Abstracts from August

Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1863 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1863

1. Russell S Malcolm, specialty doctor

Newman’s investigation of chronic fatigue syndrome and long covid supports the development of specialised multidisciplinary support for patients with long covid.1 But compartmentalisation of a problem like chronic fatigue syndrome can sometimes miss the point.
Dysregulated systems, by their nature, cannot be manipulated into functionality, so the clinical modelling of a system disturbance is often best undertaken by a clinician with dedicated expertise in multisystem assessment who can pull the “hard” and “soft” data together.
Specialised teams, such as the fatigue clinic at the Royal London Hospital for Integrated Medicine, routinely individualise chronic fatigue syndrome cases to a high level of detail. In the absence of objective data, the use of advanced and holistic history taking can explore the factors that perpetuate the clinical state.
The “forensic” part of the inquiry searches for the symptomatic features of pathophysiological change, hypothalamic dysregulation, or ongoing immunological disturbance. The physical and functional inquiry is then contextualised by an empathic and holistic psychosocial survey.
Each patient has a unique combination of perpetuating factors in chronic fatigue syndrome and long covid, so treatment approaches should also be individualised to a high degree. This level of individualisation is not always possible using a compartmentalised method of assessment.

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Long covid: reshaping conversations about medically unexplained symptoms
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1859 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1859

1. Sean L Davidson, psychiatry registrar1,  
2. David B Menkes, academic psychiatrist2
3. [email protected]

Newman’s article, a linked patient commentary, and the tranche of rapid responses show how “long covid” has reignited debate about the causes and management of chronic fatigue syndrome.1 Rather than moving beyond the controversy, most of the ensuing arguments have fallen back into familiar grooves deepened by confirmation bias and dualistic thinking.123 On a more positive note, the intense media attention on and public interest in long covid present a golden opportunity to reshape and extend discussions about medically unexplained symptoms.
Patients presenting with symptoms in the presence of normal diagnostic tests account for 26-35% of consultations in primary care.4 The banner of medically unexplained symptoms encompasses heterogeneous issues—simple transient problems, recognised symptom complexes such as chronic fatigue syndrome, and emerging phenomena like long covid. All present challenges to the doctor-patient relationship, confer risks of overdiagnosis and overtreatment, and can provoke frustration and anxiety in junior and experienced clinicians alike.25
These common clinical scenarios emphasise the pressing need for a framework to aid communication with patients who are frustrated by the mismatch of disabling symptoms and normal investigations. The contrasting societal and medical narratives that Newman outlines regarding chronic fatigue exemplify the challenges that doctors and patients face together in coming to a shared understanding of diagnosis and management options.12 These consultations often carry the weight of decades of power imbalance, psychological stigma, and bitter dualistic debate, leaving both doctor and patient dissatisfied.13
In contrast to most medical specialties, neurologists have made remarkable progress in establishing a patient led terminology and common framework to positively identify and manage functional disorders.6 Other disciplines should strive to match this example but recognise that complex and undifferentiated presentations will doubtless persist and require skill and judgment to investigate appropriately and to constructively manage uncertainty. Crucially, this approach must leave room for an evolving evidence base because “unexplained” does not mean “unexplainable.” Long covid provides an opportunity for the medical profession to move beyond stale controversies and to reconsider how we discuss symptoms lacking clear cause with patients, students, and colleagues.
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Exclusive: Four members of NICE’s guideline committee on ME/CFS stand down
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1937 (Published 03 August 2021)Cite this as: BMJ 2021;374:n1937

1. Ingrid Torjesen

Four members of the NICE guideline development committee for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) left the group just weeks before the final guideline was due to be published, The BMJ has learnt.
The departures suggest divisions within the committee over the guideline’s final content, which is an update on 2007 guidance on diagnosing and managing ME/CFS. Three have resigned, and one has been removed by NICE.
The draft guidance, published in November 2020,1 included significant changes to the 2007 recommendations2 and raised questions about how the evidence could have shifted so substantially.
In 2007 NICE recommended interventions such as cognitive behavioural therapy and graded exercise therapy for people with mild or moderate ME/CFS, whereas the draft update cites a “lack of evidence for the effectiveness of these interventions.” …
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Nutrients. 2021 May; 13(5): 1397.
Published online 2021 Apr 21. doi: 10.3390/nu13051397 PMCID: PMC8143286 PMID: 33919346
Véronique Morel,1 Marie-Eva Pickering,2 Jonathan Goubayon,1 Marguérite Djobo,1 Nicolas Macian,1 and Gisèle Pickering1,*
Maria Perticone, Academic Editor


