Long Covid: ‘It’s like someone has piled sandbags on top of me’
Reece caught coronavirus during the first wave of the pandemic in March 2020, but like many twenty-somethings, he wasn’t hospitalised overnight.
What he thought would be a mild illness became a protracted nightmare with his partner Alice becoming his carer.
Months after his initial infection, he was diagnosed with CFS/ME (Chronic Fatigue Syndrome/Myalgic Encephalomyelitis) by his GP and referred to a specialist. His CFS/ME consultant later confirmed his CFS/ME symptoms were a form of ‘long Covid’ and referred him to a long Covid clinic [England].
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options.
To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis.
Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter.
Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
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Dear Stakeholder,
Because of the large number of comments received during consultation on the ME/CFS guideline, and the additional work needed to respond to them fully, the publication date has changed. The guideline will now publish on 18th August 2021.
A comparative survey of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) patients was carried out in three countries, with the aim of identifying appropriate policy measures designed to alleviate the burden of disease both on patients and their families, and also on public institutions.
The survey addressed demographic features, the economic impact of the disease on household incomes, patterns of medical and social care, specific therapies, social relationships, and the impact of the illness on quality of life.
Materials and Methods:
Parallel surveys were undertaken in Italy, Latvia, and the UK. There were 88 completed responses from Italy, 75 from Latvia, and 448 from the UK. To facilitate comparisons, 95% confidence intervals were calculated in respect of responses to questions from all three countries. To explore to what extent general practitioners (GPs) manage ME/CFS disease, a separate questionnaire for GPs, with questions about the criteria for granting a diagnosis, laboratory examinations, the involvement of specialists, and methods of treatment, was undertaken in Latvia, and there were 91 completed responses from GPs.
Results:
The results are presented in respect of sociodemographic information, household income, disease progression and management, perceived effectiveness of treatment, responsibility for medical care, personal care, difficulty explaining the illness, and quality of life. Demographic details were similar in all three countries, and the impact of illness on net household incomes and quality of life. There were significant differences between the three countries in illness progression and management, which may reflect differences in patterns of health care and in societal attitudes. Graded exercise therapy, practiced in the UK, was found to be universally ineffective.
Conclusions:
There were similarities between respondents in all three countries in terms of demographic features, the impact of the illness on household incomes and on quality of life, and on difficulties experienced by respondents in discussing their illness with doctors, but also differences in patterns of medical care, availability of social care, and societal attitudes to ME/CFS.
WAMES statement on post-viral illnesses: COVID-19 and ME/CFS
WAMES is calling on all political parties in Wales to support an inclusive approach to responding to COVID-19 and ME/CFS.
Wales needs a strategy to recognise and treat illnesses triggered by ALL viruses.
What we know about post-COVID illness:
Almost 70% of people affected by COVID experience damage to organs and lingering symptoms. https://www.bmj.com/content/371/bmj.m4470
10-20% are thought to experience a collection of symptoms which is being called Long COVID, including fatigability, breathlessness, brain fog, pain, sleep disturbance, palpitations. In Wales there are an estimated 15,000 patients with Long COVID.
Long COVID is being recognised as a health crisis and the NHS is beginning to consider how they can support patients, some offering psychological and exercise therapies.
People who have been hospitalised by COVID-19 are offered referrals, management advice and treatment. People with minor symptoms (or who are asymptomatic) can also develop long lasting symptoms but are not always believed by their GP and can be refused support or referrals.
Some Health Boards are developing exercise therapy or virtual self-management classes. The COVID Recovery app has been launched in Wales “to reassure those people that there is support available to them and that they are not alone.” Not everyone has been able to access the app.
Based on data from other viruses, including a previous SARS virus, a percentage of survivors will go on to develop the long term condition ME/CFS, possibly as high as 27% https://www.meresearch.org.uk/covid-19-and-me-cfs-cases/
What we know about ME/CFS:
A large percentage of people with ME/CFS are aware that they developed the condition following a virus. Doctors suspect that many more also experienced a virus but haven’t made the connection between that and developing ME/CFS.
