Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis

Abstract:

Introduction: Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features.

There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis.

The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.

Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”.

Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.

Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index.

Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value.

All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.

Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.

Source: Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M. Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis. Autoimmun Rev. 2022 Aug;21(8):103129. doi: 10.1016/j.autrev.2022.103129. Epub 2022 Jun 9. PMID: 35690247. https://www.sciencedirect.com/science/article/abs/pii/S1568997222000994?via%3Dihub

Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID

Abstract:

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions.

Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS.

Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Arnhild Grothey, Samuel Keating, Irene Mena-Palomo, Stephanie Lamer, Andreas Schlosser, Agnes Kaiping, Carsten Scheller, Franziska Sotzny, Anna Horn, Carolin Nuernberger, Vladimir Cejka, Boshra Afshar, Thomas Bahmer, Stefan Schreiber, Joerg Janne Vehreschild, Olga Milljukov, Christian Schaefer, Luzie Kretzler, Thomas Keil, Jens-Peter Reese, Felizitas A Eichner, Lena Schmidbauer, Peter U Heuschmann, Stefan Stoerk, Caroline Morbach, Gabriela Riemekasten, Niklas Beyersdorf, Carmen Scheibenbogen, Robert K Naviaux, Marshall Williams, Maria E Ariza, Bhupesh Kumar Prusty. Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID. medRxiv 2023.06.23.23291827; doi: https://doi.org/10.1101/2023.06.23.23291827 https://www.medrxiv.org/content/10.1101/2023.06.23.23291827v1 (Full text available as PDF file)

Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies

Summary:

In this Personal View, we discuss current knowledge on SARS-CoV-2 RNA or antigen persistence in children infected with SARS-CoV-2. Based on the evidence that the virus can persist in adults, we have done a literature review and analysed studies that looked for SARS-CoV-2 RNA or antigens in children undergoing autopsy, biopsy, or surgery for either death from COVID-19 or multisystem inflammatory syndrome, or assessments for long COVID-19 or other conditions.
Our analysis suggests that in children, independent from disease severity, SARS-CoV-2 can spread systemically and persist for weeks to months. We discuss what is known about the biological effects of viral persistence for other viral infections and highlight new scenarios for clinical, pharmacological, and basic research exploration. Such an approach will improve the understanding and management of post-viral syndromes.
Source: Danilo Buonsenso, Laura Martino, Rosa Morello, Francesco Mariani, Kelly Fearnley, Piero . Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies. The Lancet Microbe. Published: June 26, 2023. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(23)00115-5/fulltext (Full text)

Cardiac MRI Findings in Patients Clinically Referred for Evaluation of Post-Acute Sequelae of SARS-CoV-2 Infection

Abstract:

Persistent or recurrent cardiovascular symptoms have been identified as one of the hallmarks of long-COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The purpose of this study was to determine the prevalence and extent of cardiac abnormalities in patients referred for cardiac MRI due to clinical evidence of PASC. To investigate this, two tertiary care hospitals identified all patients who were referred for cardiac MRI under the suspicion of PASC in a 2-year period and retrospectively included them in this study.
Patients with previously known cardiac diseases were excluded. This resulted in a total cohort of 129 patients (63, 51% female; age 41 ± 16 years). The majority of patients (57%) showed normal cardiac results. No patient had active myocarditis or an acute myocardial infarction. However, 30% of patients had evidence of non-ischemic myocardial fibrosis, which exceeds the prevalence in the normal adult population and suggests that a possible history of myocarditis might explain persistent symptoms in the PASC setting.
Source: Halfmann MC, Luetkens JA, Langenbach IL, Kravchenko D, Wenzel P, Emrich T, Isaak A. Cardiac MRI Findings in Patients Clinically Referred for Evaluation of Post-Acute Sequelae of SARS-CoV-2 Infection. Diagnostics. 2023; 13(13):2172. https://doi.org/10.3390/diagnostics13132172 https://www.mdpi.com/2075-4418/13/13/2172 (Full text)

The COVID-19 Pandemic and the $16 Trillion Virus

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic is the greatest threat to prosperity and well-being the US has encountered since the Great Depression. This Viewpoint aggregates mortality, morbidity, mental health conditions, and direct economic losses to estimate the total cost of the pandemic in the US on the optimistic assumption that it will be substantially contained by the fall of 2021. These costs far exceed those associated with conventional recessions and the Iraq War, and are similar to those associated with global climate change. However, increased investment in testing and contact tracing could have economic benefits that are at least 30 times greater than the estimated costs of the investment in these approaches.

Read the full text here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604733/

Also see: The Economic Cost of Long COVID: An Update: https://scholar.harvard.edu/files/cutler/files/long_covid_update_7-22.pdf

Source: Cutler DM, Summers LH. The COVID-19 Pandemic and the $16 Trillion Virus. JAMA. 2020;324(15):1495–1496. doi:10.1001/jama.2020.19759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604733/ (Full text)

The Economic Cost of Long COVID: An Update

Relative to my earlier estimate with Lawrence Summers of the cost of long COVID of $2.6 trillion, the higher number here is higher: $3.7 trillion in total. The higher estimate is largely a result of the greater prevalence of long COVID than we had guessed at the time. There are about 10 times the number of people with long COVID as have died of COVID. Because long COVID is so new, there is uncertainty about all of the numbers involved in the calculations. Still, the costs here are conservative, based on only cases to date. The enormity of these costs implies that policy to address long COVID are urgently needed. With costs this high, virtually any amount spent on long COVID detection, treatment, and control would result in benefits far above what it costs.

