As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts
Rita Rubin, MA
JAMA. 2020;324(14):1381-1383. doi:10.1001/jama.2020.17709
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For 32-year-old Hanna Lockman of Louisville, Kentucky, it all started March 12. She was at work when she suddenly felt a stabbing pain in her chest.
“It just got worse and worse and worse, to the point I was crying from the pain,” she recalled in a recent interview. At 3 am, the pain sent her to the emergency department. “I had developed a dry cough, maybe a mild fever. I don’t remember.”
Five months, 16 emergency department trips, and 3 short hospitalizations later, Lockman can’t remember a lot of things. She places the blame squarely on coronavirus disease 2019 (COVID-19).
“I joke, ‘Well, COVID has eaten my brain, because I can’t remember how to remember words, keep track of medication,’” she said. “My brain just feels like there’s a fog.”
Lockman considers herself to be a “long hauler,” someone who still hasn’t fully recovered from COVID-19 weeks or even months after symptoms first arose. She serves as an administrator of 2 “Long Haul COVID Fighters” Facebook groups, whose members now number more than 8000.
The longer the pandemic drags on, the more obvious it becomes that for some patients, COVID-19 is like the unwelcome houseguest who won’t pack up and leave.
“Anecdotally, there’s no question that there are a considerable number of individuals who have a postviral syndrome that really, in many respects, can incapacitate them for weeks and weeks following so-called recovery and clearing of the virus,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in July during a COVID-19 webinar organized by the International AIDS Society.
That appeared to be the case with the first severe acute respiratory syndrome (SARS), which emerged in 2002 and was also caused by a coronavirus. Some people who were hospitalized with SARS still had impaired lung function 2 years after their symptoms began, according to a prospective study of 55 patients in Hong Kong. But only 8096 people were diagnosed with SARS worldwide—a fraction of the COVID-19 cases reported each day in the US alone.
In a recent JAMA research letter, 125 of 143 Italian patients ranging in age from 19 to 84 years still experienced physician-confirmed COVID-19–related symptoms an average of 2 months after their first symptom emerged. All had been hospitalized, with their stays averaging about 2 weeks; 80% hadn’t received any form of ventilation.
Physicians at a Paris hospital recently reported that they saw an average of 30 long haulers every week between mid-May, when the COVID-19 lockdown ended in France, and late July. The patients’ average age was around 40 years, and women outnumbered men 4 to 1.
As with SARS, many COVID-19 long haulers are health care workers who had massive exposure to the virus early in the pandemic, neuroimmunologist Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), noted in a recent editorial.
Overall, approximately 10% of people who’ve had COVID-19 experience prolonged symptoms, a UK team estimated in a recently published Practice Pointer on postacute COVID-19 management. And yet, the authors wrote, primary care physicians have little evidence to guide their care.
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Fatigue: Biomedicine, Health & Behavior
A hierarchical logistic regression predicting rapid respiratory rates from post-exertional malaise
Joseph Cotler ,Ben Z. Katz,Corine Reurts-Post,Ruud Vermeulen &Leonard A. Jason
Received 01 Sep 2020, Accepted 28 Oct 2020, Published online: 16 Nov 2020
https://doi.org/10.1080/21641846.2020.1845287
ABSTRACT
Background
Past research has found high rates of hyperventilation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but hyperventilation can be influenced by psychological factors. Clinical respiratory rates have been less frequently assessed.
Aim
This study aimed to identify the predictors of rapid respiratory rates in patients referred an outpatient clinic specializing in ME/CFS.
Methods
Adults (n = 216) referred to an outpatient clinic specializing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) participated in a two-day cardiopulmonary exercise test. As part of that evaluation, subjects had resting respiratory rates measured on two consecutive days. The current study used questionnaires to assess the relationship between tachypnea (rapid respiratory rates) and a variety of domains including post-exertional malaise (PEM), a common complaint in patients with ME/CFS, and psychiatric/somatic symptoms, using hierarchical logistic regression analysis.
Results
PEM was a significant predictor of tachypnea, while psychological/somatic assessments and sedentary behaviors were not significantly predictive of tachypnea.
Conclusions
These findings suggest that respiratory rate may be useful as an objective clinical metric of PEM, and potentially ME/CFS.
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A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic 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 and Xia Wang-Steverding
Author to whom correspondence should be addressed.
Medicina 2021, 57(1), 7; https://doi.org/10.3390/medicina57010007
Received: 24 November 2020 / Revised: 11 December 2020 / Accepted: 21 December 2020 / Published: 24 December 2020
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.
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Network and Systems MedicineVol. 3, No. 1
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan Narayan Shivapurkar , and James N. Baraniuk
Published Online:18 Nov 2020https://doi.org/10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.
Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.
Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.
Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.
Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
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Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study
Ludovic Giloteaux, Adam O’Neal, Jesús Castro-Marrero, Susan M. Levine & Maureen R. Hanson
Journal of Translational Medicine volume 18, Article number: 387 (2020) Published: 12 October 2020
Abstract:
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.
Methods
We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.
Results
ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.
Conclusions
Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.
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Neurology: May 12, 2020; 94 (19) SPECIAL EDITORIAL
View ORCID Profile Avindra Nath
First published March 30, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009455
In 1896, Sir William Osler1 said, “Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever.” This rings true even today.
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has stricken fear and panic among the public, health care workers, patients, politicians, and financial markets. Fear strikes the minds of the unprepared. So we must ask ourselves why have we been caught by surprise? In the recent past, there have been many major epidemics. This includes Ebola, Zika, dengue, chikungunya, acute flaccid myelitis, and H1N1 influenza, to name a few. But SARS-CoV2 is different. It struck home! And so very rapidly. It emerged in the region of Wuhan in China around December last year, and by March, every state in the United States and over a hundred countries have reported cases of the infection with deaths in all the adult age groups. The predictions are dire. The entire health care system could potentially be overwhelmed and could crumble. Signs of that are already evident in New York and Washington state. Grocery stores have empty shelves, pharmacies are running out of critical medications, and there is scarcity of personal protection equipment and ventilators.
The major clinical manifestations of the SARS-CoV2 infection are due to pulmonary complications. Although most have mild symptoms, such as fever, headache, cough, dyspnea, myalgia, and anosmia, some develop acute respiratory distress syndrome about a week into the illness, which can result in death.2 Rhabdomyolysis can be a late complication of the infection.3 The mortality rate is about 3%–4%. Terminally, patients go into coma, which is thought to be due to hypoxia or multiorgan failure. But many unanswered questions remain. Could the headache be symbolic of viral meningitis? There is a report of detection of the virus in the CSF of 1 patient (encephalitis.info/blog/coronavirus). Does anosmia suggest involvement of the olfactory bulbs? In mouse models of coronavirus encephalitis, the virus can enter the brain transneuronally through the olfactory pathways.4 Hence, this relatively innocuous symptom could be indicative of a potentially more serious complication. Can the respiratory syndrome be due to brainstem involvement? Brain imaging and pathologic evaluation of the brain are necessary to understand the full impact of the virus. The elderly and immunocompromised patients are particularly vulnerable. Many have underlying neurologic comorbidities. Hypertension and diabetes seem to stand out as the most common comorbidities in patients with more severe manifestations of the infection. An interesting hypothesis has emerged around the use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension and diabetes to explain this phenomenon. ACE2 is the receptor for SARS-CoV2.5 The use of ACE inhibitors leads to increased expression of ACE2, making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. ACE2 can be found on endothelial cells in the brain and can be induced in neurons, raising the possibility that strokes associated with SARS-CoV2 might be directly related to the infection, and encephalitis could be a potential complication.
