Introduction
What is the clinical problem?
The COVID-19 pandemic and the burden of subsequent limited recovery from COVID-191 present some of the greatest clinical challenges of a generation. Such individuals not fully recovered from COVID-19 may self-identify under the collective patient-advocated term ‘long COVID’ and/or meet one of the various clinical definitions created to describe persistent symptoms.2 National data from March 2023 indicate that around 3% of the UK population had not recovered fully from COVID-19 infection. The most common associated symptoms are fatigue (72%), difficulty concentrating (51%), muscle aches/pain (49%) and shortness of breath (48%).3 However, more than 200 symptoms, expressed across multiple organ systems, are associated with delayed recovery following acute COVID-19 infection.1 A history of infection with COVID-19 is now commonplace,4 so a precise and mechanistic understanding of factors that predispose to enduring symptoms and limit recovery will help design and deliver effective healthcare to improve the quality of life of millions of affected individuals worldwide. Evidently, the presentation of long COVID is heterogeneous.5 These distinct profiles need further characterisation in order to design personalised care and to target effective treatment across populations and age groups.
What do we know about long COVID at this point?
In addition to demographic factors, notably female sex, the likelihood of developing long COVID appears to be increased by the presence of pre-existing activity-limiting health conditions or disabilities.3 Fibromyalgia, irritable bowel syndrome, migraine, anxiety, depression and back pain6 are among a number of conditions identified as raising the risk of long COVID. However, other studies on long COVID have failed to find specific associations, particularly in relation to pre-existing affective disorders.7 There is growing awareness of the symptomatic overlap with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), in which viral infection is often implicated as a trigger. Indeed, such research may help elucidate the aetiology of long COVID.8 Moreover, cardiovascular autonomic dysfunction, particularly postural orthostatic tachycardia syndrome (POTS), may be precipitated by COVID-19 and expressed in long COVID.9 POTS is a chronic and often disabling disorder characterised by orthostatic intolerance with an excessive increase in heart rate without hypotension during upright posture. Patients often experience a constellation of other typical symptoms overlapping with long COVID including fatigue and exercise intolerance, and it is established that the onset of POTS may be precipitated by immunological stressors. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the precise aetiology of the syndrome is incompletely understood and is undoubtedly multifaceted.10 Indeed, the presence of POTS is considered to be a major sub-phenotype of long COVID, with an estimated prevalence of 30–75% in symptomatic patients, depending on methodology.11–13 These conditions (POTS, ME/CFS) are archetypes of seemingly complex poorly-understood multisystem illnesses, alongside hypermobility spectrum disorder (HSD)14 and Ehlers–Danlos syndrome, which we discuss further below.15 The mechanisms and pathobiology behind the association of long COVID with these multiple co-occurring conditions are currently poorly understood. However, convergent biological mechanisms, including dysregulated autonomic, inflammatory and metabolic processes, are increasingly implicated in the expression and maintenance of long COVID.1 16 17 Understanding and managing such complexity can be challenging to clinicians who may resort to heuristic classifications such as ‘functional’ disorder. As a consequence, many patients report stigmatisation and can wait years for a diagnosis to access appropriately targeted and potentially effective treatment.18 Similar perceptions appear to be emerging in relation to long COVID.19 20 This may compromise the planning and delivery of cost-effective and timely therapy, both at the level of the individual patients and the level of healthcare service provision.
There is growing interest in how variant connective tissue (often recognised by the presence of generalised joint hypermobility (GJH)) may represent a common constitutional factor predisposing to such complex multisystem conditions and disorders (see box 1). GJH is a characteristic marker of hereditary disorders of connective tissue, which ultimately compromises a matrix of proteins that includes collagens, elastins, fibrillins and tenascins. Joint hypermobility is typically more common in females and declines with age. GJH itself is not necessarily a medical problem, but certain clinical phenotypes, notably hypermobile Ehlers–Danlos syndrome (hEDS; previously known as EDS hypermobility type/EDS type-III) and hypermobility spectrum disorder (HSD) are associated with clinically significant issues, including chronic disabling fatigue and dysautonomia.14 Around 20% of the UK population fulfil the criteria for GJH as an indicator of variant connective tissue structure.21 However, less clear is whether individuals with GJH are predisposed to COVID-19 infection and impaired recovery.
Clinical phenomena associated with symptomatic joint hypermobility (HSD/EDS)
Strong association with symptomatic joint hypermobility (HSD/EDS):
Chronic pain (including headache, migraine and orofacial pain due to temporomandibular joint disease; visceral pain; musculoskeletal pain including oligoarticular/polyarticular pain, and neuropathic pain).
Chronic fatigue sufficiently disabling to interfere with day-to-day function.
Functional gastrointestinal disorders (Rome IV criteria), including slow gastrointestinal transit.
Postural orthostatic tachycardia syndrome, orthostatic hypotension, orthostatic intolerance.
Neurological manifestations (in adults): atlanto-axial/cranio-cervical joint instability, Chiari 1 malformation, small fibre neuropathy/disease, local anaesthetic resistance.
Developmental coordination disorder.
Anxiety disorders, phobias, depression.
Evolving evidence of clinical association with symptomatic joint hypermobility (HSD/EDS), however this remains an area with clinical and scientific uncertainties:
Neurally-mediated hypotension.
Neurological manifestations (in children and adolescents).
Interstitial cystitis.
Underactive and hyperactive bladder.
Dysmenorrhoea or dysmenorrhagia.
Attention deficit/hyperactivity disorder and autism.
Immune dysregulation, intolerances and allergies.
Adapted and reproduced with permission of the hEDS/HSD Working Group, The International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders.
Aim of this study
The aim of this study was to determine, from the UK COVID Symptom Study Biobank (CSSB), if the presence of GJH is associated with an increased risk of not recovering fully from infection with COVID-19.
