Category: Overlapping Illnesses

Severe COVID-19 induces prolonged elevation of the acute-phase protein pentraxin 3

Abstract:

Introduction: During the acute-phase of COVID-19, elevated levels of several acute-phase proteins, such as C-reactive protein (CRP), mannose-binding lectin (MBL), pentraxin 3 (PTX-3), serum amyloid A (SAA) and surfactant protein D (SP-D), are associated with severe to fatal clinical outcomes. Typically, these markers return to baseline within days after resolution of the acute infection.

Methods: In this study, we assessed the plasma levels of these proteins in a well-defined cohort of 141 COVID-19 convalescent patients 10 weeks after infection and compared them to 98 non-infected controls. In addition, we performed genetic analyses in a subgroup of patients and related the findings with structural equation modelling to disease severity.

Results: In contrast to other acute-phase proteins, PTX-3 levels were significantly higher in severe COVID-19 convalescent patients than in the control group. Furthermore, a higher proportion of patients with severe COVID-19 exhibited PTX-3 levels above 5000 pg/ml even 10 months post-infection, compared to those with mild disease. To explore potential genetic influences, a genetic analysis was performed on all severely affected patients (n=36) and on an age- and sex-matched subset of mild COVID-19 patients (n=38). Results revealed a significantly higher frequency (p<0.0001) of the homozygous wildtype genotype of the PTX-3 SNP rs971145291 in severe (15 out of 36) versus mild (1 out of 38) COVID-19 patients. Using structural equation modelling, the association of this PTX-3 genotype and disease severity was shown to be mediated by elevated PTX-3 levels, with no contribution from other analyzed (clinical) confounders.

Discussion: In summary, severe COVID-19 patients show high PTX-3 serum levels which may be influenced by genetic predisposition, specifically the absence of the rs971145291 SNP variant. PTX-3 may thus serve both as a biomarker for tissue damage and/or long-term immune activation and eventually post-COVID-19 complications.

Source: Kratzer B, Stieger RB, Durmus S, Trapin D, Gattinger P, Ettel P, Sehgal ANA, Borochova K, Dorofeeva Y, Tulaeva I, Grabmeier-Pfistershammer K, Tauber PA, Gerdov M, Perkmann T, Fae I, Wenda S, Kundi M, Wrighton S, Fischer GF, Valenta R, Pickl WF. Severe COVID-19 induces prolonged elevation of the acute-phase protein pentraxin 3. Front Immunol. 2025 Oct 1;16:1672485. doi: 10.3389/fimmu.2025.1672485. PMID: 41103408; PMCID: PMC12520919. https://pmc.ncbi.nlm.nih.gov/articles/PMC12520919/ (Full text)

Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Abstract:

Purpose: In individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC), physical activity can exacerbate symptoms for days-to-weeks, referred to as post-exertional symptom exacerbation (PESE). This study characterized the trajectory of PESE symptoms before and for 7 days after a sub-maximal exercise task in individuals with ME/CFS or PASC.

Methods: Individuals with ME/CFS (n=30) or PASC (n=30) and matched controls (n=30) were recruited from a university hospital and the community setting. Participants completed a 25-minute moderate intensity exercise on a whole-body cycle ergometer. The trajectory of 8 commonly reported PESE symptoms (physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep dysfunction, anxiety) before and for 7 days after exercise.

Results: There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually. An aggregate score of 4-5 symptoms that includes physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, was more comprehensive in capturing maximal changes in PESE. Changes were greatest during the 72h post-exercise and for those with ME/CFS. The aggregate score shows 8/30 of individuals with ME/CFS and 12/30 with PASC show minimal-to-no increase in PESE, while 6-7/30 show increases greater than 3/10 points.

Conclusions: PESE to a clinically relevant exercise task is variable in individuals with ME/CFS and PASC as submaximal exercise does not exacerbate symptoms for some, while modifications of intensity may be necessary to minimize PESE in others.