Clinical Investigation Center, Inserm CIC 1405, Bat 3C, University Hospital Clermont-Ferrand, F-63000 Clermont-Ferrand, France; rf.dnarreftnomrelc-uhc@lerom_v (V.M.); rf.dnarreftnomrelc-uhc@noyabuogj (J.G.); rf.dnarreftnomrelc-uhc@obojdm (M.D.); rf.dnarreftnomrelc-uhc@naicamn (N.M.)
Abstract
Background: Magnesium (Mg) is commonly used in clinical practice for acute and chronic pain and has been reported to reduce pain intensity and analgesics consumption in a number of studies. Results are, however, contested. 
Objectives: This review aims to investigate randomised clinical trials (RCTs) on the effectiveness of Mg treatment on pain and analgesics consumption in situations including post-operative pain, migraine, renal pain, chronic pain, neuropathic pain and fibromyalgia. 
Results: The literature search identified 81 RCTs (n = 5447 patients) on Mg treatment in pain (50 RCTs in post-operative pain, 18 RCTs in migraine, 5 RCTs in renal pain, 6 RCTs in chronic/neuropathic pain, 2 RCTs in fibromyalgia). 
Conclusion: The level of evidence for the efficacy of Mg in reducing pain and analgesics consumption is globally modest and studies are not very numerous in chronic pain. A number of gaps have been identified in the literature that need to be addressed especially in methodology, rheumatic disease, and cancer. Additional clinical trials are needed to achieve a sufficient level of evidence and to better optimize the use of Mg for pain and pain comorbidities in order to improve the quality of life of patients who are in pain.

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Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen,Peter C. Rowe, Frans C. Visser
 Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. 
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy, Shaun Bhatia, Mohammed Islam, Leonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.  

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The Lonely, Isolating, and Alienating Implications of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Samir Boulazreg, Ami Rokach
Faculty of Education, University of Western Ontario, London, ON N6A 3K7, Canada
Department of Psychology, York University, Toronto, ON M3J 1P3, Canada
*Healthcare 2020, 8(4), 413; https://doi.org/10.3390/healthcare8040413
Received: 17 July 2020 / Revised: 27 September 2020 / Accepted: 11 October 2020 / Published: 20 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
This article provides a narrative review on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through a psychosocial lens and examines how this impairment affects its sufferers during adolescence and adulthood, as well as how it impacts family caregivers and healthcare professionals’ mental health. Since there has been a lack of investigation in the literature, the primary psychosocial stressor that this review focuses on is loneliness. As such, and in an attempt to help establish a theoretical framework regarding how loneliness may impact ME/CFS, loneliness is comprehensively reviewed, and its relation to chronic illness is described. We conclude by discussing a variety of coping strategies that may be employed by ME/CFS individuals to address their loneliness. Future directions and ways with which the literature may investigate loneliness and ME/CFS are discussed.
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Heliyon. 2021 Aug;7(8):e07665.
 doi: 10.1016/j.heliyon.2021.e07665. Epub 2021 Jul 29.
The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data
João Malato 1 2, Franziska Sotzny 3, Sandra Bauer 3, Helma Freitag 3, André Fonseca 4, Anna D Grabowska 5, Luís Graça 1, Clara Cordeiro 2 4, Luís Nacul 6 7, Eliana M Lacerda 6, Jesus Castro-Marrero 8, Carmen Scheibenbogen 3, Francisco Westermeier 9 10, Nuno Sepúlveda 2 3 11
PMID: 34341773   PMCID: PMC8320404   DOI: 10.1016/j.heliyon.2021.e07665
Abstract
People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Given that this reporting agrees with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed at answering whether the expression of the human angiotensin-converting enzyme 2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in these patients. In particular, a low expression of ACE2 could be indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients when compared to healthy controls. Accordingly, in newly collected data, there was evidence for a significant higher proportion of samples with an ACE2 expression below the limit of detection in patients than healthy controls. Altogether, patients with ME/CFS can be at a higher COVID-19 risk and, if so, they should be considered a priority group for vaccination by public health authorities. To further support this conclusion, similar research is recommended for other human cell entry receptors and cell types, namely, those cells targeted by the virus.
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Orthostatic stress testing in myalgic encephalomyelitis/chronic fatigue syndrome patients with or without concomitant fibromyalgia: effects on pressure pain thresholds and temporal summation
 C.(L.)M.C. van Campen1 , P.C. Rowe2 , F.W.A. Verheugt3 , F.C. Visser
ABSTRACT 
Objective. Muscle pain and fibromyalgia (FM) are common among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). We recently demonstrated that during orthostatic stress testing, adults with ME/CFS reported increased pain. In the current study, we hypothesised that pain pressure thresholds (PPT) would decrease and temporal summation (windup) would increase after head-up tilt testing (HUT), and that the presence of co-morbid FM would be associated with greater change in both measures. 
Methods. We studied adult ME/CFS patients undergoing HUT. PPT and temporal summation (or windup) measurements were obtained pre- and post-HUT at the finger and shoulder. 
Conclusion. Pressure pain threshold decreased in ME/CFS patients with or without fibromyalgia after head-up tilt test (HUT), but did not change postHUT in healthy controls. Windup preand post-HUT was significantly higher compared to healthy controls, but did not change from pre- to post-HUT. These results demonstrate that, like exercise, orthostatic stress can negatively influence the physiology of pain perception in ME/CFS. Furthermore, the physiology of pain perception is even more negatively influenced by concomitant fibromyalgia. 
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Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome
Annamaria De Bellis, Giuseppe Bellastella, Vlenia Pernice, Paolo Cirillo, Miriam Longo, Antonietta Maio, Lorenzo Scappaticcio, Maria Ida Maiorino, Antonio Bellastella, Katherine Esposito ... Show more
The Journal of Clinical Endocrinology & Metabolism, dgab429, https://doi.org/10.1210/clinem/dgab429     Published:13 July 2021
 Context
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.
Objective
This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Methods
This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results
Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).
Conclusion
Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