There are several human coronaviruses (HCoVs). Most cause mild respiratory symptoms and resolve. However, in recent years, new coronaviruses have jumped species and infected humans with devastating consequences. Several acute neurologic syndromes have been associated with coronaviruses (table). Severe acute respiratory syndrome coronavirus 1 has been detected in the CSF of a patient with encephalitis and acute respiratory distress syndrome.6 Middle East respiratory syndrome coronavirus can cause a severe acute disseminated encephalomyelitis and a vasculopathy.7 A postinfectious brainstem encephalitis and Guillain-Barré syndrome have also been described.8 HCoV-OC43 can also cause an acute disseminated encephalomyelitis with lesions scattered throughout the brain, cerebellum, and spinal cord.9 Immunocompromised individuals are particularly vulnerable. A fatal encephalitis can occur in immunocompromised patients with HCoV-OV43. In these patients, infection of neurons has been demonstrated at autopsy.10 A similar concern has been raised with SARS-CoV2. Many patients with autoimmune syndromes such as multiple sclerosis, myasthenia gravis, neuromyelitis optica, or sarcoidosis are on a wide variety of immunosuppressive therapies. Drugs that cause systemic immune suppression wound be of concern. It might be prudent for such patients to take extra precautions to prevent exposure to the virus and to reevaluate the dosages of the medications. However, it may not be advisable to take them off treatment because the underlying illness will surely re-emerge, causing serve manifestations in many. With restrictions on travel being imposed and all elective patient appointments being canceled, there is an urgent cry for teleneurology as a substitute for face-to-face interactions with patients. However, to make this work, we need to develop a centralized system to license physicians in the entire country and not in each state individually.
Seropositivity for coronaviruses has been reported in a variety of neurologic disorders, which include encephalitis,11 optic neuritis,12 multiple sclerosis,13 and Parkinson disease.14 Virus has also been isolated from the CSF and brain of patients with multiple sclerosis.15 Viruses implicated include HCoV-229E, HCoV-293, and HCoV-OC43. But the significance of these findings is not clear because these viruses are very prevalent and their causative role in these diseases has not been established.
In the past century, we have made tremendous progress in the prevention, diagnosis, and treatment of diseases. We can dissolve clots in the carotids, we can fix mutated genes before they can cause harm, and we can image the brain and its networks with exquisite precision, yet we have been brought down to our knees by the tiniest of organisms, about 60 nm in size. We need to retool and rethink how we train physicians in the practice of neurology and physician scientists in the academic neurology and how we prioritize drug development for neurologic diseases, and we need to enable academia and pharma to develop treatments not based on profits but rather on costs to humanity. Although we all recognize the hundreds of viruses that can cause encephalitis and result in devastation to large populations, we have no treatment for any of these organisms except for herpes encephalitis. It is time for us to recognize that we are facing a crisis in neurology.16 The time to take action is now.
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Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*
Introduction
Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (14, 15). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual's ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3, 8–10); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (20, 21); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.
This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS
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Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With FibromyalgiaA Systematic Review and Meta-analysis
Rodrigo Oliveira Mascarenhas, MSc1; Mateus Bastos Souza, BAppSc2; Murilo Xavier Oliveira, PhD2; et alAna Cristina Lacerda, PhD2; Vanessa Amaral Mendonça, PhD2; Nicholas Henschke, PhD3; Vinícius Cunha Oliveira, PhD2
JAMA Intern Med. 2021;181(1):104-112. doi:10.1001/jamainternmed.2020.5651
Key Points
Question What is the association of therapies with reduced pain and improved quality of life in patients with fibromyalgia?
Findings In this systematic review, the effectiveness of most therapies for fibromyalgia was not supported. Strong evidence supported only cognitive behavioral therapy for pain, as well as antidepressants and central nervous system depressants for pain and quality of life, but these associations were small.
Meaning Some therapies may be associated with small reductions in pain and improvements in quality of life in people with fibromyalgia; however, current evidence is lacking for most therapies.
Abstract
Importance Fibromyalgia is a chronic condition that results in a significant burden to individuals and society.
Objective To investigate the effectiveness of therapies for reducing pain and improving quality of life (QOL) in people with fibromyalgia.
Data Sources Searches were performed in the MEDLINE, Cochrane, Embase, AMED, PsycInfo, and PEDro databases without language or date restrictions on December 11, 2018, and updated on July 15, 2020.
Study Selection All published randomized or quasi-randomized clinical trials that investigated therapies for individuals with fibromyalgia were screened for inclusion.
Data Extraction and Synthesis Two reviewers independently extracted data and assessed risk of bias using the 0 to 10 PEDro scale. Effect sizes for specific therapies were pooled using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment (GRADE) approach.
Main Outcomes and Measures Pain intensity measured by the visual analog scale, numerical rating scales, and other valid instruments and QOL measured by the Fibromyalgia Impact Questionnaire.
Results A total of 224 trials including 29 962 participants were included. High-quality evidence was found in favor of cognitive behavioral therapy (weighted mean difference [WMD], −0.9; 95% CI, −1.4 to −0.3) for pain in the short term and was found in favor of central nervous system depressants (WMD, −1.2 [95% CI, −1.6 to −0.8]) and antidepressants (WMD, −0.5 [95% CI, −0.7 to −0.4]) for pain in the medium term. There was also high-quality evidence in favor of antidepressants (WMD, −6.8 [95% CI, −8.5 to −5.2]) for QOL in the short term and in favor of central nervous system depressants (WMD, −8.7 [95% CI, −11.3 to −6.0]) and antidepressants (WMD, −3.5 [95% CI, −4.5 to −2.5]) in the medium term. However, these associations were small and did not exceed the minimum clinically important change (2 points on an 11-point scale for pain and 14 points on a 101-point scale for QOL). Evidence for long-term outcomes of interventions was lacking.
Conclusions and Relevance This systematic review and meta-analysis suggests that most of the currently available therapies for the management of fibromyalgia are not supported by high-quality evidence. Some therapies may reduce pain and improve QOL in the short to medium term, although the effect size of the associations might not be clinically important to patients.
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ORIGINAL RESEARCH ARTICLE
Front. Med., 27 January 2021 | https://doi.org/10.3389/fmed.2020.602894
Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
C (Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1
Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.
Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Major Impact on Lives of Both Patients and Family Members
by
Esme Brittain1,Nina Muirhead,Andrew Y. Finlay 1 and Jui Vyas
Medicina 2021, 57(1), 43; https://doi.org/10.3390/medicina57010043
Received: 3 December 2020 / Revised: 23 December 2020 / Accepted: 30 December 2020 / Published: 7 January 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and objectives: To explore the impacts that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has on the patient and their family members using the WHOQOL-BREF (Abbreviated World Health Organisation Quality of Life questionnaire) and FROM-16 (Family Reported Outcome Measure-16) quality of life assessments. Materials and Methods: A quantitative research study using postal questionnaires was conducted. A total of 39 adult volunteers expressed an interest in participating in the study: 24 returned appropriately completed questionnaires. Patients with ME/CFS completed the WHOQOL-BREF and up to four of their family members completed the FROM-16 questionnaire. Results: ME/CFS negatively affects the quality of life of the patient (median scores WHOQOL-BREF: Physical health = 19, Psychological = 44, Social relationships = 37.5, Environment = 56, n = 24) and their family members’ quality of life (FROM-16: Emotional = 9.5, Personal and social = 11.5, Overall = 20.5, n = 42). There was a significant correlation between the patient’s reported quality of life scores and their family members’ mean FROM-16 total scores. Conclusions: This study identifies the major impact that having an adult family member with ME/CFS has on the lives of partners and of other family members. Quality of life of ME/CFS patients was reduced most by physical health compared to the other domains. Quality of life of family members was particularly impacted by worry, family activities, frustration and sadness. This highlights the importance of measuring the impact on the lives of family members using tools such as the FROM-16 in the ME/CFS clinical encounter and ensuring appropriate support is widely available to family members.
Keywords: ME/CFS; QoL; family impact; FROM-16; WHOQOL-BREF
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Published: 04 November 2020
Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions
A. M. Helliwell, E. C. Sweetman, P. A. Stockwell, C. D. Edgar, A. Chatterjee & W. P. Tate
Clinical Epigenetics volume 12, Article number: 167 (2020)
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.
Results
DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.
Conclusions
Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.
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Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate
Journal of Translational Medicine volume 18, Article number: 365 (2020) Cite this article
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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2020 Nov 18;3(1):142-158. doi: 10.1089/nsm.2019.0009. eCollection 2020.
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan 1, Narayan Shivapurkar 1, James N Baraniuk 1
PMID: 33274349 PMCID: PMC7703497 DOI: 10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise. Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise. Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia. Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS. Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
Keywords: cerebrospinal fluid; informatics; micro-RNA (miRNA); myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); pathway analysis.
© Vaishnavi Narayan et al., 2020; Published by Mary Ann Liebert, Inc.