Source: Berardi G, Janowski A, McNally S, Post A, Garg A, Sluka KA. Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19. Med Sci Sports Exerc. 2025 Nov 4. doi: 10.1249/MSS.0000000000003891. Epub ahead of print. PMID: 41185151. https://pubmed.ncbi.nlm.nih.gov/41185151/

The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity

Abstract:

Environmental sensitivity illnesses-including fibromyalgia syndrome (FMS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and multiple chemical sensitivity (MCS)-are chronic, disabling disorders characterized by hypersensitivity to environmental stimuli, persistent fatigue, widespread pain, and neurocognitive and autonomic dysfunction. Although their diagnostic criteria differ, increasing evidence suggests overlapping clinical features and shared biological mechanisms. A unifying hypothesis highlights the gut-brain-immune axis, where alterations in the intestinal microbiome, epithelial barrier dysfunction, and aberrant immune signaling interact with central sensitization and systemic metabolic dysregulation.

Recent studies demonstrate reduced microbial diversity, depletion of anti-inflammatory taxa (e.g., Faecalibacterium prausnitzii, Bifidobacterium), and enrichment of pro-inflammatory Clostridium species across these conditions. These shifts likely alter production of short-chain fatty acids, amino acid metabolites, and complex lipids, with downstream effects on mitochondrial function, neuroinflammation, and host energy metabolism. Moreover, emerging clinical interventions-including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation-suggest a potential role for microbiome-targeted therapies, though controlled evidence remains limited.

This review synthesizes current knowledge on microbiome alterations in FMS, ME/CFS, and MCS, emphasizing their convergence on metabolic and immune pathways. By integrating microbial, immunological, and neurophysiological perspectives, we propose a microbiome-centered framework for understanding environmental sensitivity illnesses and highlight avenues for translational research and therapeutic innovation.

Source: Watai K, Taniguchi M, Azuma K. The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity. Int J Mol Sci. 2025 Oct 14;26(20):9997. doi: 10.3390/ijms26209997. PMID: 41155291. https://www.mdpi.com/1422-0067/26/20/9997 (Full text)

Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the prolonged sequelae after COVID-19 (>3 months; Long COVID) have similar symptomology, are both associated with autonomic dysfunction, and a growing proportion of Long COVID patients are developing ME/CFS. We aimed to determine an autonomic phenotype of patients with ME/CFS vs Long COVID. We hypothesized that the groups would differ from controls yet be similar to one another.

We recruited sedentary controls (n = 10), mild/moderate ME/CFS patients (n = 12), and Long COVID patients (n = 9) to undergo 1) breathing 5 % CO2, 2) breathing 10 % O2, and 3) 5-minutes of 70° head-up tilt. Respiratory, hemodynamic, and cerebrovascular variables were measured throughout the 3 trials. Resting vascular function and cognitive-motor-integration were also assessed. ME/CFS and Long COVID were similar to the healthy controls and each other with regard to resting vascular function and the hemodynamic responses to hypoxia, hypercapnia, and head-up tilt (p > 0.05). However, in ME/CFS we observed a greater reduction of cerebrovascular resistance (p = 0.041) and impaired autoregulation (p = 0.042) during hypercapnia alongside impaired cognitive-motor integration (p < 0.02), and in Long COVID we observed reduced peripheral and end-tidal oxygen (p < 0.04) and less vagal withdrawal during tilt (p = 0.028).

Our findings suggest unique phenotypes when comparing ME/CFS and Long COVID whereby we have shown that Long COVID patients experience hypoxia while upright contributing to less vagal withdrawal, and ME/CFS patients experience impaired cerebrovascular control during potentially leading to reduced cognitive-motor integration. These differences could stem from disease severity/duration or some unique aspect of the COVID-19 virus.

