Long COVID and hypermobility spectrum disorders have shared pathophysiology

Abstract:

Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) are the most common joint hypermobility conditions encountered by physicians, with hypermobile and classical EDS accounting for >90% of all cases. Hypermobility has been detected in up to 30-57% of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, postural orthostatic tachycardia syndrome (POTS), and long COVID (LC) compared to the general population.

Extrapulmonary symptoms, including musculoskeletal pain, dysautonomia disorders, cognitive disorders, and fatigue, are seen in both LC and HSD. Additionally, ME/CFS has overlapping symptoms with those seen in HSD. Mast cell activation and degranulation occurring in both LC and ME/CFS may result in hyperinflammation and damage to connective tissue in these patients, thereby inducing hypermobility.

Persistent inflammation may result in the development or worsening of HSD. Hence, screening for hypermobility and other related conditions including fibromyalgia, POTS, ME/CFS, chronic pain conditions, joint pain, and myalgia is essential for individuals experiencing LC. Pharmacological treatments should be symptom-focused and geared to a patient’s presentation. Paced exercise, massage, yoga, and meditation may also provide benefits.

Source: Ganesh R, Munipalli B. Long COVID and hypermobility spectrum disorders have shared pathophysiology. Front Neurol. 2024 Sep 5;15:1455498. doi: 10.3389/fneur.2024.1455498. PMID: 39301475; PMCID: PMC11410636. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410636/ (Full text)

Impact of COVID-19 on myalgic encephalomyelitis/chronic fatigue syndrome-like illness prevalence: A cross-sectional survey

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can be triggered by infectious agents including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the impact of the coronavirus disease 2019 (COVID-19) pandemic on ME/CFS prevalence is not well characterized.

Methods: In this population-based cross-sectional study, we enrolled a stratified random sample of 9,825 adult participants in the Kaiser Permanente Northern California (KPNC) integrated health system from July to October 2022 to assess overall ME/CFS-like illness prevalence and the proportion that were identified following COVID-19 illness. We used medical record and survey data to estimate the prevalence of ME/CFS-like illness based on self-reported symptoms congruent with the 2015 Institute of Medicine ME/CFS criteria. History of COVID-19 was based on a positive SARS-CoV-2 nucleic acid amplification test or ICD-10 diagnosis code in the medical record, or self-report of prior COVID-19 on a survey.

Results: Of 2,745,374 adults in the eligible population, an estimated 45,892 (95% confidence interval [CI]: 32,869, 58,914) or 1.67% (CI 1.20%, 2.15%) had ME/CFS-like illness. Among those with ME/CFS-like illness, an estimated 14.12% (CI 3.64%, 24.6%) developed the illness after COVID-19. Among persons who had COVID-19, those with ME/CFS-like illness after COVID-19 were more likely to be unvaccinated and to have had COVID-19 before June 1, 2021. All persons with ME/CFS-like illness had significant impairment in physical, mental, emotional, social, and occupational functioning compared to persons without ME/CFS-like illness.

Conclusions: In a large, integrated health system, 1.67% of adults had ME/CFS-like illness and 14.12% of all persons with ME/CFS-like illness developed it after COVID-19. Though COVID-19 did not substantially increase ME/CFS-like illness in the KPNC population during the study time period, ME/CFS-like illness nevertheless affects a notable portion of this population and is consistent with estimates of ME/CFS prevalence in other populations. Additional attention is needed to improve awareness, diagnosis, and treatment of ME/CFS.

Source: Wood MS, Halmer N, Bertolli J, Amsden LB, Nugent JR, Lin JS, Rothrock G, Nadle J, Chai SJ, Cope JR, Champsi JH, Yang J, Unger ER, Skarbinski J; for STOP-ME/CFS and COVID-SELECT. Impact of COVID-19 on myalgic encephalomyelitis/chronic fatigue syndrome-like illness prevalence: A cross-sectional survey. PLoS One. 2024 Sep 18;19(9):e0309810. doi: 10.1371/journal.pone.0309810. PMID: 39292671; PMCID: PMC11410243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410243/ (Full text)

Virtual reality education on myalgic encephalomyelitis for medical students and healthcare professionals: a pilot study

Abstract:

Introduction: Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) is a chronic condition which may be characterised by debilitating fatigue, post-exertional malaise, unrefreshing sleep, and cognitive difficulties. ME/CFS has significant negative impact on quality of life for those living with the condition. This may be exacerbated by a lack of knowledge within healthcare regarding the condition. Previous research has found that immersive virtual reality (VR) educational experiences within healthcare education can increase knowledge and empathy.

