Category: Pathogenesis

Increased risk of chronic fatigue syndrome following pneumonia: A population-based Cohort study

Abstract:

Background: Chronic fatigue syndrome (CFS) has been linked to several conditions, including infections, immune system changes, or emotional stress. Our study aimed to assess the risk of CFS after a pneumonia diagnosis using data from National Health Insurance Research Database of Taiwan.

Methods: In this nested case-control study, we identified 2,000,000 adult patients from a nationwide population-based health insurance claims database spanning from January 1, 2000, to December 31, 2017. Each case diagnosed with a pathogenic infection was matched with a corresponding control using propensity scores. We excluded individuals under 20 years of age, those with a history of pathogenic infections before the index date, or those with more than one potential pathogen. To estimate hazard ratios (HR) and the adjusted hazard ratio (aHR) with their respective 95 % confidence intervals (CI), we applied univariable and multivariable Cox proportional hazard models. The multivariable analysis incorporated adjustments for age, sex, and comorbidity-related confounders.

Results: The relationship between infection and the subsequent risk of CFS was assessed using Cox proportional hazards regression analysis. The incidence density rates were 6.13 and 8.70 per 1000 person-years among the non-pulmonary infection and pulmonary infection populations, respectively (adjusted hazard ratio [HR] = 1.4, 95 % confidence interval [CI] 1.32-1.5). Patients infected with Pseudomonas, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, and influenza virus exhibited a significantly higher risk of CFS than those without these pathogens (p < 0.05). Additionally, patients with pneumonia had a significantly increased risk of thromboembolism compare with control group (p < 0.05).

Source: Hsu HJ, Chang H, Lin CL, Yao WC, Hung CL, Pang SP, Kuo CF, Tsai SY. Increased risk of chronic fatigue syndrome following pneumonia: A population-based Cohort study. J Infect Public Health. 2024 Jul 14;17(8):102495. doi: 10.1016/j.jiph.2024.102495. Epub ahead of print. PMID: 39018725. https://www.sciencedirect.com/science/article/pii/S1876034124002296 (Full text)

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

Abstract:

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.

Source: Nunes, M., Vlok, M., Proal, A. et al. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovasc Diabetol 23, 254 (2024). https://doi.org/10.1186/s12933-024-02315-x https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02315-x (Full text)

Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances.

A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology.

It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress.

Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Source: Manuel Ruiz-Pablos, Bruno Paiva, Aintzane Zabaleta. Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis. Front. Immunol., 08 July 2024, Sec. Viral Immunology, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1422940 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full (Full text)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)

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

Abstract:

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.

Source: Apostolou E, Rosén A. Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses. J Intern Med. 2024 May 1. doi: 10.1111/joim.13792. Epub ahead of print. PMID: 38693641. https://onlinelibrary.wiley.com/doi/10.1111/joim.13792 (Full text)

An approach to finding specific forms of dysbiosis that associate with different disorders

Abstract:

Background Many disorders display dysbiosis of the enteric microbiome, compared with healthy controls. Different disorders share a pattern of dysbiosis that may reflect ‘reverse causation’, due to non-specific effects of illness-in-general. Combining a range of disorders into an ‘aggregate non-healthy active control’ (ANHAC) group should highlight such non-specific dysbiosis. Differential dysbiosis between the ANHAC group and specific disorders may then reflect effects of treatment or bowel dysfunction, or may potentially be causal. Here, we illustrate this logic by testing if individual genera can differentiate an ANHAC group from two specific diagnostic groups.

Methods We constructed an ANAHC group (n=17) that had 14 different disorders. We then used random forest analyses to test differential dysbiosis between the ANHAC group and two other disorders that have no known pathology, but: (i) symptoms of illness (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome – ME/CFS – n = 38); or (ii) both illness and bowel dysfunction (ME/CFS comorbid with Irritable Bowel Syndrome – IBS – n=27).

Results Many genera differentiated the ANHAC group from co-morbid IBS. However, only two genera – Roseburia and Dialister – discriminated the ANHAC group from ME/CFS.

Conclusions Different disorders can associate with specific forms of dysbiosis, over-and-above non-specific effects of illness-in-general. Bowel dysfunction may contribute to dysbiosis in IBS via reverse causation. However, ME/CFS has symptoms of illness-in-general, but lacks known pathology or definitive treatment that could cause dysbiosis. Therefore, the specific dysbiosis in ME/CFS may be causal. [230 words]

Contribution to the field Many disorders associate with enteric dysbiosis. The pattern of dysbiosis is largely consistent between unrelated disorders, which suggests that it mainly reflects non-specific secondary effects of illness-in-general (e.g. due to changes in activity levels, or diet). However, faecal microbiome transplantation (FMT) can be therapeutic in some disorders. This implies that unique features of dysbiosis may cause those specific disorders. Here, we propose a way to assess causal effects of dysbiosis, by testing if individual genera can discriminate individual disorders from an ‘aggregate non-healthy active control’ (ANHAC) group. Dysbiosis in the ANHAC group can control for non-specific effects of illness-in-general on the microbiome and so highlight potentially-causal forms of dysbiosis in specific disorders. This approach may provide insight into pathogenetic mechanisms of individual disorders and help to design specific forms of FMT to counteract them.

