Estimates of Incidence and Predictors of Fatiguing Illness after SARS-CoV-2 Infection.

This study aimed to estimate the incidence rates of post-COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020-February 2021 who were followed for a median of 11.4 (interquartile range 7.8-15.5) months and compared them to data from 9,022 propensity score-matched non-COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non-COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48-1.92) for fatigue and 4.32 (95% CI 2.90-6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

Autoimmunity's enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complicated, heterogeneous condition distinguished by post-exertional neuroimmune exhaustion and multisystem symptoms. Its complexity poses challenges for physicians, researchers and those inflicted by its presence. Due to conflicting evidence and limiting consensus, the association and contribution autoimmunity serves in the pathophysiology or aetiology of ME/CFS is yet to be confirmed. This systematic review synthesises the currently available data to clarify the role autoimmunity has in the pathogenesis of ME/CFS and explore the therapeutic limitations. METHODS: This systematic review was conducted in accordance with the PRISMA and Cochrane guidelines. Full-text articles containing the primary key terms "Autoimmunity/Autoimmune" and "ME/CFS" were included provided their suitability to the inclusion and exclusion criteria. RESULTS: Ten publications investigating the role of autoimmunity in ME/CFS were examined. One investigated the role of cytokine signalling; Three investigated the genetic nature of autoimmunity in ME/CFS patients; One examined the immune lineage of ME/CFS patients; Six investigated the presence and role of autoantibodies in ME/CFS patients. CONCLUSION: The findings generated from this systematic review highlight inconsistent and insufficient evidence to classify ME/CFS as an autoimmune disease. Additionally, it further emphasises the complexity of ME/CFS and highlights the challenges in distinguishing autoreactivity from deregulatory processes. Future research is urgently needed to advance the development of diagnostic and treatment strategies. PROSPERO REGISTRATION CODE: CRD42024533447.

The potential role of ocular and otolaryngological mucus proteins in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat. Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body. These mucosal pathways contribute to the body's defense mechanisms involving pathogenic onset. When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection. Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.

Repeated cold stress, an animal model for fibromyalgia, elicits proprioceptor-induced chronic pain with microglial activation in mice.

BACKGROUND: Fibromyalgia is characterized by chronic pain, fatigue, and other somatic symptoms. We have recently revealed that proprioceptor hyperactivation induces chronic pain in a rat model of myalgic encephalomyelitis. The present study explores whether similar proprioceptor-induced pain is elicited in a mouse model of fibromyalgia. METHODS: Repeated cold stress (RCS) was used as a fibromyalgia model. Pain behavior was examined using the von Frey test, and neuronal activation was examined immunohistochemically as activating transcription factor (ATF)3 expression. The Atf3:BAC transgenic mouse, in which mitochondria in hyperactivated neurons are specifically labeled by green fluorescent protein, was used to trace the activated neuronal circuit. PLX3397 (pexidartinib) was used for microglial suppression. RESULTS: RCS elicited long-lasting pain in mice. ATF3, a marker of cellular hyperactivity and injury, was expressed in the lumbar dorsal root ganglion (DRG) 2 days after RCS initiation; the majority of ATF3-expressing DRG neurons were tropomyosin receptor kinase C- and/or vesicular glutamate transporter 1-positive proprioceptors. Microglial activation and increased numbers of microglia were observed in the medial part of the nucleus proprius 5 days after RCS initiation, and in the dorsal region of the ventral horn 7 days after RCS. In the ventral horn, only a subset of motor neurons was positive for ATF3; these neurons were surrounded by activated microglia. A retrograde tracer study revealed that ATF3-positive motor neurons projected to the intrinsic muscles of the foot (IMF). Using Atf3:BAC transgenic mice, we traced hyperactivated neuronal circuits along the reflex arc. Green fluorescent protein labeling was observed in proprioceptive DRG neurons and their processes originating from the IMF, as well as in motor neurons projecting to the IMF. Microglial activation was observed along this reflex arc, and PLX3397-induced microglial ablation significantly suppressed pain behavior. CONCLUSION: Proprioceptor hyperactivation leads to local microglial activation along the reflex arc; this prolonged microglial activation may be responsible for chronic pain in the present model. Proprioceptor-induced microglial activation might be the common cause of chronic pain in both the fibromyalgia and myalgic encephalomyelitis models, although the experimental models are different.

Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function. The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome. In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness medically unexplained, affecting approximately 1% of the global population. Due to the subjective complaint, assessing the exact severity of fatigue is a clinical challenge, thus, this study aimed to produce comprehensive features of fatigue severity in ME/CFS patients. METHODS: We systematically extracted the data for fatigue levels of participants in randomized controlled trials (RCTs) targeting ME/CFS from PubMed, Cochrane Library, Web of Science, and CINAHL throughout January 31, 2024. We normalized each different measurement to a maximum 100-point scale and performed a meta-analysis to assess fatigue severity by subgroups of age, fatigue domain, intervention, case definition, and assessment tool, respectively. RESULTS: Among the total of 497 relevant studies, 60 RCTs finally met our eligibility criteria, which included a total of 7088 ME/CFS patients (males 1815, females 4532, and no information 741). The fatigue severity of the whole 7,088 patients was 77.9 (95% CI 74.7-81.0), showing 77.7 (95% CI 74.3-81.0) from 54 RCTs in 6,706 adults and 79.6 (95% CI 69.8-89.3) from 6 RCTs in 382 adolescents. Regarding the domain of fatigue, 'cognitive' (74.2, 95% CI 65.4-83.0) and 'physical' fatigue (74.3, 95% CI 68.3-80.3) were a little higher than 'mental' fatigue (70.1, 95% CI 64.4-75.8). The ME/CFS participants for non-pharmacological intervention (79.1, 95% CI 75.2-83.0) showed a higher fatigue level than those for pharmacological intervention (75.5, 95% CI 70.0-81.0). The fatigue levels of ME/CFS patients varied according to diagnostic criteria and assessment tools adapted in RCTs, likely from 54.2 by ICC (International Consensus Criteria) to 83.6 by Canadian criteria and 54.2 by MFS (Mental Fatigue Scale) to 88.6 by CIS (Checklist Individual Strength), respectively. CONCLUSIONS: This systematic review firstly produced comprehensive features of fatigue severity in patients with ME/CFS. Our data will provide insights for clinicians in diagnosis, therapeutic assessment, and patient management, as well as for researchers in fatigue-related investigations.

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology.

OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date. METHODS: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models. RESULTS: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown. CONCLUSIONS: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

BACKGROUND: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. METHODS: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. RESULTS: Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1ß (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. CONCLUSIONS: Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions.

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CBV compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CBV.NEW & NOTEWORTHY We evaluated cognitive function before and after CO2, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms. A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS. We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes - thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S - were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant. The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus.

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms. METHODS: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software. RESULTS: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and ß1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), ß2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01). CONCLUSION: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is associated with long-term disability and poor quality of life (QoL). Cardinal ME/CFS symptoms (including post-exertional malaise, cognitive dysfunction and sleep disturbances) have been observed in Post COVID-19 Condition (PCC). To gain further insight into the potential role of ME/CFS as a post-COVID-19 sequela, this study investigates associations between symptoms and patient-reported outcomes, as well as symptom clusters. METHODS: Participants included Australian residents aged between 18 and 65 years formally diagnosed with ME/CFS fulfilling the Canadian or International Consensus Criteria or PCC meeting the World Health Organization case definition. Validated, self-administered questionnaires collected participants' sociodemographic and illness characteristics, symptoms, QoL and functional capacity. Associations between symptoms and patient-reported outcomes were investigated with multivariate linear regression models. Hierarchical cluster analysis was performed to identify symptom clusters. RESULTS: Most people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) were female (n = 48/60, 80.0% and n = 19/30, 63.3%, respectively; p = 0.12). PwME/CFS were significantly younger (x̄=41.75, s = 12.91 years) than pwPCC (x̄=48.13, s =10.05 years; p =0.017). Autonomic symptoms (notably dyspnoea) were associated with poorer scores in most patient-reported outcome domains for both cohorts. None of the four symptom clusters identified were unique to ME/CFS or PCC. Clusters were largely delineated by the presence of gastrointestinal and neurosensory symptoms, illness duration, ME/CFS criteria met and total symptoms. CONCLUSIONS: Illness duration may explain differences in symptom burden between pwME/CFS and pwPCC. PCC diagnostic criteria must be refined to distinguish pwPCC at risk of long-term ME/CFS-like illness and subsequently deliver necessary care and support.

