Tag: 2025

Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Debilitating symptoms for many years can follow acute COVID-19 (“long COVID”), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms.

In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural circuits constitute a symptom-generating pathway, activated by neuroinflammation, which may be targeted by therapeutics to quell neuroinflammation.

Many factors cause the symptoms to become chronic, including persistent infectious agents (and/or their nucleic acids and antigens) and the fact that many of the underlying biological abnormalities reinforce each other, creating ongoing physiological vicious cycles.

Source:Komaroff AL, Dantzer R. Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Cell Rep Med. 2025 Jul 25:102259. doi: 10.1016/j.xcrm.2025.102259. Epub ahead of print. PMID: 40744021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00332-5 (Full text)

Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Post-COVID-19 condition, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), are characterized by fatigue, pain, shortness of breath, sleep disturbances, cognitive dysfunction and other symptoms, heavily impacting on patients daily functioning. Moreover, over half of patients end up fulfilling ME/CFS and/or FM clinical criteria after a few months of SARS-CoV-2 infection.

Expression of the toxic human endogenous retrovirus (HERV)-W ENV protein can be induced by viral infection and HERV-W detection was correlated with acute COVID-19 severity and found significantly expressed in post-COVID-19 condition. This study shows that HERV-W ENV may also be present in prepandemic cases of ME/CFS, FM or co-diagnosed with both clinical criteria, suggesting viral participation in these chronic diseases.

To learn whether associated antiviral mechanisms may also show differing patterns of immunological responses, we measured IgM, IgG, IgA and IgE antibody isotypes against SARS-CoV-2 spike and nucleocapsid antigens, the levels of IL-6, IL-8, IL-10, IFNγ and TNFα cytokines, the level of NfL, a neural damage biomarker, as well as some blood cell markers potentially related with fatigue.

Importantly, some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms. Interestingly, the detected markers showed moderate-to-strong correlations with patient symptoms pointing at novel therapeutic opportunities.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Lemarinier M, Fried S, Lucas A, Perron H, Oltra E. Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. Brain Behav Immun Health. 2025 Jul 4;48:101058. doi: 10.1016/j.bbih.2025.101058. PMID: 40726775; PMCID: PMC12302357. https://pmc.ncbi.nlm.nih.gov/articles/PMC12302357/ (Full text)

Comparing DNA Methylation Landscapes in Peripheral Blood from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Patients

Abstract:

Post-viral conditions, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC), share > 95% of their symptoms, but the connection between disturbances in their underlying molecular biology is unclear. This study investigates DNA methylation patterns in peripheral blood mononuclear cells (PBMC) from patients with ME/CFS, LC, and healthy controls (HC).

Reduced Representation Bisulphite Sequencing (RRBS) was applied to the DNA of age- and sex-matched cohorts: ME/CFS (n = 5), LC (n = 5), and HC (n = 5). The global DNA methylomes of the three cohorts were similar and spread equally across all chromosomes, except the sex chromosomes, but there were distinct minor changes in the exons of the disease cohorts towards more hypermethylation.

A principal component analysis (PCA) analysing significant methylation changes (p < 0.05) separated the ME/CFS, LC, and HC cohorts into three distinct clusters. Analysis with a limit of >10% methylation difference and at p < 0.05 identified 214 Differentially Methylated Fragments (DMF) in ME/CFS, and 429 in LC compared to HC. Of these, 118 DMFs were common to both cohorts. Those in promoters and exons were mainly hypermethylated, with a minority hypomethylated. There were rarer examples with either no change in methylation in ME/CFS but a change in LC, or a methylation change in ME/CFS but in the opposite direction in LC. The differential methylation in a number of fragments was significantly greater in the LC cohort than in the ME/CFS cohort.

Our data reveal a generally shared epigenetic makeup between ME/CFS and LC but with specific, distinct changes. Differences between the two cohorts likely reflect the stage of the disease from onset (LC 1 year vs. ME/CFS 12 years), but specific changes imposed by the SARS-CoV-2 virus in the case of the LC patients cannot be discounted. These findings provide a foundation for further studies with larger cohorts at the same disease stage and for functional analyses to establish clinical relevance.