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2021 Feb 2;2021.01.29.21250755.
doi: 10.1101/2021.01.29.21250755. Preprint
A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses
Phillip H Comella, Edgar Gonzalez-Kozlova, Roman Kosoy, Alexander W Charney, Irene Font Peradejordi, Shreya Chandrasekar, Scott R Tyler, Wenhui Wang, Bojan Losic, Jun Zhu, Gabriel E Hoffman, Seunghee Kim-Schulze, Jingjing Qi, Manishkumar Patel, Andrew Kasarskis, Mayte Suarez-Farinas, Zeynep H Gümüş, Carmen Argmann, Miriam Merad, Christian Becker, Noam D Beckmann, Eric E Schadt
PMID: 33564792 PMCID: PMC7872387
Abstract
The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
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Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19 The Writing Committee for the COMEBAC Study Group
JAMA. Published online March 17, 2021. doi:10.1001/jama.2021.3331
COVID-19 Resource Center
Key Points
Question What are the clinical outcomes after hospitalization for COVID-19?
Findings Four months after hospitalization, in an uncontrolled cohort study of 478 survivors of COVID-19, at least 1 new-onset symptom was reported by telephone interview by 244 patients (51%), including fatigue in 134 of 431 (31%), cognitive symptoms in 86 of 416 (21%), and dyspnea in 78 of 478 (16%). Computed tomographic lung scan abnormalities were reported in 63% of 171 patients assessed at an ambulatory visit, mainly subtle ground-glass opacities. Fibrotic lesions were observed in 19% of these 171 patients.
Meaning This study provides clinical status of a cohort of patients 4 months after hospitalization for COVID-19, but further research is needed to understand longer-term outcomes.
Abstract
Importance Little is known about long-term sequelae of COVID-19.
Objective To describe the consequences at 4 months in patients hospitalized for COVID-19.
Design, Setting, and Participants In a prospective uncontrolled cohort study, survivors of COVID-19 who had been hospitalized in a university hospital in France between March 1 and May 29, 2020, underwent a telephone assessment 4 months after discharge, between July 15 and September 18, 2020. Patients with relevant symptoms and all patients hospitalized in an intensive care unit (ICU) were invited for further assessment at an ambulatory care visit.
Exposures Survival of hospitalization for COVID-19.
Main Outcomes and Measures Respiratory, cognitive, and functional symptoms were assessed by telephone with the Q3PC cognitive screening questionnaire and a checklist of symptoms. At the ambulatory care visit, patients underwent pulmonary function tests, lung computed tomographic scan, psychometric and cognitive tests (including the 36-Item Short-Form Health Survey and 20-item Multidimensional Fatigue Inventory), and, for patients who had been hospitalized in the ICU or reported ongoing symptoms, echocardiography.
Results Among 834 eligible patients, 478 were evaluated by telephone (mean age, 61 years [SD, 16 years]; 201 men, 277 women). During the telephone interview, 244 patients (51%) declared at least 1 symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. There was further evaluation in 177 patients (37%), including 97 of 142 former ICU patients. The median 20-item Multidimensional Fatigue Inventory score (n = 130) was 4.5 (interquartile range, 3.0-5.0) for reduced motivation and 3.7 (interquartile range, 3.0-4.5) for mental fatigue (possible range, 1 [best] to 5 [worst]). The median 36-Item Short-Form Health Survey score (n = 145) was 25 (interquartile range, 25.0-75.0) for the subscale “role limited owing to physical problems” (possible range, 0 [best] to 100 [worst]). Computed tomographic lung-scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 of 171 patients (19%), involving less than 25% of parenchyma in all but 1 patient. Fibrotic lesions were observed in 19 of 49 survivors (39%) with acute respiratory distress syndrome. Among 94 former ICU patients, anxiety, depression, and posttraumatic symptoms were observed in 23%, 18%, and 7%, respectively. The left ventricular ejection fraction was less than 50% in 8 of 83 ICU patients (10%). New-onset chronic kidney disease was observed in 2 ICU patients. Serology was positive in 172 of 177 outpatients (97%).
Conclusions and Relevance Four months after hospitalization for COVID-19, a cohort of patients frequently reported symptoms not previously present, and lung-scan abnormalities were common among those who were tested. These findings are limited by the absence of a control group and of pre-COVID assessments in this cohort. Further research is needed to understand longer-term outcomes and whether these findings reflect associations with the disease.
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Global Health March 16, 2021
Most Patients Hospitalized With COVID-19 Have Lasting Symptoms
Bridget M. Kuehn, MSJ JAMA. 2021;325(11):1031. doi:10.1001/jama.2021.2974
COVID-19 Resource Center
Three-quarters of patients hospitalized with coronavirus disease 2019 (COVID-19) still had at least 1 symptom 6 months after they became ill, according to recently published follow-up research.
The study included 1733 patients who were hospitalized in Wuhan, China, and discharged between January and May 2020. Fatigue and ongoing muscle weakness were reported by 63% of the patients and roughly one-quarter reported difficulty sleeping or anxiety and depression. A subset of patients still had reduced lung function and below normal results on a 6-minute walking test. Ongoing lung and mobility impairments were more prevalent among the most severely ill patients. Among 1378 patients with estimated glomerular filtration rates available during their acute illness and at follow-up, about one-third had reduced kidney function at 6 months.
Among a subgroup of 94 patients who provided plasma samples during their acute illness and 6 months later, neutralizing antibody levels had dropped by about half at the follow-up visit, raising concerns about potential reinfection, the authors warned.
“Our analysis indicates that most patients continue to live with at least some of the effects of the virus after leaving hospital, and highlights a need for post-discharge care, particularly for those who experience severe infections,” senior author Bin Cao, MD, of the National Center for Respiratory Medicine in Beijing, China, said in a statement.
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy,Shaun Bhatia,Mohammed Islam andLeonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.
Keywords: ME/CFS; chronic fatigue syndrome; myalgic encephalomyelitis; illness severity; homebound; bedridden
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In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Arnaud Germain,Susan M. Levine and Maureen R. Hanson
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Proteomes 2021, 9(1), 6; https://doi.org/10.3390/proteomes9010006
Received: 1 January 2021 / Revised: 24 January 2021 / Accepted: 25 January 2021 / Published: 29 January 2021
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Keywords: ME/CFS; proteomics; plasma; ephrin-Eph pathway; immune metabolism; adherens junction; glucose; SOMAscan®; diagnosis
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ORIGINAL RESEARCH – Brain and Behaviour
Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
Sara Haghighi Sara Forsmark Olof Zachrisson Arvid Carlsson Marie K. L. Nilsson Maria L. Carlsson Robert C. Schuit Carl‐Gerhard Gottfries
First published: 02 February 2021 https://doi.org/10.1002/brb3.2040
Abstract
Objectives
The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (‐)‐OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (‐)‐OSU6162 in ME/CFS was evaluated by means of observer‐rated scales and self‐assessment rating scales.
Materials and Methods
In the current study using an open‐label single‐arm design ME/CFS patient received treatment with (‐)‐OSU6162 during 12 weeks. The patients received the following doses of (‐)‐OSU6162: 15 mg b.i.d. during the first 4‐week period, up to 30 mg b.i.d. during the second 4‐week period and up to 45 mg b.i.d. during the third 4‐week period, with follow‐up visits after 16 and 20 weeks.
Results
Out of 33 included patients, 28 completed the 12 weeks treatment period. (‐)‐OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.
Conclusions
(‐)‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.
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UK Moves to Revise Guidelines for Treatment of Chronic Fatigue Syndrome
AJN, American Journal of Nursing: March 2021 - Volume 121 - Issue 3 - p 16
doi: 10.1097/01.NAJ.0000737248.67484.2e
Abstract
Advocates hail rejection of debunked exercise and cognitive behavior therapies.
Proposed guidelines for management of myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS), from the United Kingdom's National Institute for Health and Care Excellence (NICE) are being hailed for their rejection of graded exercise therapy and cognitive behavior therapy (CBT) as routine treatment. Major medical organizations, advocacy groups, and patients have strongly advocated for NICE to align guidelines with scientific evidence.
The U.S. Centers for Disease Control and Prevention (CDC) in 2017 eliminated these largely useless and, in some cases, harmful therapies from its recommendations. That NICE is now following suit is good news, though many say it is long overdue. Moreover, patients are unlikely to see immediate results as new science can take years to reach clinical practice.