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Front. Med., 18 June 2021 | https://doi.org/10.3389/fmed.2021.688486
The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson*

• Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, United States

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
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GPs need awareness about post-covid ME/CFS
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1995 (Published 12 August 2021)Cite this as: BMJ 2021;374:n1995

1. Caroline Kamau-Mitchell, senior lecturer
2. [email protected]

Wise reports that general practitioners might be under-reporting long covid in patient records.1 Approximately 25% of people infected with SARS-CoV-1 developed debilitating fatigue and other symptoms that met diagnostic criteria for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) that continued for more than four years.2 So patients with long covid who have had chronic fatigue for six or more months, together with other mandatory symptoms, are likely to be diagnosed as having ME/CFS.
A recent inquiry report for the House of Lords discussed the need for GPs to follow-up patients with suspected long covid and to determine whether those still experiencing severe fatigue after six months meet the other diagnostic criteria for ME/CFS.3 Although there is no known cure, viruses are known to be one of the possible causes of ME/CFS,4 so recognising the chronic fatigue reported by many patients with long covid can help GPs direct them to appropriate support.3 Without enough awareness, patients presenting with long covid symptoms might not be believed by some GPs or might receive misdiagnoses for mental conditions. Not all patients with long covid have ME/CFS but, for those who do, GPs must identify the need for appropriate support, including referrals to occupational rehabilitation support services.3
Data are needed to clarify rates of ME/CFS after covid-19, and GPs can help by conducting six month follow-up of patients who report long covid.
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Long covid—mechanisms, risk factors, and management
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1648 (Published 26 July 2021)Cite this as: BMJ 2021;374:n1648
Harry Crook, research assistant1,  Sanara Raza, research assistant1,  Joseph Nowell, research assistant1,  Megan Young, clinical research officer1,  Paul Edison, clinical senior lecturer, honorary professor12

