Unpacking post-covid symptoms
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1173 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1173 E[email protected]
Common, burdensome, and highly variable
Our understanding of long covid (also known as post-covid syndrome) has progressed considerably since the first follow-up of people discharged from hospital in 2020 after SARS-CoV-2 infection.12 People who were not admitted to hospital with their covid-19 infection but who have enduring symptoms have driven the wider recognition of long covid symptoms, including organ impairment.3 Much evidence comes from small, observational studies or surveys using different case definitions and sampling frames, resulting in a wide range of prevalence estimates.4 Larger surveys found that enduring symptoms were more often reported among people who had had covid-19 than among controls who had not,56 including reporting of cognitive deficits.7 However, reliance on self-reporting in many studies has been criticised by some commentators.
In a linked paper, Daugherty and colleagues (doi:10.1136/bmj.n1098) used a large electronic records dataset to describe the prevalence and risks of post-covid sequelae in patients both admitted to hospital and in the community in the United States.8 Several studies have retrospectively reviewed ICD-10 (international classification of diseases, 10th revision) codes in electronic health records, including a large study reporting that people admitted to hospital with covid-19 were 3.5 times more likely to be readmitted and 7.7 times more likely to die within five months of discharge than controls admitted to hospital without covid-19.9 Researchers using US Department of Veterans Affairs databases found increased use of analgesics, antidepressants, antihypertensives, and oral hypoglycaemics in the six months after confirmed covid-19 compared with controls,10 and data from the US TriNetX electronic health records network showed that nearly 34% of people testing positive for SARS-CoV-2 had a neurological or psychiatric diagnosis in the following six months.11
Daugherty and colleagues found that certain conditions were more commonly diagnosed after covid-19 than after other viral lower respiratory tract infections.8 The estimated 14% incidence of new diagnoses up to six months after SARS-CoV-2 infection is strikingly similar to the 13.7% incidence of self-reported symptoms lasting more than 12 weeks found by the UK Office for National Statistics.6 While both studies report higher incidence in people admitted to hospital, new symptoms and diagnoses were also seen in those who remained at home.6810 The absolute number of people reporting long covid symptoms will be higher in the community owing to the (at least) 10-fold difference in the numbers admitted to hospital and those who stayed at home.12 Primary care clinicians should expect patients with mild initial infections to report long covid or post-covid symptoms just as frequently as those who were critically ill.
In common with most studies, Daugherty and colleagues report that enduring symptoms are more common in women, those living with social deprivation, and those with pre-existing comorbidities.8 Importantly, they found that 10% of people developed new diagnoses requiring medical attention more than three weeks after the initial infection, with 4% developing more than one new diagnosis. This feature is well described by people with real life experience, who call it the “corona-coaster.” People who present with late onset symptoms (particularly those not admitted to hospital) report that some healthcare professionals do not associate symptoms with covid-19 and do not provide appropriate assessment and treatment.4
It is too early to predict how long clinical sequelae will persist after covid-19, but these symptoms clearly create a major personal burden for many people, with some individuals experiencing difficulty returning to work and some unable to care for dependents.4 Long covid is also putting a strain on healthcare services, which have been already decimated by the pandemic. Identifying risk factors would facilitate triage and faster access to specialist care. However, one of the peculiarities of long covid is its non-linear progression, hampering attempts to predict who will develop particular symptoms and when. Risk factors differ for different new diagnoses, suggesting that a variety of mechanisms could be at play.81011 Applying these risk factors to clinical practice will probably need long covid to be subdivided into more specific phenotypes.
Daugherty and colleagues’ analyses included people aged 18-65, and although symptom reporting is less common outside this age band,6 evidence is growing that children also experience long covid.1314 In older adults, symptoms could be under-reported because of assumptions that they are due to aging or comorbidities. Healthcare professionals should be alert to the possibility of long covid in anyone with confirmed or suspected covid-19. How to treat these longer term consequences is now an urgent research priority.
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Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1098 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1098
Sarah E Daugherty, senior researcher1, Yinglong Guo, director1, Kevin Heath, national medical director for clinical intelligence and physician2 , Micah C Dasmariñas, data scientist1, Karol Giuseppe Jubilo, data scientist1, Jirapat Samranvedhya, principal data scientist1, Marc Lipsitch, professor3, Ken Cohen, executive director of translational research and clinician2 4
Objective To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65.
Design Retrospective cohort study.
Setting Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database.
Participants Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness.
Main outcome measures More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated.
Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.
Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.
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Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome
WakiroSatoabHirohikoOnoaTakajiMatsutanicMasakazuNakamuraaIsuShindKeikoAmanoeRyujiSuzukicTakashiYamamuraab
https://doi.org/10.1016/j.bbi.2021.03.023Get rights and content
Brain, Behavior, and Immunity Volume 95, July 2021, Pages 245-255
Highlights
ME/CFS is characterized by skewed B cell receptor gene usage.
Upregulation of specific IGHV genes correlated to infection-related episodes at onset.
Plasmablasts of ME/CFS patients upregulated interferon response genes.
B cell receptor repertoire analysis can provide a useful diagnostic marker in ME/CFS.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.
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Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)Journal of Translational Medicine volume 19, Article number: 193 (2021)
Abstract
Background
Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).
Methods and results
In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.
Conclusion
This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.
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Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Klaus J. Wirth & Carmen Scheibenbogen
Journal of Translational Medicine volume 19, Article number: 162 (2021)
Abstract
Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.
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Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS
Bianka Jäkel, Claudia Kedor, Patricia Grabowski, Kirsten Wittke, Silvia Thiel, Nadja Scherbakov, Wolfram Doehner, Carmen Scheibenbogen & Helma Freitag
Journal of Translational Medicine volume 19, Article number: 159 (2021)
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters.
Methods
We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC.
Results
ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p ≤ 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p ≤ 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion.
Conclusion
Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS.
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J Clin Med 2020 Oct 11;9(10):3246. doi: 10.3390/jcm9103246.
Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial
Juan P Sanabria-Mazo 1 2 3 4, Jesus Montero-Marin 5, Albert Feliu-Soler 1 2 3, Virginia Gasión 6, Mayte Navarro-Gil 6 7, Héctor Morillo-Sarto 8, Ariadna Colomer-Carbonell 1 2 3, Xavier Borràs 3, Mattie Tops 9, Juan V Luciano 1 2, Javier García-Campayo 6 7
PMID: 33050630 PMCID: PMC7599726
Abstract
The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial (RCT) was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-ons of treatment as usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate to large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effect sizes. The number needed to treat was three based on the criteria of ≥50% Fibromyalgia Impact Questionnaire (FIQ) reduction post-treatment. Compared to RT, the MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR, as an adjuvant of treatment-as-usual (TAU), appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.
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Trends in Molecuar medicine Available online 7 June 2021
Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome
Anthony L.Komaroff1W. IanLipkin2 https://doi.org/10.1016/j.molmed.2021.06.002Get rights and content
Highlights
In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.
Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.
The US and other developed nations have committed considerable support for research on post-COVID illnesses.
Abstract
SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.
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Integr Med Res . 2021 Jun;10(2):100664. doi: 10.1016/j.imr.2020.100664. Epub 2020 Sep 22.
Effectiveness a herbal medicine ( Sipjeondaebo-tang) on adults with chronic fatigue syndrome: A randomized, double-blind, placebo-controlled trial
Seungwon Shin 1 2, Soo Jung Park 3, Minwoo Hwang 4
PMID: 33101925 PMCID: PMC7578262
Abstract
Background: Sipjeondaebo-tang (SJDBT, Shi-quan-da-bu-tang in Chinese) is a widely prescribed herbal medicine in traditional Korean medicine. This study aimed to evaluate the effectiveness and safety of SJDBT for treating chronic fatigue syndrome (CFS).
Methods: Ninety-six eligible participants were randomly allocated to either the SJDBT or placebo groups in a 1:1 ratio. Nine grams of SJDBT or placebo granules were administered to the patients for 8 weeks. The primary outcome was the response rate, defined as the proportion of participants with a score of 76 or higher in the Checklist Individual Strength assessment. Other measurements for fatigue severity, quality of life, and qi/blood/yin/yang deficiency were included. Safety was assessed throughout the trial.
Results: At week 8, the response rate did not significantly differ between the groups (SJDBT: 35.4%; placebo: 54.2%; P = 0.101, effect size [95% confidence interval] = 0.021 [-0.177, 0.218]). However, the scores of the visual analogue scale (P = 0.001, -0.327 [-0.506, -0.128]), Fatigue Severity Scale (P = 0.020, 0.480 [0.066, 0.889]), and Chalder fatigue scale (P = 0.004, -0.292 [-0.479, -0.101]) for the SJDBT group showed significant improvements in fatigue severity at the endpoint. Quality of life was not significantly different. Furthermore, SJDBT significantly ameliorated the severity of qi deficiency compared to that in the placebo group. No serious adverse events were observed.
Conclusion: This trial failed to show a significant improvement in fatigue severity, as assessed by the CIS-deprived response rate. It merely showed that SJDBT could alleviate the severity of fatigue and qi deficiency in patients with CFS. However, the further study is needed to confirm the details.
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Postdengue chronic fatigue syndrome in an adolescent boy
Thadchanamoorthy V and Dayasiri K.
BMJ Case Reports. 2021 Jun 7;14(6):e238605
Abstract
Chronic fatigue syndrome (CFS) is often preceded by a viral illness and has recurrent ‘flulike’ symptoms which include a wide spectrum of musculoskeletal and neurological clinical features. The condition is also known as myalgic encephalomyelitis and systemic exertional intolerance syndrome.
CFS has been reported following dengue among adult patients. We report the case of an 11-year-old boy who developed CFS following recovery of dengue haemorrhagic fever (DHF). The reported child was initially managed as for DHF and was clinically asymptomatic on post-discharge day 3. He was re-admitted after 3 weeks with severe joint pains, myalgia and unbearable headache.
As his symptoms persisted, he was investigated in-depth. All investigations were normal except mild elevation of liver functions. The diagnosis of CFS secondary to DHF was made by exclusion of differential diagnosis. At 1-year follow-up, patient continues to have symptoms after treatment with physiotherapy and nutrition counselling.
