Category: Overlapping Illnesses

Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

Abstract:

Background: Myalgic encephalomyelitis (also known as ME/CFS or simply ME) has severely impacted the lives of tens of millions of people globally, but the disease currently has no accurate diagnostic tools or effective treatments. Identifying the biological causes of ME has proven challenging due to its wide range of symptoms and affected organs, and the lack of reproducible genetic associations across ME populations. This has prolonged misunderstanding, lack of awareness, and denial of the disease, further harming patients.

Methods: We used the PrecisionLife combinatorial analytics platform to identify disease signatures (i.e., combinations of 1-4 SNP-genotypes) that are significantly enriched in two cohorts of ME participants from DecodeME relative to controls from UK Biobank (UKB). We tested whether the number of these signatures possessed by an individual is significantly associated with increased prevalence of ME in a third disjoint cohort of DecodeME participants. We characterized a number of drug repurposing opportunities for a set of candidate core genes whose disease signatures had the strongest association with ME and which were linked to different mechanisms. We then tested gene overlap between the ME signatures identified and previous studies in long COVID, using two independent approaches to explore these shared genetic commonalities.

Results: We identified 22,411 reproducible disease signatures, comprising combinations of 7,555 unique SNPs, that are consistently associated with increased prevalence of ME in three disjoint patient cohorts. The count of reproducible signatures was significantly associated with increased prevalence of ME (p = 4×10-21), and participants with a top 10% signature count had an odds ratio of disease 1.64 times greater than participants with a bottom 10% signature count, confirming that these genetic signatures increase susceptibility for developing ME. These disease signatures map to 2,311 genes. We identified substantial overlap between the genes found by this combinatorial analysis and previous studies. We found that the 259 candidate core genes most strongly associated with ME are enriched in disease mechanisms including neurological dysregulation, inflammation, cellular stress responses and calcium signaling. We demonstrated that 76 out of 180 genes previously linked to long COVID in UKB and the US All of Us cohorts are also significantly associated with ME in the DecodeME cohort. These findings allowed identification of many existing and novel repurposing opportunities, including candidates linked to several genes with shared etiology for long COVID.

Conclusion: These findings provide further evidence that ME is a complex multisystemic condition where the risk of developing the disease has a very clear genetic and biological basis. They give a substantially deeper level of insight into the genetic risk factors and mechanisms involved in ME. The discovery of so many multiply reproducible genetic associations implies that ME is highly polygenic, which has important consequences for its future study and the delivery of clinical care to patients. The striking overlap in genes and mechanisms between long COVID and ME (76 / 180 long COVID genes tested) suggests the potential for development of novel or repurposed drug therapies that could be used to successfully treat either condition. However, although they share significant genetic commonalities, long COVID and ME appear to be best considered as partially overlapping but different diseases.

Source: Lu J, Sun W, Li S, Qu Y, Liu T, Guo S, Feng C, Yang T. Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales. Front Neurol. 2025 Nov 18;16:1618272. doi: 10.3389/fneur.2025.1618272. PMCID: PMC12668935. https://pmc.ncbi.nlm.nih.gov/articles/PMC12668935/ (Full text available as PDF file)

Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Long-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are disabling diseases characterised by ongoing fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome typically follows viral infections, whereas Long-COVID exclusively follows SARS-CoV-2 infection, with overlapping but distinct features. This review uses comprehensive searches of online databases to compare their clinical presentations, pathophysiologies, and treatments.

Both Long-COVID and ME/CFS appear to involve multifactorial mechanisms, including viral persistence, immune dysregulation, endothelial dysfunction, and autoimmunity, though their relative contributions remain uncertain. Symptom management strategies are consistent, however. Cognitive behaviour therapy has been successful, and there are minimal drug treatments. Graded exercise therapy occupies a contested place, recommending individualised pacing and multidisciplinary rehabilitation.

Common and exclusive mechanisms must be identified to formulate valuable therapies. A more significant body of research focusing on immune dysfunction as a pathogenic mechanism for advancing the disease and enabling more effective therapies and diagnostics is needed.

Source: Ivanovska M, Homadi MS, Angelova G, Taskov H, Murdjeva M. Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2025 Nov 17;13(11):2797. doi: 10.3390/biomedicines13112797. PMID: 41301889; PMCID: PMC12650534. https://pmc.ncbi.nlm.nih.gov/articles/PMC12650534/ (Full text)

Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study

Abstract:

Post-COVID-19 syndrome (PCS) affects a significant proportion of individuals, with olfactory impairment and fatigue as prominent long-term symptoms. A subset of PCS patients with pronounced fatigue meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), here referred to as PCS-ME/CFS. This study explores the relationship between PCS, fatigue, and olfactory function, and investigates the potential of olfactory impairment as a diagnostic and prognostic marker.