ME/CFS is classified by the World Health Organisation as ‘a condition of the nervous system’ at G93.3 along with other recognised neurological conditions.
Research is uncovering widespread dysfunction in many of the body’s systems with the body unable to produce energy to maintain those systems efficiently. The key characteristic for patients is Post-Exertional Symptom Exacerbation (PESE) also known as Post-exertional Malaise (PEM), which is also experienced by many people with long COVID.
There are an estimated 13,000 people of all ages with ME/CFS in Wales, approximately 25% of whom are severely affected. If up to 27% with long COVID were to go on to develop long term ME/CFS, the number of people with ME/CFS could rise to over 17,000 in a year or two.
Many doctors still do not recognise ME/CFS as a serious long-term, life altering condition and do not refer disabled patients to support services.
Health Boards in Wales have been resistant in recognising and offering services for ME/CFS. Three offer psychological and exercise therapies for small numbers of patients with fatigue, alongside pain patients. ME researchers have been warning about the dangers of exercise therapy for decades so many people with ME/CFS have chosen not to access those services.
Infections, alongside activity, can lead to relapse and severe illness in ME/CFS, but the condition has not been specifically recognised and included with other neurological conditions, amongst those needing to shield from COVID-19, or be prioritised for vaccination.
What does the WHO and NICE say about long COVID & ME/CFS?
The WHO calls on countries to recognise the ‘impact on the individual, on society, and on the economy’ of Post-COVID syndrome, to prioritise rehabilitation and systematically gather information – to practice the “three Rs”—recognition, research, and rehabilitation.
The WHO has made no statement about ME/CFS, which affects an estimated 20 million people worldwide.
NICE issued a cautionary notice in 2020 for Long COVID which questioned the appropriateness of exercise therapy.
NICE issued rapid guidelines for COVID-19 in Dec 2020 which acknowledged the need for supported self-management based on multi-disciplinary clinics and goal-setting, but without specific guidance on the nature of management options.
NICE reversed its 2014 ME/CFS guidelines in the 2020 draft, no longer recommending exercise therapy and highlighting the need to manage Post-Exertional Symptom Exacerbation (aka PEM). The final version, which is expected to continue to recommend multi-disciplinary services for ME/CFS, is due out 21 April 2021.
WAMES believes it is right that people suffering from post-COVID symptoms should receive appropriate support from health and social care. It is not right that the NHS and social services should continue to minimise and ignore the debility triggered by other viruses. Now is the time to put right past omissions and put in place appropriate services for ALL survivors of viruses.
In 2020 WAMES called on the Welsh Government to lead the way in caring for ALL survivors of viruses, without discrimination. The response from the Health Minister did not address the issue. WAMES is able to supply more information about any of the issues mentioned above.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms.
To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range.
Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. (Medline)
We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance.
Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients.
Research Question
Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?
Study Design and Methods
We analyzed 1516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls. Rest-to-peak changes in cardiac output (Qc) were compared to oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.
Results
During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01).
In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.
Interpretation
These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.
Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.
Avoid the Tower of Babel phenomenon
The biblical parable of the Tower of Babel cautions that the pursuit of truth may lead to the inability to communicate. Although case definition criteria appear to have become more specific over time, the various names for and definitions of ME/CFS have created confusion and consternation in the patient and clinical communities. Already, several different labels for long COVID exist, even while optimal diagnostic criteria remain unclear. The consensus of the patient community has coalesced around referring to their experiences as “long COVID” and to themselves as “long haulers.” The clinical and research communities should honor the patient perspective by using this label to avoid alienating the patient community and creating confusion. Patients ultimately own and derive meaning from their diagnostic label, not any single area of clinical and scientific endeavor.