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Front. Immunol., 06 April 2021 | https://doi.org/10.3389/fimmu.2021.644548
Delineating the Association Between Soluble CD26 and Autoantibodies Against G-Protein Coupled Receptors, Immunological and Cardiovascular Parameters Identifies Distinct Patterns in Post-Infectious vs. Non-Infection-Triggered Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marvin Szklarski1*, Helma Freitag1, Sebastian Lorenz1, Sonya C. Becker1, Franziska Sotzny1, Sandra Bauer1, Jelka Hartwig1, Harald Heidecke2, Kirsten Wittke1, Claudia Kedor1, Leif G. Hanitsch1, Patricia Grabowski1, Nuno Sepúlveda1 and Carmen Scheibenbogen1
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Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology
Lluis Capdevila Jesús Castro-Marrero José Alegre Juan Ramos-Castro 3 and Rosa M Escorihuela
Departament de Psicologia Bàsica, Sport Research Institute, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Sensors 2021, 21(11), 3746; https://doi.org/10.3390/s21113746
Received: 20 April 2021 / Revised: 20 May 2021 / Accepted: 22 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue Smartphones and Wearable Sensors for Monitoring Heart Rate and Heart Rate Variability)
Abstract
In a previous study using mobile-health technology (mHealth), we reported a robust association between chronic fatigue symptoms and heart rate variability (HRV) in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study explores HRV analysis as an objective, non-invasive and easy-to-apply marker of ME/CFS using mHealth technology, and evaluates differential gender effects on HRV and ME/CFS core symptoms. In our methodology, participants included 77 ME/CFS patients (32 men and 45 women) and 44 age-matched healthy controls (19 men and 25 women), all self-reporting subjective scores for fatigue, sleep quality, anxiety, and depression, and neurovegetative symptoms of autonomic dysfunction. The inter-beat cardiac intervals are continuously monitored/recorded over three 5-min periods, and HRV is analyzed using a custom-made application (iOS) on a mobile device connected via Bluetooth to a wearable cardiac chest band. Male ME/CFS patients show increased scores compared with control men in all symptoms and scores of fatigue, and autonomic dysfunction, as with women in the first study. No differences in any HRV parameter appear between male ME/CFS patients and controls, in contrast to our findings in women. However, we have found negative correlations of ME/CFS symptomatology with cardiac variability (SDNN, RMSSD, pNN50, LF) in men. We have also found a significant relationship between fatigue symptomatology and HRV parameters in ME/CFS patients, but not in healthy control men. Gender effects appear in HF, LF/HF, and HFnu HRV parameters. A MANOVA analysis shows differential gender effects depending on the experimental condition in autonomic dysfunction symptoms and HF and HFnu HRV parameters. A decreased HRV pattern in ME/CFS women compared to ME/CFS men may reflect a sex-related cardiac autonomic dysfunction in ME/CFS illness that could be used as a predictive marker of disease progression. In conclusion, we show that HRV analysis using mHealth technology is an objective, non-invasive tool that can be useful for clinical prediction of fatigue severity, especially in women with ME/CFS.
Keywords: mHealth; heart rate variability; HRV; ME/CFS; myalgic encephalomyelitis; chronic fatigue syndrome; gender differences
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settings
Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients
Sławomir Kujawski Joanna Słomko Lynette Hodges Derek F. H. Pheby Modra Murovska
Julia L. Newton Paweł Zalewski
J. Clin. Med. 2021, 10(11), 2327; https://doi.org/10.3390/jcm10112327
Received: 25 March 2021 / Revised: 21 May 2021 / Accepted: 23 May 2021 / Published: 26 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Post-exertional malaise (PEM) is regarded as the hallmark symptom in chronic fatigue syndrome (CFS). The aim of the current study is to explore differences in CFS patients with and without PEM in indicators of aortic stiffness, autonomic nervous system function, and severity of fatigue. One-hundred and one patients met the Fukuda criteria. A Chronic Fatigue Questionnaire (CFQ) and Fatigue Impact Scale (FIS) were used to assess the level of mental and physical fatigue. Aortic systolic blood pressure (sBPaortic) and the autonomic nervous system were measured with the arteriograph and Task Force Monitor, respectively. Eighty-two patients suffered prolonged PEM according to the Fukuda criteria, while 19 did not. Patients with PEM had higher FIS scores (p = 0.02), lower central systolic blood pressure (p = 0.02) and higher mental fatigue (p = 0.03). For a one-point increase in the mental fatigue component of the CFQ scale, the risk of PEM increases by 34%. For an sBPaortic increase of 1 mmHg, the risk of PEM decreases by 5%. For a one unit increase in sympathovagal balance, the risk of PEM increases by 330%. Higher mental fatigue and sympathetic activity in rest are related to an increased risk of PEM, while higher central systolic blood pressure is related to a reduced risk of PEM. However, none of the between group differences were significant after FDR correction, and therefore conclusions should be treated with caution and replicated in further studies.
Keywords: PEM; myalgic encephalomyelitis; brain fog; vascular stiffness
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Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*
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COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Leonard A. Jason,Mohammed F. Islam,Karl Conroy,Joseph Cotler,Chelsea Torres,Mady Johnson
Received 21 Apr 2021, Accepted 22 Apr 2021, Published online: 05 May 2021
https://doi.org/10.1080/21641846.2021.1922140
ABSTRACT
Introduction
Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods
278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
Results
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
Conclusions
These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
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How can we manage covid fatigue?
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1610 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1610 Fiona Godlee, editor in chief
What’s the long term outlook after covid? And what’s the prognosis for health systems and staff struggling with covid pressures, waiting lists, and stretched resources?
Most people make a good recovery, but the wide range of covid related illness and organ damage weave a complex prognostic picture. Of patients discharged from hospital, more than one in 10 will die within six months, writes Emily Fraser (doi:10.1136/bmj.n1565).1 Some patients with lung damage will have persisting respiratory symptoms, but for those who were previously fit and without other complications the outlook is good, with functional recovery better than expected from the radiological evidence.
Up to 376 000 people in the UK have reported ongoing symptoms more than 12 months after contracting the virus, with persistent mental and physical fatigue a troubling reality for many (doi:10.1136/bmj.n1559).2 This presents clinicians with a range of challenges. Should patients with fatigue follow the dominant advice of the CFS/ME communities: that pacing rather than graded exercise therapy is the safest route, as is now also recommended in controversial draft guidance from the UK National Institute for Health and Care Excellence? Or does this risk sentencing patients to a lifetime of symptom monitoring and long term disability? What of the researchers braving this often toxic academic terrain?
Promisingly, away from the “fire and fury” of debate, doctors and others are quietly working out how best to treat each patient without causing harm (doi:10.1136/bmj.n1559).2 Careful screening for post-exertional malaise and individualised treatment plans seem to be the way forward. But it’s also crucial to tackle endemic power imbalances between patients and professionals and to co-produce knowledge and services (https://blogs.bmj.com/bmj/2021/06/23/how-power-imbalances-in-the-narratives-research-and-publications-around-long-covid-can-harm-patients).3
The needs of patients with long covid are just one of many calls on stretched healthcare resources. We also need a primary care led vaccine infrastructure (doi:10.1136/bmj.n1578) and a full recovery plan for the NHS (https://blogs.bmj.com/bmj/2021/06/18/chris-ham-the-governments-response-to-the-nhs-backlog-has-fallen-short).45 We can’t recoup the vast sums squandered on test and trace, but perhaps a rethink will soon be in order after the US Food and Drug Administration’s warning against using the Innova rapid test (doi:10.1136/bmj.n1582).6 This comes on top of continuing grave concerns about the test’s reliability and evaluation (doi:10.1136/bmj.n1058) and now a call for trials in schools to be suspended (https://blogs.bmj.com/bmj/2021/06/17/daily-contact-testing-trials-in-schools-are-unethical-and-extending-them-to-include-the-delta-variant-puts-everyone-at-risk).78 Despite all this, the UK regulator has extended authorisation for two more months (doi:10.1136/bmj.n1582),6 so it will be worth brushing up your understanding of how to interpret lateral flow tests (doi:10.1136/bmj.n1411).9 In case you need reminding, context and pre-test probability are everything (https://blogs.bmj.com/bmj/2021/06/15/sheila-bird-diagnostic-tests-must-be-more-rigorously-regulated).10
Sadly, the pressure on healthcare systems and staff is causing moral distress and injury (doi:10.1136/bmj.n1543),11 which won’t be helped by doctors in the UK retiring in greater numbers and at a younger age (doi:10.1136/bmj.n1594).12 Tax rules on pensions are a major factor (doi:10.1136/bmj.n1517).13 The government has changed the rules for judges and must do the same for doctors if this haemorrhaging of vital talent and experience is to be stemmed.
This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
https://bmj.com/coronavirus/usage
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Neurological and psychiatric complications in patients with COVID-19
Heather Mason | 23 June 2021
A study published in Brain Communications has found an 11 per cent prevalence of neuropsychiatric symptoms among hospitalised COVID-19 patients, with a wide range of associated neurological and psychiatric complications.
The researchers analysed 245 adult COVID-19 patients with a de novo neurological or psychiatric manifestation to better understand the detailed spectrum of neuropsychiatric disorders.
The results show that the most frequent neuropsychiatric symptoms were motor weakness, cognitive disturbances, impaired consciousness, psychiatric disturbance, headache, and behavioural disturbance. Some symptoms appeared soon after COVID-19 onset, such as myalgia, headache, or anosmia, while others had a delayed onset, such as sensory symptoms and psychiatric disturbances.
The most frequent neuropsychiatric syndromes were encephalopathy, critical illness polyneuropathy and myopathy, psychiatric disturbances, and cerebrovascular complications.
Other syndromes, such as isolated disabling headache, seizures, isolated movement disorders, and encephalitis, were much rarer. Guillain-Barré syndrome was observed in five patients.
The most commonly observed psychiatric disorders in the context of COVID-19 infection were anxiety disorders, depression, acute psychosis, adjustment disorders and acute stress, although some of the patients had a pre-existing condition.
The study described a wide range of neuropsychiatric complications, and further studies are needed to understand their underlying mechanisms and potential long-term problems, the authors concluded.
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Dysregulation of brain and choroid plexus cell types in severe COVID-19
Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller & Tony Wyss-Coray
Nature Published: 21 June 2021
Abstract
Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1–3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.
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BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1626 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1626
Adrian O’Dowd
Around a third of people in England who developed covid-19 went on to experience long term symptoms sometimes called “long covid,” a UK study has found and experts believe that more than two million people could have been affected in this way.
