Papers by Caroline C Kingdon
MOESM1 of A logistic regression analysis of risk factors in ME/CFS pathogenesis
Additional file 1. Participant Questionnaires.
Developing a blood cell-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome using peripheral blood mononuclear cells
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fati... more Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients’ lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, we utilized a single-cell Raman platform and artificial intelligence to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. Our results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, we identified specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the devel...
Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice... more Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice has largely relied on clinical history, which can be subjective in nature. Clinical signs are often subtle, overlap with other conditions, and are not formally included as part of diagnostic workup. The characterization of clinical signs and biomarkers is needed for better diagnosis and classification of patients and to monitor treatment response. Hand grip strength (HGS) has been used as an objective measure of muscle strength and fatigue, which is a primary symptom of ME/CFS. We assessed the potential usefulness of HGS as a diagnostic marker in ME/CFS. Methods: We compared HGS measurements from participants in the UK ME/CFS Biobank, with groups consisting of people with ME/CFS of differing severity (n = 272), healthy (n = 136), multiple sclerosis (n = 76) controls, and others with chronic fatigue not meeting the diagnosis of ME/CFS (n = 37). We correlated the maximum and minimum of, and differences between, 3 repeated HGS measurements with parameters of disease severity, including fatigue and pain analog scales, and physical and mental component summaries from the SF-36v2TM questionnaire across recruitment groups. Results: HGS indicators were associated with having ME/CFS, with magnitudes of association stronger in severely affected than in mild/moderately affected patients. Compared with healthy controls, being severely affected was associated with a reduction in minimum HGS of 15.3 kg (95%CI 19.3-11.3; p < 0.001), while being mild/moderately affected was associated with a 10.5 kg (95%CI 13.2-7.8; p < 0.001) reduction. The association persisted after adjusting for age, sex and body mass index. ME/CFS cases also showed lower values of maximum HGS and significant drops in values from the first to second and third trials, compared to other study groups. There were significant correlations between HGS indicators and clinical parameters of disease severity, including fatigue analog scale (Spearman's Rho = −0.40, p < 0.001), pain analog scale (Rho = −0.38, p < 0.001), and physical component summary (Rho = 0.42, p < 0.001). Nacul et al. Hand Grip in ME/CFS Discussion: HGS is markedly reduced in ME/CFS, particularly in patients with more severe disease, and may indicate muscle and fatigue related symptoms. HGS is a potential diagnostic tool in ME/CFS, and could also be used to enhance patient phenotyping and as an outcome measure following interventions
The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published... more The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations. It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test. The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes. It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount. The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for...
BMC Neurology, 2019
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whos... more Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls. Methods This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset). Results A ...
Frontiers in Immunology, 2019
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unkn... more Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown aetiology, Myalgic encephalomyelitis unclear pathophysiology and with no diagnostic test or biomarker available. Many patients report their ME/CFS began after an acute infection, and subsequent increased frequency of infections, such as colds or influenza, is common. These factors imply an altered immunological status exists in ME/CFS, in at least a proportion of patients, yet previous studies of peripheral immunity have been discrepant and inconclusive. The UK ME/CFS Biobank, which has collected blood samples from nearly 300 clinically-confirmed ME/CFS patients, enables large-scale studies of immunological function in phenotypically well-characterised participants. In this study, herpes virus serological status and T cell, B cell, NK cell and monocyte populations were investigated in 251 ME/CFS patients, including 54 who were severely affected, and compared with those from 107 healthy participants and with 46 patients with Multiple Sclerosis. There were no differences in seroprevalence for six human herpes viruses between ME/CFS and healthy controls, although seroprevalence for the Epstein-Barr virus was higher in multiple sclerosis patients. Contrary to previous reports, no significant differences were observed in NK cell numbers, subtype proportions or in vitro responsiveness between ME/CFS patients and healthy control participants. In contrast, the T cell compartment was altered in ME/CFS, with increased proportions of effector memory CD8 + T cells and decreased proportions of terminally differentiated effector CD8 + T cells. Conversely, there was a significantly increased proportion of mucosal associated invariant T cells (MAIT) cells, especially in severely affected ME/CFS patients. These abnormalities demonstrate that an altered immunological state does exist in ME/CFS, particularly in severely affected people. This may simply reflect ongoing or recent infection, or may indicate future increased susceptibility to infection. Longitudinal studies of ME/CFS patients are needed to help to determine cause and effect and thus any potential benefits of immuno-modulatory treatments for ME/CFS.
Diagnostics, 2019
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting ... more Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass ...
