Tag: chronic fatigue

Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial

Abstract:

Background: In the context of long COVID, persistent fatigue is among the most prevalent symptoms that can develop after SARS-CoV-2 infection. Mitochondrial myopathy and endothelial dysfunction, which are triggers of inflammation, have emerged as prominent causes of long COVID-induced fatigue. Interestingly, the intake of flavanols, particularly (−)-epicatechin (EC), has been associated with the positive modulation of endothelial and mitochondrial structure and function.
Methods: In this work, we conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether an EC-enriched supplement (ECES) improves plasma markers of inflammation, endothelial structure, and fatigue-related endpoints in patients with long COVID-19.
Results: The study included 46 subjects (mean age 52 years) who were instructed to consume two capsules/day for 90 days of either ECES (n = 23) or placebo (n = 23). Endpoints assessed included mean changes in plasma inflammatory markers (IL-1β, IL-6, and TNF-α) and endothelial dysfunction markers (syndecan-1), handgrip strength, fatigue scale, and quality of life (QoL). The results showed significant improvements in the ECES group for inflammatory markers, syndecan-1, and fatigue compared with the placebo group.
Conclusions: The results yield intriguing positive findings for EC and open a new avenue for treating long COVID.
Source: Munguía L, Silva S, Villarreal F, Nájera N, Ceballos G. Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial. Journal of Clinical Medicine. 2026; 15(4):1468. https://doi.org/10.3390/jcm15041468 https://www.mdpi.com/2077-0383/15/4/1468 (Full text)

Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical condition characterized by extreme fatigue lasting at least 6 months. Based upon case reports, patients infected with Babesia or Bartonella spp. have reported a history of chronic fatigue and concurrent neurological symptoms.

In this study, 50 study participants reporting fatigue lasting from six months to 19 years and one or more neurological symptoms were selected. PCR assays were used to amplify Babesia and Bartonella spp. DNA from blood and enrichment blood cultures.

Using targeted qPCR amplification and DNA sequencing, infection with Babesia spp., Bartonella spp. or both genera was confirmed in 10, 11, and 2 individuals, respectively. Of 50 participants, 12 (24%, 95% CI: 12-36%) were infected with a Babesia species, while Bartonella species infection was documented in 13/50 individuals (26%, 95% CI: 13.8-38.2%).

This study provides documentation supporting a potential role for Babesia and Bartonella infection in patients with presentations consistent with ME/CFS. Prospective case-control studies, using highly sensitive direct pathogen detection techniques, are needed to determine whether or the extent to which infection with members of these two genera contributes to or causes ME/CFS.

Source: Breitschwerdt EB, Maggi RG, Bush JC, Kingston E. Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms. Pathogens. 2025 Dec 19;15(1):2. doi: 10.3390/pathogens15010002. PMID: 41598986. https://www.mdpi.com/2076-0817/15/1/2 (Full text)

Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies

Introduction:

Fatigue and weariness have been universal experiences throughout human history, coexisting with humanity since its earliest days across all cultures and times. It occurs in ancient stories, including Genesis, in which Adam’s fatigue was linked to the toil imposed upon him as part of the consequences of disobedience, a condition that made sustaining life a laborious task. Acute fatigue, which arises naturally in response to stress or work, is a normal physiological process experienced by all humans regardless of era or place. It signals the body’s need to rest and adapt, playing a vital role in maintaining health and balance.

In contrast, chronic fatigue, as seen in aging populations and conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complex and often debilitating disorder that extends beyond normal tiredness. It involves sustained disruption of metabolic, neurological, and immune functions, resisting typical recovery mechanisms. The 14 papers in this Research Topic collectively explore the multifaceted nature of fatigue, presenting advances in mechanistic research, epidemiology, clinical interventions, rehabilitation techniques, and innovative monitoring technologies aimed at improving diagnosis, treatment, and management of this persistent condition.

Source: Kujawski S, Hodges L, Morten KJ, Zalewski P. Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies. Front Neurosci. 2025 Dec 10;19:1751667. doi: 10.3389/fnins.2025.1751667. PMCID: PMC12728026. https://pmc.ncbi.nlm.nih.gov/articles/PMC12728026/ (Full text)

Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment

Abstract:

Fatigue negatively impacts health, safety, and productivity, yet current monitoring methods are often subjective, labor-intensive, and inaccurate. To address these challenges, this study presents a capacitive sensor-based eye tracker leveraging cylindrical carbon nanotube-paper composite (CCPC) sensors for chronic fatigue (CF) assessment.