Findings from the React-2 (Real-time Assessment of Community Transmission) study from Imperial College London used self-reported data from 508 707 adults aged 18 or older who took part in three rounds of surveys that were carried out between September 2020 and February 2021, in which they were asked about 29 different symptoms.
The study, published as a preprint and not yet peer reviewed,1 found that around a fifth (19.2%) of those surveyed reported having had contracted covid-19 previously, with more than a third (37.7%) reporting at least one persistent symptom and 14.8% experiencing three or more symptoms lasting at least 12 weeks.
Almost a third of people (30.5%) with at least one symptom lasting 12 weeks or more reported having had severe covid-19 symptoms that had a “significant effect on my daily life” at the time of their illness.
Overall, 5.8% of the study population had one or more persistent symptoms for 12 weeks or more, a proportion that could translate to more than two million people in England. The most common persistent symptoms included tiredness, shortness of breath, muscle aches, and difficulty sleeping.
In addition, the researchers found that long covid was more common among women than men (1.5 times as likely) and in people who were overweight or obese, who smoked, lived in deprived areas, or had been admitted to hospital. In contrast, persistent covid-19 symptoms were lower in people of Asian ethnicity.
The findings also indicated that prevalence of persistent symptoms increased with age, with a 3.5% increase in likelihood for each decade of life.
At a press briefing to launch the study, Paul Elliott, director of the REACT programme and chair in epidemiology and public health medicine at Imperial, was asked how long “long” covid may be for some people.
“For some people, I think they will have very long term consequences of having had the infection,” said Elliott. “There are certainly people who have got organ damage, so if they have that they will continue to have the consequences.
“Long covid is still poorly understood, but we hope through our research that we can contribute to better identification and management of this condition, which our data and others’ suggest may ultimately affect millions of people in the UK alone.”
The authors suggested various possible reasons why women seemed to be more likely to have long covid symptoms. Fellow report author Helen Ward, professor of public health at Imperial, told The BMJ, “There are a lot of theories. It may be that it is to do with a more active immune response in women that reduces symptoms initially but then produces prolonged symptoms.”
After the briefing the government said that covid-19 was still a relatively new disease and that it was providing scientists with £50m (€60m; $70m) of research funding to better understand its long term effects.
Similar themes to the React-2 study’s findings emerged in another study, led by researchers at University College London and King’s College London.2 It found that a sixth (17%) of middle aged people who reported being infected with SARS-CoV-2 also reported long covid symptoms but that this proportion fell to 7.8% in younger adults.
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A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
KlausWirthaCarmenScheibenbogenb
https://doi.org/10.1016/j.autrev.2020.102527Get rights and content
Autoimmunity Reviews Volume 19, Issue 6, June 2020, 102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
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Wirth and Scheibenbogen J Transl Med (2021) 19:162 https://doi.org/10.1186/s12967-021-02833-2
REVIEW Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS)
Klaus J. Wirth1 and Carmen Scheibenbogen2*
Abstract Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The fnding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor infuences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the frst hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufcient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload afects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronifcation. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle.
Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.
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Tolerability and Efficacy of s.c. IgG Self-Treatment in ME/CFS Patients with IgG/IgG Subclass Deficiency: A Proof-of-Concept Study
Carmen Scheibenbogen Franziska Sotzny Jelka Hartwig Sandra Bauer Helma Freitag ,
Kirsten Wittke Wolfram Doehner Nadja Scherbakov Madlen Loebel Patricia Grabowski
Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
2
Academic Editors: Giovanni Ricevuti and Lorenzo Lorusso
J. Clin. Med. 2021, 10(11), 2420; https://doi.org/10.3390/jcm10112420
Received: 19 April 2021 / Revised: 26 May 2021 / Accepted: 27 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Background: Chronic fatigue syndrome (ME/CFS) is a complex disease frequently triggered by infections. IgG substitution may have therapeutic effect both by ameliorating susceptibility to infections and due to immunomodulatory effects. Methods: We conducted a proof of concept open trial with s.c. IgG in 17 ME/CFS patients suffering from recurrent infections and mild IgG or IgG subclass deficiency to assess tolerability and efficacy. Patients received s.c. IgG therapy of 0.8 g/kg/month for 12 months with an initial 2 months dose escalation phase of 0.2 g and 0.4 g/kg/month. Results: Primary outcome was improvement of fatigue assessed by Chalder Fatigue Scale (CFQ; decrease ≥ 6 points) and of physical functioning assessed by SF-36 (increase ≥ 25 points) at month 12. Of 12 patients receiving treatment per protocol 5 had a clinical response at month 12. Two additional patients had an improvement according to this definition at months 6 and 9. In four patients treatment was ceased due to adverse events and in one patient due to disease worsening. We identified LDH and soluble IL-2 receptor as potential biomarker for response. Conclusion: Our data indicate that self-administered s.c. IgG treatment is feasible and led to clinical improvement in a subset of ME/CFS patients.
Keywords: chronic fatigue syndrome; myalgic encephalomyelitis; autoimmunity; immunology; IgG replacement; IgG deficiency; biomarker
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Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients
J. Blauensteiner, R. Bertinat, L. E. León, M. Riederer, N. Sepúlveda & F. Westermeier
Scientific Reports volume 11, Article number: 10604 (2021)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients. Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS. The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients. Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network. In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.
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European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe
by
Luis Nacul et al
London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Academic Editor: Tibor Hortobágyi
Medicina 2021, 57(5), 510; https://doi.org/10.3390/medicina57050510
Received: 11 April 2021 / Revised: 13 May 2021 / Accepted: 13 May 2021 / Published: 19 May 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)—COST action 15111—from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; diagnosis; health services; care
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Front. Immunol., 31 October 2019 | https://doi.org/10.3389/fimmu.2019.02545
Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Helene Cabanas1,2,3*, Katsuhiko Muraki3,4, Donald Staines1,2,3 and Sonya Marshall-Gradisnik1,2,3
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.
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The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE)
by
Derek F. H. Pheby, Diana Araja, Uldis Berkis, Elenka Brenna, John Cullinan, Jean-Dominique de Korwin,Lara Gitto,Dyfrig A. Hughes,Rachael M. Hunter,Dominic Trepel, Xia Wang-Steverding
Academic Editor: Edgaras Stankevičius
Medicina 2021, 57(4), 388; https://doi.org/10.3390/medicina57040388
Received: 13 March 2021 / Revised: 12 April 2021 / Accepted: 13 April 2021 / Published: 16 April 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.
Keywords: prevention; economic impact; chronic fatigue syndrome; myalgic encephalomyelitis; ME/CFS
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settings
Open AccessReview
Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders
by Sarah Jane Annesley Paul Robert Fisher
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Academic Editors: Anna Atlante and Daniela Valenti
Int. J. Mol. Sci. 2021, 22(9), 4536; https://doi.org/10.3390/ijms22094536
Received: 1 April 2021 / Revised: 23 April 2021 / Accepted: 24 April 2021 / Published: 26 April 2021
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions)
Abstract
Neurological disorders, including neurodegenerative diseases, are collectively a major cause of death and disability worldwide. Whilst the underlying disease mechanisms remain elusive, altered mitochondrial function has been clearly implicated and is a key area of study in these disorders. Studying mitochondrial function in these disorders is difficult due to the inaccessibility of brain tissue, which is the key tissue affected in these diseases. To overcome this issue, numerous cell models have been used, each providing unique benefits and limitations. Here, we focussed on the use of lymphoblastoid cell lines (LCLs) to study mitochondrial function in neurological disorders. LCLs have long been used as tools for genomic analyses, but here we described their use in functional studies specifically in regard to mitochondrial function. These models have enabled characterisation of the underlying mitochondrial defect, identification of altered signalling pathways and proteins, differences in mitochondrial function between subsets of particular disorders and identification of biomarkers of the disease. The examples provided here suggest that these cells will be useful for development of diagnostic tests (which in most cases do not exist), identification of drug targets and testing of pharmacological agents, and are a worthwhile model for studying mitochondrial function in neurological disorders.
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Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol
by C. (Linda) M. C. van Campen * and Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
Academic Editors: Filipe Manuel Clemente and Parisi Attilio
Healthcare 2021, 9(6), 682; https://doi.org/10.3390/healthcare9060682
Received: 11 April 2021 / Revised: 1 May 2021 / Accepted: 3 June 21 / Published: 5 June 2021
Abstract
Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; VO2 peak; ventilatory threshold; VO2AT; RER; myalgic encephalitis; workload; idiopathic chronic fatigue
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settingsOpen AccessReview
Identifying and Managing Suicidality in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Lily Chu , Meghan Elliott,Eleanor Stein 3 and Leonard A. Jason
Academic Editors: Kenneth J. Friedman, Lucinda Bateman and Kenny Leo De Meirleir
Healthcare 2021, 9(6), 629; https://doi.org/10.3390/healthcare9060629
Received: 30 March 2021 / Revised: 14 May 2021 / Accepted: 16 May 2021 / Published: 25 May 2021
(This article belongs to the Collection ME/CFS – the Severely and Very Severely Affected)
Abstract
Adult patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are at an increased risk of death by suicide. Based on the scientific literature and our clinical/research experiences, we identify risk and protective factors and provide a guide to assessing and managing suicidality in an outpatient medical setting. A clinical case is used to illustrate how information from this article can be applied. Characteristics of ME/CFS that make addressing suicidality challenging include absence of any disease-modifying treatments, severe functional limitations, and symptoms which limit therapies. Decades-long misattribution of ME/CFS to physical deconditioning or psychiatric disorders have resulted in undereducated healthcare professionals, public stigma, and unsupportive social interactions. Consequently, some patients may be reluctant to engage with mental health care. Outpatient medical professionals play a vital role in mitigating these effects. By combining evidence-based interventions aimed at all suicidal patients with those adapted to individual patients’ circumstances, suffering and suicidality can be alleviated in ME/CFS. Increased access to newer virtual or asynchronous modalities of psychiatric/psychological care, especially for severely ill patients, may be a silver lining of the COVID-19 pandemic.
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Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Bruce K. Patterson, Edgar B. Francisco, Ram Yogendra, Emily Long, Amruta Pise, Hallison Rodrigues, Eric Hall, Monica Herrara, Purvi Parikh, Jose Guevara-Coto, Xaiolan Chang, Jonah B Sacha, Rodrigo A Mora-Rodríguez, Javier Mora
doi: https://doi.org/10.1101/2021.06.25.449905
This article is a preprint and has not been certified by peer review [what does this mean?].