1. Correspondence to P Edison [email protected]

Abstract
Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Lucinda Bateman, MD,Alison C. Bested, MD,Hector F. Bonilla, MD,Ilene S. Ruhoy, MD, PhD, Maria A. Vera-Nunez, MD, MSBI, Brayden P. Yellman, MD
Open Access Published:August 25, 2021DOI:https://doi.org/10.1016/j.mayocp.2021.07.004
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
CBT (cognitive behavioral therapy), GET (graded exercise therapy), ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), NAM (National Academy of Medicine), PEM (post-exertional malaise)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multi-system disease affecting millions of people worldwide. Despite its high prevalence and disabling nature, medical education programs rarely cover ME/CFS and guidance for practicing clinicians is often outdated and inappropriate. 
 Standard tests typically return normal results, and some clinicians are wholly unaware of or question the legitimacy of ME/CFS.
 Consequently, up to 91% of affected people are undiagnosed or misdiagnosed with other conditions, such as depression.
 To obtain a diagnosis, patients frequently have had to see multiple clinicians over a number of years. Even after diagnosis, patients struggle to obtain appropriate care and have often been prescribed treatments, such as cognitive-behavioral therapy (CBT) and graded exercise therapy (GET), that could worsen their condition.
In 2015, the US National Academy of Medicine (NAM, previously the Institute of Medicine) created new ME/CFS clinical diagnostic criteria that required the hallmark symptom of post-exertional malaise (PEM).
 The US Centers for Disease Control and Prevention have adopted these new criteria, have removed recommendations for CBT and GET, and have begun to incorporate the best clinical practices of ME/CFS experts. These steps will help improve the speed and accuracy of diagnosis and the quality of clinical care.
Lingering symptoms including fatigue follow various types of infectious illnesses.
 These “postinfectious” fatigue syndromes resemble ME/CFS.
 Moreover, ME/CFS itself often follows an infectious-like illness.
 On occasion, the infectious illness preceding ME/CFS, such as infectious mononucleosis,
 Coxiella burnetii infection,
 giardiasis,
 or severe acute respiratory syndrome (caused by a coronavirus similar to the etiologic agent of COVID-19), has been well documented, but often, no attempt has been made to diagnose the infectious agent.
Following acute COVID-19, whether hospitalized or not, many patients continue to experience debility and symptoms for many months.
 Some of these “long haulers” may have symptoms reflecting organ damage, such as to the lungs or heart, from the acute disease.
 Other long haulers are symptomatic despite having no clear evidence of such organ damage.
 A study of patients ill 6 months after mild or moderate acute COVID-19 found that about half met criteria for ME/CFS.
 One review suggested that the number of cases of ME/CFS could double as a result of the pandemic.
 Like ME/CFS patients, those with post-COVID conditions have recounted being dismissed by health care professionals.
This article provides essential information about how to diagnose and care for adults with ME/CFS and echoes other recent ME/CFS guidance
 Accurately and expeditiously diagnosing ME/CFS is important. There are many steps a clinician can take to improve the health, function, and quality of life of these patients. Even if they do not go on to develop ME/CFS, some patients with post-COVID conditions may also benefit from approaches such as pacing.
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Front. Syst. Neurosci., 01 September 2021 | https://doi.org/10.3389/fnsys.2021.698240
Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
 Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman2Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett
1Cortene Inc., Burlingame, CA, United States
Bateman Horne Center, Salt Lake City, UT, United States

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

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Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study
Michela Antonelli et al-based,
Published:September 01, 2021 DOI:https://doi.org/10.1016/S1473-3099(21)00460-6 nested, Summary
Background
COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.
Methods
This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.
Findings
Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.
Interpretation
To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.

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2021 Jul 13;12:687806.Frontiers in Immunology  doi: 10.3389/fimmu.2021.687806. eCollection 2021.
Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment
Helene Cabanas 1 2, Katsuhiko Muraki 2 3, Natalie Eaton-Fitch 1 2, Donald Ross Staines 1 2, Sonya Marshall-Gradisnik 1 2 PMID: 34326841 PMCID: PMC8313851  
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0-5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS. As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique. We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.
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Published by De Gruyter April 22, 2020
Diagnosis of mast cell activation syndrome: a global “consensus-2”
Lawrence B. Afrin , Mary B. Ackerley, Linda S. Bluestein, Joseph H. Brewer, Jill B. Brook, Ariana D. Buchanan, Jill R. Cuni, William P. Davey, Tania T. Dempsey , Shanda R. Dorff, Martin S. Dubravec, Alena G. Guggenheim, Kimberly J. Hindman, Bruce Hoffman, David L. Kaufman, Stephanie J. Kratzer, Theodore M. Lee, Mindy S. Marantz, Andrew J. Maxwell, Kelly K. McCann, Dwight L. McKee, Laurie Menk Otto, Laura A. Pace, Dahra D. Perkins, Laurie Radovsky, Mary S. Raleigh, Sonia A. Rapaport, Emma J. Reinhold, Mark L. Renneker, William A. Robinson, Aaron M. Roland, E. Scott Rosenbloom, Peter C. Rowe, Ilene S. Ruhoy, David S. Saperstein, David A. Schlosser, Jill R. Schofield, Janet E. Settle, Leonard B. Weinstock, Martina Wengenroth, Mark Westaway, Shijun Cindy Xi and Gerhard J. Molderings
From the journal Diagnosis   https://doi.org/10.1515/dx-2020-0005
Abstract
The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
Keywords: chronic illness; mast cell activation disease; mast cell activation syndrome; medical controversies; medically unexplained symptoms; misdiagnosis