Source: Jonathan Williams, Inga Williams, Karl Morten, Julian Kenyon. An approach to finding specific forms of dysbiosis that associate with different disorders. medRxiv 2024.04.23.24306162; doi: https://doi.org/10.1101/2024.04.23.24306162 https://www.medrxiv.org/content/10.1101/2024.04.23.24306162v1 (Full text available as PDF file)

Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities.

Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

Source: Fereshteh Jahanbani1, Justin C. Sing, Rajan D. Maynard, Shaghayegh Jahanbani, Janet Dafoe, Whitney Dafoe, Nathan Jones, Kelvin J. Wallace, Azuravesta Rastan, Hannes Rost, Holden Maecker, Michael P. Snyder, Ronald W. Davis. Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity. Front. Immunol. Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders. Volume 15 – 2024 | doi: 10.3389/fimmu.2024.1369295 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract

A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts

Abstract:

Lipid droplets (LDs) are dynamic cellular organelles that play an essential role in lipid metabolism and storage. LD dysregulation has been implicated in various diseases. However, investigations into the cellular LD dynamics under disease conditions have been rarely reported, possibly due to the absence of high performing LD imaging agents.

Here a novel fluorogenic probe, AM-QTPA, is reported for specific LD imaging. AM-QTPA demonstrates viscosity sensitivity and aggregation-induced emission enhancement characteristics. It is live cell permeable and can specifically light up LDs in cells, with low background noise and superior signals that can be quantified.

After validation in cell model with LD accumulation induced by oleic acid treatment, AM-QTPA is applied in a small proof-of-concept number of human fibroblast samples derived from people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex and debilitating disease with unknown cause.

The results indicate the presence of larger but fewer LDs in ME/CFS fibroblasts compared to the healthy counterparts, accompanying with frequent LD-mitochondria contacts, suggesting potential upregulation of lipolysis in ME/CFS connective tissue like fibroblasts.

Overall, AM-QTPA provides new understanding of the anomalous LD dynamics in disease status, which, potentially, will facilitate in-depth investigation of the pathogenesis of ME/CFS.

Source: Ding, S., Sanislav, O., Missailidis, D., Allan, C.Y., Owyong, T.C., Wu, M.-Y., Chen, S., Fisher, P.R., Annesley, S.J. and Hong, Y. (2024), A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts. Adv. Sensor Res. 2300178. https://doi.org/10.1002/adsr.202300178 https://onlinelibrary.wiley.com/doi/full/10.1002/adsr.202300178 (Full text)

Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link

Abstract:

Chronic Fatigue Syndrome (CFS) can be triggered by different factors and create a complex health situation. In the last decades incidence has been increasing. This situation is a clear example of how humans, viruses, and the environment are all connected.
In the 90s cases related to CFS, complaints about a feeling of chronic fatigue, inability for everyday tasks, dull pain, cephalalgia, de-pression, anxiety, poor concentration. Clinical tests for EBV, HHV, CMV, IgG, IgM, T4 and T8 subsets were tested, along with hormones and hemogram tests. Most of the cases were women. The timeline of the medical history showed also myomas, breast lumps, premenstrual syndrome previously to CFS development. The nature of these conditions promoted the idea of a possible common link among them and CFS. Some cases also suffered from allergies, food intolerances, candidiasis, intestinal impairment, thyroid implications, endometriosis.
As an initial working hypothesis, The Liver Link (TLL) was proposed in order to understand those different conditions affecting body, mind and emotional wellbeing. Considering liver implication can make a difference in treatment and recovery. Low grade inflammatory conditions are related to Th2 predominance and liver functions. Functional disharmonies are very important because they usually still do not appear in any conventional tests.
In 2002, TLL was presented as a framework to explain the concomitance of CFS and other conditions and the relationship with some viruses such as EBV, HHV, CMV, as a lecture in a congress at the University of Westminster (London). When SARS-CoV-2 outbroke, TLL helped to warn about the post-covid syndrome more likely to occur in specific individuals.
Source: Lorite-Ayán, N. Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link. Preprints 2024, 2024011654. https://doi.org/10.20944/preprints202401.1654.v1 https://www.preprints.org/manuscript/202401.1654/v1 (Full text available as PDF file)

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

Abstract:

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.

Source: Lee JS, Kang JY, Park SY, Hwang SJ, Bae SJ, Son CG. Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology. J Transl Med. 2024 Jan 8;22(1):34. doi: 10.1186/s12967-023-04808-x. PMID: 38191373. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04808-x (Full text)