We assessed olfactory function up to 28 months post-COVID-19 in 45 PCS patients (22 PCS, 23 PCS-ME/CFS) using the extended Sniffin’ Sticks test, which evaluates odor threshold, discrimination, and identification, providing a composite score. Fatigue severity and health-related quality of life were assessed using validated questionnaires, a standardized test measured cognitive function, and handgrip strength indicated physical fatiguability. Both PCS and PCS-ME/CFS patients showed significant improvement in olfactory function, with all patients returning to normosmia after 20 months, regardless of diagnosis.

While odor threshold was the most affected olfactory measure in Sniffin’ Sticks testing, odor identification was the only measure that remained impaired over time. Olfactory impairment correlated with cognitive, physical, and mental performance, with stronger correlations in the PCS group, particularly linking better odor discrimination at baseline to improved daily functioning and health-related quality of life after 20 months.

Our findings suggest that odor identification assessed in standardized testing may remain impaired the longest in patients with persisting symptoms after COVID-19, reflecting persisting central processing difficulties. Correlations between olfactory performance, cognitive function, and physical ability point to shared underlying mechanisms. Early olfactory improvements may be linked to better long-term cognitive outcomes, highlighting a possible prognostic role of olfactory function in these patients.

Source: Meyer-Arndt L, Pierchalla G, Mödl L, Wohlrab F, Legler F, Hoppmann U, Kedor C, Wittke K, Freitag H, Konietschke F, Olze H, Paul F, Scheibenbogen C, Bellmann-Strobl J, Förster-Ruhrmann U. Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study. Brain Behav Immun Health. 2025 Oct 14;50:101124. doi: 10.1016/j.bbih.2025.101124. PMID: 41281896; PMCID: PMC12634829. https://pmc.ncbi.nlm.nih.gov/articles/PMC12634829/ (Full text)

Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study

Abstract:

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2-infection (PASC) is challenging to diagnose and treat, and its molecular pathophysiology remains unclear. Urinary peptidomics can provide valuable information on urine peptides that may enable improved and specified PASC diagnosis.
Using standardized capillary electrophoresis-MS, we examined the urinary peptidomes of 50 patients with PASC 10 months after COVID-19 and 50 controls, including healthy individuals (n = 42) and patients with non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 8).Based on peptide abundance differences between cases and controls, we developed a diagnostic model using a support vector machine. The abundance of 195 urine peptides among PASC patients significantly differed from that in controls, with a predominant abundance of collagen alpha chains. This molecular signature (PASC195) effectively distinguished PASC cases from controls in the training set (AUC of 0.949 [95% CI 0.900–0.998; p < 0.0001]) and independent validation set (AUC of 0.962 [95% CI 0.897–1.00]; p < 0.0001]). In silico assessment suggested exercise, GLP-1RAs and mineralocorticoid receptor antagonists (MRAs) as potentially efficacious interventions. We present a novel and non-invasive diagnostic model for PASC. Reflecting its molecular pathophysiology, PASC195 has the potential to advance diagnostics and inform therapeutic interventions.

Statement of Significance of the Study

Despite the recent emergence of omics-derived candidates for post-acute sequelae of SARS-CoV-2 infection (PASC), the pending validation of proposed markers and lack of consensus result in the continuous reliance on symptom-based criteria, being subject to diagnostic uncertainties and potential recall bias. Building upon prior findings of renal involvement in acute COVID-19 pathophysiology and PASC-associated alterations, we hypothesized that the use of urinary peptides for PASC-specific biomarker discovery, unlike conventional specimens that have been utilized thus far, may offer complementary information on putative disease mechanisms.

In the present study, 195 significantly expressed peptides were used to form a classifier termed PASC195, which effectively discriminated PASC from non-PASC (p < 0.0001), including healthy individuals and non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome, in both the derivation (n = 60) and an independent validation set (n = 40). The peptidome profile associated with PASC was consistent with a shift in collagen turnover, with most PASC195 peptides derived from alpha chains. Ongoing inflammatory responses, hemostatic imbalances, and endothelial damage were indicated by cross-sectional variations in endogenous peptide excretion.