200011406
ABSTRACT
The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 also contained SARS-CoV-2 RNA. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5.
Summary SARS CoV-2 S1 Protein in CD16+ Monocytes In PASC
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Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3
Affiliations expand PMID: 34262570 PMCID: PMC8273732 : 10.3389/fimmu.2021.700782
Abstract
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.
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2021 Jun 28;12:700782.
doi: 10.3389/fimmu.2021.700782. eCollection 2021.
Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.
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A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome
Diego Garcia-Borreguero MD, PhD, Celia Garcia-Malo MD, Juan José Granizo MD, Sergi Ferré MD, PhD
First published: 17 June 2021 Movement Disorders
https://doi.org/10.1002/mds.28668
ABSTRACT
Background
New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.
Objective
The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.
Methods
A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.
Results
Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).
Conclusions
Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson
Front. Med. 2021:8:688486
Abstract
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.
Keywords: myalgic encephalomyelitis, chronic fatigue syndrome, enterovirus, chronic infection, RT-PCR, serology, immunohistochemistry, cell culture
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MEDICAL NEWS
COVID-19 linked to reactivation of Epstein-Barr virus
Dawn O'Shea | 26 July 2021
Two recently published studies suggest that Epstein-Barr virus (EBV) reactivation may play a role in the development of long COVID-19 symptoms and severe disease.
In the first study, researchers ran EBV serological tests on COVID-19 patients at least 90 days after testing positive for SARS-CoV-2, comparing EBV reactivation rates of those with long COVID symptoms to those who did not. They found that over 73 per cent of patients with long COVID-19 symptoms were positive for EBV reactivation.
The second study found EBV reactivation may also be associated with COVID-19 severity.
This retrospective single-centre study included 67 COVID-19 patients divided into an EBV/SARS-CoV-2 coinfection group and a SARS-CoV-2 infection alone group.
Among COVID-19 patients, 37 (55.2%) were seropositive for EBV viral capsid antigen (VCA) IgM antibody.
Coinfected patients had a 3.09-fold risk of fever (P=.03). C-reactive protein (P=.02) and aspartate aminotransferase (P=.04) were also higher in this group, along with higher corticosteroid use (P=.03).
The authors speculate that EBV reactivation may be associated with the severity of COVID-19.
The relationships described in these studies open up new possibilities for the diagnosis and treatment of initial COVID-19 infection and long COVID.
References
Chen T, Song J, Liu H, Zheng H, Chen C. Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep. 2021 May 25;11(1):10902. doi: 10.1038/s41598-021-90351-y. PMID: 34035353; PMCID: PMC8149409.
Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens. 2021 Jun 17;10(6):763. doi: 10.3390/pathogens10060763. PMID: 34204243; PMCID: PMC8233978.
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Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis
Adonis Sfera, Carolina Osorio, [...], and Zisis Kozlakidis
Frontiers in neurovascular science
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.
Keywords: endothelial cells, cellular senescence, gut microbial community, endotoxin tolerance, microbial translocation
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Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis
Adonis Sfera 1, Carolina Osorio 2, Nyla Jafri 1, Eddie Lee Diaz 1, Jose E Campo Maldonado 3
Front Immunol2020 Jun 19;11:1472. doi: 10.3389/fimmu.2020.01472. eCollection 2020.PMID: 32655579 PMCID: PMC7325923 DOI: 10.3389/fimmu.2020.01472
Abstract
Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).
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Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Rebekah Maksoud Natalie Eaton-Fitch Michael Matula Hélène Cabanas Donald Staines
Sonya Marshall-Gradisnik
National Centre for Neuroimmunology and Emerging Diseases (NCNED), Menzies Health Institute Queensland, Griffith University, Gold Coast 4222, Australia
Healthcare 2021, 9(5), 568; https://doi.org/10.3390/healthcare9050568
Received: 13 April 2021 / Revised: 1 May 2021 / Accepted: 7 May 2021 / Published: 11 May 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
(1) Background—Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifaceted illness characterized by profound and persistent fatigue unrelieved by rest along with a range of other debilitating symptoms. Experiences of unrefreshing and disturbed sleep are frequently described by ME/CFS patients. This is the first systematic review assessing sleep characteristics in ME/CFS. The aim of this review is to determine whether there are clinical characteristics of sleep in ME/CFS patients compared to healthy controls using objective measures such as polysomnography and multiple sleep latency testing. (2) Methods—the following databases—Pubmed, Embase, Medline (EBSCO host) and Web of Science, were systematically searched for journal articles published between January 1994 to 19 February 2021. Articles that referred to polysomnography or multiple sleep latency testing and ME/CFS patients were selected, and further refined through use of specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute checklist. (3) Results—twenty observational studies were included in this review. The studies investigated objective measures of sleep quality in ME/CFS. Subjective measures including perceived sleep quality and other quality of life factors were also described. (4) Conclusions—Many of the parameters measured including slow- wave sleep, apnea- hypopnea index, spectral activity and multiple sleep latency testing were inconsistent across the studies. The available research on sleep quality in ME/CFS was also limited by recruitment decisions, confounding factors, small sample sizes and non-replicated findings. Future well-designed studies are required to understand sleep quality in ME/CFS patients.
Keywords: Myalgic Encephalomyelitis; chronic fatigue syndrome; sleep; polysomnography; multiple sleep latency testing
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Effect of Melatonin Plus Zinc Supple mentation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Jesús Castro-Marrero Maria-Cleofé Zaragozá Irene López-Vílchez José Luis Galmés Begoña Cordobilla, Sara Maurel, Joan Carles Domingo, José Alegre-Martín
Antioxidants 2021, 10(7), 1010; https://doi.org/10.3390/antiox10071010
Received: 30 May 2021 / Revised: 14 June 2021 / Accepted: 21 June 2021 / Published: 23 June 2021
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment. Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS. The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS. Secondary measures included participants’ sleep disturbances, anxiety/depression and health-related quality of life. A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily. Endpoint outcomes were evaluated at baseline, and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures. The most relevant results were the significant reduction in the perception of physical fatigue in the Mel-Zinc group at the final treatment follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group. Urinary 6-sulfatoxymelatonin levels were significantly elevated though the treatment in experimental group vs. placebo (p < 0.0001); however, no significantly differences were observed for zinc concentration among participants. Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS. This clinical study was registered on ClinicalTrials.gov (NCT03000777).
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Open AccessArticle
Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol
C. (Linda) M. C. van Campen Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
ealthcare 2021, 9(6), 683; https://doi.org/10.3390/healthcare9060683
Received: 22 April 2021 / Revised: 3 June 2021 / Accepted: 3 June 2021 / Published: 5 June 2021
Abstract
(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. (2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. (3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. (4) Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
Free access | 10.1172/JCI150377
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Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Øystein Fluge,1,2 Karl J. Tronstad,3 and Olav Mella1,2
Published July 15, 2021 -
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with unknown etiology, no validated specific and sensitive biomarker, and no standard approved effective treatment. ME/CFS has a profound impact on the quality of life of both patients and caregivers and entails high costs for society. The severity varies among patients who are able to participate to some extent in social life (mild), those who are mainly housebound (moderate) or bedridden (severe), and the very severely ill who are completely dependent on assistance for all daily living tasks, such as feeding or turning around in bed.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often starts in previously healthy individuals after an infection, the most common being infectious mononucleosis (EBV). It is more frequent in women and influenced by genetic predisposition. The main symptoms are postexertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction. The prevalence is 0.1% to 0.8%, and ME/CFS must be distinguished from general fatigue, which is much more common in the population.
Historically, there has been limited scientific interest in ME/CFS. However, research efforts have increased in the last decade. Although this has led to different hypotheses, a firmly established pathomechanism is lacking.
Herein, we suggest a framework model for the initiation and maintenance of ME/CFS consisting of three principal steps: (a) an initial aberrant immune response; (b) an effector system for symptom generation and maintenance; and (c) compensatory adaptations.
The model and possible therapeutic opportunities are summarized in Figure 1.
Figure 1
Proposed model for ME/CFS pathomechanisms. We suggest three principal steps underlie the initiation and maintenance of ME/CFS. (i) Immune response after infection serves as a triggering event, with a role for B cells/plasma cells and autoantibodies in the underlying pathology. (ii) The vascular system and possibly GPCRs are potential targets for autoantibodies, which may affect endothelium or neurovascular control and autonomic small nerve fibers. The autoantibodies could be pathogenic IgGs or functional autoantibodies that normally occur after infection, but persist and fail to resolve over time. This disturbed homeostasis involves endothelial dysfunction in large and small arteries, impaired venous return and preload failure, and arteriovenous shunting, presumed to result in impaired autoregulation of blood flow and tissue hypoxia on exertion. (iii) Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.
Our proposed pathomechanistic model (Figure 1) is compatible with the lack of obvious histologic inflammation in tissue samples from ME/CFS, lack of overt organ damage, and the potential for recovery — sometimes spontaneous and without sequelae. Future research should focus on the natural course of ME/CFS over time to identify the mechanisms that induce and maintain disease, find targets for intervention, and specifically aim to elucidate immune dysregulation and patterns of autoantibodies with mechanisms for circulatory disturbances.
In our model, clinical symptoms of ME/CFS are related primarily to the inadequate autoregulation of blood flow yielding tissue hypoxia on exertion, but are also influenced by the compensatory adaptations from increased sympathetic output and from metabolic shifts. We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output. If so, one would expect a greater benefit for patients with less ongoing immune activation and less vascular dysregulation, but with main symptom contributions from the secondary autonomic adaptations. Conversely, patients with active immune disturbance and ongoing vascular dysregulation as the main symptom generators would have less impact from cognitive intervention, although psychosocial support and coping strategies may still have a beneficial impact on their quality of life.
In conclusion, we suggest that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, with a role for B cells/plasma cells and a pattern of autoantibodies emerging after infection and persisting over time. Key symptoms may result from the consequent functional disturbance in blood flow autoregulation causing tissue hypoxia on exertion and associated autonomic and metabolic responses to maintain energy homeostasis.
Finally, there is growing concern for patients with “long COVID.” Research is needed to determine whether the symptoms, which may resemble those of ME/CFS, are caused by subtle organ damage from the viral infection or whether subgroups of “long haulers” actually have a postinfectious immune disturbance and pathomechanism similar to those in ME/CFS.