The illness is characterized by debilitating fatigue and difficulty with concentration and memory. An estimated 2.5 million Americans are diagnosed with ME/CFS, most of them women. Because symptoms can range widely and standard laboratory tests yield little insight as to cause, ME/CFS has been viewed as a stress-induced disorder in some women.
Graded exercise therapy and CBT became the go-to therapies for ME/CFS based on findings of a 2011 study, known as PACE, published in the Lancet. According to the study investigators, these treatments produced a sustained improvement in patients' levels of fatigue and physical function, even leading to recovery for some. Top researchers who reviewed the study, however, found major flaws. Patients also reacted negatively, saying the study's results did not reflect their experiences and reinforced inaccurate and stigmatizing beliefs about the illness as a psychological and behavioral disorder. Eventually, over 100 academics, patient groups, and others called for an independent reanalysis of the data. Despite this forceful opposition, the study remained influential with clinicians and continued to underpin treatment recommendations of major medical organizations, including the CDC and NICE.
Perceptions began to change with the 2015 release of the Institute of Medicine's landmark report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, in which the authors described ME/CFS as a “serious, chronic, complex, systemic disease” and cited newly identified biomarkers indicating immunological and neurological dysfunction. The report and continuing pressure from scientists, clinicians, and patients led the CDC to remove recommendations for graded exercise therapy and CBT as its British counterpart, NICE, now proposes to do.--Karen Roush, PhD, RN, FNP-BC,
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2021 Feb 11. doi: 10.1089/ars.2020.8230. Online ahead of print.
Are Circulating Fibroblast Growth Factor 21 and N-Terminal Prohormone of Brain Natriuretic Peptide Promising Novel Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Joan Carles Domingo 1, Begoña Cordobilla 1, Roser Ferrer 2, Marina Giralt 2, José Alegre-Martín 3 4, Jesús Castro-Marrero 4 PMID: 33353469
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling, and complex multisystem illness of unknown etiology. The protein fibroblast growth factor 21 (FGF21) regulates glucose homeostasis and lipid metabolism, and the protein N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is strongly associated with an elevated cardiovascular risk; however, little is known about their role in ME/CFS patients. To address this gap, we explored the association between FGF21 and NT-proBNP and oxidative stress and inflammatory markers in ME/CFS. Twenty-one ME/CFS patients and 20 matched healthy controls were included in the study. Participants filled out validated self-reported questionnaires on their current health status covering demographic and clinical characteristics. Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxide levels (p = 0.009 and p = 0.021, respectively) in ME/CFS. These ME/CFS patients also had significantly increased levels of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-10, TNF-α, and C-reactive protein) (p < 0.05 for all) but not for IL-8 (p = 0.833), indicating low-grade systemic inflammation status. Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls. Significantly positive correlations were found between NT-proBNP levels and IL-1β and IL-6 (p = 0.04 and p = 0.01) in ME/CFS patients but not between FGF21 and these cytokines. In contrast, no significant correlations were found for either FGF21 or NT-proBNP in controls. These findings lead to the hypothesis that elevated FGF21 and NT-proBNP levels and the association between NT-proBNP and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS.
Keywords: FGF21; NT-proBNP; chronic fatigue syndrome; cytokines; myalgic encephalomyelitis; oxidative stress.
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2021 Apr;132(4):967-974.Clin.Neurophysiology doi: 10.1016/j.clinph.2020.11.043. Epub 2021 Jan29.
Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load
E G Klaver-Krol 1, H J Hermens 2, R C Vermeulen 3, M M Klaver 4, H Luyten 5, N R Henriquez 6, M J Zwarts 7PMID: 33639451 : 10.1016/j.clinph.2020.11.043
Abstract
Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of - especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.
Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.
Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.
Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.
Significance: These findings help to detangle the underlying mechanisms of CFS.
Keywords: Chronic fatigue syndrome; Force generation; Muscle fiber conduction velocity; Muscle membrane dysfunction; Surface electromyography.
Copyright © 2021. Published by Elsevier B.V.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!
Maria Eugenia Ariza
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA2
Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Academic Editors: Maria Teresa Sciortino and Marshall Williams
Biomolecules 2021, 11(2), 185; https://doi.org/10.3390/biom11020185
Published: 29 January 2021
(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
Keywords: myalgic encephalomyelitis/chronic fatigue syndrome; epstein-barr virus (EBV); human herpesvirus 6 (HHV-6); immune dysfunction; BRRF1; BLLF3; deoxyuridine triphosphate nucleotidohydrolase (dUTPase)
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Experiences of Living with Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Victoria Strassheim,Julia L. Newton3 and Tracy Collins
CRESTA Fatigue Clinic, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE4 6BE, UK
Academic Health Science Network–North East & North Cumbria, Newcastle upon Tyne NE4 5PL, UK
Population Health Science Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
Department of Social Work, Education and Community Wellbeing, Coach Lane Campus, Northumbria University, Newcastle upon Tyne NE7 7AX, UK*
Healthcare 2021, 9(2), 168; https://doi.org/10.3390/healthcare9020168
Received: 17 December 2020 / Revised: 27 January 2021 / Accepted: 28 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness. Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered. This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely. Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.
Keywords: ME/CFS; severe; very severe; housebound; qualitative; interview; experience
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Covid-19: Middle aged women face greater risk of debilitating long term symptoms
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n829 (Published 25 March 2021)Cite this as: BMJ 2021;372:n8
Ingrid Torjesen
Middle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and “brain fog” after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.
Seven in 10 patients admitted to hospital with covid-19 reported “long covid” symptoms an average of five months after discharge in the larger PHOSP-COVID study, and symptoms were more prevalent in women aged 40-60.1 White ethnicity, two or more comorbidities at admission, and receiving invasive ventilation while in hospital increased the risk, but severity of acute covid-19 disease did not seem to affect the likelihood of experiencing long covid symptoms.
Only 29% of the 1077 patients studied felt fully recovered when followed up, on average five months after discharge. Over a quarter had clinically significant symptoms of anxiety and depression, 12% had symptoms of post-traumatic stress disorder, 17% had at least mild cognitive impairment, 46% had lower physical performance than age and sex matched controls, and 20% had a new disability.
Before hospital admission 68% of patients had worked full time, but 18% of these had not returned to work and 19% had had to change their way of working because of longlasting effects.
The researchers grouped patients into four clusters according to the severity of their physical and mental symptoms post-covid: very severe (17% of patients), severe (21%), moderate with cognitive impairment (17%), and mild (46%).
Rachael Evans, National Institute for Health Research clinical scientist at the University of Leicester and a study author, said, “The symptoms are very real, but they don’t have a straightforward relationship with heart and lung damage, or certainly heart and lung damage can’t explain all the symptoms.”
Immune response
A smaller second study, from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC), found that women under 50 were five times less likely to report feeling recovered, twice as likely to report worse fatigue, seven times more likely to become more breathless, and more likely to have greater disability than men of the same age who had been admitted to hospital with covid-19.2 Disability usually affected memory, mobility, communication, vision, or hearing. More than half of the 327 patients assessed in this study did not feel fully recovered when followed up on average seven months later, and persistent symptoms were reported by 93.3%, with fatigue and breathlessness the most common.
Chris Brightling, professor of respiratory medicine at the University of Leicester and a PHOSP-COVID study researcher, speculated that sex based differences in the immune response may be responsible for the higher prevalence of long covid symptoms in women, noting that autoimmune diseases were more prevalent in women than in men at age 40-60.
“Maybe there’s a difference in the immune response acutely, such that men are more likely to have a more severe condition at the time of the infection,” he told a press conference at the Science Media Centre on 24 March. “It may be that the immune response is different in women, so you then have a continued inflammatory reaction that then leads to a higher likelihood of having long covid.”
Higher levels of C reactive protein, a marker of systemic inflammation, were seen in patients in the most severe long covid symptoms. Brightling said that a number of immune and chronic inflammatory conditions can also cause elevated C reactive protein.
About 450 000 people have been admitted to hospital with covid-19 in the UK, so a “very large” proportion of these would potentially be affected by long covid, he said, adding, “Clearly there’s an even larger number of people that have had covid in the community, and a portion of those will also have long covid.”