Post COVID-19 Condition (PCC), or Long COVID, refers to the ongoing symptoms experienced after acute COVID-19 illness. The symptoms reported by people with PCC (pwPCC) resemble Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, existing diagnostic criteria for PCC are broad and cannot discern PCC subtypes (such as pwPCC experiencing ME/CFS-like illness), which may require different approaches to care. This study contributes to improving PCC case criteria and approaches to care for both ME/CFS and PCC by investigating the relationships between symptoms and patient-reported outcomes among pwPCC and people with ME/CFS (pwME/CFS).For both cohorts, symptoms had a negative relationship with all aspects of health. Autonomic symptoms, notably breathing issues, returned the most negative associations. Pain, flu-like symptoms and lack of temperature control appeared more burdensome among pwPCC. These symptoms may signify the early stages of ME/CFS. Symptom clusters were also identified for the first time among a combined cohort of pwME/CFS and pwPCC in this study. Importantly, none of the symptom clusters were specific to ME/CFS or PCC. Instead, symptom clusters were defined by the prevalence of gastrointestinal and neurosensory symptoms, illness duration, ME/CFS criteria met and the total number of symptoms.This study suggests that the few differences between ME/CFS and PCC may be explained by illness duration. These findings further implicate ME/CFS as a potential post-COVID-19 outcome. As ME/CFS is associated with profound reductions in quality of life and functioning, identifying pwPCC experiencing ME/CFS-like illness through refined diagnostic criteria must be prioritised to ensure the delivery of necessary care.

Illness presentation and quality of life in myalgic encephalomyelitis/chronic fatigue syndrome and post COVID-19 condition: a pilot Australian cross-sectional study.

PURPOSE: Post COVID-19 Condition (PCC), being persistent COVID-19 symptoms, is reminiscent of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-a chronic multi-systemic illness characterised by neurocognitive, autonomic, endocrinological and immunological disturbances. This novel cross-sectional investigation aims to: (1) compare symptoms among people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) to inform developing PCC diagnostic criteria; and (2) compare health outcomes between patients and people without acute or chronic illness (controls) to highlight the illness burdens of ME/CFS and PCC. METHODS: Sociodemographic and health outcome data were collected from n = 61 pwME/CFS, n = 31 pwPCC and n = 54 controls via validated, self-administered questionnaires, including the 36-Item Short-Form Health Survey version 2 (SF-36v2) and World Health Organization Disability Assessment Schedule version 2.0 (WHODAS 2.0). PwME/CFS and pwPCC also provided self-reported severity and frequency of symptoms derived from the Canadian and International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC. RESULTS: Both illness cohorts similarly experienced key ME/CFS symptoms. Few differences in symptoms were observed, with memory disturbances, muscle weakness, lymphadenopathy and nausea more prevalent, light-headedness more severe, unrefreshed sleep more frequent, and heart palpitations less frequent among pwME/CFS (all p < 0.05). The ME/CFS and PCC participants' SF-36v2 or WHODAS 2.0 scores were comparable (all p > 0.05); however, both cohorts returned significantly lower scores in all SF-36v2 and WHODAS 2.0 domains when compared with controls (all p < 0.001). CONCLUSION: This Australian-first investigation demonstrates the congruent and debilitating nature of ME/CFS and PCC, thereby emphasising the need for multidisciplinary care to maximise patient health outcomes.

Graded exercise therapy compared to activity management for paediatric chronic fatigue syndrome/myalgic encephalomyelitis: pragmatic randomized controlled trial.

The MAGENTA pragmatic parallel groups randomized controlled trial compared graded exercise therapy (GET) with activity management (AM) in treating paediatric myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Children aged 8-17 years with mild/moderate ME/CFS and presenting to NHS specialist paediatric services were allocated at random to either individualised flexible treatment focussing on physical activity (GET, 123 participants) or on managing cognitive, school and social activity (AM, 118 participants) delivered by NHS therapists. The primary outcome was the self-reported short-form 36 physical function subscale (SF-36-PFS) after 6 months, with higher scores indicating better functioning. After 6 months, data were available for 201 (83%) participants who received a mean of 3.9 (GET) or 4.6 (AM) treatment sessions. Comparing participants with measured outcomes in their allocated groups, the mean SF-36-PFS score changed from 54.8 (standard deviation 23.7) to 55.7 (23.3) for GET and from 55.5 (23.1) to 57.7 (26.0) for AM giving an adjusted difference in means of -2.02 (95% confidence interval -7.75, 2.70). One hundred thirty-five participants completed the mean SF-36-PFS at 12 months, and whilst further improvement was observed, the difference between the study groups remained consistent with chance. The two study groups showed similar changes on most of the secondary outcome measures: Chalder Fatigue, Hospital Anxiety and Depression Scale: Depression, proportion of full-time school attended, a visual analogue pain scale, participant-rated change and accelerometer measured physical activity, whether at the 6-month or 12-month assessment. There was an isolated finding of some evidence of an improvement in anxiety in those allocated to GET, as measured by the Hospital Anxiety and Depression Scale at 6 months, with the 12-month assessment, and the Spence Children's Anxiety scale being aligned with that finding. There was weak evidence of a greater risk of deterioration with GET (27%) than with AM (17%; p = 0.069). At conventional UK cost per QALY thresholds, the probability that GET is more cost-effective than AM ranged from 18 to 21%. Whilst completion of the SF-36-PFS, Chalder Fatigue Scale and EQ-5D-Y was good at the 6-month assessment point, it was less satisfactory for other measures, and for all measures at the 12-month assessment.  Conclusion: There was no evidence that GET was more effective or cost-effective than AM in this setting, with very limited improvement in either study group evident by the 6-month or 12-month assessment points.  Trial registration: The study protocol was registered at www.isrctn.com (3rd September 2015; ISRCTN 23962803) before the start of enrolment to the initial feasibility phase.