Methods: The present study employed a quasi-experimental pre-test-post-test design to investigate the impact of a short immersive VR educational experience on knowledge of ME/CFS and empathy for those living with the condition. The VR experience placed participants into a virtual scene which told real life stories of the experience of people living with ME/CFS and their families. 43 participants completed in this pilot study: 28 medical students and 15 primary care health professionals. Participants completed measures of knowledge of ME/CFS and empathy before and after engagement with the experience.

Results: A statistically significant increase was found for levels of knowledge (p < .001, d = 0.74) and empathy (p < .001, d = 1.56) from pre-VR experience levels to post-VR experience levels with a medium and large effect size, respectively. Further analysis revealed no statistically significant difference between baseline levels of knowledge of ME/CFS between healthcare professionals and medical students.

Discussion: The present study is the first to explore the use of this short immersive VR experience as an education tool within healthcare to increase knowledge of ME/CFS, and empathy for those living with the condition. Findings allude to the previously established lack of knowledge of ME/CFS within healthcare although promisingly the increases in knowledge and empathy found suggest that this immersive VR experience has potential to address this. Such changes found in this small-scale pilot study suggest that future research into the use of VR as an educational tool within this setting may be beneficial. Use of a control group, and larger sample size as well as investigation of retention of these changes may also enhance future research.

Source: Anderson T, Duffy G, Corry D. Virtual reality education on myalgic encephalomyelitis for medical students and healthcare professionals: a pilot study. BMC Med Educ. 2024 Sep 17;24(1):1018. doi: 10.1186/s12909-024-05990-2. PMID: 39289650; PMCID: PMC11409778. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409778/ (Full text)

How Long is Long COVID? Evaluation of Long-Term Health Status in Individuals Discharged from a Specialist Community Long COVID Service

Abstract:

Background: Post COVID-19 syndrome or Long Covid (LC) is a novel fluctuating condition with a protracted course in some patients. Specialist LC services have been operational in the UK since 2020 and deal with a high caseload of patients. Aims: To evaluate long-term outcomes in patients discharged from a community-based LC specialist service.

Methods: A service evaluation study that included patients who were well engaged in the services [completed the standard Patient Reported Outcome Measures (PROMs) and received intervention from clinician(s)] and had been discharged for at least 3 months from the service. They consented to the study and completed standard PROMs: COVID-19 Yorkshire Rehabilitation Scale (C19-YRS), EQ-5D-5L, and National Institute for Health and Care Excellence (NICE) criteria for Myalgia Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS).

Results: Out of 460 patients contacted, 112 (average of 37.6 months since infection and 9.8 months post-discharge) completed the PROMs. 90.2% patients continued to experience LC symptoms and disability and had not returned to their pre-COVID health status. The average EQ-5D-5L index score was 0.53 (SD 0.29) highlighting a significant disability and that LC had become a long-term condition (LTC) in majority of patients who responded to the survey. 43% patients met the criteria for suspected ME/CFS.

Conclusion: A proportion of LC patients develop Persistent Long Covid (PLC) consistent with a LTC and had a significant overlap with ME/CFS.

Source: Bodey, R.; Grimaldi, J.; Tait, H.; Godfrey, B.; Witton, S.; Sharda, J.; Tarrant, R.; Sivan, M. How Long is Long COVID? Evaluation of Long-Term Health Status in Individuals Discharged from a Specialist Community Long COVID Service. Preprints 2024, 2024090813. https://doi.org/10.20944/preprints202409.0813.v1 https://www.preprints.org/manuscript/202409.0813/v1 (Full text available as PDF file)

Manual Therapy Improves Fibromyalgia Symptoms by Downregulating SIK1

Abstract:

Fibromyalgia (FM), classified by ICD-11 with code MG30.0, is a chronic debilitating disease characterized by widespread pain, fatigue, cognitive impairment, sleep, and intestinal alterations, among others. FM affects a large proportion of the worldwide population, with increased prevalence among women. The lack of understanding of its etiology and pathophysiology hampers the development of effective treatments.

Our group had developed a manual therapy (MT) pressure-controlled custom manual protocol on FM showing hyperalgesia/allodynia, fatigue, and patient’s quality of life benefits in a cohort of 38 FM cases (NCT04174300). With the aim of understanding the therapeutic molecular mechanisms triggered by MT, this study interrogated Peripheral Blood Mononuclear Cell (PBMC) transcriptomes from FM participants in this clinical trial using whole RNA sequencing (RNAseq) and reverse transcription followed by quantitative Polymerase Chain Reaction (RT-qPCR) technologies.

The results show that the salt-induced kinase SIK1 gene was consistently downregulated by MT in FM, correlating with improvement of patient symptoms. In addition, this study compared the findings in a non-FM control cohort subjected to the same MT protocol, evidencing that those changes in SIK1 expression with MT only occurred in individuals with FM. This positions SIK1 as a potential biomarker to monitor response to MT and as a therapeutic target of FM, which will be further explored by continuation studies.