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
Rita Rubin, MA
JAMA. 2020;324(14):1381-1383. doi:10.1001/jama.2020.17709
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For 32-year-old Hanna Lockman of Louisville, Kentucky, it all started March 12. She was at work when she suddenly felt a stabbing pain in her chest.
“It just got worse and worse and worse, to the point I was crying from the pain,” she recalled in a recent interview. At 3 am, the pain sent her to the emergency department. “I had developed a dry cough, maybe a mild fever. I don’t remember.”
Five months, 16 emergency department trips, and 3 short hospitalizations later, Lockman can’t remember a lot of things. She places the blame squarely on coronavirus disease 2019 (COVID-19).
“I joke, ‘Well, COVID has eaten my brain, because I can’t remember how to remember words, keep track of medication,’” she said. “My brain just feels like there’s a fog.”
Lockman considers herself to be a “long hauler,” someone who still hasn’t fully recovered from COVID-19 weeks or even months after symptoms first arose. She serves as an administrator of 2 “Long Haul COVID Fighters” Facebook groups, whose members now number more than 8000.
The longer the pandemic drags on, the more obvious it becomes that for some patients, COVID-19 is like the unwelcome houseguest who won’t pack up and leave.
“Anecdotally, there’s no question that there are a considerable number of individuals who have a postviral syndrome that really, in many respects, can incapacitate them for weeks and weeks following so-called recovery and clearing of the virus,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in July during a COVID-19 webinar organized by the International AIDS Society.
That appeared to be the case with the first severe acute respiratory syndrome (SARS), which emerged in 2002 and was also caused by a coronavirus. Some people who were hospitalized with SARS still had impaired lung function 2 years after their symptoms began, according to a prospective study of 55 patients in Hong Kong. But only 8096 people were diagnosed with SARS worldwide—a fraction of the COVID-19 cases reported each day in the US alone.
In a recent JAMA research letter, 125 of 143 Italian patients ranging in age from 19 to 84 years still experienced physician-confirmed COVID-19–related symptoms an average of 2 months after their first symptom emerged. All had been hospitalized, with their stays averaging about 2 weeks; 80% hadn’t received any form of ventilation.
Physicians at a Paris hospital recently reported that they saw an average of 30 long haulers every week between mid-May, when the COVID-19 lockdown ended in France, and late July. The patients’ average age was around 40 years, and women outnumbered men 4 to 1.
As with SARS, many COVID-19 long haulers are health care workers who had massive exposure to the virus early in the pandemic, neuroimmunologist Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), noted in a recent editorial.
Overall, approximately 10% of people who’ve had COVID-19 experience prolonged symptoms, a UK team estimated in a recently published Practice Pointer on postacute COVID-19 management. And yet, the authors wrote, primary care physicians have little evidence to guide their care.
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Fatigue: Biomedicine, Health & Behavior
A hierarchical logistic regression predicting rapid respiratory rates from post-exertional malaise
Joseph Cotler ,Ben Z. Katz,Corine Reurts-Post,Ruud Vermeulen &Leonard A. Jason
Received 01 Sep 2020, Accepted 28 Oct 2020, Published online: 16 Nov 2020
https://doi.org/10.1080/21641846.2020.1845287
ABSTRACT
Background
Past research has found high rates of hyperventilation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but hyperventilation can be influenced by psychological factors. Clinical respiratory rates have been less frequently assessed.
Aim
This study aimed to identify the predictors of rapid respiratory rates in patients referred an outpatient clinic specializing in ME/CFS.
Methods
Adults (n = 216) referred to an outpatient clinic specializing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) participated in a two-day cardiopulmonary exercise test. As part of that evaluation, subjects had resting respiratory rates measured on two consecutive days. The current study used questionnaires to assess the relationship between tachypnea (rapid respiratory rates) and a variety of domains including post-exertional malaise (PEM), a common complaint in patients with ME/CFS, and psychiatric/somatic symptoms, using hierarchical logistic regression analysis.
Results
PEM was a significant predictor of tachypnea, while psychological/somatic assessments and sedentary behaviors were not significantly predictive of tachypnea.
Conclusions
These findings suggest that respiratory rate may be useful as an objective clinical metric of PEM, and potentially ME/CFS.
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A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic 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 and Xia Wang-Steverding
Author to whom correspondence should be addressed.
Medicina 2021, 57(1), 7; https://doi.org/10.3390/medicina57010007
Received: 24 November 2020 / Revised: 11 December 2020 / Accepted: 21 December 2020 / Published: 24 December 2020
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.
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Network and Systems MedicineVol. 3, No. 1
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan Narayan Shivapurkar , and James N. Baraniuk
Published Online:18 Nov 2020https://doi.org/10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.
Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.
Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.
Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.
Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
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Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study
Ludovic Giloteaux, Adam O’Neal, Jesús Castro-Marrero, Susan M. Levine & Maureen R. Hanson
Journal of Translational Medicine volume 18, Article number: 387 (2020) Published: 12 October 2020
Abstract:
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.
Methods
We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.
Results
ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.
Conclusions
Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.
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Neurology: May 12, 2020; 94 (19) SPECIAL EDITORIAL
View ORCID Profile Avindra Nath
First published March 30, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009455
In 1896, Sir William Osler1 said, “Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever.” This rings true even today.
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has stricken fear and panic among the public, health care workers, patients, politicians, and financial markets. Fear strikes the minds of the unprepared. So we must ask ourselves why have we been caught by surprise? In the recent past, there have been many major epidemics. This includes Ebola, Zika, dengue, chikungunya, acute flaccid myelitis, and H1N1 influenza, to name a few. But SARS-CoV2 is different. It struck home! And so very rapidly. It emerged in the region of Wuhan in China around December last year, and by March, every state in the United States and over a hundred countries have reported cases of the infection with deaths in all the adult age groups. The predictions are dire. The entire health care system could potentially be overwhelmed and could crumble. Signs of that are already evident in New York and Washington state. Grocery stores have empty shelves, pharmacies are running out of critical medications, and there is scarcity of personal protection equipment and ventilators.
The major clinical manifestations of the SARS-CoV2 infection are due to pulmonary complications. Although most have mild symptoms, such as fever, headache, cough, dyspnea, myalgia, and anosmia, some develop acute respiratory distress syndrome about a week into the illness, which can result in death.2 Rhabdomyolysis can be a late complication of the infection.3 The mortality rate is about 3%–4%. Terminally, patients go into coma, which is thought to be due to hypoxia or multiorgan failure. But many unanswered questions remain. Could the headache be symbolic of viral meningitis? There is a report of detection of the virus in the CSF of 1 patient (encephalitis.info/blog/coronavirus). Does anosmia suggest involvement of the olfactory bulbs? In mouse models of coronavirus encephalitis, the virus can enter the brain transneuronally through the olfactory pathways.4 Hence, this relatively innocuous symptom could be indicative of a potentially more serious complication. Can the respiratory syndrome be due to brainstem involvement? Brain imaging and pathologic evaluation of the brain are necessary to understand the full impact of the virus. The elderly and immunocompromised patients are particularly vulnerable. Many have underlying neurologic comorbidities. Hypertension and diabetes seem to stand out as the most common comorbidities in patients with more severe manifestations of the infection. An interesting hypothesis has emerged around the use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension and diabetes to explain this phenomenon. ACE2 is the receptor for SARS-CoV2.5 The use of ACE inhibitors leads to increased expression of ACE2, making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. ACE2 can be found on endothelial cells in the brain and can be induced in neurons, raising the possibility that strokes associated with SARS-CoV2 might be directly related to the infection, and encephalitis could be a potential complication.
