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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other.

We examined two separate groups of ME/CFS, one with (n=15) and one without (n=15) fibromyalgia. We quantified a total of 2,083 proteins using immunoaffinity depletion, tandem mass tag isobaric labeling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1,789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p-value < 0.05. This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.

Source: Steven E. Schutzer, Tao Liu, Chia-Feng Tsai, Vladislav A. Petyuk, Athena A. Schepmoes, Yi-Ting Wang, Karl K. Weitz, Jonas Bergquist, Richard D. Smith, Benjamin H Natelson. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes. bioRxiv 2022.09.14.506792; doi: https://doi.org/10.1101/2022.09.14.506792 https://www.biorxiv.org/content/10.1101/2022.09.14.506792v2.full (Full text)

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

Summary:

ME/CFS is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we used single-cell RNA-seq (scRNA-seq) to examine immune cells in cohorts of patients and controls. Post-exertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. Thus, to detect changes coincident with PEM, we also performed scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients displayed dysregulation of classical monocytes suggestive of inappropriate differentiation and migration to tissue. We were able to identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlated with metrics of disease severity. Comparing the transcriptome at baseline and post-exercise challenge, we discovered patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation following exercise.

Highlights ME/CFS is a debilitating disease with unknown causes. Here, we provide, for the first time, an extensive single cell resolution dataset detailing the gene expression programs of circulating immune cells of ME/CFS cases at baseline and after symptom provocation. We were able to detect robust dysregulation in certain immune cells from patients, with dysregulation of classical monocytes manifesting the strongest signal. Indeed, the fraction of aberrant monocytes in ME/CFS patients correlated with the degree of disease severity. Surprisingly, platelet transcriptomes were also altered in ME/CFS, and they were the only component of the immune system that showed large-scale changes following symptom provocation.

Source: Faraz Ahmed, Luyen Tien Vu, Hongya Zhu, David Shing Huk Iu, Elizabeth A. Fogarty, Yeonui Kwak, Weizhong Chen, Carl J. Franconi, Paul R. Munn, Susan M. Levine, Jared Stevens, Xiangling Mao, Dikoma C. Shungu, Geoffrey E. Moore, Betsy A. Keller, Maureen R. Hanson, Jennifer K. Grenier, Andrew Grimson. Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation. bioRxiv 2022.10.13.512091; doi: https://doi.org/10.1101/2022.10.13.512091 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00602-X (Full text)

Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain

Abstract:

Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the “Chronic Pain Autonomic Stress Test”.

Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain.

These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.

Source: Contreras-Merino AM, Davydov DM, Galvez-Sánchez CM, Reyes Del Paso GA. Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain. Int J Psychophysiol. 2022 May;175:61-70. doi: 10.1016/j.ijpsycho.2022.03.001. Epub 2022 Mar 11. PMID: 35283267. https://www.sciencedirect.com/science/article/pii/S0167876022000599?via%3Dihub (Full text)

What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults

Abstract:

The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations. It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test.

The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes. It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount. The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for ME/CFS and emphasises that cognitive behavioural therapy (CBT) should only be offered as a supportive intervention.

Because of the rigorous methodology required by NICE Committee review and the inclusion of the testimony of people with lived experience as committee members, this guideline will influence the future diagnosis and management of ME/CFS in the UK and beyond.

Source:  Kingdon, C.C.; Lowe, A.; Shepherd, C.; Nacul, L. What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults . Preprints 2022, 2022110016 (doi: 10.20944/preprints202211.0016.v1).  https://www.preprints.org/manuscript/202211.0016/v1 (Full text available as PDF file)

Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Over the years, several pathogenic agents have been implicated with no one pathogen being conclusively identified as responsible for induction of a large number of cases. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in chronic infection sites, including the central nervous system, muscle, and heart, potentially resulting in chronic conditions that have symptom constellations like those of ME/CFS.

To gain insight into the association between EVs and ME/CFS, I conducted a comprehensive review of EV studies in ME/CFS and followed this with 1) a broad serological survey of ME/CFS antibody levels to 122 pathogenic antigens and 2) designed and conducted EV-specific targeted RNA sequencing.