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1173 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1173 E[email protected]
Common, burdensome, and highly variable
Our understanding of long covid (also known as post-covid syndrome) has progressed considerably since the first follow-up of people discharged from hospital in 2020 after SARS-CoV-2 infection.12 People who were not admitted to hospital with their covid-19 infection but who have enduring symptoms have driven the wider recognition of long covid symptoms, including organ impairment.3 Much evidence comes from small, observational studies or surveys using different case definitions and sampling frames, resulting in a wide range of prevalence estimates.4 Larger surveys found that enduring symptoms were more often reported among people who had had covid-19 than among controls who had not,56 including reporting of cognitive deficits.7 However, reliance on self-reporting in many studies has been criticised by some commentators.
In a linked paper, Daugherty and colleagues (doi:10.1136/bmj.n1098) used a large electronic records dataset to describe the prevalence and risks of post-covid sequelae in patients both admitted to hospital and in the community in the United States.8 Several studies have retrospectively reviewed ICD-10 (international classification of diseases, 10th revision) codes in electronic health records, including a large study reporting that people admitted to hospital with covid-19 were 3.5 times more likely to be readmitted and 7.7 times more likely to die within five months of discharge than controls admitted to hospital without covid-19.9 Researchers using US Department of Veterans Affairs databases found increased use of analgesics, antidepressants, antihypertensives, and oral hypoglycaemics in the six months after confirmed covid-19 compared with controls,10 and data from the US TriNetX electronic health records network showed that nearly 34% of people testing positive for SARS-CoV-2 had a neurological or psychiatric diagnosis in the following six months.11
Daugherty and colleagues found that certain conditions were more commonly diagnosed after covid-19 than after other viral lower respiratory tract infections.8 The estimated 14% incidence of new diagnoses up to six months after SARS-CoV-2 infection is strikingly similar to the 13.7% incidence of self-reported symptoms lasting more than 12 weeks found by the UK Office for National Statistics.6 While both studies report higher incidence in people admitted to hospital, new symptoms and diagnoses were also seen in those who remained at home.6810 The absolute number of people reporting long covid symptoms will be higher in the community owing to the (at least) 10-fold difference in the numbers admitted to hospital and those who stayed at home.12 Primary care clinicians should expect patients with mild initial infections to report long covid or post-covid symptoms just as frequently as those who were critically ill.
In common with most studies, Daugherty and colleagues report that enduring symptoms are more common in women, those living with social deprivation, and those with pre-existing comorbidities.8 Importantly, they found that 10% of people developed new diagnoses requiring medical attention more than three weeks after the initial infection, with 4% developing more than one new diagnosis. This feature is well described by people with real life experience, who call it the “corona-coaster.” People who present with late onset symptoms (particularly those not admitted to hospital) report that some healthcare professionals do not associate symptoms with covid-19 and do not provide appropriate assessment and treatment.4
It is too early to predict how long clinical sequelae will persist after covid-19, but these symptoms clearly create a major personal burden for many people, with some individuals experiencing difficulty returning to work and some unable to care for dependents.4 Long covid is also putting a strain on healthcare services, which have been already decimated by the pandemic. Identifying risk factors would facilitate triage and faster access to specialist care. However, one of the peculiarities of long covid is its non-linear progression, hampering attempts to predict who will develop particular symptoms and when. Risk factors differ for different new diagnoses, suggesting that a variety of mechanisms could be at play.81011 Applying these risk factors to clinical practice will probably need long covid to be subdivided into more specific phenotypes.
Daugherty and colleagues’ analyses included people aged 18-65, and although symptom reporting is less common outside this age band,6 evidence is growing that children also experience long covid.1314 In older adults, symptoms could be under-reported because of assumptions that they are due to aging or comorbidities. Healthcare professionals should be alert to the possibility of long covid in anyone with confirmed or suspected covid-19. How to treat these longer term consequences is now an urgent research priority.
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Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1098 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1098
Sarah E Daugherty, senior researcher1, Yinglong Guo, director1, Kevin Heath, national medical director for clinical intelligence and physician2 , Micah C Dasmariñas, data scientist1, Karol Giuseppe Jubilo, data scientist1, Jirapat Samranvedhya, principal data scientist1, Marc Lipsitch, professor3, Ken Cohen, executive director of translational research and clinician2 4
- Accepted 26 April 2021
Objective To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65.
Design Retrospective cohort study.
Setting Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database.
Participants Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness.
Main outcome measures More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated.
Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.
Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.
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Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome
WakiroSatoabHirohikoOnoaTakajiMatsutanicMasakazuNakamuraaIsuShindKeikoAmanoeRyujiSuzukicTakashiYamamuraab
https://doi.org/10.1016/j.bbi.2021.03.023Get rights and content
Brain, Behavior, and Immunity Volume 95, July 2021, Pages 245-255
Highlights
ME/CFS is characterized by skewed B cell receptor gene usage.
Upregulation of specific IGHV genes correlated to infection-related episodes at onset.
Plasmablasts of ME/CFS patients upregulated interferon response genes.
B cell receptor repertoire analysis can provide a useful diagnostic marker in ME/CFS.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.
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Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)Journal of Translational Medicine volume 19, Article number: 193 (2021)
Abstract
Background
Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).
Methods and results
In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.
Conclusion
This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.
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Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Klaus J. Wirth & Carmen Scheibenbogen
Journal of Translational Medicine volume 19, Article number: 162 (2021)
Abstract
Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.
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Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS
Bianka Jäkel, Claudia Kedor, Patricia Grabowski, Kirsten Wittke, Silvia Thiel, Nadja Scherbakov, Wolfram Doehner, Carmen Scheibenbogen & Helma Freitag
Journal of Translational Medicine volume 19, Article number: 159 (2021)
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters.
Methods
We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC.
Results
ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p ≤ 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p ≤ 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion.
Conclusion
Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS.
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J Clin Med 2020 Oct 11;9(10):3246. doi: 10.3390/jcm9103246.
Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial
Juan P Sanabria-Mazo 1 2 3 4, Jesus Montero-Marin 5, Albert Feliu-Soler 1 2 3, Virginia Gasión 6, Mayte Navarro-Gil 6 7, Héctor Morillo-Sarto 8, Ariadna Colomer-Carbonell 1 2 3, Xavier Borràs 3, Mattie Tops 9, Juan V Luciano 1 2, Javier García-Campayo 6 7
PMID: 33050630 PMCID: PMC7599726
Abstract
The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial (RCT) was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-ons of treatment as usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate to large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effect sizes. The number needed to treat was three based on the criteria of ≥50% Fibromyalgia Impact Questionnaire (FIQ) reduction post-treatment. Compared to RT, the MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR, as an adjuvant of treatment-as-usual (TAU), appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.
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Trends in Molecuar medicine Available online 7 June 2021
Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome
Anthony L.Komaroff1W. IanLipkin2 https://doi.org/10.1016/j.molmed.2021.06.002Get rights and content
Highlights
In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.
Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.
The US and other developed nations have committed considerable support for research on post-COVID illnesses.
Abstract
SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.
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Integr Med Res . 2021 Jun;10(2):100664. doi: 10.1016/j.imr.2020.100664. Epub 2020 Sep 22.
Effectiveness a herbal medicine ( Sipjeondaebo-tang) on adults with chronic fatigue syndrome: A randomized, double-blind, placebo-controlled trial
Seungwon Shin 1 2, Soo Jung Park 3, Minwoo Hwang 4
PMID: 33101925 PMCID: PMC7578262
Abstract
Background: Sipjeondaebo-tang (SJDBT, Shi-quan-da-bu-tang in Chinese) is a widely prescribed herbal medicine in traditional Korean medicine. This study aimed to evaluate the effectiveness and safety of SJDBT for treating chronic fatigue syndrome (CFS).
Methods: Ninety-six eligible participants were randomly allocated to either the SJDBT or placebo groups in a 1:1 ratio. Nine grams of SJDBT or placebo granules were administered to the patients for 8 weeks. The primary outcome was the response rate, defined as the proportion of participants with a score of 76 or higher in the Checklist Individual Strength assessment. Other measurements for fatigue severity, quality of life, and qi/blood/yin/yang deficiency were included. Safety was assessed throughout the trial.
Results: At week 8, the response rate did not significantly differ between the groups (SJDBT: 35.4%; placebo: 54.2%; P = 0.101, effect size [95% confidence interval] = 0.021 [-0.177, 0.218]). However, the scores of the visual analogue scale (P = 0.001, -0.327 [-0.506, -0.128]), Fatigue Severity Scale (P = 0.020, 0.480 [0.066, 0.889]), and Chalder fatigue scale (P = 0.004, -0.292 [-0.479, -0.101]) for the SJDBT group showed significant improvements in fatigue severity at the endpoint. Quality of life was not significantly different. Furthermore, SJDBT significantly ameliorated the severity of qi deficiency compared to that in the placebo group. No serious adverse events were observed.
Conclusion: This trial failed to show a significant improvement in fatigue severity, as assessed by the CIS-deprived response rate. It merely showed that SJDBT could alleviate the severity of fatigue and qi deficiency in patients with CFS. However, the further study is needed to confirm the details.
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Postdengue chronic fatigue syndrome in an adolescent boy
Thadchanamoorthy V and Dayasiri K.
BMJ Case Reports. 2021 Jun 7;14(6):e238605
Abstract
Chronic fatigue syndrome (CFS) is often preceded by a viral illness and has recurrent ‘flulike’ symptoms which include a wide spectrum of musculoskeletal and neurological clinical features. The condition is also known as myalgic encephalomyelitis and systemic exertional intolerance syndrome.
CFS has been reported following dengue among adult patients. We report the case of an 11-year-old boy who developed CFS following recovery of dengue haemorrhagic fever (DHF). The reported child was initially managed as for DHF and was clinically asymptomatic on post-discharge day 3. He was re-admitted after 3 weeks with severe joint pains, myalgia and unbearable headache.
As his symptoms persisted, he was investigated in-depth. All investigations were normal except mild elevation of liver functions. The diagnosis of CFS secondary to DHF was made by exclusion of differential diagnosis. At 1-year follow-up, patient continues to have symptoms after treatment with physiotherapy and nutrition counselling.