Source: Badhwar S, Pereira TJ, Kerr K, Bray R, Tabassum F, Sergio L, Edgell H. Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. Auton Neurosci. 2025 Oct 14;262:103358. doi: 10.1016/j.autneu.2025.103358. Epub ahead of print. PMID: 41138391. https://www.autonomicneuroscience.com/article/S1566-0702(25)00120-1/fulltext (Full text)

HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions

Abstract:

Viral infections have been widely implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) pathogenesis. Recent evidence has also identified certain Human Leukocyte Antigen (HLA) alleles that are significantly associated with ME/CFS risk/protection. Here we tested the hypothesis that ME/CFS risk or protection conferred from those HLA alleles is associated with binding affinity to antigens of HHV viruses, a critical step in initiating the adaptive immune system response to foreign antigens.

Specifically, we determined in silico the predicted binding affinity of two susceptibility alleles (C*07:04, DQB1*03:03) and two protective alleles (B*08:01, DPB1*02:01) to > 10,000 antigens of the 9 Human Herpes Viruses (HHV1, HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8) which have been implicated in the etiology of ME/CFS. We found that the binding affinity of all HHV antigens to the susceptibility alleles was significantly weaker than the binding affinity to the protective alleles (P < 0.001). In fact, none of the HHV antigens showed strong binding to the susceptibility alleles, in contrast to the strong bindings showed by the protective alleles. These findings are in keeping with the hypothesis that the effect of a putative HHV insult in contributing to ME/CFS is modulated by the host’s HLA immunogenetic makeup.

We speculate that strong HLA-antigen binding likely protects against ME/CFS via elimination of virus antigens; conversely, weak HLA-antigen binding may permit persistence of foreign antigens, contributing to ME/CFS and other chronic conditions. Finally, with respect to the latter, we determined the binding affinities to the 4 HLA alleles above to pathogens causing two chronic diseases with very similar symptomatology to ME/CFS, namely Long COVID and post-treatment Lyme disease syndrome (PTLDS).

We found that the 2 ME/CFS susceptibility HLA alleles above had very weak binding with SARS-CoV-2 virus glycoprotein (involved in Long COVID) and 5 proteins of Borrelia burgdorferi (involved in PTLDS), in contrast to the ME/CFS protective alleles that showed strong bindings. These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.

Source: Georgopoulos AP, James LM, Peterson PK. HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions. Sci Rep. 2025 Oct 24;15(1):37303. doi: 10.1038/s41598-025-21230-z. PMID: 41136524. https://www.nature.com/articles/s41598-025-21230-z (Full text)

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome

Abstract:

Background: Hypermobility Spectrum Disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are multisystemic connective tissue disorders involving joint hypermobility and numerous other manifestations. Autonomic dysfunction, chronic pain, and chronic fatigue are known comorbidities of HSD and h-EDS that can affect patient quality of life (QoL), but there are limited data on the severity of autonomic symptoms, prevalence of comorbid conditions and QoL in patients with HSD/h-EDS.

Methods: We utilized the Composite Autonomic Symptom Scale (COMPASS-31) to assess autonomic symptom severity, Short-Form 36 (SF-36) to assess QoL, and the Beck Depression Inventory Second Edition (BDI-II) in a cohort of women with physician-diagnosed HSD or h-EDS, who completed these questionnaires anonymously.

Results: 84 women (mean age of 37.1 ± 8.4 years) completed the study. 58.3 % reported having physician-diagnosed postural orthostatic tachycardia syndrome (POTS), 32.1 % had mast cell activation syndrome (MCAS), 54.8 % had migraine, 26.2 % had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 98.8 % reported experiencing chronic pain. Importantly, 25 % of patients reported having all three diagnoses: HSD/h-EDS, POTS and MCAS. Mean COMPASS-31 score was 54.45 (range 18.79-80.93), indicating severe autonomic dysfunction, which was significantly higher than in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis as shown in prior studies. Mean SF-36 score was 32.38 (SD = 22.91) indicating poor QoL, which was worse than in patients with POTS, multiple sclerosis, rheumatoid arthritis, and lupus as determined by prior studies.

Conclusions: This study demonstrates that women with HSD/h-EDS experience severe autonomic dysfunction, chronic pain, chronic comorbid conditions and reduced QoL. More than half of participants in this cohort had POTS and migraine, with one in four having a clinical triad of HSD/h-EDS, POTS and MCAS.