A review of prior ME/CFS investigations in ME/CFS revealed a strong prevalence of chronic EV infections across ME/CFS cohorts. The broad survey of anti-pathogen antibody levels in ME/CFS cases did not implicate any one pathogen as a causative factor in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, the results did reveal sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.

Furthermore, I find that our EV-specific probe set allows efficient viral detection when as few as 10 molecules are present in 1ml of blood. However, whether the technology is employed directly on patient samples or following attempts at in vitro biological amplification, EVs were undetected in both ME/CFS and healthy control samples despite all approaches that were pursued.

This work establishes a thorough understanding of the current EV-ME/CFS related literature while simultaneously providing an acutely sensitive and comprehensive approach that will be useful in the future for screening biopsy or cadaver samples from any individuals suspected of having a chronic EV infection.

Source: O’Neal, Adam James. Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Dissertation, Cornell. https://ecommons.cornell.edu/handle/1813/112023 (Full text will be made available)

Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics

Abstract:

Background: Brain 18F-FDG PET imaging has the potential to provide an objective assessment of brain involvement in post-COVID-19 conditions but previous studies of heterogeneous patient series yield inconsistent results. The current study aimed to investigate brain 18F-FDG PET findings in a homogeneous series of outpatients with post-COVID-19 conditions and to identify associations with clinical patient characteristics.

Methods: We retrospectively included 28 consecutive outpatients who presented with post-COVID-19 conditions between September 2020 and May 2022 and who satisfied the WHO definition, and had a brain 18F-FDG PET for suspected brain involvement but had not been hospitalized for COVID-19. A voxel-based group comparison with 28 age- and sex-matched healthy controls was performed (p-voxel at 0.005 uncorrected, p-cluster at 0.05 FWE corrected) and identified clusters were correlated with clinical characteristics.

Results: Outpatients with post-COVID-19 conditions exhibited diffuse hypometabolism predominantly involving right frontal and temporal lobes including the orbito-frontal cortex and internal temporal areas. Metabolism in these clusters was inversely correlated with the number of symptoms during the initial infection (r = – 0.44, p = 0.02) and with the duration of symptoms (r = – 0.39, p = 0.04). Asthenia and cardiovascular, digestive, and neurological disorders during the acute phase and asthenia and language disorders during the chronic phase (p ≤ 0.04) were associated with these hypometabolic clusters.

Conclusion: Outpatients with post-COVID-19 conditions exhibited extensive hypometabolic right fronto-temporal clusters. Patients with more numerous symptoms during the initial phase and with a longer duration of symptoms were at higher risk of persistent brain involvement.

Source: Goehringer F, Bruyere A, Doyen M, Bevilacqua S, Charmillon A, Heyer S, Verger A. Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics. Eur J Nucl Med Mol Imaging. 2022 Nov 2. doi: 10.1007/s00259-022-06013-2. Epub ahead of print. PMID: 36322190. https://link.springer.com/article/10.1007/s00259-022-06013-2 (Full text)

Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery

Abstract:

Background: Lingering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gut tissue might be a source of infection during bariatric surgery. This study aimed to confirm the presence of SARS-CoV-2 nucleocapsid in gastric and gallbladder tissues removed during bariatric surgery in individuals previously infected with coronavirus disease 2019 (COVID-19) who had negative polymerase chain reaction results prior to the surgery.

Methods: Gastric and gallbladder specimens from 80 patients who underwent bariatric surgery between November 2021 and May 2022 and had a history of COVID-19 infection with gastrointestinal symptoms were examined for the presence of lingering SARS-CoV-2 nucleocapsid proteins using immunohistochemistry.

Results: Gastric specimens from 26 (32.5%) patients and 4 (100%) cholecystectomy specimens showed positive cytoplasmic staining for the anti-SARS-CoV-2 nucleocapsid protein in surface mucosal epithelial cells. The mean age was 37.8 ± 10.3 years. The average body mass index was 44.2 ± 7.0 kg/m2; most of the patients were females (71.3%). The positive staining group was significantly younger than the negative staining group (p = 0.007). The full-dose vaccination rate was 58.8%, with a median of 91 days after the last vaccine dose. A positive serological anti-spike IgG response was observed in 99% of the patients. The median time between initial COVID-19 infection and surgery was 274 and 380 days in the positive and negative staining groups, respectively (p = 0.371).