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Front. Immunol., 06 April 2021 | https://doi.org/10.3389/fimmu.2021.644548
Delineating the Association Between Soluble CD26 and Autoantibodies Against G-Protein Coupled Receptors, Immunological and Cardiovascular Parameters Identifies Distinct Patterns in Post-Infectious vs. Non-Infection-Triggered Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marvin Szklarski1*, Helma Freitag1, Sebastian Lorenz1, Sonya C. Becker1, Franziska Sotzny1, Sandra Bauer1, Jelka Hartwig1, Harald Heidecke2, Kirsten Wittke1, Claudia Kedor1, Leif G. Hanitsch1, Patricia Grabowski1, Nuno Sepúlveda1 and Carmen Scheibenbogen1
- 1Institute of Medical Immunology, Charité –Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- 2CellTrend, Luckenwalde, Germany
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Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology
Lluis Capdevila Jesús Castro-Marrero José Alegre Juan Ramos-Castro 3 and Rosa M Escorihuela
Departament de Psicologia Bàsica, Sport Research Institute, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Sensors 2021, 21(11), 3746; https://doi.org/10.3390/s21113746
Received: 20 April 2021 / Revised: 20 May 2021 / Accepted: 22 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue Smartphones and Wearable Sensors for Monitoring Heart Rate and Heart Rate Variability)
Abstract
In a previous study using mobile-health technology (mHealth), we reported a robust association between chronic fatigue symptoms and heart rate variability (HRV) in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study explores HRV analysis as an objective, non-invasive and easy-to-apply marker of ME/CFS using mHealth technology, and evaluates differential gender effects on HRV and ME/CFS core symptoms. In our methodology, participants included 77 ME/CFS patients (32 men and 45 women) and 44 age-matched healthy controls (19 men and 25 women), all self-reporting subjective scores for fatigue, sleep quality, anxiety, and depression, and neurovegetative symptoms of autonomic dysfunction. The inter-beat cardiac intervals are continuously monitored/recorded over three 5-min periods, and HRV is analyzed using a custom-made application (iOS) on a mobile device connected via Bluetooth to a wearable cardiac chest band. Male ME/CFS patients show increased scores compared with control men in all symptoms and scores of fatigue, and autonomic dysfunction, as with women in the first study. No differences in any HRV parameter appear between male ME/CFS patients and controls, in contrast to our findings in women. However, we have found negative correlations of ME/CFS symptomatology with cardiac variability (SDNN, RMSSD, pNN50, LF) in men. We have also found a significant relationship between fatigue symptomatology and HRV parameters in ME/CFS patients, but not in healthy control men. Gender effects appear in HF, LF/HF, and HFnu HRV parameters. A MANOVA analysis shows differential gender effects depending on the experimental condition in autonomic dysfunction symptoms and HF and HFnu HRV parameters. A decreased HRV pattern in ME/CFS women compared to ME/CFS men may reflect a sex-related cardiac autonomic dysfunction in ME/CFS illness that could be used as a predictive marker of disease progression. In conclusion, we show that HRV analysis using mHealth technology is an objective, non-invasive tool that can be useful for clinical prediction of fatigue severity, especially in women with ME/CFS.
Keywords: mHealth; heart rate variability; HRV; ME/CFS; myalgic encephalomyelitis; chronic fatigue syndrome; gender differences
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Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients
Sławomir Kujawski Joanna Słomko Lynette Hodges Derek F. H. Pheby Modra Murovska
Julia L. Newton Paweł Zalewski
J. Clin. Med. 2021, 10(11), 2327; https://doi.org/10.3390/jcm10112327
Received: 25 March 2021 / Revised: 21 May 2021 / Accepted: 23 May 2021 / Published: 26 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Post-exertional malaise (PEM) is regarded as the hallmark symptom in chronic fatigue syndrome (CFS). The aim of the current study is to explore differences in CFS patients with and without PEM in indicators of aortic stiffness, autonomic nervous system function, and severity of fatigue. One-hundred and one patients met the Fukuda criteria. A Chronic Fatigue Questionnaire (CFQ) and Fatigue Impact Scale (FIS) were used to assess the level of mental and physical fatigue. Aortic systolic blood pressure (sBPaortic) and the autonomic nervous system were measured with the arteriograph and Task Force Monitor, respectively. Eighty-two patients suffered prolonged PEM according to the Fukuda criteria, while 19 did not. Patients with PEM had higher FIS scores (p = 0.02), lower central systolic blood pressure (p = 0.02) and higher mental fatigue (p = 0.03). For a one-point increase in the mental fatigue component of the CFQ scale, the risk of PEM increases by 34%. For an sBPaortic increase of 1 mmHg, the risk of PEM decreases by 5%. For a one unit increase in sympathovagal balance, the risk of PEM increases by 330%. Higher mental fatigue and sympathetic activity in rest are related to an increased risk of PEM, while higher central systolic blood pressure is related to a reduced risk of PEM. However, none of the between group differences were significant after FDR correction, and therefore conclusions should be treated with caution and replicated in further studies.
Keywords: PEM; myalgic encephalomyelitis; brain fog; vascular stiffness
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Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
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
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COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Leonard A. Jason,Mohammed F. Islam,Karl Conroy,Joseph Cotler,Chelsea Torres,Mady Johnson
Received 21 Apr 2021, Accepted 22 Apr 2021, Published online: 05 May 2021
https://doi.org/10.1080/21641846.2021.1922140
ABSTRACT
Introduction
Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods
278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
Results
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
Conclusions
These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
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How can we manage covid fatigue?
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1610 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1610 Fiona Godlee, editor in chief
What’s the long term outlook after covid? And what’s the prognosis for health systems and staff struggling with covid pressures, waiting lists, and stretched resources?
Most people make a good recovery, but the wide range of covid related illness and organ damage weave a complex prognostic picture. Of patients discharged from hospital, more than one in 10 will die within six months, writes Emily Fraser (doi:10.1136/bmj.n1565).1 Some patients with lung damage will have persisting respiratory symptoms, but for those who were previously fit and without other complications the outlook is good, with functional recovery better than expected from the radiological evidence.
Up to 376 000 people in the UK have reported ongoing symptoms more than 12 months after contracting the virus, with persistent mental and physical fatigue a troubling reality for many (doi:10.1136/bmj.n1559).2 This presents clinicians with a range of challenges. Should patients with fatigue follow the dominant advice of the CFS/ME communities: that pacing rather than graded exercise therapy is the safest route, as is now also recommended in controversial draft guidance from the UK National Institute for Health and Care Excellence? Or does this risk sentencing patients to a lifetime of symptom monitoring and long term disability? What of the researchers braving this often toxic academic terrain?
Promisingly, away from the “fire and fury” of debate, doctors and others are quietly working out how best to treat each patient without causing harm (doi:10.1136/bmj.n1559).2 Careful screening for post-exertional malaise and individualised treatment plans seem to be the way forward. But it’s also crucial to tackle endemic power imbalances between patients and professionals and to co-produce knowledge and services (https://blogs.bmj.com/bmj/2021/06/23/how-power-imbalances-in-the-narratives-research-and-publications-around-long-covid-can-harm-patients).3
The needs of patients with long covid are just one of many calls on stretched healthcare resources. We also need a primary care led vaccine infrastructure (doi:10.1136/bmj.n1578) and a full recovery plan for the NHS (https://blogs.bmj.com/bmj/2021/06/18/chris-ham-the-governments-response-to-the-nhs-backlog-has-fallen-short).45 We can’t recoup the vast sums squandered on test and trace, but perhaps a rethink will soon be in order after the US Food and Drug Administration’s warning against using the Innova rapid test (doi:10.1136/bmj.n1582).6 This comes on top of continuing grave concerns about the test’s reliability and evaluation (doi:10.1136/bmj.n1058) and now a call for trials in schools to be suspended (https://blogs.bmj.com/bmj/2021/06/17/daily-contact-testing-trials-in-schools-are-unethical-and-extending-them-to-include-the-delta-variant-puts-everyone-at-risk).78 Despite all this, the UK regulator has extended authorisation for two more months (doi:10.1136/bmj.n1582),6 so it will be worth brushing up your understanding of how to interpret lateral flow tests (doi:10.1136/bmj.n1411).9 In case you need reminding, context and pre-test probability are everything (https://blogs.bmj.com/bmj/2021/06/15/sheila-bird-diagnostic-tests-must-be-more-rigorously-regulated).10
Sadly, the pressure on healthcare systems and staff is causing moral distress and injury (doi:10.1136/bmj.n1543),11 which won’t be helped by doctors in the UK retiring in greater numbers and at a younger age (doi:10.1136/bmj.n1594).12 Tax rules on pensions are a major factor (doi:10.1136/bmj.n1517).13 The government has changed the rules for judges and must do the same for doctors if this haemorrhaging of vital talent and experience is to be stemmed.
This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
https://bmj.com/coronavirus/usage
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Neurological and psychiatric complications in patients with COVID-19
Heather Mason | 23 June 2021
A study published in Brain Communications has found an 11 per cent prevalence of neuropsychiatric symptoms among hospitalised COVID-19 patients, with a wide range of associated neurological and psychiatric complications.
The researchers analysed 245 adult COVID-19 patients with a de novo neurological or psychiatric manifestation to better understand the detailed spectrum of neuropsychiatric disorders.
The results show that the most frequent neuropsychiatric symptoms were motor weakness, cognitive disturbances, impaired consciousness, psychiatric disturbance, headache, and behavioural disturbance. Some symptoms appeared soon after COVID-19 onset, such as myalgia, headache, or anosmia, while others had a delayed onset, such as sensory symptoms and psychiatric disturbances.
The most frequent neuropsychiatric syndromes were encephalopathy, critical illness polyneuropathy and myopathy, psychiatric disturbances, and cerebrovascular complications.
Other syndromes, such as isolated disabling headache, seizures, isolated movement disorders, and encephalitis, were much rarer. Guillain-Barré syndrome was observed in five patients.
The most commonly observed psychiatric disorders in the context of COVID-19 infection were anxiety disorders, depression, acute psychosis, adjustment disorders and acute stress, although some of the patients had a pre-existing condition.
The study described a wide range of neuropsychiatric complications, and further studies are needed to understand their underlying mechanisms and potential long-term problems, the authors concluded.
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Dysregulation of brain and choroid plexus cell types in severe COVID-19
Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller & Tony Wyss-Coray
Nature Published: 21 June 2021
Abstract
Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1–3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.
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BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1626 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1626
Adrian O’Dowd
Around a third of people in England who developed covid-19 went on to experience long term symptoms sometimes called “long covid,” a UK study has found and experts believe that more than two million people could have been affected in this way.
Findings from the React-2 (Real-time Assessment of Community Transmission) study from Imperial College London used self-reported data from 508 707 adults aged 18 or older who took part in three rounds of surveys that were carried out between September 2020 and February 2021, in which they were asked about 29 different symptoms.
