Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome
Evelina Shikova 1 2, Valentina Reshkova 3, Аntoniya Kumanova 1, Sevdalina Raleva 1, Dora Alexandrova 2, Natasa Capo 4 5, Modra Murovska 6; European Network on ME/CFS (EUROMENE) PMID: 32129496 PMCID: PMC7687071 DOI: 10.1002/jmv.25744
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV, and HHV-6 infections in Bulgarian ME/CFS patients. In the study were included 58 patients with ME/CFS and 50 healthy controls. Virus-specific antibodies were detected by enzyme-linked immunosorbent assay and viral genomic sequences in peripheral blood mononuclear cell (PBMCs) and plasma samples by nested polymerase chain reaction (PCR). We did not observe any significant differences in virus-specific immunoglobulin G and immunoglobulin M positivity rates between patients with ME/CFS and control group. In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, and CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (P = .0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed. In conclusion, this study using both serological and PCR-based techniques for distinguishing between active and latent infection showed high rate of active EBV infection among patients with ME/CFS indicating that at least in a subset of cases, EBV is important factor for the development of disease.
Keywords: CMV; EBV; ELISA; HHV-6 infection; PCR; active infection; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.
Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms
Joeffre Braga, BSc1,2,3; Mariel Lepra, BSc1,2,3; Stephen J. Kish, PhD1,2,3,4; et alPablo. M. Rusjan, PhD5,6; Zahra Nasser1; Natasha Verhoeff, BHSc1; Neil Vasdev, PhD1,2,4; Michael Bagby, PhD2,7; Isabelle Boileau, PhD1,2,3,4; M. Ishrat Husain, MBBS, MD1,2,3,4; Nathan Kolla, MD, PhD1,2,3,4,8; Armando Garcia, BSc1,2; Thomas Chao, PhD9; Romina Mizrahi, PhD5,6; Khunsa Faiz, MD10; Erica L. Vieira, PhD1,2; Jeffrey H. Meyer, MD, PhD1,2,3,4
JAMA Psychiatry. Published online May 31, 2023. doi:10.1001/jamapsychiatry.2023.1321
Question Is translocator protein distribution volume (TSPO VT), an index of gliosis (an inflammatory change), measured by positron emission tomography, elevated in the brain after acute COVID-19 infection with sequelae of depressive and cognitive symptoms?
Findings In this case-control study, TSPO VT was elevated in 20 participants with persistent depressive and cognitive symptoms after initially mild to moderate COVID-19 infection when compared with 20 healthy controls, more prominently in the ventral striatum and dorsal putamen. The TSPO VT in the dorsal putamen of COVID-19 cases negatively correlated with motor speed.
Meaning These findings suggest that gliosis, especially in the ventral striatum and dorsal putamen, may reflect injury, ongoing inflammation, or both and provide directions for further therapeutic development.
Importance Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.
Objective To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.
Design, Setting, and Participants This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.
Main Outcomes and Measures The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.
Results The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, −0.53; 95% CI, −0.79 to −0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).
Conclusions and Relevance In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.
Comparison of Medical and Mental Health Sequelae Following Hospitalization for COVID-19, Influenza, and Sepsis
Kieran L. Quinn, MD, PhD1,2,3,4,5; et al
JAMA Intern Med. Published online June 20, 2023. doi:10.1001/jamainternmed.2023.2228
Question Is the risk of newly developing selected medical and mental health conditions greater within 1 year following hospitalization for severe COVID-19 compared with influenza or sepsis?
Findings This population-based cohort study of 26 499 people hospitalized for COVID-19 compared with 17 516 historic controls with influenza, 282 473 historic controls with sepsis, and 52 878 people concurrently hospitalized with sepsis found that COVID-19 was associated with elevated 1-year risk of venous thromboembolism but not 12 other prespecified conditions.
Meaning Apart from an elevated risk of venous thromboembolism, the burden of postacute conditions among those who survive hospitalization for COVID-19 may be comparable with other acute infections.
Importance People who survive hospitalization for COVID-19 are at risk for developing new cardiovascular, neurological, mental health, and inflammatory autoimmune conditions. It is unclear how posthospitalization risks for COVID-19 compare with those for other serious infectious illnesses.
Objective To compare risks of incident cardiovascular, neurological, and mental health conditions and rheumatoid arthritis in 1 year following COVID-19 hospitalization against 3 comparator groups: prepandemic hospitalization for influenza and hospitalization for sepsis before and during the COVID-19 pandemic.
Design, Setting, and Participants This population-based cohort study included all adults hospitalized for COVID-19 between April 1, 2020, and October 31, 2021, historical comparator groups of people hospitalized for influenza or sepsis, and a contemporary comparator group of people hospitalized for sepsis in Ontario, Canada.
Exposure Hospitalization for COVID-19, influenza, or sepsis.
Main Outcome and Measures New occurrence of 13 prespecified conditions, including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis, within 1 year of hospitalization.