Source: Peppercorn K, Sharma S, Edgar CD, Stockwell PA, Rodger EJ, Chatterjee A, Tate WP. Comparing DNA Methylation Landscapes in Peripheral Blood from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Patients. Int J Mol Sci. 2025 Jul 10;26(14):6631. doi: 10.3390/ijms26146631. PMID: 40724879. https://www.mdpi.com/1422-0067/26/14/6631 (Full text)

Growing recognition of post-acute infection syndromes

Commentary:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID affect large numbers of people, and constitute a substantial burden to the U.S. and global economies. The article by Eckey et al., in this issue of PNAS (1), adds to the growing evidence that the two illnesses have much in common. Moreover, the illnesses may represent just two examples of an even larger, recently recognized class of illness: post-acute infection syndromes (PAIS) (2).
ME/CFS
This illness first attracted attention in the 1980s. Typically, people suffering from ME/CFS previously have been healthy, and then develop a flu-like illness. While that illness appears initially not unlike previous transient illnesses, and while the respiratory symptoms and fever usually improve, people are left with a severe, persisting fatigue, cognitive problems, worsened symptoms following physical or mental exertion or upright posture, as well as unrefreshing sleep, an illness that can last for years (3, 4). The symptoms are not relieved by rest, and greatly impair a person’s ability to function at work and at home. Some individuals are homebound, some largely bedbound. People with ME/CFS often say, in so many words, “I am no longer the person I was.”
In the 1980s, some scientists suspected that a novel human pathogen was causing the illness. Such speculation seemed reasonable, since a novel virus recently had been discovered to cause the AIDS. However, no single, novel pathogen has emerged as the cause of ME/CFS.
Moreover, the standard laboratory tests that were performed in the 1980s generally came back “normal,” leading some to believe there were no underlying biological abnormalities to explain the symptoms. However, over the past 40 y, thousands of studies have identified many underlying abnormalities involving the brain, immune system, energy metabolism, redox imbalance, vascular injury, and gut microbiota (4–9). The symptoms of the illness are, indeed, accompanied by objective abnormalities.
Despite the fact that—in the United States, alone—the illness is estimated to affect up to 3.1 million people, and to generate direct and indirect expenses of approximately $36 to 51 billion annually (3, 10), relatively few investigators have sought to study the illness: the initial skepticism about whether the illness had a biological basis may have created a lingering stigma. That skepticism faded, to some degree, following publication in 2015 of a report from the U.S. National Academies of Science, Engineering and Medicine highlighting the importance of the problem (3).
Long COVID
Then, along came the COVID-19 pandemic. It was predicted that the pandemic would greatly increase the number of people with an ME/CFS-like illness (11), and that has proved to be the case. Many who have “recovered” from acute COVID-19, even from mild cases, have developed a persisting illness (called “long COVID”) with symptoms much like ME/CFS. The cumulative global incidence of long COVID may be as high as 400 million individuals (5, 8), and the costs to the U.S. and global economy (not including the direct costs of healthcare) may be several trillion dollars in the next 5 to 10 y (8, 12).
Comparing ME/CFS and Long COVID
The similarity of the symptoms seen in ME/CFS and long COVID is underscored by the report from Eckey et al. (1). The study involved a survey of nearly 4,000 people with these illnesses. Participants recorded the prevalence and severity of a large number of symptoms, comorbid illnesses, and responses to different treatments.
The authors recognize that such a survey has important limitations. The diagnoses of ME/CFS, long COVID, and comorbid illnesses were self-reported, and not determined by protocol-directed objective testing—although such testing often had been performed by their doctors. Likewise, the responses to different treatments were self-reported, not the results of randomized, placebo-controlled trials. Nevertheless, the large number of study subjects, and the consistency of their responses, suggests that their responses are valid.
Symptoms.
As seen in figure 1 of the report by Eckey et al. (1), the frequency of each of the symptoms is very similar in both illnesses. At the same time, there may be subgroups of people with both ME/CFS and long COVID in whom different symptoms are predominant: it is possible that these subgroups have different underlying pathophysiology, responses to treatments, and prognosis.
Underlying Pathophysiology.
Of course, the fact that the symptoms and symptom frequency are similar does not necessarily mean the two illnesses share an underlying pathophysiology. Nevertheless, it appears that they do. A detailed analysis of the underlying biological abnormalities seen in both illnesses reveals a striking similarity (6).
Comorbid Diseases.
The survey conducted by Eckey et al., addressed two other dimensions by which to compare the two illnesses. First, the survey found that people with the two illnesses frequently had the same comorbid conditions, particularly postural orthostatic tachycardia syndrome (POTS), migraine, dysautonomia, anxiety and depression, mast cell activation syndrome (MCAS), Ehlers–Danlos syndrome (EDS)/joint hypermobility, and attention deficit disorder (ADD) (1).