Source: Bonastre-Férez J, Giménez-Orenga K, Falaguera-Vera FJ, Garcia-Escudero M, Oltra E. Manual Therapy Improves Fibromyalgia Symptoms by Downregulating SIK1. Int J Mol Sci. 2024 Sep 1;25(17):9523. doi: 10.3390/ijms25179523. PMID: 39273470. https://www.mdpi.com/1422-0067/25/17/9523 (Full text)

Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study

Summary:

Background: Children can develop Long Covid, however long term outcomes and their predictors are poorly described in these patients. The primary aim is to describe characteristics and predictors of Long Covid in children assessed in-clinics up to 36 months post-SARS-CoV-2 infection, as well as investigate the role of vaccines in preventing Long Covid, risk of reinfections and development of autoimmune diseases.

Methods: Children aged 0–18 years old with confirmed SARS-CoV-2 infection were invited for a prospective follow-up assessment at a peadiatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12-, 18-, 24- and 36-months post-infection onset, between 01/02/2020 and 28/02/2024). Long Covid was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection.

Findings: 1319 patients were initially included, 1296 reached the 3 months follow-up or more. Of the patients who underwent multiple follow-ups, 23.2% (301), 169 (13.2%), 89 (7.9%), 67 (6.1%), 47 (7.1%) were diagnosed with Long Covid at 3-6-12-18-24 months, respectively For the primary outcome of Long Covid at three months, age >12 years (P < 0.001, OR 11.33, 95% CI 4.2; 15.15), comorbidities (P = 0.008, OR 1.83, 95% CI 1.06; 2.44), being infected with original variants (P < 0.001, OR 4.77, 95% CI 2.46; 14.47), female sex (P < 0.001, OR 1.62, 95% CI 1.02; 1.89) were statistically significant risk factors. Age >12 years (P = 0.002, OR 9.37, 95% CI 1.58; 8.64), and infection with original (P = 0.012, OR 3.52, 95% CI 1.32; 8.64) and alfa (P < 0.001, OR 4.09, 95% CI 2.01; 8.3) SARS-CoV-2 variants remained statistically significant risk factors for Long Covid duration for at least 18 months. Vaccination was associated with a lower risk of long covid at 3, 6 and 12 months for older children and a lower risk of reinfections. Being infected with the original SARS-CoV-2 variant was associated with a higher risk of new-onset autoimmune diseases ((P = 0.035, 95% CI 1.12; 2.4). One patient was diagnosed with Long Covid after a re-infection.

Interpretation: This is the longest follow-up study of children with SARS-CoV-2 infection, showing a significant and long-lasting burden of Long Covid in the pediatric population. Our findings highlight the urgent need of investing in pediatric Long Covid in order to find effective diagnostic and therapeutic approaches, as well can inform preventive strategies in case of future pandemics.

Source: Camporesi, Anna et al. Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study.  eClinicalMedicine, Volume 76, 102815 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00394-8/fulltext

Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated.

Purpose and methods: In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM.

Results: Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.

Source: Haunhorst S, Dudziak D, Scheibenbogen C, Seifert M, Sotzny F, Finke C, Behrends U, Aden K, Schreiber S, Brockmann D, Burggraf P, Bloch W, Ellert C, Ramoji A, Popp J, Reuken P, Walter M, Stallmach A, Puta C. Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome. Infection. 2024 Sep 6. doi: 10.1007/s15010-024-02386-8. Epub ahead of print. PMID: 39240417. https://link.springer.com/article/10.1007/s15010-024-02386-8 (Full text)

Two-Year Longitudinal Study Reveals That Long COVID Symptoms Peak and Quality of Life Nadirs at 6–12 Months Postinfection

Abstract:

Background: Few longitudinal studies available characterize long COVID outcomes out to 24 months, especially in people with nonsevere acute coronavirus disease 2019 (COVID-19). This study sought to prospectively characterize incidence and duration of long COVID symptoms and their association with quality of life (QoL) from 1–24 months after mild-to-moderate COVID-19 using validated tools in a diverse cohort of unvaccinated people infected with SARS-CoV-2 in 2020.

Methods: At 1–3, 6, 12, 18, and 24 months post-COVID-19, 70 participants had orthostatic vital signs measured, provided blood, and completed surveys characterizing symptoms, QoL, and return to pre-COVID-19 health and activities using validated tools (FLU-PRO+, Fatigue Severity Scale, Insomnia Severity Index, General Practitioner Assessment of Cognition, Patient Health Questionnaire Depression 8-Item, Generalized Anxiety Disorder 7-Item, 36-Item Short-Form Health Survey, EuroQol EQ-5D-5L).