Fabricated by novel wet-fracture and paper-rolling methods, CCPC sensors demonstrate superior proximity sensitivity with a small form factor. These one-dimensional sensors are seamlessly integrated into an eyeglass frame for noncontact monitoring of blink rates and eye closures. A 15-minute testing protocol, combining cognitive tasks and noise exposure, is designed to induce acute fatigue and identify CF. By analyzing changes in the digital markers against established fatigue indicators, CF is assessed with the aid of machine learning models for the evaluation of accuracy, sensitivity, and specificity.

This real-time, wearable monitoring platform provides an objective, effortless, and noncontact approach to fatigue assessment. With further testing and optimization, it holds the potential for user-friendly evaluation of acute fatigue or fatigue-associated diseases, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Source: Li T, Park SH, Lee C, Kim S, Kwon Y, Kim H, Chung JH. Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment. Adv Sens Res. 2025 Jul;4(7):e00027. doi: 10.1002/adsr.202500027. Epub 2025 May 22. PMID: 40662140; PMCID: PMC12259227. https://pmc.ncbi.nlm.nih.gov/articles/PMC12259227/ (Full text)

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules, 15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)

Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”

Introduction:

Fatigue is a common complaint experienced by most of subjects during lifetime, which affects approximately 30–50% of general population as point prevalence. According to the fatigue-lasting duration, it is classified as acute (<1 month), prolonged (>1 month, <6 months), and chronic fatigue (≥6 months), respectively. Acute fatigue is generally disappears after taking a rest or treating the causative diseases, while uncontrolled prolonged and chronic fatigue limit the physical and social activities. Especially, medically unexplained chronic fatigue is a debilitating status, such as idiopathic chronic fatigue (ICF) and chronic fatigue syndrome (CFS).

Source: Son CG. Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”. Integr Med Res. 2019 Jun;8(2):89-91. doi: 10.1016/j.imr.2019.04.005. Epub 2019 Apr 12. PMID: 31193269; PMCID: PMC6522773. https://pmc.ncbi.nlm.nih.gov/articles/PMC6522773/ (Full text)

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Highlights:

  • Though a common symptom, fatigue is difficult to define and investigate, and occurs in a wide variety of disorders, with differing pathological causes.
  • This review aims to guide clinicians in how to approach fatigue and to suggest that neurophysiological tests may allow an understanding of its origin and severity.
  • The effectiveness of neurophysiological tests as cost-effective objective biomarkers for the assessment of fatigue has been summarised.

Abstract

Though a common symptom, fatigue is difficult to define and investigate, occurs in a wide variety of neurological and systemic disorders, with differing pathological causes. It is also often accompanied by a psychological component. As a symptom of long-term COVID-19 it has gained more attention.

In this review, we begin by differentiating fatigue, a perception, from fatigability, quantifiable through biomarkers. Central and peripheral nervous system and muscle disorders associated with these are summarised. We provide a comprehensive and objective framework to help identify potential causes of fatigue and fatigability in a given disease condition. It also considers the effectiveness of neurophysiological tests as objective biomarkers for its assessment. Among these, twitch interpolation, motor cortex stimulation, electroencephalography and magnetencephalography, and readiness potentials will be described for the assessment of central fatigability, and surface and needle electromyography (EMG), single fibre EMG and nerve conduction studies for the assessment of peripheral fatigability.

The purpose of this review is to guide clinicians in how to approach fatigue, and fatigability, and to suggest that neurophysiological tests may allow an understanding of their origin and interactions. In this way, their differing types and origins, and hence their possible differing treatments, may also be defined more clearly.

Source: Tankisi H, Versace V, Kuppuswamy A, Cole J. The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability. Clin Neurophysiol Pract. 2023 Dec 18;9:39-50. doi: 10.1016/j.cnp.2023.12.004. PMID: 38274859; PMCID: PMC10808861. https://www.sciencedirect.com/science/article/pii/S2467981X23000367 (Full text)

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia

Abstract:

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS.

MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients.

RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028).

CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Source: AlAmri, Abdullah S.; AlShamrani, Foziah J.; AlMohish, Noor M.; Zafar, Azra S.; Alnaaim, Saud A.1; Alazman, Hatem A.; Al-Ghanimi, Ibrahim A.2; AlNahdi, Abdullah A.; AlDawsari, Fahad A.; AlMatrafi, Shahad B.3; Alzahrani, Ghaida R.3; Alnamlah, Muna S.; Alkhalifa, Rawan A.. Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia. Journal of Family and Community Medicine 31(1):p 63-70, Jan–Mar 2024. | DOI: 10.4103/jfcm.jfcm_73_23 https://journals.lww.com/jfcm/fulltext/2024/31010/frequency_and_characteristics_of_chronic_fatigue.9.aspx (Full text)

Is there a role for traditional and complementary medicines in managing chronic fatigue? A systematic review of randomized controlled trials

Abstract:

Introduction: Chronic fatigue syndrome (CFS) is an increasingly common condition that is challenging to treat due to unclear etiology and a lack of consensus on clinical diagnosis and treatment guidance. Many affected people resorted to using traditional and complementary medicines (T&CMs). However, the evidence for T&CMs for CF has been inconclusive and continues to evolve. The study aims to identify, summarize and assess the most recent evidence on the efficacy and safety of T&CMs for CFS.