Response to Therapies.

Patients with the two illnesses also responded similarly to specific treatments. Remarkably, even at the level of specific symptoms, responses were similar in people with the two illnesses, and the drugs most effective against particular symptoms would be expected to improve those symptoms, adding credibility to the self-reported improvement (1). Thus, the study is consistent with others in finding similar symptoms in people with the two illnesses and, additionally, finds similar comorbidities and responses to treatment.

PAIS

ME/CFS and long COVID are not the only two illnesses that share very similar symptoms. Over the past century, there have been many reports of an illness with very similar symptoms following multiple different acute bacterial, viral, fungal, and protozoal infections; hence, the proposal to call all of these illnesses PAIS (2). Long COVID surely is a PAIS (since the inciting infectious agent is known), and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) likely often is (even though the inciting agents often have not been pursued by physicians).

IACIs
PAIS, in turn, are one example of an even larger umbrella category, a group of disorders called IACIs (9, 13). As shown in Fig. 1, we distinguish three categories of IACIs: new organ injury from an infectious agent, such as the development of multiple sclerosis following primary infection with Epstein–Barr virus or duodenal ulcers caused by Helicobacter pylori; accelerated incidence of disease processes that had not yet become apparent before the time of an acute infection (including accelerated atherosclerosis and neurodegeneration post-COVID) (8, 14); and PAIS. Some observers use the term long COVID to include all three categories of illness following acute infection with SARS-CoV-2. We restrict the use of the term long COVID to just the PAIS that can follow SARS-CoV-2 infection.
Read the rest of this article here: https://www.pnas.org/doi/10.1073/pnas.2513877122
Source: A.L. Komaroff, Growing recognition of post-acute infection syndromes, Proc. Natl. Acad. Sci. U.S.A. 122 (29) e2513877122, https://doi.org/10.1073/pnas.2513877122 (2025). https://www.pnas.org/doi/10.1073/pnas.2513877122 (Full text)

Fibromyalgia syndrome—am I an autoimmune condition?

Abstract:

Assessments of serum-autoantibodies in fibromyalgia syndrome (FMS) date back to the 1980s and have yielded inconsistent results. Based on a new passive transfer paradigm, since 2021 causative involvement of immunoglobulin G–mediated autoimmunity in severe FMS has been demonstrated in several studies, which have included UK, Swedish, and Canadian patients. These findings open the path to the development of novel diagnostic and immune-therapeutic approaches.

Autoantibody targets and downstream mechanisms and the molecular processes that translate infection-, toxicity-, or stress-triggers into the FMS immune response in genetically or otherwise vulnerable individuals require study. These results in FMS also suggest that other chronic pain conditions or nonpainful symptom-based disorders may similarly be caused by noninflammatory minimally destructive autoantibody-mediated autoimmunity, thus offering hope for large groups of patients.