The study, published as a preprint and not yet peer reviewed,1 found that around a fifth (19.2%) of those surveyed reported having had contracted covid-19 previously, with more than a third (37.7%) reporting at least one persistent symptom and 14.8% experiencing three or more symptoms lasting at least 12 weeks.
Almost a third of people (30.5%) with at least one symptom lasting 12 weeks or more reported having had severe covid-19 symptoms that had a “significant effect on my daily life” at the time of their illness.
Overall, 5.8% of the study population had one or more persistent symptoms for 12 weeks or more, a proportion that could translate to more than two million people in England. The most common persistent symptoms included tiredness, shortness of breath, muscle aches, and difficulty sleeping.
In addition, the researchers found that long covid was more common among women than men (1.5 times as likely) and in people who were overweight or obese, who smoked, lived in deprived areas, or had been admitted to hospital. In contrast, persistent covid-19 symptoms were lower in people of Asian ethnicity.
The findings also indicated that prevalence of persistent symptoms increased with age, with a 3.5% increase in likelihood for each decade of life.
At a press briefing to launch the study, Paul Elliott, director of the REACT programme and chair in epidemiology and public health medicine at Imperial, was asked how long “long” covid may be for some people.
“For some people, I think they will have very long term consequences of having had the infection,” said Elliott. “There are certainly people who have got organ damage, so if they have that they will continue to have the consequences.
“Long covid is still poorly understood, but we hope through our research that we can contribute to better identification and management of this condition, which our data and others’ suggest may ultimately affect millions of people in the UK alone.”
The authors suggested various possible reasons why women seemed to be more likely to have long covid symptoms. Fellow report author Helen Ward, professor of public health at Imperial, told The BMJ, “There are a lot of theories. It may be that it is to do with a more active immune response in women that reduces symptoms initially but then produces prolonged symptoms.”
After the briefing the government said that covid-19 was still a relatively new disease and that it was providing scientists with £50m (€60m; $70m) of research funding to better understand its long term effects.
Similar themes to the React-2 study’s findings emerged in another study, led by researchers at University College London and King’s College London.2 It found that a sixth (17%) of middle aged people who reported being infected with SARS-CoV-2 also reported long covid symptoms but that this proportion fell to 7.8% in younger adults.
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A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
KlausWirthaCarmenScheibenbogenb
https://doi.org/10.1016/j.autrev.2020.102527Get rights and content
Autoimmunity Reviews Volume 19, Issue 6, June 2020, 102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
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Wirth and Scheibenbogen J Transl Med (2021) 19:162 https://doi.org/10.1186/s12967-021-02833-2
REVIEW Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS)
Klaus J. Wirth1 and Carmen Scheibenbogen2*
Abstract Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The fnding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor infuences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the frst hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufcient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload afects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronifcation. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle.
Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.
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Tolerability and Efficacy of s.c. IgG Self-Treatment in ME/CFS Patients with IgG/IgG Subclass Deficiency: A Proof-of-Concept Study
Carmen Scheibenbogen Franziska Sotzny Jelka Hartwig Sandra Bauer Helma Freitag ,
Kirsten Wittke Wolfram Doehner Nadja Scherbakov Madlen Loebel Patricia Grabowski
Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
2
Academic Editors: Giovanni Ricevuti and Lorenzo Lorusso
J. Clin. Med. 2021, 10(11), 2420; https://doi.org/10.3390/jcm10112420
Received: 19 April 2021 / Revised: 26 May 2021 / Accepted: 27 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Background: Chronic fatigue syndrome (ME/CFS) is a complex disease frequently triggered by infections. IgG substitution may have therapeutic effect both by ameliorating susceptibility to infections and due to immunomodulatory effects. Methods: We conducted a proof of concept open trial with s.c. IgG in 17 ME/CFS patients suffering from recurrent infections and mild IgG or IgG subclass deficiency to assess tolerability and efficacy. Patients received s.c. IgG therapy of 0.8 g/kg/month for 12 months with an initial 2 months dose escalation phase of 0.2 g and 0.4 g/kg/month. Results: Primary outcome was improvement of fatigue assessed by Chalder Fatigue Scale (CFQ; decrease ≥ 6 points) and of physical functioning assessed by SF-36 (increase ≥ 25 points) at month 12. Of 12 patients receiving treatment per protocol 5 had a clinical response at month 12. Two additional patients had an improvement according to this definition at months 6 and 9. In four patients treatment was ceased due to adverse events and in one patient due to disease worsening. We identified LDH and soluble IL-2 receptor as potential biomarker for response. Conclusion: Our data indicate that self-administered s.c. IgG treatment is feasible and led to clinical improvement in a subset of ME/CFS patients.
Keywords: chronic fatigue syndrome; myalgic encephalomyelitis; autoimmunity; immunology; IgG replacement; IgG deficiency; biomarker
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Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients
J. Blauensteiner, R. Bertinat, L. E. León, M. Riederer, N. Sepúlveda & F. Westermeier
Scientific Reports volume 11, Article number: 10604 (2021)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients. Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS. The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients. Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network. In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.
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European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe
by
Luis Nacul et al
London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Academic Editor: Tibor Hortobágyi
Medicina 2021, 57(5), 510; https://doi.org/10.3390/medicina57050510
Received: 11 April 2021 / Revised: 13 May 2021 / Accepted: 13 May 2021 / Published: 19 May 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)—COST action 15111—from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; diagnosis; health services; care
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Front. Immunol., 31 October 2019 | https://doi.org/10.3389/fimmu.2019.02545
Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Helene Cabanas1,2,3*, Katsuhiko Muraki3,4, Donald Staines1,2,3 and Sonya Marshall-Gradisnik1,2,3
- 1School of Medical Science, Griffith University, Gold Coast, QLD, Australia
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.
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The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE)
by
Derek F. H. Pheby, Diana Araja, Uldis Berkis, Elenka Brenna, John Cullinan, Jean-Dominique de Korwin,Lara Gitto,Dyfrig A. Hughes,Rachael M. Hunter,Dominic Trepel, Xia Wang-Steverding
Academic Editor: Edgaras Stankevičius
Medicina 2021, 57(4), 388; https://doi.org/10.3390/medicina57040388
Received: 13 March 2021 / Revised: 12 April 2021 / Accepted: 13 April 2021 / Published: 16 April 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.
Keywords: prevention; economic impact; chronic fatigue syndrome; myalgic encephalomyelitis; ME/CFS
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settings
Open AccessReview
Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders
by Sarah Jane Annesley Paul Robert Fisher
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Academic Editors: Anna Atlante and Daniela Valenti
Int. J. Mol. Sci. 2021, 22(9), 4536; https://doi.org/10.3390/ijms22094536
Received: 1 April 2021 / Revised: 23 April 2021 / Accepted: 24 April 2021 / Published: 26 April 2021
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions)
Abstract
Neurological disorders, including neurodegenerative diseases, are collectively a major cause of death and disability worldwide. Whilst the underlying disease mechanisms remain elusive, altered mitochondrial function has been clearly implicated and is a key area of study in these disorders. Studying mitochondrial function in these disorders is difficult due to the inaccessibility of brain tissue, which is the key tissue affected in these diseases. To overcome this issue, numerous cell models have been used, each providing unique benefits and limitations. Here, we focussed on the use of lymphoblastoid cell lines (LCLs) to study mitochondrial function in neurological disorders. LCLs have long been used as tools for genomic analyses, but here we described their use in functional studies specifically in regard to mitochondrial function. These models have enabled characterisation of the underlying mitochondrial defect, identification of altered signalling pathways and proteins, differences in mitochondrial function between subsets of particular disorders and identification of biomarkers of the disease. The examples provided here suggest that these cells will be useful for development of diagnostic tests (which in most cases do not exist), identification of drug targets and testing of pharmacological agents, and are a worthwhile model for studying mitochondrial function in neurological disorders.
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Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol
by C. (Linda) M. C. van Campen * and Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
Academic Editors: Filipe Manuel Clemente and Parisi Attilio
Healthcare 2021, 9(6), 682; https://doi.org/10.3390/healthcare9060682
Received: 11 April 2021 / Revised: 1 May 2021 / Accepted: 3 June 21 / Published: 5 June 2021
Abstract
Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; VO2 peak; ventilatory threshold; VO2AT; RER; myalgic encephalitis; workload; idiopathic chronic fatigue
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settingsOpen AccessReview
Identifying and Managing Suicidality in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Lily Chu , Meghan Elliott,Eleanor Stein 3 and Leonard A. Jason
Academic Editors: Kenneth J. Friedman, Lucinda Bateman and Kenny Leo De Meirleir
Healthcare 2021, 9(6), 629; https://doi.org/10.3390/healthcare9060629
Received: 30 March 2021 / Revised: 14 May 2021 / Accepted: 16 May 2021 / Published: 25 May 2021
(This article belongs to the Collection ME/CFS – the Severely and Very Severely Affected)
Abstract
Adult patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are at an increased risk of death by suicide. Based on the scientific literature and our clinical/research experiences, we identify risk and protective factors and provide a guide to assessing and managing suicidality in an outpatient medical setting. A clinical case is used to illustrate how information from this article can be applied. Characteristics of ME/CFS that make addressing suicidality challenging include absence of any disease-modifying treatments, severe functional limitations, and symptoms which limit therapies. Decades-long misattribution of ME/CFS to physical deconditioning or psychiatric disorders have resulted in undereducated healthcare professionals, public stigma, and unsupportive social interactions. Consequently, some patients may be reluctant to engage with mental health care. Outpatient medical professionals play a vital role in mitigating these effects. By combining evidence-based interventions aimed at all suicidal patients with those adapted to individual patients’ circumstances, suffering and suicidality can be alleviated in ME/CFS. Increased access to newer virtual or asynchronous modalities of psychiatric/psychological care, especially for severely ill patients, may be a silver lining of the COVID-19 pandemic.
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Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Bruce K. Patterson, Edgar B. Francisco, Ram Yogendra, Emily Long, Amruta Pise, Hallison Rodrigues, Eric Hall, Monica Herrara, Purvi Parikh, Jose Guevara-Coto, Xaiolan Chang, Jonah B Sacha, Rodrigo A Mora-Rodríguez, Javier Mora
doi: https://doi.org/10.1101/2021.06.25.449905
This article is a preprint and has not been certified by peer review [what does this mean?].