There are several human coronaviruses (HCoVs). Most cause mild respiratory symptoms and resolve. However, in recent years, new coronaviruses have jumped species and infected humans with devastating consequences. Several acute neurologic syndromes have been associated with coronaviruses (table). Severe acute respiratory syndrome coronavirus 1 has been detected in the CSF of a patient with encephalitis and acute respiratory distress syndrome.6 Middle East respiratory syndrome coronavirus can cause a severe acute disseminated encephalomyelitis and a vasculopathy.7 A postinfectious brainstem encephalitis and Guillain-Barré syndrome have also been described.8 HCoV-OC43 can also cause an acute disseminated encephalomyelitis with lesions scattered throughout the brain, cerebellum, and spinal cord.9 Immunocompromised individuals are particularly vulnerable. A fatal encephalitis can occur in immunocompromised patients with HCoV-OV43. In these patients, infection of neurons has been demonstrated at autopsy.10 A similar concern has been raised with SARS-CoV2. Many patients with autoimmune syndromes such as multiple sclerosis, myasthenia gravis, neuromyelitis optica, or sarcoidosis are on a wide variety of immunosuppressive therapies. Drugs that cause systemic immune suppression wound be of concern. It might be prudent for such patients to take extra precautions to prevent exposure to the virus and to reevaluate the dosages of the medications. However, it may not be advisable to take them off treatment because the underlying illness will surely re-emerge, causing serve manifestations in many. With restrictions on travel being imposed and all elective patient appointments being canceled, there is an urgent cry for teleneurology as a substitute for face-to-face interactions with patients. However, to make this work, we need to develop a centralized system to license physicians in the entire country and not in each state individually.
Seropositivity for coronaviruses has been reported in a variety of neurologic disorders, which include encephalitis,11 optic neuritis,12 multiple sclerosis,13 and Parkinson disease.14 Virus has also been isolated from the CSF and brain of patients with multiple sclerosis.15 Viruses implicated include HCoV-229E, HCoV-293, and HCoV-OC43. But the significance of these findings is not clear because these viruses are very prevalent and their causative role in these diseases has not been established.
In the past century, we have made tremendous progress in the prevention, diagnosis, and treatment of diseases. We can dissolve clots in the carotids, we can fix mutated genes before they can cause harm, and we can image the brain and its networks with exquisite precision, yet we have been brought down to our knees by the tiniest of organisms, about 60 nm in size. We need to retool and rethink how we train physicians in the practice of neurology and physician scientists in the academic neurology and how we prioritize drug development for neurologic diseases, and we need to enable academia and pharma to develop treatments not based on profits but rather on costs to humanity. Although we all recognize the hundreds of viruses that can cause encephalitis and result in devastation to large populations, we have no treatment for any of these organisms except for herpes encephalitis. It is time for us to recognize that we are facing a crisis in neurology.16 The time to take action is now.
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Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*
- 1Independent Researcher, Sint Martens Latem, Belgium
- 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
- 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
- 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
Introduction
Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (14, 15). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual's ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3, 8–10); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (20, 21); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.
This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS
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Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With FibromyalgiaA Systematic Review and Meta-analysis
Rodrigo Oliveira Mascarenhas, MSc1; Mateus Bastos Souza, BAppSc2; Murilo Xavier Oliveira, PhD2; et alAna Cristina Lacerda, PhD2; Vanessa Amaral Mendonça, PhD2; Nicholas Henschke, PhD3; Vinícius Cunha Oliveira, PhD2
JAMA Intern Med. 2021;181(1):104-112. doi:10.1001/jamainternmed.2020.5651
Key Points
Question What is the association of therapies with reduced pain and improved quality of life in patients with fibromyalgia?
Findings In this systematic review, the effectiveness of most therapies for fibromyalgia was not supported. Strong evidence supported only cognitive behavioral therapy for pain, as well as antidepressants and central nervous system depressants for pain and quality of life, but these associations were small.
Meaning Some therapies may be associated with small reductions in pain and improvements in quality of life in people with fibromyalgia; however, current evidence is lacking for most therapies.
Abstract
Importance Fibromyalgia is a chronic condition that results in a significant burden to individuals and society.
Objective To investigate the effectiveness of therapies for reducing pain and improving quality of life (QOL) in people with fibromyalgia.
Data Sources Searches were performed in the MEDLINE, Cochrane, Embase, AMED, PsycInfo, and PEDro databases without language or date restrictions on December 11, 2018, and updated on July 15, 2020.
Study Selection All published randomized or quasi-randomized clinical trials that investigated therapies for individuals with fibromyalgia were screened for inclusion.
Data Extraction and Synthesis Two reviewers independently extracted data and assessed risk of bias using the 0 to 10 PEDro scale. Effect sizes for specific therapies were pooled using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment (GRADE) approach.
Main Outcomes and Measures Pain intensity measured by the visual analog scale, numerical rating scales, and other valid instruments and QOL measured by the Fibromyalgia Impact Questionnaire.
Results A total of 224 trials including 29 962 participants were included. High-quality evidence was found in favor of cognitive behavioral therapy (weighted mean difference [WMD], −0.9; 95% CI, −1.4 to −0.3) for pain in the short term and was found in favor of central nervous system depressants (WMD, −1.2 [95% CI, −1.6 to −0.8]) and antidepressants (WMD, −0.5 [95% CI, −0.7 to −0.4]) for pain in the medium term. There was also high-quality evidence in favor of antidepressants (WMD, −6.8 [95% CI, −8.5 to −5.2]) for QOL in the short term and in favor of central nervous system depressants (WMD, −8.7 [95% CI, −11.3 to −6.0]) and antidepressants (WMD, −3.5 [95% CI, −4.5 to −2.5]) in the medium term. However, these associations were small and did not exceed the minimum clinically important change (2 points on an 11-point scale for pain and 14 points on a 101-point scale for QOL). Evidence for long-term outcomes of interventions was lacking.
Conclusions and Relevance This systematic review and meta-analysis suggests that most of the currently available therapies for the management of fibromyalgia are not supported by high-quality evidence. Some therapies may reduce pain and improve QOL in the short to medium term, although the effect size of the associations might not be clinically important to patients.
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ORIGINAL RESEARCH ARTICLE
Front. Med., 27 January 2021 | https://doi.org/10.3389/fmed.2020.602894
Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
C (Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1
- 1Stichting CardioZorg, Hoofddorp, Netherlands
- 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- 3Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, Netherlands
Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.
Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Major Impact on Lives of Both Patients and Family Members
by
Esme Brittain1,Nina Muirhead,Andrew Y. Finlay 1 and Jui Vyas
Medicina 2021, 57(1), 43; https://doi.org/10.3390/medicina57010043
Received: 3 December 2020 / Revised: 23 December 2020 / Accepted: 30 December 2020 / Published: 7 January 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and objectives: To explore the impacts that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has on the patient and their family members using the WHOQOL-BREF (Abbreviated World Health Organisation Quality of Life questionnaire) and FROM-16 (Family Reported Outcome Measure-16) quality of life assessments. Materials and Methods: A quantitative research study using postal questionnaires was conducted. A total of 39 adult volunteers expressed an interest in participating in the study: 24 returned appropriately completed questionnaires. Patients with ME/CFS completed the WHOQOL-BREF and up to four of their family members completed the FROM-16 questionnaire. Results: ME/CFS negatively affects the quality of life of the patient (median scores WHOQOL-BREF: Physical health = 19, Psychological = 44, Social relationships = 37.5, Environment = 56, n = 24) and their family members’ quality of life (FROM-16: Emotional = 9.5, Personal and social = 11.5, Overall = 20.5, n = 42). There was a significant correlation between the patient’s reported quality of life scores and their family members’ mean FROM-16 total scores. Conclusions: This study identifies the major impact that having an adult family member with ME/CFS has on the lives of partners and of other family members. Quality of life of ME/CFS patients was reduced most by physical health compared to the other domains. Quality of life of family members was particularly impacted by worry, family activities, frustration and sadness. This highlights the importance of measuring the impact on the lives of family members using tools such as the FROM-16 in the ME/CFS clinical encounter and ensuring appropriate support is widely available to family members.
Keywords: ME/CFS; QoL; family impact; FROM-16; WHOQOL-BREF
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Published: 04 November 2020
Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions
A. M. Helliwell, E. C. Sweetman, P. A. Stockwell, C. D. Edgar, A. Chatterjee & W. P. Tate
Clinical Epigenetics volume 12, Article number: 167 (2020)
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.
Results
DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.
Conclusions
Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.
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Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate
Journal of Translational Medicine volume 18, Article number: 365 (2020) Cite this article
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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2020 Nov 18;3(1):142-158. doi: 10.1089/nsm.2019.0009. eCollection 2020.
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan 1, Narayan Shivapurkar 1, James N Baraniuk 1
PMID: 33274349 PMCID: PMC7703497 DOI: 10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise. Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise. Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia. Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS. Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
Keywords: cerebrospinal fluid; informatics; micro-RNA (miRNA); myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); pathway analysis.
© Vaishnavi Narayan et al., 2020; Published by Mary Ann Liebert, Inc.