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Long COVID: low prevalence in SARS-CoV-2 infected children
Radtke T & al.. JAMA, 15 July 2021 Miriam Davis, PhD   |   16 September 2021
Takeaway

• Long-term symptoms after SARS-CoV-2 infection (so-called long COVID) affect 4% of children and adolescents vs 2% of uninfected control participants, according to a longitudinal cohort study.

Why this matters

• This is the first report of long COVID prevalence in a population-based cohort of children and adolescents with the use of an uninfected control group.

Study design

• Population-based longitudinal cohort study of children from randomly selected classes in 55 randomly selected schools in the canton of Zurich, Switzerland.
• SARS-CoV-2 infection was determined by serology testing at 2 points and long COVID was assessed by online symptom questionnaires.
• 109 seropositive children were compared with 1246 seronegative children (between October 2020 and March/April 2021).
• Funding: Swiss Federal Office of Public Health; University of Zurich Foundation; private funders.

Key results

• Median age, 11 years; interquartile range, 9-13 years; 54% girls.
• Age and sex patterns were similar between seropositive and seronegative children.
• Long COVID prevalence: 4% of 109 seropositive children vs 2% of seronegative control participants reported ≥1 symptom lasting >12 weeks.
• Most frequently reported symptoms in seropositive vs seronegative children were:
  • Tiredness (3% vs 1%).
  • Difficulty in concentrating (2% vs 1%).
  • Increased need for sleep (2% vs 0%).

Limitations

• Small number of seropositive children.
• Lack of information regarding exact time of SARS-CoV-2 infection.
• Potential misclassification because of false seropositive results.

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Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner, Sonya C. Becker, [...], and Carmen Scheibenbogen
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p= 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity
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MEDICAL NEWS   Rates of persistent COVID-19 symptoms a year after hospital discharge    Dawn O'Shea   |   30 August 2021
Half of hospitalised COVID-19 survivors experience at least one persistent symptom a year after discharge, suggests a study published in The Lancet.
The study assessed 1276 COVID-19 survivors at six and 12 months following discharge from Jin Yin-tan Hospital in Wuhan, China, between January 7 and May 29, 2020.
At six months, 68 per cent had at least one sequelae symptom, decreasing to 49 per cent at 12 months (P<.0001). The proportion of patients with dyspnoea, characterised by a modified British Medical Research Council (mMRC) score of ≥1, was 26 per cent at six months and 30 per cent at 12 months (P=.014). Additionally, more patients had anxiety or depression at 12 months (26%) than at six months (23%). There was no significant change in distance walked in 6 min (6MWD).
Eighty-eight per cent of patients who were employed before COVID-19 had returned to their original work at 12 months.
Compared with men, women had an odds ratio (OR) for fatigue or muscle weakness (1.43; 95% CI 1.04-1.96), anxiety or depression (OR 2.00; 95% CI 1.48-2.69), and impaired diffusion (OR 2.97; 95% CI 1.50-5.88).
At 12 months, COVID-19 survivors had more problems with mobility, pain or discomfort, and anxiety or depression, and had more prevalent symptoms than controls.