Source: Gülmez D, Siwy J, Kurz K, Wendt R, Banasik M, Peters B, Dudoignon E, Depret F, Salgueira M, Nowacki E, Kurnikowski A, Mussnig S, Krenn S, Gonos S, Löffler-Ragg J, Weiss G, Mischak H, Hecking M, Schernhammer E, Beige J; UriCoV Working Group. Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study. Proteomics. 2025 Nov 21:e70074. doi: 10.1002/pmic.70074. Epub ahead of print. PMID: 41273049. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pmic.70074 (Full text)

Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS)

Abstract:

Postural orthostatic tachycardia syndrome (POTS) is a condition defined by symptoms of orthostatic intolerance and a sustained heart rate (HR) increment of ≥ 30 beats per minute (bpm) upon postural change to the upright position in the absence of orthostatic hypotension, defined as a sustained decrease in systolic blood pressure (SBP) of ≥ 20 mmHg or a decrease in diastolic blood pressure (DBP) of ≥ 10 mmHg within 3 min of standing. In children, a sustained HR increment of at least 40 bpm is required for diagnosis of POTS. POTS is a common condition in adults and children suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In daily clinical practice, therapeutic recommendations are rare and evidence is missing.

The objective of this review is to present the current knowledge on non-pharmacological and pharmacological approaches in POTS with a special focus on POTS therapy in children and people with ME/CFS. Of 3853 studies, 45 studies were included in the systematic review.

on therapy in POTS is rare and large randomized controlled trials (RCT) on single interventions are needed. Non-pharmacological approaches such as the use of compression garments, physical training, salt supplementation and transdermal vagal nerve stimulation could be possible treatment options in POTS because they are easy to implement as first-line therapeutic measures in clinical practice. For pharmaceuticals, several studies showed significant effects following therapy with ivabradine and β-adrenergic blocking agents. There are single studies which imply that midodrine (hydrochloride) and pyridostigmine seem to have a beneficial effect on hemodynamics in POTS.

Source: Schiweck N, Langer K, Maier A, Vilser D, Spiegler J. Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS). Clin Auton Res. 2025 Nov 12. doi: 10.1007/s10286-025-01172-2. Epub ahead of print. PMID: 41225175. https://link.springer.com/article/10.1007/s10286-025-01172-2 (Full text)

Healthcare Situation of 3,345 Long COVID Patients in Germany: Results of a Nationwide Survey

Abstract:

Long COVID includes persistent symptoms after SARS CoV 2 infection and leads to multiple physical and psychosocial burdens.Between March and April 2025, a nationwide sample of long COVID patients was recruited by means of an anonymous online survey. Demographic parameters, symptoms, use of outpatient/inpatient care services and subjective satisfaction with care were recorded.

In total, 3345 people (average age 49 ± 13 years; 81.5% women) completed the survey. 83.8% reported a medically confirmed long COVID diagnosis, with a further 12.2% reporting a post-vac syndrome. The average duration of symptoms was 2.8 ± 1.1 years, with only 36.4% reporting an improvement in their symptoms over time. Almost nine out of ten patients (89.1%) were on long-term sick leave (average 1.8 ± 1.3 years), 70.8% reported total or partial incapacity for work and 46.4% applied for a pension. General practitioner care was the first point of contact for 75.7%. Over the course of the illness, 93% consulted more than three and 21.5% more than ten different doctors. Personal financial contributions were high: 41.4% invested more than € 1,000 and 11.3% more than € 10,000 in diagnostics or therapy. 60% received a rehabilitation intervention. Overall, 97.2% rated their care as “poor” or “very poor”.

This survey highlights a high and persistent burden among long COVID patients, as well as significant socioeconomic consequences, accompanied by a predominantly negative evaluation of the current care situation. Improvements require structured, easily accessible, and cross-sectoral services. Improving the primary care system, establishing clear referral pathways, and (where clinically indicated) integrating rehabilitative interventions into an interdisciplinary care concept could help to improve the care situation of patients with long COVID.

Source: Gloeckl R, Rischer R, Schneeberger T, Jarosch I, Blome C, Koczulla R. Versorgungssituation von 3345 Long-COVID-Betroffenen in Deutschland: Ergebnisse einer bundesweiten Befragung [Healthcare Situation of 3,345 Long COVID Patients in Germany: Results of a Nationwide Survey]. Pneumologie. 2025 Nov 11. German. doi: 10.1055/a-2725-5650. Epub ahead of print. PMID: 41218624. https://pubmed.ncbi.nlm.nih.gov/41218624/  https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2725-5650 (Full text available in German]