Results Of 379 366 included adults (median [IQR] age, 75 [63-85] years; 54% female), there were 26 499 people who survived hospitalization for COVID-19, 299 989 historical controls (17 516 for influenza and 282 473 for sepsis), and 52 878 contemporary controls hospitalized for sepsis. Hospitalization for COVID-19 was associated with an increased 1-year risk of venous thromboembolic disease compared with influenza (adjusted hazard ratio, 1.77; 95% CI, 1.36-2.31) but with no increased risks of developing selected ischemic and nonischemic cerebrovascular and cardiovascular disorders, neurological disorders, rheumatoid arthritis, or mental health conditions compared with influenza or sepsis cohorts.
Conclusions and Relevance In this cohort study, apart from an elevated risk of venous thromboembolism within 1 year, the burden of postacute medical and mental health conditions among those who survived hospitalization for COVID-19 was comparable with other acute infectious illnesses. This suggests that many of the postacute consequences of COVID-19 may be related to the severity of infectious illness necessitating hospitalization rather than being direct consequences of infection with SARS-CoV-2.
March 23, 2023
Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. 2023;183(6):566-580. doi:10.1001/jamainternmed.2023.0750
Question Which individuals are at risk of developing post−COVID-19 condition?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
2023 Feb; 24(3): 2698.Int J Mol Sci Published online 2023 Jan31. doi: 10.3390/ijms24032698 PMCID: PMC9916639 PMID: 36769022
Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures
Derek J. Van Booven,1 et al
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome
Circ Rep 2023; 5: 55–61 doi:10.1253/circrep.CR-22-0114
Kunihisa Miwa, MD, Ph
Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME.
Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed. Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30beats/min or an actual heart rate of ≥120beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions. Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS.
Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.
Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controlsLudovic Giloteaux, Jiayi Li, Mady Hornig,W. Ian Lipkin, David Ruppert & Maureen R. Hanson
Journal of Translational Medicine volume 21, Article number: 322 (2023)
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogenous disease characterized by unexplained persistent fatigue and other features including cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Cytokines are present in plasma and encapsulated in extracellular vesicles (EVs), but there have been only a few reports of EV characteristics and cargo in ME/CFS. Several small studies have previously described plasma proteins or protein pathways that are associated with ME/CFS.
MethodsWe prepared extracellular vesicles (EVs) from frozen plasma samples from a cohort of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) cases and controls with prior published plasma cytokine and plasma proteomics data. The cytokine content of the plasma-derived extracellular vesicles was determined by a multiplex assay and differences between patients and controls were assessed. We then performed multi-omic statistical analyses that considered not only this new data, but extensive clinical data describing the health of the subjects.
ResultsME/CFS cases exhibited greater size and concentration of EVs in plasma. Assays of cytokine content in EVs revealed IL2 was significantly higher in cases. We observed numerous correlations among EV cytokines, among plasma cytokines, and among plasma proteins from mass spectrometry proteomics. Significant correlations between clinical data and protein levels suggest roles of particular proteins and pathways in the disease. For example, higher levels of the pro-inflammatory cytokines Granulocyte-Monocyte Colony-Stimulating Factor (CSF2) and Tumor Necrosis Factor (TNFα) were correlated with greater physical and fatigue symptoms in ME/CFS cases. Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS. Machine learning classifiers were able to identify a list of 20 proteins that could discriminate between cases and controls, with XGBoost providing the best classification with 86.1% accuracy and a cross-validated AUROC value of 0.947. Random Forest distinguished cases from controls with 79.1% accuracy and an AUROC value of 0.891 using only 7 proteins.
ConclusionsThese findings add to the substantial number of objective differences in biomolecules that have been identified in individuals with ME/CFS. The observed correlations of proteins important in immune responses and hemostasis with clinical data further implicates a disturbance of these functions in ME/CFS.
Queensland scientists push for new national treatment guidelines for chronic fatigue syndromeBy Janelle Miles
Posted Tue 13 Jun 2023 at 8:11amTuesday 13 Jun 2023 at 8:11am, updated Tue 13 Jun 2023 at 9:46amTuesday 13 Jun 2023 at 9:46am
Professor Sonya Marshall-Gradisnik says Australia's clinical guidelines for treating patients with ME/CFS are well out of date.(Supplied: Griffith University )
A meeting in Canberra today will push for new national guidelines to treat chronic fatigue syndrome.
- It's estimated ME/CFS affects more than 240,000 Australians
- Symptoms include brain fog, memory loss, muscle and joint pain and post-exertional malaise
- Low-dose Naltrexone has been identified as a potential drug treatment for ME/CFS
They will join politicians, ME/CFS patient representatives and other researchers from across the country at Parliament House.
Griffith University's Sonya Marshall-Gradisnik, recognised as a world expert in ME/CFS, said Australia's treatment guidelines failed to reflect scientific advances in the pathology of the illness, conservatively estimated to affect 240,000 Australians.