Long COVID in pediatrics-epidemiology, diagnosis, and management.

This review summarizes current knowledge on post-acute sequelae of COVID-19 (PASC) and post-COVID-19 condition (PCC) in children and adolescents. A literature review was performed to synthesize information from clinical studies, expert opinions, and guidelines. PASC also termed Long COVID - at any age comprise a plethora of unspecific symptoms present later than 4 weeks after confirmed or probable infection with severe respiratory syndrome corona virus type 2 (SARS-CoV-2), without another medical explanation. PCC in children and adolescents was defined by the WHO as PASC occurring within 3 months of acute coronavirus disease 2019 (COVID-19), lasting at least 2 months, and limiting daily activities. Pediatric PASC mostly manifest after mild courses of COVID-19 and in the majority of cases remit after few months. However, symptoms can last for more than 1 year and may result in significant disability. Frequent symptoms include fatigue, exertion intolerance, and anxiety. Some patients present with postural tachycardia syndrome (PoTS), and a small number of cases fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, no diagnostic marker has been established, and differential diagnostics remains challenging. Therapeutic approaches include appropriate self-management as well as the palliation of symptoms by non-pharmaceutical and pharmaceutical strategies.    Conclusion: PASC in pediatrics present with heterogenous severity and duration. A stepped, interdisciplinary, and individualized approach is essential for appropriate clinical management. Current health care structures have to be adapted, and research was extended to meet the medical and psychosocial needs of young people with PASC or similar conditions. What is Known: • Post-acute sequelae of coronavirus 2019 (COVID-19) (PASC) - also termed Long COVID - in children and adolescents can lead to activity limitation and reduced quality of life. • PASC belongs to a large group of similar post-acute infection syndromes (PAIS). Specific biomarkers and causal treatment options are not yet available. What is New: • In February 2023, a case definition for post COVID-19 condition (PCC) in children and adolescents was provided by the World Health Organization (WHO), indicating PASC with duration of at least 2 months and limitation of daily activities. PCC can present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). • Interdisciplinary collaborations are necessary and have been established worldwide to offer harmonized, multimodal approaches to diagnosis and management of PASC/PCC in children and adolescents.

Sex and disease severity-based analysis of steroid hormones in ME/CFS.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. METHODS: Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). RESULTS: After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. CONCLUSION: Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.

Efficacy and Acceptance of Cognitive Behavioral Therapy in Adults with Chronic Fatigue Syndrome: A Meta-analysis.

BACKGROUND: The systematic aggregation of research on cognitive behavioral therapy (CBT) in chronic fatigue syndrome (CFS) needs an update. Although meta-analyses evaluating interventions typically focus on symptom reduction, they should also consider indicators of treatment acceptability, e.g., drop-out rates. METHODS: Randomized controlled trials (RCTs) investigating CBT in adults with CFS compared to inactive and non-specific control groups were included. First, efficacy was examined, considering fatigue, depression, anxiety, and perceived health. Secondly, drop-out rates through different trial stages were analyzed: Non-completion of all mandatory sessions, drop-out (primary study definition), treatment refusal (non-starters), and average of sessions completed. RESULT: We included 15 RCTs with 2015 participants. CBT was more effective than controls in fatigue (g = -0.52, 95%CI -0.69 to -0.35), perceived health, depression, and anxiety at post-treatment. At long-term follow-up the effects were maintained for fatigue and anxiety. Rates of non-completion (22%, 95%CI 3-71), drop-out (15%, 95%CI 9-25), and treatment refusal (7%, 95%CI 3-15) were relatively low, with a high average proportion of sessions completed. Total time of therapy moderated the effect on fatigue, while the number of sessions moderated the effect on perceived health. Fatigue severity influenced adherence. CONCLUSION: The results indicate that CBT for CFS is effective in reducing fatigue, fatigue related impairment, and severity of depression and anxiety. Conclusions on efficacy at follow-ups are still limited. However, adherence is high in CBT. The results may help to inform clinical practice. Future research should focus on examining the maintenance of effects, while also emphasizing the importance of treatment acceptance.

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome.

Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.