Source: Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome. Auton Neurosci. 2025 Oct 14;262:103356. doi: 10.1016/j.autneu.2025.103356. Epub ahead of print. PMID: 41118678. https://pubmed.ncbi.nlm.nih.gov/41118678/

Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report

Abstract:

Background: The COVID-19 pandemic has led to an increase in post-acute sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), potentially mediated by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are occasionally administered to ameliorate fatigue symptoms in ME/CFS; however, their psychiatric adverse effects, particularly in individuals with preexisting mood disorders, necessitate careful consideration.

Case presentation: We report the case of a 32-year-old woman with bipolar disorder who developed ME/CFS following COVID-19 infection. Initial corticosteroid therapy with betamethasone and prednisolone, agents with potent glucocorticoid receptor (GR) activity, resulted in a manic episode with psychotic features, necessitating psychiatric hospitalization. Although mood stabilization was achieved with olanzapine and valproate, corticosteroid withdrawal subsequently led to metabolic alkalosis and hypoxemia, secondary to hypothalamic hypoadrenalism. Following a comprehensive endocrinological assessment, physiological replacement therapy with hydrocortisone, characterized by relatively higher mineralocorticoid receptor (MR) activity and lower GR potency, was initiated, resulting in the resolution of physical symptoms without destabilization of psychiatric status.

Conclusion: The clinical course suggests that GR-dominant corticosteroids may exacerbate psychiatric instability in patients with mood disorders. Simultaneously, MR-favoring agents, such as hydrocortisone, may offer a safer therapeutic alternative for managing HPA axis dysfunction. This case underscores the critical role of receptor selectivity in corticosteroid therapy, particularly in patients with comorbid psychiatric conditions, and highlights the necessity for individualized treatment strategies that integrate both endocrine and neuropsychiatric considerations.

Source: Nakajima K, Ayani N, Matsuoka T, Kasahara K, Nakajima Y, Ikawa H, Kitaoka R, Akimoto T, Narumoto J. Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report. PCN Rep. 2025 Oct 12;4(4):e70222. doi: 10.1002/pcn5.70222. PMID: 41089430; PMCID: PMC12515714.

Pacing with a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a feasibility study

Abstract:

Background: People living with ME/CFS and LC frequently live with post-exertional malaise (PEM), which is associated with impairments in aerobic metabolism. They often use pacing with a heart rate monitor (HRM) to minimize time spent above the anaerobic threshold; however, there is limited research on the feasibility and efficacy.

Objective: To establish the acceptability, adherence, outcomes, and adverse events associated with pacing with an HRM for a future definitive study.

Methods: After informed consent and baseline measurements (including 10 min stand test, 5 questionnaires, accelerometry, heart rate variability, and lactate), participants were randomized into a control or intervention group using simple randomization and sealed envelopes. The intervention group used a heart rate monitor with weekly online HRM pacing advice (how to use the HRM, problem solving), and the control group received weekly online pacing advice (how to pace, problem solving). Follow-up measures were repeated, and semi-structured interviews were conducted at two and six months post-enrolment.

Results: 47 participants were recruited; however, recruiting people with LC was difficult due to wanting to use/already using HR monitoring. The interviews identified that the procedure was acceptable, and the majority of the participants completed the outcome measures. There were some changes from baseline to follow-up in all the outcome measures except the 10-minute stand test and accelerometry. There were no serious adverse events. Follow-up interviews identified 89% continued using HRM at 8 weeks and 66% after 6 months.

Conclusions: Studies of HRM are feasible and acceptable for ME/CFS and LC, although recruitment strategies should be reviewed for LC.

Clinical Trial registration number: ISRCTN10554129.