The Royal Australian College of General Practitioners' guidelines for the treatment of chronic fatigue syndrome suggest graded exercise therapy and cognitive behavioural therapy.
"They're some 20 years out of date. There needs to be new clinical guidelines," Professor Marshall-Gradisnik said.
"The research that's been published in the last 20 years clearly outlines that myalgic encephalomyelitis, or chronic fatigue syndrome, is not a psychological or psychiatric illness.
"There is actual underlying pathology."
Professor Marshall-Gradisnik said other countries had withdrawn graded exercise therapy and cognitive behavioural therapy from their ME/CFS guidelines due to "the potential detrimental outcomes to patients".
Patients with ME/CFS can experience a range of symptoms including brain fog, confusion, difficulties with memory and concentration, sleep disturbances, heart problems, muscle and joint pain and intolerances to temperature, light and noise.
A distinguishing sign is post-exertional malaise, where even minor physical or mental activity makes symptoms worse.
Patients can be left bedridden and unable to work.
Potential treatment to be trialledProfessor Marshall-Gradisnik said her team at Griffith University's National Centre for Neuro-immunology and Emerging Diseases, had found dysfunction in the cells of patients with ME/CFS patients, which "align to the symptom presentation" of people with the condition.
"They can't bring calcium inside these cells. Calcium is important for all cell functions," she said.
The Griffith University research has identified low-dose Naltrexone as a potential drug treatment for ME/CFS, recognised as one of a suite of post-infectious diseases that often follow a viral illness.
Professor Marshall-Gradisnik said an Australian trial of Naltrexone in ME/CFS patients was expected to begin later this year.
She said participants would undergo magnetic resonance imaging scans of the brain to assess the affect of the drug on cellular dysfunction identified in ME/CFS.
Professor Marshall-Gradisnik is in Canberra for the meeting of the Parliamentary Friends of ME/CFS, which includes politicians from across the party divide.
"It's hoped the meeting will facilitate new ME/CFS guidelines so doctors across Australia have accurate and up-to-date advice," she said.
Guidance on “Long COVID” as a Disability Under the ADA, Section 504, and Section 1557
Although many people with COVID-19 get better within weeks, some people continue to experience symptoms that can last months after first being infected, or may have new or recurring symptoms at a later time.1 This can happen to anyone who has had COVID-19, even if the initial illness was mild. People with this condition are sometimes called “long-haulers.” This condition is known as “long COVID.”2
In light of the rise of long COVID as a persistent and significant health issue, the Office for Civil Rights of the Department of Health and Human Services and the Civil Rights Division of the Department of Justice have joined together to provide this guidance.
This guidance explains that long COVID can be a disability under Titles II (state and local government) and III (public accommodations) of the Americans with Disabilities Act (ADA),3 Section 504 of the Rehabilitation Act of 1973 (Section 504),4 and Section 1557 of the Patient Protection and Affordable Care Act (Section 1557).5 Each of these federal laws protects people with disabilities from discrimination.6 This guidance also provides resources for additional information and best practices. This document focuses solely on long COVID, and does not address when COVID-19 may meet the legal definition of disability.
The civil rights protections and responsibilities of these federal laws apply even during emergencies.7 They cannot be waived.
1. What is long COVID and what are its symptoms?
According to the Centers for Disease Control and Prevention (CDC), people with long COVID have a range of new or ongoing symptoms that can last weeks or months after they are infected with the virus that causes COVID-19 and that can worsen with physical or mental activity.8
Examples of common symptoms of long COVID include:
- Tiredness or fatigue
- Difficulty thinking or concentrating (sometimes called “brain fog”)
- Shortness of breath or difficulty breathing
- Dizziness on standing
- Fast-beating or pounding heart (known as heart palpitations)
- Chest pain
- Joint or muscle pain
- Depression or anxiety
- Loss of taste or smell
2. Can long COVID be a disability under the ADA, Section 504, and Section 1557?
Yes, long COVID can be a disability under the ADA, Section 504, and Section 1557 if it substantially limits one or more major life activities.9 These laws and their related rules define a person with a disability as an individual with a physical or mental impairment that substantially limits one or more of the major life activities of such individual (“actual disability”); a person with a record of such an impairment (“record of”); or a person who is regarded as having such an impairment (“regarded as”).10 A person with long COVID has a disability if the person’s condition or any of its symptoms is a “physical or mental” impairment that “substantially limits” one or more major life activities.