A Comparative Study of the Coagulation Systems and Inflammatory Profiles of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Patients with Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is a chronic condition that severely debilitates patients, yet it remains largely unfamiliar to many. Faced with scepticism as a real clinical entity for decades, the recognition of ME/CFS has improved with the emergence of Long COVID. This chronic illness manifests after an acute COVID-19 infection. With two-thirds of ME/CFS cases reported to be post-viral, a clear overlap emerges with Long COVID, as both conditions arise following an infectious illness.
The parallels between post-infectious ME/CFS and Long COVID are striking, with similarities in both symptomology and pathophysiology. One overlapping mechanism in both conditions, systemic inflammation, may be perpetuated by pathogen persistence or reactivation. While inflammation alone may not be accountable for the symptoms experienced in both conditions, it can lead to disruption in other physiological mechanisms. Owing to a bi-directional link with inflammation, coagulopathy and vascular changes may be exhibited in ME/CFS and Long COVID. Given the accessibility of blood samples, it is imperative to explore these mechanisms to uncover potential biomarkers for these conditions, both of which currently lack standardised diagnostic biomarkers.
A total of 83 participants were included in the study. The control group consisted of 19 healthy controls and 10 inflammatory controls (individuals with known inflammatory conditions), used to assess inflammation in a step-increase manner. The post-infectious group included 54 individuals, subdivided into 20 ME/CFS patients and 34 Long COVID patients. Statistical analyses were performed using GraphPad Prism 10 and R-Studio, with comparisons made using parametric or non-parametric tests, depending on data distribution. Significant results were considered at P<0.05. Multiple regression analyses were conducted to control for the effects of age and sex on the outcomes.
The techniques utilised in this dissertation focused on Virchow’s triad, a model explaining that hypercoagulability, stasis, and endothelial damage contribute to the aetiology and risk of thrombosis, particularly deep vein thrombosis. Framing the dissertation around this model offered a valuable framework to investigate potential pathological mechanisms and identify relevant biomarkers for these conditions. Common viscoelastic point-of-care devices, including TEG and ClotPro, were employed to examine the hypercoagulability component of Virchow’s triad.
These techniques demonstrated how standard laboratory tests are inefficient in revealing pathological alterations in Long COVID and ME/CFS, and how the insignificance of these results has prompted researchers and healthcare professionals to question the validity of these conditions. Despite this, newly developed fluorescent microscopy techniques revealed an increased presence of plasma structures resistant to fibrinolysis in the post-infectious groups, providing evidence of coagulopathy. This technique effectively distinguished the two conditions, with the Long COVID group showing a 2.75-fold increase in these plasma structures compared to the ME/CFS group. Additionally, the post-infectious groups displayed a marked presence of hyperactivated platelets and megakaryocytes in circulation, with platelet activation and aggregation being 1.35-fold higher in the Long COVID group compared to the ME/CFS group.
However, such microscopy techniques are low-throughput and labour-intensive, making them less practical for diagnostic purposes. An innovative high-throughput diagnostic technique known as real-time deformability cytometry was employed to investigate the second component of Virchow’s triad: alterations in blood rheology.
When isolating anomalous events and large clots in whole blood using the combined filter technique, the Long COVID group showed a 1.30-fold decrease in deformation compared to the ME/CFS group, indicating greater rigidity of these structures. Additionally, the ME/CFS group had a 1.31-fold decrease in the volume of these clots compared to the Long COVID group. Although significant differences were observed in both conditions and likely impact blood rheology, this technique requires further standardisation due to its novelty.
Lastly, endothelial biomarkers previously studied in other inflammatory diseases were investigated to better understand the extent of endothelial damage, the final aspect of Virchow’s triad. The flow luminescence immunoassay revealed a 1.29-fold reduction in cadherin-5 levels in the ME/CFS group compared to healthy controls. No significant differences were found in other endothelial biomarkers between the post-infectious groups, suggesting these biomarkers cannot be repurposed for these conditions.
Furthermore, the lack of replicability in endothelial analyte concentrations among different studies raises concerns about the reproducibility of this technique. When the findings of this dissertation are considered collectively through biomarker stratification, it becomes clear that distinct subgroups may exist within the studied populations. This highlights the importance of a multiparameter approach for diagnosis, although these novel investigations require further validation and should be replicated with larger sample sizes.
Through an examination of these mechanisms, this dissertation illustrated some commonalities between these diseases and demonstrated how Virchow’s triad may be implicated to some extent in both conditions. However, key differences were also identified between the conditions, highlighting the unique challenges each presents. As we investigate whether Long COVID signals the early onset of ME/CFS and consider whether insights gained from decades of combating ME/CFS can enlighten our understanding of Long COVID, we progress toward a deeper understanding of post-infectious conditions and the creative solutions required to address them.
Source: Arron, H. E. 2025. A Comparative Study of the Coagulation Systems and Inflammatory Profiles of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Patients with Long COVID. Unpublished doctoral thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/1a98fb4e-a91f-497b-892e-716a25ee5358

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (Full text)

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/