Fatigue: Biomedicine, Health & Behavior, 2017
Frontiers in Neurology, 2018
Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice... more Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice has largely relied on clinical history, which can be subjective in nature. Clinical signs are often subtle, overlap with other conditions, and are not formally included as part of diagnostic workup. The characterization of clinical signs and biomarkers is needed for better diagnosis and classification of patients and to monitor treatment response. Hand grip strength (HGS) has been used as an objective measure of muscle strength and fatigue, which is a primary symptom of ME/CFS. We assessed the potential usefulness of HGS as a diagnostic marker in ME/CFS. Methods: We compared HGS measurements from participants in the UK ME/CFS Biobank, with groups consisting of people with ME/CFS of differing severity (n = 272), healthy (n = 136), multiple sclerosis (n = 76) controls, and others with chronic fatigue not meeting the diagnosis of ME/CFS (n = 37). We correlated the maximum and minimum of, and differences between, 3 repeated HGS measurements with parameters of disease severity, including fatigue and pain analog scales, and physical and mental component summaries from the SF-36v2TM questionnaire across recruitment groups. Results: HGS indicators were associated with having ME/CFS, with magnitudes of association stronger in severely affected than in mild/moderately affected patients. Compared with healthy controls, being severely affected was associated with a reduction in minimum HGS of 15.3 kg (95%CI 19.3-11.3; p < 0.001), while being mild/moderately affected was associated with a 10.5 kg (95%CI 13.2-7.8; p < 0.001) reduction. The association persisted after adjusting for age, sex and body mass index. ME/CFS cases also showed lower values of maximum HGS and significant drops in values from the first to second and third trials, compared to other study groups. There were significant correlations between HGS indicators and clinical parameters of disease severity, including fatigue analog scale (Spearman's Rho = −0.40, p < 0.001), pain analog scale (Rho = −0.38, p < 0.001), and physical component summary (Rho = 0.42, p < 0.001). Nacul et al. Hand Grip in ME/CFS Discussion: HGS is markedly reduced in ME/CFS, particularly in patients with more severe disease, and may indicate muscle and fatigue related symptoms. HGS is a potential diagnostic tool in ME/CFS, and could also be used to enhance patient phenotyping and as an outcome measure following interventions
BMC Neurology, 2017
Background: There are considerable phenotypic and neuroimmune overlaps between myalgic encephalom... more Background: There are considerable phenotypic and neuroimmune overlaps between myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). While the precise aetiologies of both MS and ME/ CFS are unclear, evidence suggests that deterioration in cognitive function is widely prevalent in patients with either condition. Little is known about differing risk factors or exposures, which may lead to severe cognitive or sleep symptoms. This study aims to gauge the extent of cognitive and sleep symptoms in ME/CFS and MS patients participating in the UK ME/CFS Biobank and identify the characteristics of those experiencing severe symptoms. Methods: This was a cross-sectional study of 395 UK ME/CFS Biobank participants, recruited from primary care and the community, using similar standardised protocols, and matched by age, sex and geographical area. Data were collected from participants using a standardized written questionnaire at clinical visits. Cognitive symptoms included problems with short-term memory, attention, and executive function. Sleep symptoms included unrefreshing sleep and poor quality or inadequate duration of sleep. All participants reported symptoms based on an ordinal severity scale. Multivariable logistic regression was carried out in the ME/CFS group to investigate socio-demographic factors associated with severe symptoms. Results: All cognitive and sleep symptoms were more prevalent in the ME/CFS group, with 'trouble concentrating' (98.3%) the most commonly reported symptom. Severe symptoms were also more commonly reported in the ME/CFS group, with 55% reporting 'severe, unrefreshing sleep'. Similarly, in the MS group, the most commonly reported severe symptoms were sleep-related. Logistic regression analysis revealed that ME/CFS patients aged over 50 years were more than three times as likely to experience severe symptoms than those younger than 30 (OR 3.23, p = 0.031). Current smoking was associated with severe symptoms, increasing the risk by approximately three times (OR 2.93, p = 0.003) and those with household incomes of more than £15,000 per year were less likely to experience severe symptoms compared to those earning less than this (OR 0.31, p = 0.017). Conclusions: Cognitive and sleep symptoms are more common in ME/CFS patients than in MS patients and healthy controls, providing further support for existing evidence of central nervous system abnormalities in ME/CFS. Our findings suggest that people with ME/CFS who are smokers, or have a low income, are more likely to report severe cognitive and sleep symptoms. Future research should aim to develop strategies to prevent the progression of severe cognitive and sleep symptoms through early interventions that prioritise patients identified as being at highest risk.
Fatigue: Biomedicine, Health & Behavior, 2017
; (2017) Differing case definitions point to the need for an accurate diagnosis of myalgic enceph... more ; (2017) Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue, 5 (1). pp. 1-4.