Methods: Randomized controlled trials (RCTs) investigating T&CMs for CFS published in English of Chinese between 1 January 2013 and 31 December 2022 were searched from 7 databases. RCTs comparing T&CMs with no treatment, placebo, or pharmacological medicine were included, irrespective of language or blinding.

The Consolidated Standards of Reporting Trials Statement extensions for Chinese herbal medicine Formulas (CONSORT-CHM) and the Cochrane Collaboration’s Risk of Bias tool were used to evaluate the quality and risk of bias of included studies.

Results: A total of 62 RCTs investigating 43 types of T&CMs and involving 5,231 participants with CFS were included in this review. The primary outcome measures mainly included the scoring of fatigue symptoms using the validated tool Fatigue Scale-14 (FS-14) or the TCM syndrome score.

The main interventions showing overall efficacy were Chaihu Guizhi Decoction and Buzhong Yiqi combined with Xiao Chaihu Decoction, and 148 ingredients were identified, including Astragali Radix, Glycyrrhizae Radix et Rhizoma, Atractylodis Macrocephalae Rhizoma, and Bupleuri Radix.

The most significant effect was the improvement of fatigue, followed by TCM-diagnosed symptoms and other psychological conditions. No serious adverse effect had been reported. However, the quality of the RCTs included RCTs were found to be suboptimal, and the risk of bias remained uncertain.

Conclusions: Some evidence from RCTs supported the efficacy and safety of T&CM in CFS. However, given the methodological and quality heterogenicity of the included studies, the recommendations of T&CMs in treating CFS remain inconclusive. To develop better quality evidence about T&CMs for CFS, future studies should employ more objective diagnosis standards and outcome measurements, larger sample size, and better bias control, and ensure the compliance with the corresponding reporting guidelines.

Source: Yuxiao Li, Jingya Yang, Chi Ian Chau, Junnan Shi, Xianwen Chen, Hao Hu, Carolina Oi Lam Ung. Is there a role for traditional and complementary medicines in managing chronic fatigue? A systematic review of randomized controlled trials. Frontiers in Pharmacology, Volume 14, 2023. https://www.frontiersin.org/articles/10.3389/fphar.2023.1266803/abstract

Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue

Abstract

Background: Causative genetic variants cannot yet be found for many disorders with a clear heritable component, including chronic fatigue disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These conditions may involve genes in difficult-to-align genomic regions that are refractory to short read approaches. Structural variants in these regions can be particularly hard to detect or define with short reads, yet may account for a significant number of cases. Long read sequencing can overcome these difficulties but so far little data is available regarding the specific analytical challenges inherent in such regions, which need to be taken into account to ensure that variants are correctly identified.

Research into chronic fatigue disorders faces the additional challenge that the heterogeneous patient population likely encompasses multiple aetiologies with overlapping symptoms, rather than a single disease entity, such that each individual abnormality may lack statistical significance within a larger sample. Better delineation of patient subgroups is needed to target research and treatment.

Methods: We use nanopore sequencing in a case of unexplained severe fatigue to identify and fully characterise a large inversion in a highly homologous region spanning the AKR1C gene locus, which was indicated but could not be resolved by short-read sequencing. We then use GC-MS/MS serum steroid analysis to investigate the functional consequences.

Results: Several commonly used bioinformatics tools are confounded by the homology but a combined approach including visual inspection allows the variant to be accurately resolved. The DNA inversion appears to increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory neurosteroids and impaired progesterone metabolism.

Conclusions: This study provides an example of how long read sequencing can improve diagnostic yield in research and clinical care, and highlights some of the analytical challenges presented by regions containing tandem arrays of genes. It also proposes a novel gene associated with a specific disease aetiology that may be an underlying cause of complex chronic fatigue and possibly other conditions too. It reveals biomarkers that could be assessed in a larger cohort, potentially identifying a subset of patients who might respond to treatments suggested by the aetiology.

Source: Julia Oakley, Martin Hill, Adam Giess, Mélanie Tanguy, Greg Elgar. Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue. ResearchSquare [Preprint] https://www.researchsquare.com/article/rs-3218228/v2 (Full text)