Source: Goebel A. Fibromyalgia syndrome-am I an autoimmune condition? Pain Rep. 2025 Jul 2;10(4):e1270. doi: 10.1097/PR9.0000000000001270. PMID: 40612406; PMCID: PMC12226001. https://pmc.ncbi.nlm.nih.gov/articles/PMC12226001/ (Full text)

Patients with severe ME/CFS deserve better than unproven theories

Rapid Response:

Patients with severe ME/CFS deserve better than unproven theories

Dear Editor

Miller et al argue that chronic fatigue conditions are “a dysfunctional biological response orchestrated in the brain, influenced by expectations and conditioned responses,” and as a result, even people with severe ME/CFS can recover by “reframing beliefs about illness, along with specialist rehabilitation.”

Interventions based on this model have been tested in randomised trials in people since the 1990s in people with mild to moderate symptoms. Many of the participants would not have had ME/CFS as currently diagnosed, which carries a higher risk of harm from exertion. [1-3] Even in that easier context, short-term effects have been negligible or modest, without longterm benefits. Harms were not thoroughly studied. [1-3] This does not amount to strong evidence of substantial symptomatic improvement, let alone disease modification or full recovery.

Miller et al offer no direct strong evidence to support their claim that with their approach, “even those with severe ME/CFS can recover.” They cite the experience of a unit in Leeds, based on charts of discharged patients from a quality assurance report, where no patients were rated as “not at all ill” on discharge. [4] This kind of data is not defined as research, intended to be generalisable to other patients. [5] It was a very small group, too: Only six of the patients in that report had the diagnosis ME/CFS.

The weight of the authors’ argument, then, relies on their pathophysiologic rationale, which does not account for the full range of physical impacts of the illness. They point to other literature positing similar hypotheses, but these theories remain unproven. The pathophysiology of ME/CFS remains uncertain, [1-3] and it is not even clear that there is just one type of ME/CFS with the same underlying mechanisms. [6] Heterogeneous results in studies that have attempted to establish a core part of the model – that activity level and biological impairment are related – may be related to varying diagnostic criteria. [7]

Medicine has a long history of ascribing beliefs and/or responses to stress as the cause of diseases that were not yet fully understood. It wasn’t all that long ago that asthma, rheumatoid arthritis, and peptic ulcers fell into this category. [8] It’s been proven wrong so often now, we should be highly skeptical of these theories.

Perhaps part of why psychologically-based rationales for disease can be widely accepted is because the harm this can do is underappreciated. Miller et al argued that their narrative inspires hope, and people with severe ME/CFS deserve that. But when the unproven theory can’t deliver on the claims, what then? In a study Miller et al cited, researchers found that being told the disease was psychosomatic was the most common reason for suicidal thoughts for people with ME/CFS. [9] It’s not the first study to suggest that being told they are effectively to blame for not recovering is a contributing factor to the increased risk of suicidality in people with ME/CFS. [10]

A critical part of hope for people suffering illness is being able to trust that the medical community will work objectively to find better treatments and ways to support them, rather than promote unproven theories. People with ME/CFS deserve better than being told that their minds can overcome what’s the matter with their bodies – if only they try hard enough, for long enough.

References

1. National Institute for Health and Care Excellence. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. 29 Oct 2021. https://www.nice.org.uk/guidance/ng206

2. Chou R, McDonagh M, Griffin JC, Grusing S. Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Updated Systematic Evidence Review prepared for Centers for Disease Control and Prevention. 2022. https://stacks.cdc.gov/view/cdc/156092

3. Institute for Quality and Efficiency in Health Care (IQWiG). Current scientific knowledge on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 2023. https://www.iqwig.de/en/projects/n21-01.html

4. Leeds and York Partnership NHS Foundation Trust. National Inpatient Centre for Psychological Medicine: annual review 2020-21. May 2021. https://www.leedsandyorkpft.nhs.uk/our-services/wp-content/uploads/sites…

5. Health Research Authority. Defining research. October 2022. https://www.hra-decisiontools.org.uk/research/docs/DefiningResearchTable…

6. Bastos VC, Greene KA, Tabachnikova A, et al. Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome. J Immunol 2025;vkaf087. doi:10.1093/jimmun/vkaf087 pmid:40373264

7. Sunnquist M, Jason LA. A reexamination of the cognitive behavioral model of chronic fatigue syndrome. J Clin Psychol 2018;74:7. doi:10.1002/jclp.22593 pmid:29457646