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2021 Feb 2;2021.01.29.21250755.
doi: 10.1101/2021.01.29.21250755. Preprint
A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses
Phillip H Comella, Edgar Gonzalez-Kozlova, Roman Kosoy, Alexander W Charney, Irene Font Peradejordi, Shreya Chandrasekar, Scott R Tyler, Wenhui Wang, Bojan Losic, Jun Zhu, Gabriel E Hoffman, Seunghee Kim-Schulze, Jingjing Qi, Manishkumar Patel, Andrew Kasarskis, Mayte Suarez-Farinas, Zeynep H Gümüş, Carmen Argmann, Miriam Merad, Christian Becker, Noam D Beckmann, Eric E Schadt
PMID: 33564792 PMCID: PMC7872387
Abstract
The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
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Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19 The Writing Committee for the COMEBAC Study Group
JAMA. Published online March 17, 2021. doi:10.1001/jama.2021.3331
COVID-19 Resource Center
Key Points
Question What are the clinical outcomes after hospitalization for COVID-19?
Findings Four months after hospitalization, in an uncontrolled cohort study of 478 survivors of COVID-19, at least 1 new-onset symptom was reported by telephone interview by 244 patients (51%), including fatigue in 134 of 431 (31%), cognitive symptoms in 86 of 416 (21%), and dyspnea in 78 of 478 (16%). Computed tomographic lung scan abnormalities were reported in 63% of 171 patients assessed at an ambulatory visit, mainly subtle ground-glass opacities. Fibrotic lesions were observed in 19% of these 171 patients.
Meaning This study provides clinical status of a cohort of patients 4 months after hospitalization for COVID-19, but further research is needed to understand longer-term outcomes.
Abstract
Importance Little is known about long-term sequelae of COVID-19.
Objective To describe the consequences at 4 months in patients hospitalized for COVID-19.
Design, Setting, and Participants In a prospective uncontrolled cohort study, survivors of COVID-19 who had been hospitalized in a university hospital in France between March 1 and May 29, 2020, underwent a telephone assessment 4 months after discharge, between July 15 and September 18, 2020. Patients with relevant symptoms and all patients hospitalized in an intensive care unit (ICU) were invited for further assessment at an ambulatory care visit.
Exposures Survival of hospitalization for COVID-19.
Main Outcomes and Measures Respiratory, cognitive, and functional symptoms were assessed by telephone with the Q3PC cognitive screening questionnaire and a checklist of symptoms. At the ambulatory care visit, patients underwent pulmonary function tests, lung computed tomographic scan, psychometric and cognitive tests (including the 36-Item Short-Form Health Survey and 20-item Multidimensional Fatigue Inventory), and, for patients who had been hospitalized in the ICU or reported ongoing symptoms, echocardiography.
Results Among 834 eligible patients, 478 were evaluated by telephone (mean age, 61 years [SD, 16 years]; 201 men, 277 women). During the telephone interview, 244 patients (51%) declared at least 1 symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. There was further evaluation in 177 patients (37%), including 97 of 142 former ICU patients. The median 20-item Multidimensional Fatigue Inventory score (n = 130) was 4.5 (interquartile range, 3.0-5.0) for reduced motivation and 3.7 (interquartile range, 3.0-4.5) for mental fatigue (possible range, 1 [best] to 5 [worst]). The median 36-Item Short-Form Health Survey score (n = 145) was 25 (interquartile range, 25.0-75.0) for the subscale “role limited owing to physical problems” (possible range, 0 [best] to 100 [worst]). Computed tomographic lung-scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 of 171 patients (19%), involving less than 25% of parenchyma in all but 1 patient. Fibrotic lesions were observed in 19 of 49 survivors (39%) with acute respiratory distress syndrome. Among 94 former ICU patients, anxiety, depression, and posttraumatic symptoms were observed in 23%, 18%, and 7%, respectively. The left ventricular ejection fraction was less than 50% in 8 of 83 ICU patients (10%). New-onset chronic kidney disease was observed in 2 ICU patients. Serology was positive in 172 of 177 outpatients (97%).
Conclusions and Relevance Four months after hospitalization for COVID-19, a cohort of patients frequently reported symptoms not previously present, and lung-scan abnormalities were common among those who were tested. These findings are limited by the absence of a control group and of pre-COVID assessments in this cohort. Further research is needed to understand longer-term outcomes and whether these findings reflect associations with the disease.
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Global Health March 16, 2021
Most Patients Hospitalized With COVID-19 Have Lasting Symptoms
Bridget M. Kuehn, MSJ JAMA. 2021;325(11):1031. doi:10.1001/jama.2021.2974
COVID-19 Resource Center
Three-quarters of patients hospitalized with coronavirus disease 2019 (COVID-19) still had at least 1 symptom 6 months after they became ill, according to recently published follow-up research.
The study included 1733 patients who were hospitalized in Wuhan, China, and discharged between January and May 2020. Fatigue and ongoing muscle weakness were reported by 63% of the patients and roughly one-quarter reported difficulty sleeping or anxiety and depression. A subset of patients still had reduced lung function and below normal results on a 6-minute walking test. Ongoing lung and mobility impairments were more prevalent among the most severely ill patients. Among 1378 patients with estimated glomerular filtration rates available during their acute illness and at follow-up, about one-third had reduced kidney function at 6 months.
Among a subgroup of 94 patients who provided plasma samples during their acute illness and 6 months later, neutralizing antibody levels had dropped by about half at the follow-up visit, raising concerns about potential reinfection, the authors warned.
“Our analysis indicates that most patients continue to live with at least some of the effects of the virus after leaving hospital, and highlights a need for post-discharge care, particularly for those who experience severe infections,” senior author Bin Cao, MD, of the National Center for Respiratory Medicine in Beijing, China, said in a statement.
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy,Shaun Bhatia,Mohammed Islam andLeonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.
Keywords: ME/CFS; chronic fatigue syndrome; myalgic encephalomyelitis; illness severity; homebound; bedridden
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In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Arnaud Germain,Susan M. Levine and Maureen R. Hanson
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Proteomes 2021, 9(1), 6; https://doi.org/10.3390/proteomes9010006
Received: 1 January 2021 / Revised: 24 January 2021 / Accepted: 25 January 2021 / Published: 29 January 2021
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Keywords: ME/CFS; proteomics; plasma; ephrin-Eph pathway; immune metabolism; adherens junction; glucose; SOMAscan®; diagnosis
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ORIGINAL RESEARCH – Brain and Behaviour
Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
Sara Haghighi Sara Forsmark Olof Zachrisson Arvid Carlsson Marie K. L. Nilsson Maria L. Carlsson Robert C. Schuit Carl‐Gerhard Gottfries
First published: 02 February 2021 https://doi.org/10.1002/brb3.2040
Abstract
Objectives
The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (‐)‐OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (‐)‐OSU6162 in ME/CFS was evaluated by means of observer‐rated scales and self‐assessment rating scales.
Materials and Methods
In the current study using an open‐label single‐arm design ME/CFS patient received treatment with (‐)‐OSU6162 during 12 weeks. The patients received the following doses of (‐)‐OSU6162: 15 mg b.i.d. during the first 4‐week period, up to 30 mg b.i.d. during the second 4‐week period and up to 45 mg b.i.d. during the third 4‐week period, with follow‐up visits after 16 and 20 weeks.
Results
Out of 33 included patients, 28 completed the 12 weeks treatment period. (‐)‐OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.
Conclusions
(‐)‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.
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UK Moves to Revise Guidelines for Treatment of Chronic Fatigue Syndrome
AJN, American Journal of Nursing: March 2021 - Volume 121 - Issue 3 - p 16
doi: 10.1097/01.NAJ.0000737248.67484.2e
Abstract
Advocates hail rejection of debunked exercise and cognitive behavior therapies.
Proposed guidelines for management of myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS), from the United Kingdom's National Institute for Health and Care Excellence (NICE) are being hailed for their rejection of graded exercise therapy and cognitive behavior therapy (CBT) as routine treatment. Major medical organizations, advocacy groups, and patients have strongly advocated for NICE to align guidelines with scientific evidence.
The U.S. Centers for Disease Control and Prevention (CDC) in 2017 eliminated these largely useless and, in some cases, harmful therapies from its recommendations. That NICE is now following suit is good news, though many say it is long overdue. Moreover, patients are unlikely to see immediate results as new science can take years to reach clinical practice.
