Etiology – Page 4 – American ME and CFS Society

Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome

Abstract:

Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure. Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS). This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism. Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS.

This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress. Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations. Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.

Source: Rusin A, Li M, Cocchetto A, Seymour C, Mothersill C. Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome. Med Hypotheses. 2021 Jul 27;154:110647. doi: 10.1016/j.mehy.2021.110647. Epub ahead of print. PMID: 34358921. https://pubmed.ncbi.nlm.nih.gov/34358921/

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Abstract:

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients’ population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S₀-42 patients who did not know their disease trigger; S₁-43 patients who reported a non-infection trigger; S₂-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S₃-48 patients who reported an infection trigger and that infection was confirmed by a lab test.

In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S₁ and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S₃ had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Source: Domingues TD, Grabowska AD, Lee JS, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, Cliff JM, Nacul L, Lacerda EM, Mouriño H, Sepúlveda N. Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank. Front Med (Lausanne). 2021 Jul 5;8:686736. doi: 10.3389/fmed.2021.686736. PMID: 34291062; PMCID: PMC8287507. https://pubmed.ncbi.nlm.nih.gov/34291062/

COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review

Abstract:

Coronavirus disease 2019 (COVID-19) is a viral infection which can cause a variety of respiratory, gastrointestinal, and vascular symptoms. The acute illness phase generally lasts no more than 2–3 weeks. However, there is increasing evidence that a proportion of COVID-19 patients experience a prolonged convalescence and continue to have symptoms lasting several months after the initial infection.

A variety of chronic symptoms have been reported including fatigue, dyspnea, myalgia, exercise intolerance, sleep disturbances, difficulty concentrating, anxiety, fever, headache, malaise, and vertigo. These symptoms are similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes, orthostatic intolerance, and post-exertional malaise. ME/CFS symptoms are exacerbated by exercise or stress and occur in the absence of any significant clinical or laboratory findings.

The pathology of ME/CFS is not known: it is thought to be multifactorial, resulting from the dysregulation of multiple systems in response to a particular trigger. Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein–Barr Virus, Q fever, influenza, and other coronaviruses. There are important similarities between post-acute COVID-19 symptoms and ME/CFS. However, there is currently insufficient evidence to establish COVID-19 as an infectious trigger for ME/CFS. Further research is required to determine the natural history of this condition, as well as to define risk factors, prevalence, and possible interventional strategies.

Source: Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Therapeutic Advances in Infectious Disease. January 2021. doi:10.1177/20499361211009385 https://journals.sagepub.com/doi/full/10.1177/20499361211009385 (Full article)

Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Introduction:

“Recovering” from COVID-19 does not guarantee a return to a person’s usual state of health. For one thing, some people with multi-system injury—particularly to the brain, heart and kidneys—may develop permanent dysfunction of those organs.

In addition, a more subtle form of chronic illness may develop. For some people with COVID-19, even those who are only mildly affected at first, the ensuing weeks and months of “recovery” bring a surprise and a betrayal: they do not return to full health. Although nucleic acid tests no longer detect the virus, people still suffer from ongoing symptoms. They call themselves “long haulers,” and the condition is being called “long COVID.”

Source: Komaroff AL, Bateman L. Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front Med (Lausanne). 2021 Jan 18;7:606824. doi: 10.3389/fmed.2020.606824. PMID: 33537329; PMCID: PMC7848220. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848220/ (Full text)

A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses

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.

Source: Comella PH, Gonzalez-Kozlova E, Kosoy R, Charney AW, Peradejordi IF, Chandrasekar S, Tyler SR, Wang W, Losic B, Zhu J, Hoffman GE, Kim-Schulze S, Qi J, Patel M, Kasarskis A, Suarez-Farinas M, Gümüş ZH, Argmann C, Merad M, Becker C, Beckmann ND, Schadt EE. A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses. medRxiv [Preprint]. 2021 Feb 2:2021.01.29.21250755. doi: 10.1101/2021.01.29.21250755. PMID: 33564792; PMCID: PMC7872387. https://pubmed.ncbi.nlm.nih.gov/33564792/

Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany: a first analysis of a prospective observational study

Abstract:

Objective: Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS). Methods: Setting: Charite Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charite University hospital.

Participants: 42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charite Fatigue Center from July to November 2020.

Main outcome measures: The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.

Results: The median age was 36.5, range 22-62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14-32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15-90) of 100 (healthy) and Short Form 36 (SF36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p= 0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.

Conclusions: Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

Source: Claudia Kedor, Helma Freitag, Lil-Antonia Meyer-Arndt, Kirsten Wittke, thomas Zoller, Fridolin Steinbeis, Milan Haffke, Rudolf Gordon, Bettina Heidecker, Hans Dieter Volk, Carsten Skurk, Friedemann Paul, Judith Bellmann-Strobl, Carmen Scheibenbogen. Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany: a first analysis of a prospective observational study. medRxiv 2021.02.06.21249256; doi: https://doi.org/10.1101/2021.02.06.21249256 https://www.medrxiv.org/content/10.1101/2021.02.06.21249256v1

NIH-funded study examines mono, chronic fatigue syndrome in college students

Press Release: Eurekalert, Jan 22, 2021: Many college students fully recover from infectious mononucleosis (which is almost always caused by Epstein-Barr virus) within 1-6 weeks, but some go on to develop chronic fatigue syndrome, also called myalgic encephalomyelitis (ME/CFS). A longitudinal study from DePaul University and Northwestern University followed 4,501 college students to examine risk factors that may trigger longer illness. The research appears in the journal Clinical Infectious Diseases and was funded by the National Institute of Allergy and Infectious Diseases.

