Tag: critique

Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory

To the Editor,

We read the contribution by Hunter et al., titled “Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling” in this journal, initially impressed for the large collection of data. They actually presented a novel, genome-wide epigenetic profiling approach using EpiSwitch® technology to identify potential diagnostic biomarkers for ME/CFS [1]. The use of 3D chromatin conformation signatures provides a fresh perspective on disease-specific gene regulation, moving beyond conventional transcriptomics and methylation analyses. In general, the diagnostic model demonstrates impressive sensitivity (92%) and specificity (98%) in distinguishing ME/CFS patients from controls, suggesting real clinical potential [1]. Moreover, the application of advanced machine learning techniques adds analytical robustness, while pathway analysis identifies biologically plausible immune-related mechanisms. This integrative approach sets a promising foundation for future biomarker-driven diagnostics and personalized therapy stratification in ME/CFS. Fundamentally, they presented a retrospective case-control analysis aiming to identify diagnostic epigenetic markers for ME/CFS using 3D chromatin conformation profiling (EpiSwitch®). However, while the authors make bold claims regarding diagnostic sensitivity and specificity, the paper suffers from multiple scientific weaknesses and methodological ambiguities that undermine its validity and translational relevance.

First, the article repeatedly asserts that “immune dysregulation” is a hallmark of ME/CFS, citing elevated pro-inflammatory cytokines and natural killer (NK) cell dysfunction. However, whereas the authors cite updated papers with a presumptive relationship with the issue, a critical omission here is the lack of citation of early foundational immunological studies in ME/CFS [2]. Notably absent is the 1994 work by Tirelli et al. in the Scandinavian Journal of Immunology, which documented, for the first time, immunological abnormalities in CFS patients and could serve as an important historical anchor for claims of immune dysregulation [2]. This omission raises concerns about reporting bias and selective citation to frame the narrative around newer, possibly more aligned findings with the current study methodology [2, 3].

Additionally, the paper refers to “ME/CFS inclusion criteria” as requiring severe CFS with patients being “housebound,” but fails to specify which diagnostic criteria were used, whether the Fukuda, Canadian Consensus, International Consensus, or IOM/NAM criteria [1]. This lack of precision is critical, as different case definitions yield different cohorts in terms of clinical features and biological signatures. Using “severe housebound” as a criterion, without reference to a validated clinical definition or stratification tool (e.g., Bell Disability Scale), introduces subjectivity and undermines the reproducibility of patient selection. The term “housebound” is not a recognized diagnostic stratifier and suggests imprecise cohort construction.

Further ambiguity arises when the authors discuss the control group. They state that controls had “none of the four key CFS symptoms present or in the past” and “preferably an existing history of glandular fever or COVID.” The phrase “preferably” is ambiguous and methodologically problematic [1]. Did the control group actually include individuals with prior infectious mononucleosis or COVID-19, and if so, how were these illnesses verified? The phrase “preferably” suggests either inconsistency in selection or retrospective rationalization, both of which compromise the clarity and control of variables in the study. Furthermore, it is scientifically incoherent to describe individuals as controls (i.e., free from ME/CFS) while also including those with a known post-infectious risk profile, potentially biasing the control group with latent post-viral immunogenetic changes [1].

There is further conceptual confusion when the authors state that the ME/CFS network reveals some overlap with pathways involved in multiple sclerosis (MS) and rheumatoid arthritis (RA). While such overlaps are plausible and worth exploring, the authors do not sufficiently explain the biological rationale for this claim or its relevance to ME/CFS pathophysiology [1]. They reference IL-2, IL-10, CD4, and TLR pathways as shared elements, but these are highly pleiotropic and non-specific immunological signals.

The mere presence of these markers in ME/CFS does not imply mechanistic similarity to MS or RA. Without longitudinal or functional studies, this comparison becomes speculative and possibly misleading, especially given the known heterogeneity of ME/CFS and the distinct immunopathology of autoimmune diseases like MS.

Read the rest of this letter HERE.

Source: Tirelli U, Franzini M, Chirumbolo S. Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory. J Transl Med. 2026 Jan 5;24(1):20. doi: 10.1186/s12967-025-07397-z. PMID: 41491817. https://link.springer.com/article/10.1186/s12967-025-07397-z (Full text)

Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome

Letter:

Response to B. Walitt et al. Nature Communications https://doi.org/10.1038/s41467-024-45107-3 (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, systemic disease with significant pathophysiological uncertainties and variable presentations1. Here, we challenge Walitt et al.’s2 conclusion that post-infectious (PI) ME/CFS is a disorder defined by altered effort preference, leading to activity avoidance and subsequent deconditioning. We believe this interpretation risks reinforcing skepticism about the serious biological nature of ME/CFS and its hallmark of post-exertional malaise (PEM), as well as its potential misclassification as a mental health condition.