Results: During the study period, 33% of participants experienced long COVID (had not returned to pre-COVID-19 health status and reported at least 1 symptom >90 days postinfection); 8% had not returned to their pre-COVID-19 health status 24 months postinfection. Long COVID symptoms peaked 6 months post-COVID-19, frequently causing activity limitations. Having long COVID was significantly associated with decreased QoL in multiple domains. Frequencies of orthostatic hypotension and tachycardia reflected levels reported in the general population. Within-person weight increased significantly between months 1 and 6. Long COVID was associated with pre-COVID-19 obesity and hyperlipidemia, but not with high-sensitivity C-reactive protein levels 1–3 months postinfection.

Conclusions: Long COVID occurs in a significant proportion of unvaccinated people, even if the acute illness was not severe. Long COVID prevalence peaked 6–12 months post-COVID-19, and a small proportion of participants still reported not returning to their pre-COVID-19 health status 24 months post-COVID-19.

Source: Demko ZO, Yu T, Mullapudi SK, Varela Heslin MG, Dorsey CA, Payton CB, Tornheim JA, Blair PW, Mehta SH, Thomas DL, Manabe YC, Antar AAR. Two-Year Longitudinal Study Reveals That Long COVID Symptoms Peak and Quality of Life Nadirs at 6-12 Months Postinfection. Open Forum Infect Dis. 2024 Mar 6;11(3):ofae027. doi: 10.1093/ofid/ofae027. PMID: 38449921; PMCID: PMC10917418. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917418/ (Full text)

Gut Microbiome Wellness Index 2 enhances health status prediction from gut microbiome taxonomic profiles

Abstract:

Recent advancements in translational gut microbiome research have revealed its crucial role in shaping predictive healthcare applications. Herein, we introduce the Gut Microbiome Wellness Index 2 (GMWI2), an enhanced version of our original GMWI prototype, designed as a standardized disease-agnostic health status indicator based on gut microbiome taxonomic profiles.

Our analysis involves pooling existing 8069 stool shotgun metagenomes from 54 published studies across a global demographic landscape (spanning 26 countries and six continents) to identify gut taxonomic signals linked to disease presence or absence. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the “reject option”).

This performance exceeds that of the original GMWI model and traditional species-level α-diversity indices, indicating a more robust gut microbiome signature for differentiating between healthy and non-healthy phenotypes across multiple diseases. When assessed through inter-study validation and external validation cohorts, GMWI2 maintains an average accuracy of nearly 75%.

Furthermore, by reevaluating previously published datasets, GMWI2 offers new insights into the effects of diet, antibiotic exposure, and fecal microbiota transplantation on gut health. Available as an open-source command-line tool, GMWI2 represents a timely, pivotal resource for evaluating health using an individual’s unique gut microbial composition.

Source: Chang, D., Gupta, V.K., Hur, B. et al. Gut Microbiome Wellness Index 2 enhances health status prediction from gut microbiome taxonomic profiles. Nat Commun 15, 7447 (2024). https://doi.org/10.1038/s41467-024-51651-9 https://www.nature.com/articles/s41467-024-51651-9 (Full text)

Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are chronic syndromes of unknown etiology, accompanied by numerous symptoms affecting neurological and physical conditions. Despite frequent revisions of the diagnostic criteria, clinical practice guidelines are often outdated, leading to underdiagnosis and ineffective treatment. Our aim was to identify microRNA (miRNA) biomarkers implicated in pathological mechanisms underlying these diseases.
A comprehensive literature review using publicly accessible databases was conducted. Interesting miRNAs were extracted from relevant publications on ME/CFS and/or FM, and were then linked to pathophysiological processes possibly manifesting these chronic diseases. Dysregulated miRNAs in ME/CFS and FM may serve as promising biomarkers for these diseases.
Key identified miRNAs, such as miR-29c, miR-99b, miR-128, miR-374b, and miR-766, were frequently mentioned for their roles in immune response, mitochondrial dysfunction, oxidative stress, and central sensitization, while miR-23a, miR-103, miR-152, and miR-320 were implicated in multiple crucial pathological processes for FM and/or ME/CFS.
In summary, both ME/CFS and FM seem to share many dysregulated biological or molecular processes, which may contribute to their commonly shared symptoms. This miRNA-based approach offers new angles for discovering molecular markers urgently needed for early diagnosis or therapeutics to tackle the pathology of these medically unexplained chronic diseases.
Source: Tsamou M, Kremers FAC, Samaritakis KA, Roggen EL. Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review. International Journal of Molecular Sciences. 2024; 25(17):9551. https://doi.org/10.3390/ijms25179551 https://www.mdpi.com/1422-0067/25/17/9551 (Full text)