This guidance addresses the “actual disability” part of the disability definition. The definition also covers individuals with a “record of” a substantially limiting impairment or those “regarded as” having a physical impairment (whether substantially limiting or not). This document does not address the “record of” or “regarded as” parts of the disability definition, which may also be relevant to claims regarding long COVID.
a. Long COVID is a physical or mental impairment
A physical impairment includes any physiological disorder or condition affecting one or more body systems, including, among others, the neurological, respiratory, cardiovascular, and circulatory systems. A mental impairment includes any mental or psychological disorder, such as an emotional or mental illness.11
Long COVID is a physiological condition affecting one or more body systems. For example, some people with long COVID experience:
- Lung damage
- Heart damage, including inflammation of the heart muscle
- Kidney damage
- Neurological damage
- Damage to the circulatory system resulting in poor blood flow
- Lingering emotional illness and other mental health conditions
b. Long COVID can substantially limit one or more major life activities
“Major life activities” include a wide range of activities, such as caring for oneself, performing manual tasks, seeing, hearing, eating, sleeping, walking, standing, sitting, reaching, lifting, bending, speaking, breathing, learning, reading, concentrating, thinking, writing, communicating, interacting with others, and working. The term also includes the operation of a major bodily function, such as the functions of the immune system, cardiovascular system, neurological system, circulatory system, or the operation of an organ.
The term “substantially limits” is construed broadly under these laws and should not demand extensive analysis. The impairment does not need to prevent or significantly restrict an individual from performing a major life activity, and the limitations do not need to be severe, permanent, or long-term. Whether an individual with long COVID is substantially limited in a major bodily function or other major life activity is determined without the benefit of any medication, treatment, or other measures used by the individual to lessen or compensate for symptoms. Even if the impairment comes and goes, it is considered a disability if it would substantially limit a major life activity when the impairment is active.
Long COVID can substantially limit a major life activity. The situations in which an individual with long COVID might be substantially limited in a major life activity are diverse. Among possible examples, some include:
- A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities.
- A person with long COVID who has symptoms of intestinal pain, vomiting, and nausea that have lingered for months is substantially limited in gastrointestinal function, among other major life activities.
- A person with long COVID who experiences memory lapses and “brain fog” is substantially limited in brain function, concentrating, and/or thinking.
No. An individualized assessment is necessary to determine whether a person’s long COVID condition or any of its symptoms substantially limits a major life activity. The CDC and health experts are working to better understand long COVID.
4. What rights do people whose long COVID qualifies as a disability have under the ADA, Section 504, and Section 1557?
People whose long COVID qualifies as a disability are entitled to the same protections from discrimination as any other person with a disability under the ADA, Section 504, and Section 1557. Put simply, they are entitled to full and equal opportunities to participate in and enjoy all aspects of civic and commercial life.
For example, this may mean that businesses or state or local governments will sometimes need to make changes to the way that they operate to accommodate a person’s long COVID-related limitations. For people whose long COVID qualifies as a disability, these changes, or “reasonable modifications,” may include:
- Providing additional time on a test for a student who has difficulty concentrating
- Modifying procedures so a customer who finds it too tiring to stand in line can announce their presence and sit down without losing their place in line
- Providing refueling assistance at a gas station for a customer whose joint or muscle pain prevents them from pumping their own gas
- Modifying a policy to allow a person who experience dizziness when standing to be accompanied by their service animal that is trained to stabilize them
- The Office for Civil Rights of the Department of Health and Human Services (HHS) has the following page on civil rights and COVID-19: https://www.hhs.gov/civil-rights/for-providers/civil-rights-covid19/index.html.
- If you believe that an entity covered by HHS civil rights laws has violated your rights protected under these authorities, you may file a complaint at https://www.hhs.gov/ocr/complaints/index.html.
- The Civil Rights Division of the Department of Justice has the following page on its ADA.gov website that discusses topics related to COVID-19 and the ADA: https://www.ada.gov/emerg_prep.html.
- If you believe that you or another person has been discriminated against by an entity covered by the ADA, you may file a complaint with the Disability Rights Section (DRS) in the Department of Justice. Information about how to file a complaint is available at https://www.ada.gov/fact_on_complaint.htm.
- CDC’s website has the following page on post-COVID conditions, which discusses long COVID: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html.
- The Administration for Community Living’s document, “How ACL’s Disability and Aging Networks Can Help People with Long COVID,” provides information on resources and programs to assist people with long COVID. This document is available at https://acl.gov/sites/default/files/COVID19/ACL_LongCOVID.pdf - PDF .
- While employment is outside of the scope of this guidance document, individuals who wish to learn more about COVID-19 and employment can visit the following Equal Employment Opportunity Commission page, which provides COVID-19 information and resources: www.eeoc.gov/coronavirus.
- The EEOC’s main COVID-19 publication, What You Should Know about COVID-19 and the ADA, the Rehabilitation Act, and Other EEO Laws, is available at: https://www.eeoc.gov/wysk/what-you-should-know-about-covid-19-and-ada-rehabilitation-act-and-other-eeo-laws.
- For information about filing an employment discrimination charge, see https://www.eeoc.gov/filing-charge-discrimination.
Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors Luigi di Filippo, Stefano Frara, Fabrizio Nannipieri, Alice Cotellessa, Massimo Locatelli, Patrizia Rovere Querini, Andrea GiustinaThe Journal of Clinical Endocrinology & Metabolism, dgad207, https://doi.org/10.1210/clinem/dgad207 Published:13 April 2023
AbstractLong COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors.
Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization.
Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge.
We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16).
COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.
Brain Behav Immun Health
. 2023 Apr 27;30:100627. doi: 10.1016/j.bbih.2023.100627. eCollection 2023 Jul.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde 1, Alyssa C Indart 1, Peter H R Green 1 2, Robert H Yolken 3, Dane B Cook 4, Sanjay K Shukla 5, Suzanne D Vernon 6, Armin Alaedini 1 7 2 8
PMID: 37396339 PMCID: PMC10308215
The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.
© 2023 Published by Elsevier Inc.
Jama Research Letter Pediatrics
July 19, 2023
Incidence and Characteristics in Children with Post–COVID-19 Condition in SwedenMaria Bygdell, PhD1,2; Jenny M. Kindblom, PhD, MD1,3; Jari Martikainen, MSc4; et alHuiqi Li, PhD2; Fredrik Nyberg, PhD, MD2
JAMA Netw Open. 2023;6(7):e2324246. doi:10.1001/jamanetworkopen.2023.24246
During the COVID-19 pandemic it has become increasingly clear that children have not been as severely affected as adults in the acute phase of the infection, with the exception of those affected by multisystem inflammatory syndrome in children (MIS-C).1,2 In accordance with adults, some children seem to be affected by persistent long-term symptoms of COVID-19, commonly referred to as post–COVID-19 condition (PCC).3 The frequency of PCC in the pediatric population is to a large extent unknown, and the occurrence in subgroups is not completely understood. The aim of this descriptive study was to describe the incidence of PCC in children and different subgroups of children using a unique population-based cohort with near-complete follow-up in high-quality Swedish registers.
We included all children ages 6 to 17 years residing in the 2 largest Swedish regions and retrieved information on both inpatient and outpatient care from specialists and primary health care clinicians using high-quality national or regional registers with near-complete coverage (eMethods in Supplement 1). The inclusion criterion was COVID-19 infection between January 31, 2020, and February 9, 2022. PCC was defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code U09.9 (used in Sweden since October 20204,5) as the main or secondary diagnosis occurring 28 days or more after the COVID-19 infection. Follow-up ended at the earliest of: PCC diagnosis, emigration, death, or end of study (November 30, 2022). Incidence rate (per 100 person-years) and cumulative incidence are presented for the total cohort and according to subgroups. Data were analyzed with R Statistical Software version 4.2.2 (R Project for Statistical Computing).
A total of 162 383 children (81 789 boys [50.4%], 80 594 girls [49.6%]), with a mean (SD) age of 12.0 (3.5) years at study start, had experienced a COVID-19 infection. Only a small proportion (529 [0.3%]) had been hospitalized due to COVID-19 and none of the children with PCC had been treated in intensive care. We found a PCC diagnosis in 326 children (0.2%) with COVID-19 (Figure). We observed numerically higher incidence rates of PCC cases among girls than boys (incidence rate per 100 person-years: 0.19; 95% CI, 0.16-0.22 vs 0.12; 95% CI, 0.10-0.14), older than younger children (age 12 to 17 years, 0.19; 95% CI, 0.17-0.22 vs 0.11; 95% CI, 0.09-0.14), with vs without comorbidities (any, 0.16; 95% CI, 0.14-0.18 vs none, 0.11; 95% CI, 0.07-0.15), and among hospitalized compared with nonhospitalized for acute COVID-19 (1.25; 95% CI, 0.62-2.23 vs 0.15; 95% CI, 0.13-0.17) (Table). Similar PCC occurrence was seen across categories of parental education. Children who had a diagnosis of MIS-C (63 children) showed an increased occurrence of PCC diagnosis compared with children without MIS-C. In addition, we observed a 6-fold higher occurrence of PCC if any of the parents had a PCC diagnosis (Table).
In this population-based, well-powered cohort with uniquely comprehensive data regarding COVID-19 and PCC, only 0.2% children with COVID-19 had a subsequent diagnosis of PCC. Children with PCC were more often girls, older, had comorbidities, had been hospitalized for their COVID-19, or had a parent with a PCC diagnosis. The higher cumulative incidence of PCC among children with a parent with PCC may indicate that the etiology of PCC could involve genetic susceptibility, or that parental experience of long-term symptoms raises awareness of symptoms and facilitates navigation of the health care system. Moreover, the increased occurrence of PCC among hospitalized children is well in accordance with similar results regarding hospitalized adults.6 Because none of the children with PCC had been treated in intensive care, the diagnosis cannot be explained by misclassification of post–intensive care syndrome. The number of MIS-C cases in the study population was low and therefore the association of MIS-C with PCC needs to be evaluated further. A limitation with our study was that the PCC diagnosis code is not yet validated, and the strengths include the unique comprehensive data, the large population-based cohort, and the near-complete follow-up in high-quality registers.
In this descriptive study, PCC in children was rare. We observed a higher number of children with female sex, older age, hospitalization for COVID-19, and having a parent with PCC among cases with PCC.
