a multisymptom clinical syndrome with similarities to Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). All these conditions are believed to be associated with centrally driven mechanisms such as central sensitisation. There is a lack of consensus on quantitative EEG (qEEG) changes observed in these conditions. This review aims to synthesise and appraise the literature on resting-state qEEG in LC, FMS and CFS/ME, to help uncover possible mechanisms of central sensitisation in these similar clinical syndromes. A systematic search of MEDLINE, Embase, CINHAL, PsycINFO and Web of Science databases for articles published between December 1994 and September 2023 was performed. Following screening for predetermined selection criteria and out of the initial 2510 studies identified, 17 articles were retrieved that met all the inclusion criteria, particularly of assessing qEEG changes in one of the three conditions compared to healthy controls. All studies scored moderate to high quality on the Newcastle-Ottawa scale. There was a general trend for decreased low-frequency EEG band activity (delta, theta, and alpha) and increased high-frequency EEG beta activity in FMS, whereas an opposite trend was found in CFS/ME. The limited LC studies included in this review focused mainly on cognitive impairments and showed mixed findings not consistent with patterns seen in FMS and CFS/ME. Further research is required to explore whether there are phenotypes within LC that have EEG signatures similar to FMS or CFS/ME. This could inform identification of reliable diagnostic markers and possible targets for neuromodulation therapies.

HEART rate variability biofeedback breathing programme for LOng Covid dysautonomia (HEARTLOC): results of a feasibility study (preprint)

Introduction Post-covid-19 syndrome, or Long covid (LC) refers to symptoms persisting 12 weeks after Covid-19 infection. LC comprises a wide range of dysautonomia symptoms, including fatigue, breathlessness, palpitations, dizziness, pain and brain fog. This study tested the feasibility and estimated the efficacy, of a Heart Rate Variability Biofeedback (HRV-B) technique via a standardised slow diaphragmatic breathing programme in individuals with LC. Methods and Analysis LC patients underwent a 4-week HRV-B intervention for 10 minutes twice daily for a total of 4 weeks using the Polar H10 ECG (Electrocardiogram) chest strap and Elite HRV phone application. Outcome measures C19-YRSm (Yorkshire Rehabilitation Scale modified), EQ5D- 5L (EuroQol 5 Dimensions), Composite Autonomic Symptom Score (COMPASS-31), WHO Disability Assessment Schedule (WHODAS), and Root Mean Square of Successive Differences between heartbeats (RMSSD) using a Fitbit device were completed before and after the intervention. The study was pre-registered at clinicaltrials.gov NCT05228665. Results 13 participants (54% female, 46% male) completed the study with high levels of data completeness and adherence. There was a statistically significant improvement in C19YRS-m (p=0.001), EQ5D Global Health Score (p=0.009), COMPASS-31 (p=0.007), RMSSD (p=0.047) and EHODAS (p=0.02). Qualitative feedback suggested participants were able to use it independently, were satisfied with the intervention, and reported beneficial effects from the intervention. Conclusion This is the first study in the literature to report that HRV-B is a feasible intervention for LC and seems to be potentially improving symptoms of LC and dysautonomia.

The adapted Autonomic Profile (aAP) Home-Based Test for the Evaluation of Neuro-Cardiovascular Autonomic Dysfunction (preprint)

Autonomic dysfunction is an increasingly recognised complication in chronic neurological conditions such as Parkinson’s disease , and other medical conditions, including diabetes mellitus, chronic fatigue syndrome, postural tachycardia syndrome with and without Ehlers-Danlos syndrome, fibromyalgia and recently Long Covid. Despite laboratory-based tests to evaluate normal and abnormal autonomic function, there are no home-based tests to record neuro-cardiovascular autonomic responses to common stimuli in daily life that are dependent on the normal functioning of the autonomic nervous system. We have developed an adapted blood pressure/heart Autonomic Profile (aAP) that can be used by an individual independently and repeatedly in a domiciliary setting to determine the physiological and symptomatic response to standing, food, and physical and mental (cognitive, emotional) activities. The aAP aids separating autonomic failure (often irreversible) from autonomic dysfunction. This helps the individual and attending healthcare professional understand the relationship between symptoms and common triggers in daily life and informs on self-management in debilitating conditions such as the postural tachycardia syndrome (PoTS) and Long Covid.

HEART rate variability biofeedback for LOng Covid symptoms (HEARTLOC): protocol for a feasibility study (preprint)