Walitt et al.2 utilized a single CPET to evaluate systems-level physiological responses to exercise. However, this methodology does not allow for measuring responses after an initial exertion, which is critically important for fully understanding PEM3. Over the past two decades, 2-day CPET has been used to characterize the systems-level metabolism of ME/CFS3. This paradigm uses an initial maximal CPET to establish the individual’s baseline performance and as a participant-referenced method to induce PEM4. A second maximal CPET is then conducted 24 h later to measure physiological and perceptual responses to exercise during the post-exertional state4. Standard objective criteria to evaluate effort are used to ensure maximal testing, including the respiratory exchange ratio at peak exertion4. This removes uncertainty related to effort. Meta-analyses involving participants with ME/CFS who have completed 2-day CPET indicate characteristic declines in the volume of oxygen consumed, work rate, and heart rate (HR) at submaximal exertion on the second CPET. These findings are reliably observed in people with ME/CFS but not deconditioned individuals5,6,7. Accordingly, the Institute of Medicine (IOM) cautioned that “a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise.”1 (p. 106)

Using a single CPET introduces a threat to validity in Walitt et al.’s study2, as it did not allow for the measurement of submaximal performance decrement in the post-exertional state1,3,4,5,6. This is important because deconditioning and PEM are not mutually exclusive. Special care must be taken when applying and interpreting CPET results1. Failure to use 2-day CPET prevented the authors from adequately testing their conclusion that PEM is related to participants’ effort preference, as they did not evaluate physiological performance under conditions involving objective, standardized criteria for maximal exertion. Unfortunately, the use of a single CPET in this study contributed to the authors’ misinterpretation that PEM is synonymous with reduced effort and deconditioning.

Read the rest of this letter here: https://www.nature.com/articles/s41467-025-64538-0

Source: Davenport, T.E., Scheibenbogen, C., Zinn, M.A. et al. Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 16, 9176 (2025). https://doi.org/10.1038/s41467-025-64538-0 https://www.nature.com/articles/s41467-025-64538-0 (Full text)

Unwilling or unable? Interpreting effort task performance in myalgic encephalomyelitis/chronic fatigue syndrome

Introduction:

In a recent, high-profile study of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS), Walitt et al. (2024) assessed the performance of patients and healthy volunteers on the Effort-Expenditure for Rewards Task (EEfRT), among a host of other measures. The EEfRT is a widely used behavioral index of reward motivation and effort-based decision-making that requires repeatedly choosing between an easy task and a hard task, each involving rapid, repetitive button-pressing (Treadway et al., 2009). Walitt et al.’s study—the first to investigate effort-based decision-making in PI-ME/CFS—found that patients were less likely to choose the hard task than healthy volunteers. The authors interpreted this difference as evidence of altered “effort preference,” which they defined as “how much effort a person subjectively wants to exert” (p. 9). Walitt et al. concluded that “effort preference, not fatigue, is the defining motor behavior of this illness” (p. 10). Here we interrogate this conclusion. Were PI-ME/CFS patients less likely to choose the hard task because they wanted to exert less effort, consciously or otherwise? Or were they less able to complete the hard task, and thus chose it less often? We argue that the data support the latter interpretation.

Source: Kirvin-Quamme A, Kirke KD, Junge O, Edwards JCW, Holmes KJ. Unwilling or unable? Interpreting effort task performance in myalgic encephalomyelitis/chronic fatigue syndrome. Front Psychol. 2025 Jun 13;16:1593269. doi: 10.3389/fpsyg.2025.1593269. PMCID: PMC12202612. https://pmc.ncbi.nlm.nih.gov/articles/PMC12202612/ (Full text)

Contesting oppressive regimes of truth: A critical feminist re-examination of (bio)psychosocial hegemony in the field of myalgic encephalomyelitis / chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis / chronic fatigue syndrome, a disabling condition disproportionately affecting women, is predominantly clinically managed through a (bio)psychosocial lens with psychosocial-inspired therapies, criticised for facilitating social and epistemic injustice, psychological and physical harms. Whilst most literature contesting (bio)psychosocial practices espouses a mainstream scientific perspective, politics and power relations undergirding psychosocial hegemony are better explicated through a critical lens. This article re-examines the ascendancy of psychosocial therapies and related practices through a critical feminist psychology and Foucauldian lens, with a view to locating oppressive practices in their socio-political and cultural context and promoting dialogue on possibilities for positive social change.