Source: Clague-Baker, N., Davenport, T. E., Wickens, B., Leeming, H., Dickinson, K., McBurney, E., … Hilliard, N. (2025). Pacing with a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a feasibility study. Fatigue: Biomedicine, Health &amp; Behavior, 1–23. https://doi.org/10.1080/21641846.2025.2565103 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2565103#abstract (Full text)

Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrom

Abstract:

Introduction: Epstein-Barr virus (EBV) infection is a well-established trigger and risk factor for both myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we identified elevated IgG responses to arginine-rich (poly-R) sequences within the EBV nuclear antigens EBNA4 and EBNA6 in post-infectious ME/CFS (piME/CFS). Building on these findings, this exploratory study examines IgG reactivity to poly-R-containing EBV-derived peptides and homologous human peptides in women with PCS and ME/CFS.

Methods: IgG reactivity to poly-R containing peptides derived from EBNA4 and EBNA6, and homologous human 15-mer peptides and the corresponding full-length proteins, was assessed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Serum samples were analyzed from 45 female PCS patients diagnosed according to WHO criteria, including 26 who also met the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 female patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 female healthy controls (HC).

Results: Autoantibodies targeting poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, and the angiogenesis-related protein TSPYL5, as well as full-length α-adrenergic receptor (ADRA) proteins, were more frequently detected in patient groups. Several of these autoantibodies showed positive correlations with core symptoms, including autonomic dysfunction, fatigue, cognitive impairment, and pain.

Conclusion: This exploratory study identify autoantibodies directed against EBV mimicking arginine-rich sequences in human proteins, suggesting a potential role for molecular mimicry in the pathogenesis of PCS and ME/CFS.

Source: Hoheisel Friederike , Fleischer Kathrin Maria , Rubarth Kerstin , Sepúlveda Nuno , Bauer Sandra , Konietschke Frank , Kedor Peters Claudia , Stein Annika Elisa , Wittke Kirsten , Seifert Martina , Bellmann-Strobl Judith , Mautner Josef , Behrends Uta , Scheibenbogen Carmen , Sotzny Franziska. Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Volume 16 – 2025. DOI=10.3389/fimmu.2025.1650948 ISSN=1664-3224 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1650948/full (Full text)

Impacts of long COVID on disability, function and quality of life for adults living in Australia

Abstract:

Background: To describe the impact of long COVID on disability, function and quality of life among adults living in Australia.

Method: People aged >18years with a history of COVID-19 infection confirmed by polymerase chain reaction or rapid antigen test were eligible for this cross-sectional survey. The World Health Organization Disability Assessment Schedule 2.0 measured disability and function, and the 36-Item Short Form Health Survey assessed quality of life.

Results: Participants (n =121) reported significant functional impairment and reduced quality of life compared with established population norms for these outcome measures. Most (n =104, 86%) reported clinically significant disability and participation limitations in daily activities. Mean World Health Organization Disability Assessment Schedule 2.0 scores indicated higher levels of disability than 98% of the general population. The 36-Item Short Form Health Survey scores indicated lower quality of life across all domains, but particularly in relation to vitality and social functioning. Regression analysis found significant associations between the World Health Organization Disability Assessment Schedule 2.0 and 36-Item Short Form Health Survey scores, and vaccine dose number, comorbidities and self-rated recovery.

Conclusion: Long COVID is associated with significantly reduced function and quality of life, which are distinct outcomes requiring targeted assessment and intervention. The overall impact may be exacerbated in people with pre-existing comorbidities who are more susceptible to long COVID in the first place. The findings underscore the need for targeted rehabilitation and support services for people living in Australia with long COVID, and further longitudinal research to explore the long-term impact on disability and quality of life, and inform policy and healthcare service delivery.

Source: Hitch D, Botha T, Tesfay F, Holton S, Said CM, Hensher M, Richards K, Angeles MR, Bennett CM, Pepin G, Rasmussen B, Nicola-Richmond K. Impacts of long COVID on disability, function and quality of life for adults living in Australia. Aust J Prim Health. 2025 Aug;31:PY25033. doi: 10.1071/PY25033. PMID: 40977216. https://www.publish.csiro.au/py/Fulltext/PY25033 (Full text)