8. Hange D, Bengtsson C, Sundh V, Bjorkelund. The natural history of psychosomatic symptoms and their association with psychological symptoms: Observations from the Population Study of Women in Gothenburg. Eur J Gen Pract 2007;13:2. doi:10.1080/13814780701377497 pmid:17534741

9. König RS, Paris DH, Sollberger M, Tschopp R. Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study. Heliyon 2024;10:e27031. doi:10.1016/j.heliyon.2024.e27031 pmid:3843435

10. Chu L, Elliott M, Stein E, Jason LA. Identifying and managing suicidality in Myalgic Encephalitis/Chronic Fatigue Syndrome. Healthcare (Basel) 2021;9:6. doi:10.3390/healthcare9060629 pmid:34070367

Source: Hilda Bastian. BMJ 2025;389:r977 https://www.bmj.com/content/389/bmj.r977/rr-30

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms.

By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors.

This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA.

Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms—specifically, how multi-omics dynamics are associated to the disease’s heterogeneous symptoms.

Source: Xiong, R., Aiken, E., Caldwell, R. et al. AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Med (2025). https://doi.org/10.1038/s41591-025-03788-3  https://www.nature.com/articles/s41591-025-03788-3

Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry

Abstract:

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.

Methods: Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.

Results: No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol – corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.

Conclusions: Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.

Source: Thomas, N., Ubhayasekera, S.J.K.A., Armstrong, C.W. et al. Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry. J Transl Med 23, 829 (2025). https://doi.org/10.1186/s12967-025-06841-4 https://link.springer.com/article/10.1186/s12967-025-06841-4 (Full text)

Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic disease with no FDA-approved treatments. This report describes a protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial investigating the impact of low-dose naltrexone (LDN) and pyridostigmine (Mestinon) on physiological response, symptoms, and functionality of ME/CFS patients.

Methods: Participants (target n = 160) are recruited through clinics at Massachusetts General Hospital and Brigham and Women’s Hospital, and through Open Medicine Foundation’s StudyME registry. They are then randomized into one of four arms: LDN/pyridostigmine, LDN/placebo, placebo/pyridostigmine, placebo/placebo. Treatment is administered for 13 weeks after an initial screening period of up to 4 weeks. Primary outcomes are FUNCAP-55 score, peak oxygen utilization, heart rate recovery, and oxygen uptake efficiency slope. Secondary outcomes are scores from DSQ-PEM and PROMIS-29 surveys, DANA Brain Vital score, step count, heart rate, and heart rate variability.

Discussion: The results of this trial will provide novel insights into the efficacy of and predictors of response to LDN and pyridostigmine in ME/CFS. This may inform future treatment strategies for ME/CFS. The trial will also validate what primary and secondary outcomes to use in similar clinical trials.

Source: Danielle Meadows, Johanna Squires, Joshua Dibble et al. Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial, 04 March 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-5626167/v1]

A Signal for Voice and Speech Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may report abnormalities in voice and speech; however, no formal research has been conducted in this area.
Methods: An online mixed-methods survey was completed by 685 people with ME/CFS. A total of 302 respondents completed the qualitative component (44.09%). Questions assessed disease experience with ME/CFS and post-exertional malaise without prompting on specific symptoms. Within the qualitative results, a search of the terms “speech, voice,” “words,” and “speak” was conducted.
Results: Excluding neurocognitive associations, colloquial phrases, and “speech therapy,” there were 38 mentions of the terms in the context of voice or speech changes across 28 unique qualitative survey responses (9.27%).
Conclusions: A notable portion of respondents reported voice or speech changes when responding to open-ended qualitative questions about their disease experience. More research is needed regarding the implications of voice and speech anomalies in ME/CFS pathology and disease monitoring.
Source: Grach SL, Seltzer J, Orbelo DM. A Signal for Voice and Speech Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2025; 14(14):4847. https://doi.org/10.3390/jcm14144847 https://www.mdpi.com/2077-0383/14/14/4847 (Full text)