Source: Hunt, J. E. (2023, August 10). Contesting oppressive regimes of truth: A critical feminist re-examination of (bio)psychosocial hegemony in the field of myalgic encephalomyelitis / chronic fatigue syndrome. https://doi.org/10.31235/osf.io/3g7kp https://osf.io/preprints/socarxiv/3g7kp/ (Full text)

A Concerning Display of Medical Indifference: Reply to ‘Chronic Fatigue Syndrome and an Illness-Focused Approach to Care: Controversy, Morality and Paradox’

Abstract:

In ‘Chronic fatigue syndrome and an illness-focused approach to care: controversy, morality and paradox’, authors Michael Sharpe and Monica Greco begin by characterising myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as illness-without-disease. On that basis they ask why patients reject treatments for illness-without-disease, and they answer with a philosophical idea. Whitehead’s ‘bifurcation of nature’, they suggest, still dominates public and professional thinking, and that conceptual confusion leads patients to reject the treatment they need. A great deal has occurred, however, since Whitehead characterised his culture’s confusions 100 years ago.

In our time, I suggest, experience is no longer construed as an invalid second cousin of bodily states in philosophy, in medicine or in the culture at large. More importantly, we must evaluate medical explanations before we reach for philosophical alternatives. The National Institutes of Health and the Institute of Medicine have concluded that ME/CFS is, in fact, a biomedical disease, and all US governmental health organisations now agree.

Although it would be productive for Sharpe and Greco to state and support their disagreement with the other side of the disease debate, it is no longer tenable, or safe, to ignore the possibility of disease in patients with ME/CFS, or to recommend that clinicians should do so. When we find ourselves in a framework that suggests the possibility of medical need is somehow beside the point for medical providers, it is time to reconsider our conceptual foundations.

Source: O’Leary D. A concerning display of medical indifference: reply to ‘Chronic fatigue syndrome and an illness-focused approach to care: controversy, morality and paradox’ [published online ahead of print, 2020 Jun 29]. Med Humanit. 2020;medhum-2019-011743. doi:10.1136/medhum-2019-011743 https://pubmed.ncbi.nlm.nih.gov/32601171/

Conceptualising illness and disease: reflections on Sharpe and Greco (2019)

Abstract:

In a recent paper, Sharpe and Greco suggest that chronic fatigue syndrome/myalgic encephalomyelitis (MECFS) can be viewed as an instance of “illness without disease”, and consequently, treatment should be directed towards altering the patient’s experience of, and response to, their symptoms. We discuss two broad issues that arise from Sharpe and Greco’s article, one relating to the assumptions they make about MECFS and its treatment specifically, and the other relating to their conceptualisation of the illness/disease dichotomy.

We argue that the term “illness without disease”, in the sense that Sharpe and Greco use it, is problematic because it can lead to unwarranted causal assumptions. Following these critical comments, we present a new framework for conceptualising the relationship between explanatory disease models and the experience of illness.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Source: Wilshire C, Ward T. Conceptualising illness and disease: reflections on Sharpe and Greco (2019). Med Humanit. 2019 Dec 11. pii: medhum-2019-011756. doi: 10.1136/medhum-2019-011756. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31826926 (Abstract) https://sci-hub.se/10.1136/medhum-2019-011756 (Full article)

Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency

Abstract:

Researchers studying the energy metabolism of patients with chronic fatigue syndrome have reached the conclusion that these patients have impaired pyruvate dehydrogenase function, but their measurements are not consistent with the changes we see in patients with primary genetic pyruvate dehydrogenase deficiency.

A cross-sectional study published in December 2016 found a change in the pattern of amino acids in the plasma of patients with chronic fatigue syndrome. Gene expression in white blood cells and energy metabolism in muscle cells was also found to have changed (1). The authors interpret the results as an expression of functional inhibition of the enzyme pyruvate dehydrogenase, and they postulate dysregulation of the enzyme complex as a possible key factor in the pathogenesis associated with chronic fatigue syndrome.

The study received extensive media coverage (2, 3), and the link to pyruvate dehydrogenase is published without reservations as an established fact (4, 5). At our laboratory we are now receiving samples for metabolic screening from patients with suspected fatigue syndrome. On the basis of my own experience with biochemical diagnostic workup for pyruvate dehydrogenase deficiency, I would like to point out weaknesses in the study that should have prompted much greater caution in the conclusions.

Source: Bliksrud YT. Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency. Tidsskr Nor Laegeforen. 2017 Nov 28;137(23-24). doi: 10.4045/tidsskr.17.0948. Print 2017 Dec 12. [Article in English, Norwegian] http://tidsskriftet.no/en/2017/12/debatt/tenuous-link-between-chronic-fatigue-syndrome-and-pyruvate-dehydrogenase-deficiency (Full article)

Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617

Abstract:

The paper by Brewer et al. entitled “Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605–617” is so methodologically flawed that it should never have been published in the scientific literature [1].