Article Information: Accepted for Publication: June 5, 2023.
Published: July 19, 2023. doi:10.1001/jamanetworkopen.2023.24246
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Bygdell M et al. JAMA Network Open.
Corresponding Author: Maria Bygdell, PhD, Department of Internal and Clinical Nutrition, University of Gothenburg, Vita Stråket 11, 413 45 Gothenburg, Sweden (email@example.com).
Author Contributions: Drs Bygdell and Nyberg had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Development of a Definition of Postacute Sequelae of SARS-CoV-2 InfectionTanayott Thaweethai, PhD1,2; Sarah E. Jolley, MD, MS3; Elizabeth W. Karlson, MD, MS4; et alEmily B. Levitan, ScD5; Bruce Levy, MD2,4; Grace A. McComsey, MD6; Lisa McCorkell, MPP7; Girish N. Nadkarni, MD, MPH8; Sairam Parthasarathy, MD9; Upinder Singh, MD10; Tiffany A. Walker, MD11; Caitlin A. Selvaggi, MS1; Daniel J. Shinnick, MS1; Carolin C. M. Schulte, PhD1; Rachel Atchley-Challenner, PhD12; Leora I. Horwitz, MD13; Andrea S. Foulkes, ScD1,2; RECOVER Consortium
JAMA. 2023;329(22):1934-1946. doi:10.1001/jama.2023.8823 COVID-19 Resource Center
Question What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases?
Findings In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score.
Meaning A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC.
Importance SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.
Objective To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.
Design, Setting, and Participants Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.
Exposure SARS-CoV-2 infection.
Main Outcomes and Measures PASC and 44 participant-reported symptoms (with severity thresholds).
Results A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.
Conclusions and Relevance A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
Brain Research Bulletin Available online 7 July 2023, 110702Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndromeMaia Chaves a, Olivia Braniff a, Angelina Angelova b, Yuru Deng c, Marie-Ève Tremblay a d e f g
https://doi.org/10.1016/j.brainresbull.2023.110702Get rights and content
Highlights Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbonePls have antioxidant properties and are important for curved membrane assemblies
Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS
Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome
Pls replacement is a promising tool against neuroinflammation in these two conditions
After five waves of COVID-19 outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogens contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.
Long COVID Brain Fog 'Comparable to Ageing 10 Years'Rob Hicks | 25 July 2023
The condition often referred to as 'brain fog' in people with long COVID could have a similar effect to ageing a decade, according to UK researchers, who called for more work to understand why this was the case and what could be done to help.
Cognitive impairment has been reported after many types of infection, including SARS-CoV-2, highlighted the team from King's College London (KCL), but it was unclear whether deficits following SARS-CoV-2 improve over time. They underlined that to date, studies had focused on hospitalised individuals with up to a year follow-up, but that the presence, magnitude, persistence, and correlations of effects in community-based cases remained "relatively unexplored".
The prospective cohort study, published in the journal eClinicalMedicine, set out to explore the impact of long COVID on thinking and memory skills. Researchers assessed cognitive performance — working memory, attention, reasoning, and motor control — of participants from the UK COVID Symptom Study Biobank in the first round between July and August, 2021, and the second, between April and June, 2022. Round one comprised 3335 individuals with and without SARS-CoV-2 infection and varying symptom duration, while data was available on 1768 individuals who also completed round two.
The effect of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated, and the role of ongoing symptoms after SARS-CoV-2 infection was examined.
Claire Steves, professor of ageing and health at KCL, and a corresponding study author, said investigators "used sensitive tests to measure speed and accuracy across a range of brain challenges."
Decreased Cognitive AccuracyThe researchers found that at round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy than negative controls.
Cognitive deficits were largest for individuals with "longer symptom durations, ongoing symptoms, and/or more severe infection", identified the researchers. Following SARS-CoV-2 infection, these deficits were detectable nearly 2 years post infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19, the authors said.
"Deficits were largest for positive individuals with ≥12 weeks of symptoms," the researchers reported, with effects "comparable to hospital presentation during illness and 10 years age difference in the whole study population," they alerted.
Dr Nathan Cheetham, a senior postdoctoral data scientist at KCL, who led the research team, said: "This study shows the need to monitor those people whose brain function is most affected by COVID-19 to see how their cognitive symptoms continue to develop and provide support towards recovery."
Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel they had recovered from COVID-19, whereas individuals who reported full recovery showed no deficits.
Longitudinal analysis showed no evidence of cognitive change over time, which suggested that cognitive deficits for affected individuals "persisted" at almost 2 years since initial infection.
Professor Steves emphasised that the study showed that some individuals had "measurable changes" in cognitive function after COVID-19 going on for "nearly two years".
"The deficits in composite task accuracy scores were comparable in scale to the effect of presentation to hospital during illness, an increase in age of approximately 10 years, or exhibiting mild or moderate symptoms of psychological distress, but smaller than other effects such as lower educational attainment or above threshold fatigue level," according to the authors.