IntroductionLong covid (LC), also known as Post-COVID-19 syndrome, refers to symptoms persisting 12 weeks after COVID-19 infection. It affects up to 1 in 7 people contracting the illness and causes a wide range of symptoms, including fatigue, breathlessness, palpitations, dizziness, pain and brain fog. Many of these symptoms can be linked to dysautonomia or dysregulation of the autonomic nervous system after SARS-CoV2 infection. This study aims to test the feasibility and estimate the efficacy, of the Heart Rate Variability Biofeedback (HRV-B) technique via a standardised slow diaphragmatic breathing programme in individuals with LC. Methods and Analysis30 adult LC patients with symptoms of palpitations or dizziness and an abnormal NASA Lean Test (NLT) will be selected from a specialist Long COVID rehabilitation service. They will undergo a 4-week HRV-B intervention using a Polar chest strap device linked to the Elite HRV phone application while undertaking the breathing exercise technique for two 10-min periods every day for at least 5 days a week. Quantitative data will be gathered during the study period using: HRV data from the chest strap and wrist-worn Fitbit, the modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), composite autonomic symptom score (COMPASS 31), World Health Organisation Disability Assessment Schedule (WHODAS 2.0) and EQ-5D-5L health related quality of life measures. Qualitative feedback on user experience and feasibility of using the technology in a home setting will also be gathered. Standard statistical tests for correlation and significant difference will be used to analyse the quantitate data. Ethics and DisseminationThe study has received ethical approval from Health Research Authority (HRA) Leicester South Research Ethics Committee (21/EM/0271). Dissemination plans include academic and lay publications. Study RegistrationClinicaltrials.gov No: NCT05228665 Strengths and limitations of the studyO_LITo our knowledge, this is the first study of HRVB in long covid and will provide new information regarding the feasibility of the technology-based intervention in this condition. C_LIO_LIThe estimation of efficacy will determine the scope and sample size for a larger controlled trial in the condition that currently has no definitive treatments C_LIO_LIThe study will provide preliminary evidence on the correlation between long covid symptoms and dysautonomia. C_LIO_LIThe limitation of this study is the small sample size of 30 participants which might not give an accurate estimate of efficacy. C_LIO_LIHRV-B is a technology-based intervention, therefore its take-up could be limited in those with a lack of experience in using digital technology in daily life, particularly those from less privileged backgrounds. C_LI

Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review (preprint)

Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises evidence for the effectiveness of non-pharmacological treatments for symptoms of PVS. It also summarises the symptoms and health impacts of PVS in individuals recruited to studies evaluating treatments. Methods and findings: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1st January 2001 to 29th October 2021. We anticipated that there would be few RCTs specifically pertaining to Long COVID, so we also included observational studies only if they assessed interventions in individuals where the viral pathogen was SARS-COV-2. Relevant outcome data were extracted, study quality appraised using the Cochrane Risk of Bias tool, and the findings were synthesised narratively. Quantitative synthesis was not planned due to substantial heterogeneity between the studies. Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Conclusions: In this study, we observed a lack of robust evidence evaluating non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS as well as what may work for certain sub-groups of patients with differential symptom presentation. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022. Keywords: Post-viral syndromes, PVS, COVID-19, Long COVID, post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection (PASC), rehabilitation, systematic review, non-pharmacological intervention

Protocol for mixed-method study by LOng COvid Multidisciplinary consortium: Optimising Treatments and servIces acrOss the NHS (LOCOMOTION) (preprint)

Introduction Long COVID, a new condition whose origins and natural history are not yet fully established, currently affects 1.5 million people in the UK. Most do not have access to specialist long COVID services. We seek to optimise long COVID care both within and outside specialist clinics, including improving access, reducing inequalities, helping patients manage their symptoms effectively at home, and providing guidance and decision support for primary care. We aim to establish a ‘gold standard’ of care by systematically analysing symptom clusters and current practices, iteratively improving pathways and systems of care, and working to disseminate better practices. Methods and analysis This mixed-method, multi-site study is informed by the principles of applied health services research, quality improvement, co-design, and learning health systems. It was developed in close partnership with patients (whose stated priorities are prompt clinical assessment; evidence-based advice and treatment; and help with returning to work and other roles) and with front-line clinicians. Workstreams and tasks to optimise assessment, treatment and monitoring are based in three contrasting settings: [1] specialist management in 10 long COVID clinics across the UK, via a quality improvement collaborative, experience-based co-design and targeted efforts to reduce inequalities of access; [2] patient self-management at home, with technology-supported monitoring; and [3] generalist management in primary care, harnessing electronic record data to study population phenotypes and develop evidence-based decision support, referral pathways and prioritisation criteria across the primary-secondary care interface, along with analysis of costs. Study governance includes an active patient advisory group. Ethics and dissemination LOCOMOTION is sponsored by the University of Leeds and approved by Yorkshire & The Humber - Bradford Leeds Research Ethics Committee (ref: 21/YH/0276). Dissemination plans include academic and lay publications, and partnerships with national and regional policymakers to influence service specifications and targeted funding streams. Study registration ClinicalTrials.gov NCT05057260 ; ISRCTN15022307 .