200011406
ABSTRACT
The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 also contained SARS-CoV-2 RNA. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5.
Summary SARS CoV-2 S1 Protein in CD16+ Monocytes In PASC
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Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3
Affiliations expand PMID: 34262570 PMCID: PMC8273732 : 10.3389/fimmu.2021.700782
Abstract
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.
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2021 Jun 28;12:700782.
doi: 10.3389/fimmu.2021.700782. eCollection 2021.
Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3
- PMID: 34262570 PMCID: PMC8273732 DOI: 10.3389/fimmu.2021.700782
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.
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A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome
Diego Garcia-Borreguero MD, PhD, Celia Garcia-Malo MD, Juan José Granizo MD, Sergi Ferré MD, PhD
First published: 17 June 2021 Movement Disorders
https://doi.org/10.1002/mds.28668
ABSTRACT
Background
New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.
Objective
The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.
Methods
A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.
Results
Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).
Conclusions
Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson
Front. Med. 2021:8:688486
Abstract
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.
Keywords: myalgic encephalomyelitis, chronic fatigue syndrome, enterovirus, chronic infection, RT-PCR, serology, immunohistochemistry, cell culture
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MEDICAL NEWS
COVID-19 linked to reactivation of Epstein-Barr virus
Dawn O'Shea | 26 July 2021
Two recently published studies suggest that Epstein-Barr virus (EBV) reactivation may play a role in the development of long COVID-19 symptoms and severe disease.
In the first study, researchers ran EBV serological tests on COVID-19 patients at least 90 days after testing positive for SARS-CoV-2, comparing EBV reactivation rates of those with long COVID symptoms to those who did not. They found that over 73 per cent of patients with long COVID-19 symptoms were positive for EBV reactivation.
The second study found EBV reactivation may also be associated with COVID-19 severity.
This retrospective single-centre study included 67 COVID-19 patients divided into an EBV/SARS-CoV-2 coinfection group and a SARS-CoV-2 infection alone group.
Among COVID-19 patients, 37 (55.2%) were seropositive for EBV viral capsid antigen (VCA) IgM antibody.
Coinfected patients had a 3.09-fold risk of fever (P=.03). C-reactive protein (P=.02) and aspartate aminotransferase (P=.04) were also higher in this group, along with higher corticosteroid use (P=.03).
The authors speculate that EBV reactivation may be associated with the severity of COVID-19.
The relationships described in these studies open up new possibilities for the diagnosis and treatment of initial COVID-19 infection and long COVID.
References
Chen T, Song J, Liu H, Zheng H, Chen C. Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep. 2021 May 25;11(1):10902. doi: 10.1038/s41598-021-90351-y. PMID: 34035353; PMCID: PMC8149409.
Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens. 2021 Jun 17;10(6):763. doi: 10.3390/pathogens10060763. PMID: 34204243; PMCID: PMC8233978.
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Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis
Adonis Sfera, Carolina Osorio, [...], and Zisis Kozlakidis
Frontiers in neurovascular science
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.
Keywords: endothelial cells, cellular senescence, gut microbial community, endotoxin tolerance, microbial translocation
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Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis
Adonis Sfera 1, Carolina Osorio 2, Nyla Jafri 1, Eddie Lee Diaz 1, Jose E Campo Maldonado 3
Front Immunol2020 Jun 19;11:1472. doi: 10.3389/fimmu.2020.01472. eCollection 2020.PMID: 32655579 PMCID: PMC7325923 DOI: 10.3389/fimmu.2020.01472
Abstract
Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).
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Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Rebekah Maksoud Natalie Eaton-Fitch Michael Matula Hélène Cabanas Donald Staines
Sonya Marshall-Gradisnik
National Centre for Neuroimmunology and Emerging Diseases (NCNED), Menzies Health Institute Queensland, Griffith University, Gold Coast 4222, Australia
Healthcare 2021, 9(5), 568; https://doi.org/10.3390/healthcare9050568
Received: 13 April 2021 / Revised: 1 May 2021 / Accepted: 7 May 2021 / Published: 11 May 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
(1) Background—Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifaceted illness characterized by profound and persistent fatigue unrelieved by rest along with a range of other debilitating symptoms. Experiences of unrefreshing and disturbed sleep are frequently described by ME/CFS patients. This is the first systematic review assessing sleep characteristics in ME/CFS. The aim of this review is to determine whether there are clinical characteristics of sleep in ME/CFS patients compared to healthy controls using objective measures such as polysomnography and multiple sleep latency testing. (2) Methods—the following databases—Pubmed, Embase, Medline (EBSCO host) and Web of Science, were systematically searched for journal articles published between January 1994 to 19 February 2021. Articles that referred to polysomnography or multiple sleep latency testing and ME/CFS patients were selected, and further refined through use of specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute checklist. (3) Results—twenty observational studies were included in this review. The studies investigated objective measures of sleep quality in ME/CFS. Subjective measures including perceived sleep quality and other quality of life factors were also described. (4) Conclusions—Many of the parameters measured including slow- wave sleep, apnea- hypopnea index, spectral activity and multiple sleep latency testing were inconsistent across the studies. The available research on sleep quality in ME/CFS was also limited by recruitment decisions, confounding factors, small sample sizes and non-replicated findings. Future well-designed studies are required to understand sleep quality in ME/CFS patients.
Keywords: Myalgic Encephalomyelitis; chronic fatigue syndrome; sleep; polysomnography; multiple sleep latency testing
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Effect of Melatonin Plus Zinc Supple mentation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Jesús Castro-Marrero Maria-Cleofé Zaragozá Irene López-Vílchez José Luis Galmés Begoña Cordobilla, Sara Maurel, Joan Carles Domingo, José Alegre-Martín
Antioxidants 2021, 10(7), 1010; https://doi.org/10.3390/antiox10071010
Received: 30 May 2021 / Revised: 14 June 2021 / Accepted: 21 June 2021 / Published: 23 June 2021
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment. Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS. The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS. Secondary measures included participants’ sleep disturbances, anxiety/depression and health-related quality of life. A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily. Endpoint outcomes were evaluated at baseline, and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures. The most relevant results were the significant reduction in the perception of physical fatigue in the Mel-Zinc group at the final treatment follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group. Urinary 6-sulfatoxymelatonin levels were significantly elevated though the treatment in experimental group vs. placebo (p < 0.0001); however, no significantly differences were observed for zinc concentration among participants. Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS. This clinical study was registered on ClinicalTrials.gov (NCT03000777).
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Open AccessArticle
Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol
C. (Linda) M. C. van Campen Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
ealthcare 2021, 9(6), 683; https://doi.org/10.3390/healthcare9060683
Received: 22 April 2021 / Revised: 3 June 2021 / Accepted: 3 June 2021 / Published: 5 June 2021
Abstract
(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. (2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. (3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. (4) Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
Free access | 10.1172/JCI150377
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Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Øystein Fluge,1,2 Karl J. Tronstad,3 and Olav Mella1,2
Published July 15, 2021 -
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with unknown etiology, no validated specific and sensitive biomarker, and no standard approved effective treatment. ME/CFS has a profound impact on the quality of life of both patients and caregivers and entails high costs for society. The severity varies among patients who are able to participate to some extent in social life (mild), those who are mainly housebound (moderate) or bedridden (severe), and the very severely ill who are completely dependent on assistance for all daily living tasks, such as feeding or turning around in bed.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often starts in previously healthy individuals after an infection, the most common being infectious mononucleosis (EBV). It is more frequent in women and influenced by genetic predisposition. The main symptoms are postexertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction. The prevalence is 0.1% to 0.8%, and ME/CFS must be distinguished from general fatigue, which is much more common in the population.
Historically, there has been limited scientific interest in ME/CFS. However, research efforts have increased in the last decade. Although this has led to different hypotheses, a firmly established pathomechanism is lacking.
Herein, we suggest a framework model for the initiation and maintenance of ME/CFS consisting of three principal steps: (a) an initial aberrant immune response; (b) an effector system for symptom generation and maintenance; and (c) compensatory adaptations.
The model and possible therapeutic opportunities are summarized in Figure 1.
Figure 1
Proposed model for ME/CFS pathomechanisms. We suggest three principal steps underlie the initiation and maintenance of ME/CFS. (i) Immune response after infection serves as a triggering event, with a role for B cells/plasma cells and autoantibodies in the underlying pathology. (ii) The vascular system and possibly GPCRs are potential targets for autoantibodies, which may affect endothelium or neurovascular control and autonomic small nerve fibers. The autoantibodies could be pathogenic IgGs or functional autoantibodies that normally occur after infection, but persist and fail to resolve over time. This disturbed homeostasis involves endothelial dysfunction in large and small arteries, impaired venous return and preload failure, and arteriovenous shunting, presumed to result in impaired autoregulation of blood flow and tissue hypoxia on exertion. (iii) Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.
Our proposed pathomechanistic model (Figure 1) is compatible with the lack of obvious histologic inflammation in tissue samples from ME/CFS, lack of overt organ damage, and the potential for recovery — sometimes spontaneous and without sequelae. Future research should focus on the natural course of ME/CFS over time to identify the mechanisms that induce and maintain disease, find targets for intervention, and specifically aim to elucidate immune dysregulation and patterns of autoantibodies with mechanisms for circulatory disturbances.
In our model, clinical symptoms of ME/CFS are related primarily to the inadequate autoregulation of blood flow yielding tissue hypoxia on exertion, but are also influenced by the compensatory adaptations from increased sympathetic output and from metabolic shifts. We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output. If so, one would expect a greater benefit for patients with less ongoing immune activation and less vascular dysregulation, but with main symptom contributions from the secondary autonomic adaptations. Conversely, patients with active immune disturbance and ongoing vascular dysregulation as the main symptom generators would have less impact from cognitive intervention, although psychosocial support and coping strategies may still have a beneficial impact on their quality of life.
In conclusion, we suggest that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, with a role for B cells/plasma cells and a pattern of autoantibodies emerging after infection and persisting over time. Key symptoms may result from the consequent functional disturbance in blood flow autoregulation causing tissue hypoxia on exertion and associated autonomic and metabolic responses to maintain energy homeostasis.
Finally, there is growing concern for patients with “long COVID.” Research is needed to determine whether the symptoms, which may resemble those of ME/CFS, are caused by subtle organ damage from the viral infection or whether subgroups of “long haulers” actually have a postinfectious immune disturbance and pathomechanism similar to those in ME/CFS.
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