Hear, validate, and empower patients with long COVID
It has been estimated that 90% of ME/CFS cases may remain undiagnosed,5 suggesting that people with postviral fatigue already are substantially undercounted, underdiagnosed, and undertreated. The time between initial symptoms and diagnosis in ME/CFS cases is often long. The diagnostic process for ME/CFS is frustrating, because it is often seen as a diagnosis of exclusion. This process of medical evaluation is often exhaustive and expensive, and does not yield a result that leads to a cure.5
Mischaracterization of ME/CFS as a psychiatric condition is common.5 It is a generally stigmatizing condition, because symptoms and activity limitations may wax and wane from day to day, resulting in “good days” and “crash days.” This symptom pattern, which may appear as malingering or secondary gain to the uninitiated or uncompassionate clinician, is characterized by an invisible source of disablement underpinned by a fluctuating physiological baseline. Physical therapists should respect and validate symptom reports made by patients in good faith.
Acknowledge the apparent physiological basis of long COVID
People with ME/CFS generally demonstrate a blunted rise in heart rate with increasing activity intensity on cardiopulmonary exercise testing, which is called chronotropic intolerance.3 Heart rate responses to activity are further blunted during the postexertional state, which is observed at peak exertion and the ventilatory anaerobic threshold.3Chronotropic intolerance may provide important insight into the physiological basis of fluctuating activity tolerance in ME/CFS cases, because it suggests cardiac autonomic dysregulation.3 The cardiac autonomic dysregulation observed on cardiopulmonary exercise testing may be associated with clinical observations of postural orthostatic tachycardia and orthostatic hypotension in ME/CFS.
Patients with long COVID also have reported aberrant heart rate responses to exercise, including an increase in resting heart rate and orthostatic impairments. The apparent similarity in aberrant heart rate responses to exercise between ME/CFS and long COVID should be the subject of careful study. Yet, this relationship also suggests that activity pacing through heart rate monitoring may be useful for patients with long COVID, as it is for patients with ME/CFS.
Teach Respect for physiological activity limits in long COVID
Physical therapists must approach exercise prescription in long COVID with vigilance and caution, to ensure that the exercise program is restorative and not making the patient’s symptoms worse. Exercise should not cause symptoms of postexertional malaise. One useful way to monitor symptoms is to specifically ask about them in all patients with long COVID as part of the assessment process. The physical therapist may use validated questionnaires or a narrative approach to asking the patient to characterize her or his top lon COVID symptoms in response to exercise.
Further, exercise should not be undertaken to the exclusion of the patient’s desired daily activities. Black et al2 found that a graded exercise program increased step counts in people with ME/CFS. A secondary analysis of the data revealed that an increased step count was a self-fulfilling prophecy of the graded exercise program, because it did not increase the accelerometer count associated with usual daily activity.1 Physical therapists should be aware that patients with long COVID may adhere to graded exercise programs that cause diminishing returns in daily functioning.
Conclusion
While we are learning something new each day about the consequences of SARS-CoV-2 infection, our collective experience with postviral fatigue is not entirely new. We know enough as a clinical and scientific community to avoid the same perils and pitfalls of ME/CFS when dealing with a novel coronavirus, even as we continue to research the best possible diagnostics and therapeutics.
References
Black CD, McCully KK. Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005;4:10. https://doi.org/10.1186/1476-5918-4-10
Black CD, O’Connor P J, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med. 2005;4:3. https://doi.org/10.1186/1476-5918-4-3
Davenport TE, Lehnen M, Stevens SR, VanNess JM, Stevens J, Snell CR. Chronotropic intolerance: an overlooked determinant of symptoms and activity limitation in myalgic encephalomyelitis/chronic fatigue syndrome? Front Pediatr. 2019;7:82. https://doi.org/10.3389/fped.2019.00082
Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact [preprint]. medRxiv. 2020. https://doi.org/10.1101/2020.12.24.20248802
Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
[Reuse of JOSPT blog content is permitted under the Creative Commons BY-NC-ND (CC-BY-NC-ND) license.]