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Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
Theory: Treatments for Prolonged ICU Patients May Provide New Therapeutic Avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
• 3Analytical Chemistry and Neurochemistry, Department of Chemistry–Biomedical Center, Uppsala University, Uppsala, Sweden
• 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

We here provide an overview of treatment trials for prolonged intensive care unit (ICU) patients and theorize about their relevance for potential treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these treatment trials generally target: (a) the correction of suppressed endocrine axes, notably through a “reactivation” of the pituitary gland's pulsatile secretion of tropic hormones, or (b) the interruption of the “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. There are significant parallels in the treatment trials for prolonged critical illness and ME/CFS; this is consistent with the hypothesis of an overlap in the mechanisms that prevent recovery in both conditions. Early successes in the simultaneous reactivation of pulsatile pituitary secretions in ICU patients—and the resulting positive metabolic effects—could indicate an avenue for treating ME/CFS. The therapeutic effects of thyroid hormones—including in mitigating O&NS and inflammation and in stimulating the adreno-cortical axis—also merit further studies. Collaborative research projects should further investigate the lessons from treatment trials for prolonged critical illness for solving ME/CFS.

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Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116546/#
Lindsay S. Petracek, Stacy J. Suskauer, [...], and Peter C. Rowe
Abstract
Introduction: Fatigue is a common acute symptom following SARS-CoV-2 infection (COVID-19). The presence of persistent fatigue and impaired daily physical and cognitive function has led to speculation that like SARS-CoV-1 infection, COVID-19 will be followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods and Results: We describe three adolescent and young adult patients who had confirmed or probable COVID-19 infections early on during the pandemic and were referred for evaluation to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients reported orthostatic intolerance symptoms within the first 2 weeks of illness, and 10-min passive standing tests were consistent with postural tachycardia syndrome. After 6 months of illness, all three patients met criteria for ME/CFS. Clinical features of interest included strong histories of allergies in all three patients, two of whom had elevations in 
plasma histamine. Each demonstrated limitations in symptom-free range of motion of the limbs and spine and two presented with pathological Hoffman reflexes. These comorbid features have been reported in adolescents and young adults with ME/CFS.
Conclusion: ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities.

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Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT
Melanie L. Bell , Collin J. Catalfamo,Leslie V. Farland,Kacey C. Ernst,Elizabeth T. Jacobs,Yann C. Klimentidis, 
Megan Jehn, Kristen Pogreba-Brown

Published: August 4, 2021    https://doi.org/10.1371/journal.pone.0254347

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30–250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1–20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.

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Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study 
Linda W G Luijten, Sonja E Leonhard, Annemiek A van der Eijk, Alex Y Doets, Luise Appeltshauser, Samuel Arends, Shahram Attarian, Luana Benedetti, Chiara Briani, Carlos Casasnovas  
Brain, awab279, https://doi.org/10.1093/brain/awab279  Published: 23 September 2021

Abstract
In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12–22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not.
*
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Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study
Suzanne McDonald, Smuel X. Tan, Shamima Banu, Mieke van Driel, James M. McGree, Geoffrey Mitchell & Jane Nikles 
The Patient - Patient-Centered Outcomes Research (2021)Published: 09 August 2021


Abstract Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level.
Methods and Analysis
Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6–12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview.
Discussion
This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management.

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Causal attributions and perceived stigma for myalgic encephalomyelitis/chronic fatigue syndrome
Laura Froehlich, Daniel BR Hattesohl, Joseph Cotler, .First Published July 9, 2021 Research Article   https://doi.org/10.1177/13591053211027631  J of Health Psychology

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with the hallmark symptom of post-exertional malaise. Evidence for physiological causes is converging, however, currently no diagnostic test or biomarker is available. People with ME/CFS experience stigmatization, including the perception that the disease is psychosomatic. In a sample of 499 participants with self-diagnosed ME/CFS, we investigated perceived stigma as a pathway through which perceived others’ causal attributions relate to lower satisfaction with social roles and activities and functional status. Higher perceived attributions by others to controllable and unstable causes predicted lower health-related and social outcomes via higher perceived stigma.

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Mayo Clinic Proceedings
Available online 25 August 2021
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Author links open overlay panelLucindaBatemanMDaAlison C.BestedMDbHector F.BonillaMDdBela V.ChhedaMDeLilyChuMD, MSHSfJennifer M.CurtinMDeTania T.DempseyMDgMary E.DimmockBAhTheresa G.DowellDNP, MPTiDonnaFelsensteinMDjDavid L.KaufmanMDeNancy G.KlimasMDcAnthony L.KomaroffMDkCharles W.LappMBME, MDlSusan M.LevineMDmJose G.MontoyaMDnBenjamin H.NatelsonMDoDaniel L.PetersonMDp…Brayden P.YellmanMDa
https://doi.org/10.1016/j.mayocp.2021.07.004Get rights and content
Under a Creative Commons license
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
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