Lives "Continue to be Impacted by COVID-19"The researchers found "no evidence" of an effect of SARS-CoV-2 infection on average reaction time during tasks. This, they emphasised, was "reassuring" given the importance of processing speed within cognition and extensive relationships with outcomes such as frailty, dementia, and later mortality.
However, the scale of the deficits identified in the study may have "detrimental impacts" on quality-of-life and daily functioning at an individual level, as well as socio-economic impacts on society more broadly due to both a reduced capacity to work and an increased need for support, the authors cautioned.
They called for further work to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms.
"The fact remains that two years on from their first infection, some people don't feel fully recovered and their lives continue to be impacted by the long-term effects of the coronavirus," commented Professor Steves, who said there was a need for "more work to understand why this is the case and what can be done to help".
Gene Volume 877, 15 August 2023, 147568
A unique circular RNA expression pattern in the peripheral blood of ME/chronic fatigue syndrome patients
Yuning Cheng a, SiMei Xu a, Konii Takenaka a, Grace Lindner a, Ashton Curry-Hyde a, Michael Janitz a b
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.
In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS. Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.
Journal of Translational Medicine
Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/ chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis
Ryuhei Jinushi1,2,3,4* , Sakue Masuda2 , Yuki Tanisaka1 , Sho Nishiguchi3 , Kento Shionoya2 , Ryo Sato1 , Kei Sugimoto1 , Takahiro Shin1 , Rie Shiomi1 , Akashi Fujita1 , Masafumi Mizuide1 and Shomei Ryozawa1
Background Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/ SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specifc test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufcient knowledge about the disease. Prior studies have shown that patients with ME/CFS/ SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the diferences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.
Methods This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the diference in serum acylcarnitine levels between the two groups.
Results The electronic search identifed 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.
Conclusion The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.
Brain, Behavior, & Immunity - Health Volume 30, July 2023, 100627
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde a 1, Alyssa C. Indart a 1, Peter H.R. Green a c, Robert H. Yolken d, Dane B. Cook e, Sanjay K. Shukla f, Suzanne D. Vernon g, Armin Alaedini a b c h
https://doi.org/10.1016/j.bbih.2023.100627Get rights and content
Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
Enhanced IL-10 regulatory response may drive the observed immunosuppression.
Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Long COVID 'Brain Fog' Confounds Doctors, but New Research Offers Hope - Sara Novak
July 03, 2023 Long COVID Resource Center.
Kate Whitley was petrified of COVID-19 from the beginning of the pandemic because she has Hashimoto disease, an autoimmune disorder that she knew put her at high risk for complications.
She was right to be worried. Two months after contracting the infection in September 2022, the 42-year-old Nashville resident was diagnosed with long COVID. For Whitley, the resulting brain fog has been the most challenging factor. She is the owner of a successful paper goods store, and she can't remember basic aspects of her job. She can't tolerate loud noises and gets so distracted that she has trouble remembering what she was doing.
Whitley doesn't like the term "brain fog" because it doesn't begin to describe the dramatic disruption to her life over the past 7 months.
"I just can't think anymore," she said. "It makes you realize that you're nothing without your brain. Sometimes I feel like a shell of my former self."
Brain fog is among the most common symptoms of long COVID, and also one of the most poorly understood. A reported 46% of those diagnosed with long COVID complain of brain fog or a loss of memory. Many clinicians agree that the term is vague and often doesn't truly represent the condition. That, in turn, makes it harder for doctors to diagnose and treat it. There are no standard tests for it, nor are there guidelines for symptom management or treatment.
"There's not a lot of imprecision in the term because it might mean different things to different patients," said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine and author of a new book, Clearing the Fog: From Surviving to Thriving With Long COVID ― A Practical Guide.
Jackson, who began treating Whitley in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn't occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.
Even among those with milder cases of acute COVID, there's some evidence that persistent neuro-inflammation in the brain caused by an activated immune system may also cause damage.
In both cases, the results can be debilitating. Whitley also has dysautonomia — a disorder of the autonomic nervous system that can cause dizziness, sweating, and headaches along with fatigue and heart palpitations.
She said that she's so forgetful that when she sees people socially, she's nervous of what she'll say. "I feel like I'm constantly sticking my foot in my mouth because I can't remember details of other people's lives," she said.
Although brain disorders such as Alzheimer's disease and other forms of dementia are marked by a slow decline, ABI occurs more suddenly and may include a loss of executive function and attention.
"With a brain injury, you're doing fine, and then some event happens (in this case COVID), and immediately after that, your cognitive function is different," said Jackson.
Additionally, ABI is an actual diagnosis, whereas brain fog is not.
"With a brain injury, there's a treatment pathway for cognitive rehabilitation," said Jackson.
Treatments may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for treatment of the mental and behavioral disorders that may result. Jackson said that while many patients aren't functioning cognitively or physically at 100%, they can make enough strides that they don't have to give up things such as driving and, in some cases, their jobs.