This was submitted (December 2020) to NICE in response to the new draft ME/CFS guidance of November 2020, which had removed the recommendation for Graded Exercise Therapy (GET), and downgraded CBT from therapeutic to a ‘supportive’ option.
I appear to be the first UK psychiatrist to be openly critical of the PACE trial.
My submission:
The PACE trial was seriously unethical. The senior researchers continue to deny this, despite the clear evidence. Therefore the trial is not only at ‘high risk of bias’, but at significant risk of fraud, and it should be retracted as a trial of treatments…
…The PACE trial may be of some historical interest and even future relevance in relation to depression and anxiety in ME/CFS, and on the issue as to whether CFS might validly be considered a separate condition from both ME and depression, as appears to be the view and experience of some patients and some PACE-independent professionals.
The reported rates of anxiety syndromes plus depression (47%) and depression alone (34%) were high. Many people do find CBT helpful as a form of support for those conditions, so it is reasonable for NICE to recommend CBT as a form of support, but a caution should be added about the risk of harm, especially if coercion might encroach. This caution might be reinforced by adopting the term ‘cognitive behavioural support’, or ‘CBS’, in place of ‘CBT’. NICE should also recommend research into other forms of psychosocial support.
The reported rate of ‘post-exertional malaise’ (PEM/PENE) was also high (82-87%), suggesting that its presence or absence cannot be used as the sole criterion for ME/CFS. That is an issue which continues to concern ME/CFS patients and PACE-independent professionals, and therefore justifies further research, especially on the question of whether some people with non-ME/CFS depression have similar PEM. If there is a separate ‘CFS’ entity, then the nature and degree of PEM in that would also be relevant.
COVID-19: A methyl-group assault? by Andrew McCaddon, Björn Regland inMedical Hypotheses Vol 149, Apr 2021, 110543 [ doi.org/10.1016/j.mehy.2021.110543]
Research abstract:
The socio-economic implications of COVID-19 are devastating. Considerable morbidity is attributed to ‘long-COVID’ – an increasingly recognized complication of infection. Its diverse symptoms are reminiscent of vitamin B12 deficiency, a condition in which methylation status is compromised.
We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon metabolism. We propose these might explain the varied symptoms of long-COVID. Our suggested mechanism might also apply to similar conditions such as myalgic encephalomyelitis/chronic fatigue syndrome.
The hypothesis is evaluable by detailed determination of vitamin B12 and folate status, including serum formate as well as homocysteine and methylmalonic acid, and correlation with viral and host RNA methylation and symptomatology. If confirmed, methyl-group support [supplementation] should prove beneficial in such individuals.
Conclusion
We suggest that SARS-CoV-2 induces an increased demand for methyl-groups whilst simultaneously impairing their supply due to viral-induced oxidative stress.
The biochemical implications of our hypothesis might explain the diverse symptoms experienced by patients with long-COVID and, if confirmed, suggests possible approaches to treatment.
It would be ironic if the socio-economic devastation of COVID-19, by intensifying world-wide research in a viral pandemic, leads to valuable insights into other conditions such as ME/CFS, as well as providing additional clues to the aetiology of memory disorders and dementia, including Alzheimer’s disease.
Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that 
A comparative survey of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) patients was carried out in three countries, with the aim of identifying appropriate policy measures designed to alleviate the burden of disease both on patients and their families, and also on public institutions.
WAMES is calling on all political parties in Wales to support an inclusive approach to responding to COVID-19 and ME/CFS.
We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the 
Avoid the Tower of Babel phenomenon
…The PACE trial may be of some historical interest and even future relevance in relation to depression and anxiety in ME/CFS, and on the issue as to whether CFS might validly be considered a separate condition from both ME and depression, as appears to be the view and experience of some patients and some PACE-independent professionals.
We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon 