Conclusion: Gastric and gallbladder tissues can retain SARS-CoV-2 particles for a long time after COVID-19 infection, handling stomach specimens from patients during an operation must be done with care, as we usually do, but now with the knowledge that in 1/3 of patients they can be present. Performing LSG on post-COVID patients did not seem to increase perioperative morbidity.

Source: Hany, M., Zidan, A., Gaballa, M. et al. Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery. OBES SURG (2022). https://doi.org/10.1007/s11695-022-06338-9  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628579/ (Full text)

Long COVID: long-term health outcomes and implications for policy and research

Long COVID, which refers to post-acute and chronic sequelae of SARS-CoV-2 infection, can affect nearly every organ system and all demographic groups. The high and growing toll of long COVID calls for an urgent need to understand how to prevent and treat it. Governments and health systems must address the care needs of people with long COVID.

Shortly after the beginning of the COVID-19 global pandemic, reports emerged showing that some individuals infected with SARS-CoV-2 developed persistent symptoms and new health problems that arose long after the acute phase of infection and could not be explained by other factors1. The patient community who, to their credit, first recognized and reported this new syndrome used the term ‘long COVID’ to describe the post-acute and chronic sequelae of SARS-CoV-2 infection1. Long COVID can affect people across the lifespan — children, young adults and older adults — and across sex, race and ethnicity, and baseline health status2. Importantly, this syndrome not only affects patients who had severe COVID-19, but is also observed in individuals who were asymptomatic or mildly symptomatic during the acute phase of SARS-CoV-2 infection.

Read the rest of this article HERE. 

Source: Al-Aly, Z., Agarwal, A., Alwan, N. et al. Long COVID: long-term health outcomes and implications for policy and research. Nat Rev Nephrol (2022). https://doi.org/10.1038/s41581-022-00652-2  (Full text)

The autoimmune aetiology of unexplained chronic pain

Abstract:

Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system.

Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details.

The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

Source: Goebel A, Andersson D, Helyes Z, Clark JD, Dulake D, Svensson C. The autoimmune aetiology of unexplained chronic pain. Autoimmun Rev. 2022 Mar;21(3):103015. doi: 10.1016/j.autrev.2021.103015. Epub 2021 Dec 10. PMID: 34902604. https://www.sciencedirect.com/science/article/abs/pii/S1568997221002974 (Full text)

Doctors’ attitudes toward specific medical conditions

Abstract:

This study uses machine learning and natural language processing tools to examine the language used by healthcare professionals on a global online forum. It contributes to an underdeveloped area of knowledge, that of physician attitudes toward their patients. Using comments left by physicians on Reddit’s ”Medicine” subreddit (r/medicine), we test if the language from online discussions can reveal doctors’ attitudes toward specific medical conditions. We focus on a set of chronic conditions that usually are more stigmatized and compare them to ones well accepted by the medical community.

We discovered that when comparing diseases with similar traits, doctors discussed some conditions with more negative attitudes. These results show bias does not occur only along the dimensions traditionally analyzed in the economics literature of gender and race, but also along the dimension of disease type. This is meaningful because the emotions associated with beliefs impact physicians’ decision making, prescribing behavior, and quality of care. First, we run a binomial LASSO-logistic regression to compare a range of 21 diseases against myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), depression, and the autoimmune diseases multiple sclerosis and rheumatoid arthritis.

Next, we use dictionary methods to compare five more chronic diseases: Lyme disease, Ehlers-Danlos syndrome (EDS), Alzheimer’s disease, osteoporosis, and lupus. The results show physicians discuss ME/CFS, depression, and Lyme disease with more negative language than the other diseases in the set. The results for ME/CFS included over four times more negative words than the results for depression.

Source: Brooke Scoles, Catia Nicodemo. Doctors’ attitudes toward specific medical conditions. Journal of Economic Behavior & Organization, Volume 204, December 2022, Pages 182-199. https://www.sciencedirect.com/science/article/pii/S016726812200347X (Full text)