In this paper, the authors measure the presence of mycotoxins in the urine of 112 patients suffering from chronic fatigue syndrome (CFS). These finding are then compared to urine samples from 55 healthy control subjects “… with no history of exposure to WDB (water damaged buildings) or moldy environment…” (sic). Not surprisingly, there were more people from the CFS group with mold exposure than in the comparison group. These results are not surprising because, BY DEFINITION, the control group had no history of exposure to mold. By purposely choosing a control group with no history of mold exposure, the authors have statistically rigged their results in such a way that only a positive relationship will be found when compared to the CFS group.

Using the same approach, the authors could test urine from their CFS patients for the presence of caffeine metabolites and compare the results to urine from a group not exposed to caffeinated beverages; they would find more caffeine metabolites in the CFS group for the same methodological reasons, the control group having been purposely selected to be not exposed. The same would be true for nicotine metabolites in the CFS patients’ urine using urine from non-smokers as a comparison group or comparing urinary animal protein metabolites from the CFS group to animal protein metabolites in urine from vegetarians. The results from these studies would show a positive but erroneous association between CFS and caffeine, nicotine and animal protein. The same is true for the relationship that Brewer et al. purportedly found in this study of CFS and mold. The findings from this study are misleading and meaningless.

This study is an example of extreme selection bias and is akin to showing that men are shorter than women by comparing the height of an average group of men to that of women on the national basketball team!

Given the mountain of “junk” science on the Internet, I feel that a credible on-line scientific journal must ensure rigorous methodological standards for the papers it publishes. Such was not the case for this paper.

 

Source: Osterman JW. Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617. Toxins (Basel). 2016 Nov 7;8(11). pii: E322. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127119/ (Full article)

 

Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Letter to the Editor:

With interest we read the article by Billing-Ross et al. [1] about 193 patients with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda or Canadian Consensus criteria and undergoing sequencing of the mtDNA, the DePaul Symptom questionnaire and the Medical Outcome Survey Short Form-36. The study showed that CFS is associated with mtDNA haplogroups J, U and H, that 8 mtDNA single nucleotide polymorphisms (SNPs) were associated with 16 symptom categories, and that three haplogroups were associated with six symptom categories [1]. We have the following comments and concerns.

The main limitation of this study is that only the mtDNA was investigated for sequence variants. Since it is well-known that mitochondrial disorders (MIDs) may be also caused by mutations in nDNA-located genes, particularly in children [2], disease-causing mutations or SNPs facilitating the development of CFS may have been missed. Furthermore, MIDs may not only be due to respiratory chain dysfunction but also due to disruption of other mitochondrial pathways, such as the beta-oxidation, the hem synthesis, the calcium handling, the coenzyme-Q metabolism, or the urea cycle. There is also consensus that investigations of mtDNA mutations or SNPs in mtDNA from lymphocytes may not be constructive since some mutations may not be present or heteroplasmy rates may be lower than in more severely affected tissues [3].

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/

 

Source: Finsterer J, Zarrouk-Mahjoub S. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? J Transl Med. 2016 Jun 18;14(1):182. doi: 10.1186/s12967-016-0939-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/ (Full article)

 

Response to: fibromyalgia and chronic fatigue syndrome caused by non-celiac gluten sensitivity

Dear Editor:

We have closely read the article published by Isasi et al.1 in Reumatologia Clínica presenting a case of fibromyalgia (FM) and chronic fatigue syndrome (CFS) caused by non-celiac sensitivity to gluten (NGCD). We would like to comment our experience with this attractive topic regarding patients with FM/CFS, which I hope will contribute to an improved knowledge of this association. The authors have reasonably ruled out celiac disease (CD) and have hypothesized that NGCD is the cause of FM and CFS in their patient; upon complete remission (CR) of symptoms, both digestive and musculoskeletal, with a gluten-free diet (GFD).

You can read the rest of this letter here: http://www.reumatologiaclinica.org/en/response-to-fibromyalgia-chronic-fatigue/articulo/S217357431400166X/

 

Source: Qanneta R, Fontova R, Castel A. Response to: fibromyalgia and chronic fatigue syndrome caused by non-celiac gluten sensitivity. Reumatol Clin. 2015 May-Jun;11(3):185. doi: 10.1016/j.reuma.2014.09.008. Epub 2014 Nov 7. http://www.reumatologiaclinica.org/en/response-to-fibromyalgia-chronic-fatigue/articulo/S217357431400166X/ (Full article)