The illness is characterized by debilitating fatigue and difficulty with concentration and memory. An estimated 2.5 million Americans are diagnosed with ME/CFS, most of them women. Because symptoms can range widely and standard laboratory tests yield little insight as to cause, ME/CFS has been viewed as a stress-induced disorder in some women.
Graded exercise therapy and CBT became the go-to therapies for ME/CFS based on findings of a 2011 study, known as PACE, published in the Lancet. According to the study investigators, these treatments produced a sustained improvement in patients' levels of fatigue and physical function, even leading to recovery for some. Top researchers who reviewed the study, however, found major flaws. Patients also reacted negatively, saying the study's results did not reflect their experiences and reinforced inaccurate and stigmatizing beliefs about the illness as a psychological and behavioral disorder. Eventually, over 100 academics, patient groups, and others called for an independent reanalysis of the data. Despite this forceful opposition, the study remained influential with clinicians and continued to underpin treatment recommendations of major medical organizations, including the CDC and NICE.
Perceptions began to change with the 2015 release of the Institute of Medicine's landmark report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, in which the authors described ME/CFS as a “serious, chronic, complex, systemic disease” and cited newly identified biomarkers indicating immunological and neurological dysfunction. The report and continuing pressure from scientists, clinicians, and patients led the CDC to remove recommendations for graded exercise therapy and CBT as its British counterpart, NICE, now proposes to do.--Karen Roush, PhD, RN, FNP-BC,
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2021 Feb 11. doi: 10.1089/ars.2020.8230. Online ahead of print.
Are Circulating Fibroblast Growth Factor 21 and N-Terminal Prohormone of Brain Natriuretic Peptide Promising Novel Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Joan Carles Domingo 1, Begoña Cordobilla 1, Roser Ferrer 2, Marina Giralt 2, José Alegre-Martín 3 4, Jesús Castro-Marrero 4 PMID: 33353469
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling, and complex multisystem illness of unknown etiology. The protein fibroblast growth factor 21 (FGF21) regulates glucose homeostasis and lipid metabolism, and the protein N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is strongly associated with an elevated cardiovascular risk; however, little is known about their role in ME/CFS patients. To address this gap, we explored the association between FGF21 and NT-proBNP and oxidative stress and inflammatory markers in ME/CFS. Twenty-one ME/CFS patients and 20 matched healthy controls were included in the study. Participants filled out validated self-reported questionnaires on their current health status covering demographic and clinical characteristics. Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxide levels (p = 0.009 and p = 0.021, respectively) in ME/CFS. These ME/CFS patients also had significantly increased levels of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-10, TNF-α, and C-reactive protein) (p < 0.05 for all) but not for IL-8 (p = 0.833), indicating low-grade systemic inflammation status. Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls. Significantly positive correlations were found between NT-proBNP levels and IL-1β and IL-6 (p = 0.04 and p = 0.01) in ME/CFS patients but not between FGF21 and these cytokines. In contrast, no significant correlations were found for either FGF21 or NT-proBNP in controls. These findings lead to the hypothesis that elevated FGF21 and NT-proBNP levels and the association between NT-proBNP and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS.
Keywords: FGF21; NT-proBNP; chronic fatigue syndrome; cytokines; myalgic encephalomyelitis; oxidative stress.
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2021 Apr;132(4):967-974.Clin.Neurophysiology doi: 10.1016/j.clinph.2020.11.043. Epub 2021 Jan29.
Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load
E G Klaver-Krol 1, H J Hermens 2, R C Vermeulen 3, M M Klaver 4, H Luyten 5, N R Henriquez 6, M J Zwarts 7PMID: 33639451 : 10.1016/j.clinph.2020.11.043
Abstract
Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of - especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.
Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.
Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.
Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.
Significance: These findings help to detangle the underlying mechanisms of CFS.
Keywords: Chronic fatigue syndrome; Force generation; Muscle fiber conduction velocity; Muscle membrane dysfunction; Surface electromyography.
Copyright © 2021. Published by Elsevier B.V.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!
Maria Eugenia Ariza
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA2
Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Academic Editors: Maria Teresa Sciortino and Marshall Williams
Biomolecules 2021, 11(2), 185; https://doi.org/10.3390/biom11020185
Published: 29 January 2021
(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
Keywords: myalgic encephalomyelitis/chronic fatigue syndrome; epstein-barr virus (EBV); human herpesvirus 6 (HHV-6); immune dysfunction; BRRF1; BLLF3; deoxyuridine triphosphate nucleotidohydrolase (dUTPase)
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Experiences of Living with Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Victoria Strassheim,Julia L. Newton3 and Tracy Collins
CRESTA Fatigue Clinic, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE4 6BE, UK
Academic Health Science Network–North East & North Cumbria, Newcastle upon Tyne NE4 5PL, UK
Population Health Science Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
Department of Social Work, Education and Community Wellbeing, Coach Lane Campus, Northumbria University, Newcastle upon Tyne NE7 7AX, UK*
Healthcare 2021, 9(2), 168; https://doi.org/10.3390/healthcare9020168
Received: 17 December 2020 / Revised: 27 January 2021 / Accepted: 28 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness. Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered. This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely. Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.
Keywords: ME/CFS; severe; very severe; housebound; qualitative; interview; experience
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Covid-19: Middle aged women face greater risk of debilitating long term symptoms
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n829 (Published 25 March 2021)Cite this as: BMJ 2021;372:n8
Ingrid Torjesen
Middle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and “brain fog” after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.
Seven in 10 patients admitted to hospital with covid-19 reported “long covid” symptoms an average of five months after discharge in the larger PHOSP-COVID study, and symptoms were more prevalent in women aged 40-60.1 White ethnicity, two or more comorbidities at admission, and receiving invasive ventilation while in hospital increased the risk, but severity of acute covid-19 disease did not seem to affect the likelihood of experiencing long covid symptoms.
Only 29% of the 1077 patients studied felt fully recovered when followed up, on average five months after discharge. Over a quarter had clinically significant symptoms of anxiety and depression, 12% had symptoms of post-traumatic stress disorder, 17% had at least mild cognitive impairment, 46% had lower physical performance than age and sex matched controls, and 20% had a new disability.
Before hospital admission 68% of patients had worked full time, but 18% of these had not returned to work and 19% had had to change their way of working because of longlasting effects.
The researchers grouped patients into four clusters according to the severity of their physical and mental symptoms post-covid: very severe (17% of patients), severe (21%), moderate with cognitive impairment (17%), and mild (46%).
Rachael Evans, National Institute for Health Research clinical scientist at the University of Leicester and a study author, said, “The symptoms are very real, but they don’t have a straightforward relationship with heart and lung damage, or certainly heart and lung damage can’t explain all the symptoms.”
Immune response
A smaller second study, from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC), found that women under 50 were five times less likely to report feeling recovered, twice as likely to report worse fatigue, seven times more likely to become more breathless, and more likely to have greater disability than men of the same age who had been admitted to hospital with covid-19.2 Disability usually affected memory, mobility, communication, vision, or hearing. More than half of the 327 patients assessed in this study did not feel fully recovered when followed up on average seven months later, and persistent symptoms were reported by 93.3%, with fatigue and breathlessness the most common.
Chris Brightling, professor of respiratory medicine at the University of Leicester and a PHOSP-COVID study researcher, speculated that sex based differences in the immune response may be responsible for the higher prevalence of long covid symptoms in women, noting that autoimmune diseases were more prevalent in women than in men at age 40-60.
“Maybe there’s a difference in the immune response acutely, such that men are more likely to have a more severe condition at the time of the infection,” he told a press conference at the Science Media Centre on 24 March. “It may be that the immune response is different in women, so you then have a continued inflammatory reaction that then leads to a higher likelihood of having long covid.”
Higher levels of C reactive protein, a marker of systemic inflammation, were seen in patients in the most severe long covid symptoms. Brightling said that a number of immune and chronic inflammatory conditions can also cause elevated C reactive protein.
About 450 000 people have been admitted to hospital with covid-19 in the UK, so a “very large” proportion of these would potentially be affected by long covid, he said, adding, “Clearly there’s an even larger number of people that have had covid in the community, and a portion of those will also have long covid.”
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