Journal of Health Psychology, 2017
Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting ... more Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care. A major constraint limiting progress has been the lack of a ‘gold standard’ for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome. We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.
Open journal of bioresources, 2017
The UK ME/CFS Biobank was launched in August 2011 following extensive consultation with professio... more The UK ME/CFS Biobank was launched in August 2011 following extensive consultation with professionals and patient representatives. The bioresource aims to enhance research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), related to pathophysiology, biomarkers and therapeutic approaches. The cohort includes 18-60 year olds, encompassing 284 clinically-confirmed ME/CFS cases, 60 neurologist-diagnosed multiple sclerosis (MS) cases, and 135 healthy individuals. The Biobank contains blood samples, aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA (totalling 29,863 aliquots). Extensive dataset (700 clinical and socio-demographic variables/participant) enables comprehensive phenotyping. Potential reuse is conditional to ethical approval.
Frontiers in Neurology, 2018
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized ... more Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis. This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique research infrastructure specifically designed to expedite biomedical research into ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants. The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points. As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analyzed within our research team but have also been shared with researchers across Europe, America and the Middle East. We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.
PharmacoEconomics - Open, 2018
Background People with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) continue to s... more Background People with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) continue to struggle to have their condition recognised as disabling in the face of public and professional prejudice and discrimination. Objective The aim of this study was to compare the functional status and well-being of people with well-characterised ME/CFS with people with multiple sclerosis (PWMS), as well as healthy controls (HCs). Methods In this cross-sectional study, we used data collected as part of the UK ME/CFS Biobank to compare actual participant scores from the Medical Outcomes Survey Short Form-36 v2 TM (SF-36v2 TM ) between groups, as a proxy for impact of disability, and from a bespoke questionnaire seeking data on employment and income. Results People with ME/CFS scored significantly lower than PWMS or HCs in almost all SF-36v2 TM areas. Prominent were lower scores for people with ME/CFS in the Physical Component Summary and Role Physical and Social Function domains, while the smallest differences were seen in the Mental Health domain. Responses to the bespoke questionnaire indicated that people with ME/CFS in this study work fewer hours and have lower incomes compared with people in the other two groups. Conclusions Using SF-36v2 TM scores as a proxy, people with ME/CFS were measurably more disabled than PWMS or HCs in this study population. Furthermore, employment and income data are consistent with loss of functional status. These findings should encourage the health community to recognise the disabling effects of ME/CFS, to advocate for the needs of people with ME/CFS, and to investigate strategies to address the cost of the disease to both individuals and society. This study suggests that at a group level people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are more disabled than people affected by multiple sclerosis (MS), as measured by the SF-36v2 TM . ME/CFS is associated with a reduction in time spent at work and lower income, compared with people affected by MS.
A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Frontiers in Medicine
We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyel... more We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using a natural history of disease approach to outline the distinct disease stages, with an emphasis on cases following infection to provide insights into prevention. Moving away from the method of subtyping patients based on the various phenotypic presentations and instead reframing along the lines of disease progression could help with defining the distinct stages of disease, each of which would benefit from large prospective cohort studies to accurately describe the pathological mechanisms taking place therein. With a better understanding of these mechanisms, management and research can be tailored specifically for each disease stage. Pre-disease and early disease stages call for management strategies that may decrease the risk of long-term morbidity, by focusing on avoidance of further insults, adequate rest to enable recovery, and pacing of act...
Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome
Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affec... more Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation. It is frequently reported to have been triggered by an infection, particularly with herpes virus family members; however, there are no clear differences in exposure to, or seroprevalence of, any herpes virus in people with ME/CFS and healthy individuals. Herpes viruses exist in lytic and latent forms, and it is possible that ME/CFS is associated with viral reactivation, which has not been detectable previously due to insensitive testing methods.Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for six months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine human herpes viruses was determined by digital droplet PCR. Symptoms w...
How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS
Frontiers in Neurology
Healthcare
Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive... more Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive no care from healthcare professionals, while some have become distanced from all statutory medical services. Paradoxically, it is often the most seriously ill and needy who are the most neglected by those responsible for their healthcare. Reasons for this include tensions around the complexity of making an accurate diagnosis in the absence of a biomarker, the bitter debate about the effectiveness of the few available treatments, and the very real stigma associated with the diagnosis. Illness severity often precludes attendance at healthcare facilities, and if an individual is well enough to be able to attend an appointment, the presentation will not be typical; by definition, patients who are severely affected are home-bound and often confined to bed. We argue that a holistic model, such as ‘‘Compassion in Practice’’, can help with planning appointments and caring for people severely af...
Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / MS) is an incapacitating chronic dise... more Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases. Here the expression of Endogenous retroviruses K and W
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Papers by Caroline C Kingdon