Read the full text here: https://scholar.harvard.edu/files/cutler/files/long_covid_update_7-22.pdf

Note: See The COVID-19 Pandemic and the $16 Trillion Virus for background.

Source: David M. Cutler. The Economic Cost of Long COVID: An Update. Harvard University.

Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes

Introduction: Cognitive impairment is experienced by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of COVID-19 (PASC). Patients report difficulty remembering, concentrating, and making decisions. Our objective was to determine whether orthostatic hemodynamic changes were causally linked to cognitive impairment in these diseases.

Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.

Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.

Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.

Source: Day Heather, Yellman Brayden, Hammer Sarah, Rond Candace, Bell Jennifer, Abbaszadeh Saeed, Stoddard Greg, Unutmaz Derya, Bateman Lucinda, Vernon Suzanne D. Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes. Frontiers in Neuroscience, VOLUME=17, 2023. DOI=10.3389/fnins.2023.1203514. ISSN=1662-453X. https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514 (Full text)

Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca2+) is crucial for NK cell effector functions.
Growing research recognises Ca2+ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca2+-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca2+ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques.
Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation.
Findings from this investigation suggest that TRPM7-dependent Ca2+ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.
Source: Du Preez S, Eaton-Fitch N, Smith PK, Marshall-Gradisnik S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Biomolecules. 2023; 13(7):1039. https://doi.org/10.3390/biom13071039 https://www.mdpi.com/2218-273X/13/7/1039 (Full text)

Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by disrupted daily patterns of activity, sleep, and physiology. Past studies in ME/CFS patients have examined circadian rhythms, suggested that desynchronization between central and peripheral rhythms may be an important pathological feature, and identified associated changes in post-inflammatory cytokines such as transforming growth factor beta (TGFB). However, no previous studies have examined circadian rhythms in ME/CFS using cellular models or studied the role of cytokines on circadian rhythms.

In this study, we used serum samples previously collected from ME/CFS patients (n = 20) selected for the presence of insomnia symptoms and matched controls (n = 20) to determine the effects of serum factors and TGFB on circadian rhythms in NIH3T3 mouse immortalized fibroblasts stably transfected with the Per2-luc bioluminescent circadian reporter.

Compared to control serum, ME/CFS serum caused a significant loss of rhythm robustness (decreased goodness of fit) and nominally increased the rate of damping of cellular rhythms. Damping rate was associated with insomnia severity in ME/CFS patients using the Pittsburgh Sleep Quality Index (PSQI). Recombinant TGFB1 peptide applied to cells reduced rhythm amplitude, caused phase delay and decreased robustness of rhythms.

However, there was no difference in TGFB1 levels between ME/CFS and control serum indicating the effects of serum on cellular rhythms cannot be explained by levels of this cytokine. Future studies will be required to identify additional serum factors in ME/CFS patients that alter circadian rhythms in cells.

Source: Heather Wei, Zoe Adelsheim, Rita Fischer, Michael J. McCarthy. Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms. Journal of Neuroimmunology. Available online 24 June 2023, 578142. https://doi.org/10.1016/j.jneuroim.2023.578142 https://www.sciencedirect.com/science/article/abs/pii/S0165572823001285

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multifactorial disease that causes increasing morbidity worldwide, and many individuals with ME/CFS symptoms remain undiagnosed due to the lack of diagnostic biomarkers. Its etiology is still unknown, but increasing evidence supports a role of herpesviruses (including HHV-6A and HHV-6B) as potential triggers.
Interestingly, the infection by these viruses has been reported to impact the expression of microRNAs (miRNAs), short non-coding RNA sequences which have been suggested to be epigenetic factors modulating ME/CFS pathogenic mechanisms. Notably, the presence of circulating miRNAs in plasma has raised the possibility to use them as valuable biomarkers for distinguishing ME/CFS patients from healthy controls.
Thus, this study aimed at determining the role of eight miRNAs, which were selected for their previous association with ME/CFS, as potential circulating biomarkers of the disease. Their presence was quantitatively evaluated in plasma from 40 ME/CFS patients and 20 healthy controls by specific Taqman assays, and the results showed that six out of the eight of the selected miRNAs were differently expressed in patients compared to controls; more specifically, five miRNAs were significantly upregulated (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448), and one was downmodulated (miR-140-5p). MiRNA levels directly correlated with disease severity, whereas no significant correlations were observed with the plasma levels of seven pro-inflammatory cytokines or with the presence/load of HHV-6A/6B genome, as judged by specific PCR amplification.
The results may open the way for further validation of miRNAs as new potential biomarkers in ME/CFS and increase the knowledge of the complex pathways involved in the ME/CFS development.
Source: Soffritti I, Gravelsina S, D’Accolti M, Bini F, Mazziga E, Vilmane A, Rasa-Dzelzkaleja S, Nora-Krukle Z, Krumina A, Murovska M, et al. Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(13):10582. https://doi.org/10.3390/ijms241310582 https://www.mdpi.com/1422-0067/24/13/10582 (Full text)