Previous retrospective studies found that risk factors for developing ME/CFS after catching mono included preexisting physical symptoms and the number of days spent in bed, according to co-principal investigators Leonard A. Jason, professor of psychology at DePaul University; and Dr. Ben Z. Katz, a professor of pediatrics at Northwestern University Feinberg School of Medicine and a pediatric infectious disease specialist at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“We are the only study to collect comprehensive biological and behavioral data prior to illness onset, which for the first time allowed us to identify some of the predisposing circumstances or conditions that make certain individuals more likely to get ill due to mono and stay ill,” says Jason, director of the Center for Community Research at DePaul.

Of the 4,501 college students in the study, 238 or 5.3% developed mononucleosis; and 55 of those (23%) met criteria for ME/CFS six months later, 20 of whom (8%) met criteria for severe ME/CFS. Researchers found that those who developed ME/CFS had more physical symptoms and immune irregularities at baseline, but they did not start out with statistically significantly more psychological symptoms such as stress, depression, anxiety or abnormal coping.

“Some people who are attacked by a virus stay sick. What we’ve found is that their emotional functioning and psychological states are not statistically different from those who get attacked by the same virus and recover. This becomes important validating information for those people who have this illness,” says Jason.

Participants in the study each completed seven different surveys to assess potential symptoms of ME/CFS. They also received a comprehensive psychiatric exam, and provided samples of serum, plasma and white blood cells. In future publications, researchers aim to analyze cytokine networks in participants’ blood and other risk factors. Deficiencies in certain cytokines “might suggest predisposing irregularities in immune response,” write the researchers. Vicky Whittemore, the Program Director at the National Institute of Neurological Disorders and Stroke (NINDS), stated that NINDS is supporting follow-up research to continue to study this cohort, and to examine possible predictors of COVID-19 as well.

“Since we have baseline data on nearly all of the 4500 students, we can use our same database to tease out risk factors for COVID infection as well as prolonged recovery from that illness,” says Katz.

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Other co-authors on the study are Joseph Colter, Mohammed F. Islam and Madison Sunnquist of DePaul’s Center for Community Research.

The study, “Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study” was supported by the National Institute of Allergy and Infectious Diseases, grant number AI 105781.

Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through the Stanley Manne Children’s Research Institute. The Manne Research Institute is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. It is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 220,000 children from 48 states and 49 countries.

Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched

Abstract:

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies.

Methods: We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study’s factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice’s description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups.

Results: We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case-control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants.

Conclusion: The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.

Source: Muller AE, Tveito K, Bakken IJ, Flottorp SA, Mjaaland S, Larun L. Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched. J Transl Med. 2020 Dec 14;18(1):484. doi: 10.1186/s12967-020-02665-6. PMID: 33317576. https://pubmed.ncbi.nlm.nih.gov/33317576/

Pain in adolescent chronic fatigue following Epstein-Barr virus infection

Abstract:

Objectives: Acute Epstein-Barr virus (EBV) infection is a trigger of Chronic Fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to investigate pain symptoms and pressure pain thresholds in fatigued and non-fatigued adolescents six months after acute EBV-infection, and in healthy controls. This study is part of the CEBA-project (CF following acute EBV infection in adolescents).

Methods: A total of 195 adolescents (12-20 years old) that had undergone an acute EBV infection six months prior to assessment were divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of seventy healthy controls was included. Symptoms were mapped with questionnaires. Pressure pain thresholds were measured through pressure algometry. One way ANOVA were used for between-group analyses. Linear regression analyses were used to explore associations between Pediatric Quality of Life (dependent variable), pain symptoms and other variables within the EBV (CF+) group.

Results: The EBV CF+ group had significantly higher scores for pain symptoms as compared with the EBV CF- group and healthy controls, but pressure pain threshold did not differ significantly. The number of pain symptoms as well as pain severity were strongly and independently associated with quality of life.

Conclusions: CF and CFS following acute EBV-infection in adolescents is characterized by high pain symptom burden, which in turn is associated with a decline in quality of life. Pain in CF and CFS is of considerable clinical importance, and should be a focal point for further investigation and intervention in these patient groups.

Source: Brodwall EM, Pedersen M, Asprusten TT, Wyller VBB. Pain in adolescent chronic fatigue following Epstein-Barr virus infection [published online ahead of print, 2020 Sep 7]. Scand J Pain. 2020;/j/sjpain.ahead-of-print/sjpain-2020-0031/sjpain-2020-0031.xml. doi:10.1515/sjpain-2020-0031 https://pubmed.ncbi.nlm.nih.gov/32892183/

Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis

Abstract:

Objective: To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome.

Design: Population-based self-controlled case series.

Setting: Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers.

Participants: 869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16.

Main outcome measures: Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses.

Results: During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)).

Conclusions: When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.

Source: Hviid A, Thorsen NM, Valentiner-Branth P, Frisch M, Mølbak K. Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis. BMJ. 2020;370:m2930. Published 2020 Sep 2. doi:10.1136/bmj.m2930 https://pubmed.ncbi.nlm.nih.gov/32878745/