The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) patient-reported outcome measure for Long Covid or Post-COVID syndrome (preprint)

ABSTRACT Background The C19-YRS was the first validated scale reported in the literature for patient assessment and monitoring in Long Covid or Post-COVID syndrome. The 22-item scale contains four subscales measuring symptom severity, functional disability, overall health and additional symptoms. Objectives This study aimed to modify and refine the scale based on psychometric properties, emerging evidence on additional Long Covid symptoms, and feedback from a working group of patients and healthcare professionals. Methods Data were collected from 370 patients who completed the C19-YRS scale in a community Long COVID service. The psychometric properties of the Symptom Severity and Functional Disability subscales were assessed using a Rasch Measurement Theory framework, where all individual scale items were assessed for model fit, local dependency, response category functioning and differential item functioning (DIF) by age group and sex. Additionally, the subscales were assessed for targeting, reliability and unidimensionality. The overall health subscale is a single item, and the additional symptoms subscale is not intended to be summed, therefore neither is appropriate for Rasch analyses. Psychometric results and implications were relayed back to the working group for discussion, alongside clinical evidence of emerging and relevant symptoms not covered by the original C19-YRS. Results Rasch analysis revealed promising psychometric properties of the symptom severity and functional disability subscales, with both displaying good targeting and reliability, although some individual measurement anomalies were noted. The original 0-10 item response category structure did not operate as intended for both the subscales. Post-hoc rescoring suggested that a 4-point response category structure would be more appropriate for both the subscales, and this aligned with patient feedback. This scoring change was implemented, alongside changes in the item composition of the symptom severity and additional symptoms subscales. The functional disability item set, and the overall health single-item subscale remained unchanged. Conclusion A modified version of the C19-YRS was developed based on a combination of psychometric evidence, clinical relevance of the content and feedback from the working group (comprising patients and healthcare professionals). Future studies including NIHR funded LOCOMOTION study will undertake large-scale, multi-centre validation of the modified C19-YRS.

The COVID-19 Yorkshire Rehabilitation Scale (C19-YRS): application and psychometric analysis in a post-COVID-19 syndrome cohort (preprint)

Background: As our understanding of the nature and prevalence of Post-COVID-19 syndrome (PCS) is increasing, a measure of the impact of COVID-19 could provide valuable insights into patients' perceptions in clinical trials and epidemiological studies, as well as routine clinical practice. Objective: To evaluate the clinical usefulness and psychometric properties of the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) in patients with PCS. Design: A prospective, observational study of 187 consecutive patients attending a post-COVID-19 rehabilitation clinic. The C19-YRS was used to record patients' symptoms, functioning and disability. A global health question was used to measure the overall impact of PCS on health. Classical psychometric methods (data quality, scaling assumptions, targeting, reliability and validity) were used to assess the C19-YRS. Results: For the overall scale, missing data were low, scaling and targeting assumptions were satisfied, and internal consistency was high (Cronbach's alpha = 0.891). Relationships between perception of health and patients' reports of symptoms, functioning and disability demonstrated good concordance. Conclusions: This is the first study to examine the psychometric properties of an outcome measure in patients with PCS. In this sample of patients, the C19-YRS was clinically useful and satisfied standard psychometric criteria, providing preliminary evidence of its suitability as a measure of PCS.

LONG-TERM CLINICAL OUTCOMES IN SURVIVORS OF CORONAVIRUS OUTBREAKS AFTER HOSPITALISATION OR ICU ADMISSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF FOLLOW-UP STUDIES (preprint)

Objective: To determine the long-term clinical problems in adult survivors of coronavirus (CoV) infection [Coronavirus disease 2019 (COVID-19), Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)] after hospitalisation or Intensive Care Unit (ICU) admission. Design: Systematic review and meta-analysis of the literature. Data sources: Ovid MEDLINE, EMBASE, CINAHL Plus and PsycINFO were searched using the strategy: (Coronavirus OR Coronavirus Infections OR COVID OR SARS virus OR Severe acute respiratory syndrome OR MERS OR Middle east respiratory syndrome) AND (Follow-up OR Follow-up studies OR Prevalence). Original studies reporting the clinical outcomes of adult survivors of coronavirus outbreaks two months after discharge or three months after admission were included. The quality of the studies was assessed using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2009 Level of Evidence Tool. Meta-analysis was conducted to derive pooled estimates of prevalence and severity for different outcomes at time points up to 6 months follow-up and beyond 6 months follow-up. Results: The search yielded 1169 studies of which 28 were included in this review. There were 15 Level 1b, 8 Level 2b, 2 Level 3b and 3 Level 4 studies by OCEBM grading. Pooled analysis of studies revealed that complications commonly observed were impaired diffusing capacity for carbon monoxide (DLCO) [prevalence of 27.26%, 95% CI 14.87 to 44.57] and reduced exercise capacity [(6-minute walking distance (6MWD) mean 461m, 95% CI 449.66 to 472.71] at 6 months with limited improvement beyond 6 months. Coronavirus survivors had considerable prevalence of psychological disorders such as post-traumatic stress disorder (PTSD) [38.80%, CI 30.93 to 47.31], depression [33.20%, CI 19.80 to 50.02] and anxiety [30.04%, CI 10.44 to 61.26) beyond 6 months. These complications were accompanied by low Short Form 36 (SF-36) scores at 6 months and beyond indicating reduced quality of life which is present long-term. Conclusions: The long term clinical problems in survivors of CoV infections (SARS and MERS) after hospitalisation or Intensive Care Unit (ICU) admission include respiratory dysfunction, reduced exercise capacity, psychological problems such as PTSD, depression and anxiety, and reduced quality of life. Critical care, rehabilitation and mental health services should anticipate a high prevalence of these problems following COVID-19 and ensure their adequate and timely management with the aim of restoring premorbid quality of life.