Other experts agree that long COVID may damage the brain. An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.
Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.
Calling it a "fog" makes it easier for clinicians and the general public to dismiss its severity, said Tyler Reed Bell, PhD, a researcher who specializes in viruses that cause brain injury. He is a fellow in the Department of Psychiatry at the University of California, San Diego. Brain fog can make driving and returning to work especially dangerous. Because of difficulty focusing, patients are much more likely to make mistakes that cause accidents.
"The COVID virus is very invasive to the brain," Bell said.
Others contend this may be a rush to judgment. Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic, agrees that in more serious cases of COVID that cause a lack of oxygen to the brain, it's reasonable to call it a brain injury. But brain fog can also be associated with other long COVID symptoms, not just damage to the brain.
Chronic fatigue and poor sleep are both commonly reported symptoms of long COVID that negatively affect brain function, she said. Sleep disturbances, cardiac problems, dysautonomia, and emotional distress could also affect the way the brain functions post COVID. Finding the right treatment requires identifying all the factors contributing to cognitive impairment.
Part of the problem in treating long COVID brain fog is that diagnostic technology is not sensitive enough to detect inflammation that could be causing damage.
Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio, said her team is working on identifying biomarkers that could detect brain inflammation in a way similar to the manner researchers have identified biomarkers to help diagnose chronic fatigue syndrome. Additionally, a new study published last month in JAMA for the first time clearly defined 12 symptoms of long COVID, and brain fog was listed among them. All of this contributes to the development of clear diagnostic criteria.
"It will make a big difference once we have some consistency among clinicians in diagnosing the condition," said McComsey.
Whitley is thankful for the treatment that she's received thus far. She's seeing a cognitive rehabilitation therapist, who assesses her memory, cognition, and attention span and gives her tools to break up simple tasks, such as driving, so that they don't feel overwhelming. She's back behind the wheel and back to work.
But perhaps most importantly, Whitley joined a support group, led by Jackson, that includes other people experiencing the same symptoms she is. When she was at her darkest, they understood.
"Talking to other survivors has been the only solace in all this," Whitley said. "Together, we grieve all that's been lost."
The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort studyNathan J. Cheetham Rose Penfold Valentina Giunchiglia Vicky Bowyer Carole H. Sudre Liane S. Canas et al.
Published:July 21, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.102086
SummaryBackgroundCognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored.
MethodsCognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds.
Findings3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs, 95% confidence intervals, CI: −0.21, −0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, β = −0.22 SDs, 95% CI: −0.35, −0.09). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs, 95% CI: −0.44, −0.18), and 10 years age difference (60–70 years vs. 50–60 years, β = −0.21 SDs, 95% CI: −0.30, −0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection.
InterpretationCognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms.
CLINICAL SUMMARY FROM UNIVADISInfection Duration Linked to Long COVID-19Liz Scherer | 29 July 2023
Among healthcare workers, the likelihood of developing long COVID-19 (at least one symptom lasting longer than 4 weeks) appeared to increase proportionally to the duration of COVID-19 positivity, although adjusted analysis suggested that BNT162b2 vaccination (two doses plus a booster) reduced this probability, even during the Omicron wave.
The study was conducted by Italian researchers and appeared in the journal Clinical Infectious Diseases.
The longer COVID-19 symptoms last, the greater the risk for developing long COVID-19, especially in older female patients. Clinicians should continue to encourage patients to complete recommended BNT162b2 vaccination schedules to avert symptom severity, duration, and poor outcomes.
Just over a third (34.1%) of the study cohort who had been previously infected with COVID-19 developed long COVID-19; the entire analysed cohort (n=1293) received three BNT162b2 vaccine doses. Compared with a reference group of all males with no allergy, infected during wave 1, unvaccinated and with a positivity for <10 days, vaccination and infection in wave 3 correlated with a lower probability of long COVID-19.
Conversely, self-reported positivity lasting 11-14 days increased long COVID-19 risk more than 2-fold, lasting 15-20 days increased more than 4-fold, and risk increased more than 5-fold when positivity lasted more than 21 days.
Only 14.5% of individuals with positivity lasting 10 days or fewer developed long COVID-19 vs 42.5% infected 15-21 days, and 56.2% for those infected more than 21 days. In a subgroup analysis and after adjustment, there was a 1.5-fold increased risk for long COVID-19 based on symptom duration, and vaccination with three doses decreased this risk by more than half.
Italian researchers conducted an observational study of 1293 fully vaccinated (two doses and one booster shot with BNT162b2) healthcare workers previously infected with SARS-CoV-2 and developing a COVID-19 infection during one of three waves in which the following variants were dominating: wave 1, wild-type; wave 2, Alpha variant; wave 3, Delta and Omicron variants.
The study goal was to determine the likelihood of developing long COVID-19 based on the duration of SARS-CoV-2 positivity. Long COVID-19 was defined as >1 symptoms lasting >4 weeks post-first COVID-19 infection.