Category: Overview

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating chronic illnesses with considerable symptom overlap. Their symptoms include profound fatigue, widespread pain, post-exertional deterioration, sleep disturbance, dysautonomia, and cognitive impairment. These illnesses frequently co-occur; ME/CFS often develops first, particularly after infection. This overlap creates a diagnostic grey area and contributes to severe reductions in quality of life. Despite these shared features, key distinctions remain essential. ME/CFS is characterised by post-exertional neuroimmune exhaustion (PENE)/post-exertional malaise (PEM), a hallmark of post-exertional worsening and multisystem involvement. Contrastingly, FM centres on chronic widespread pain and symptom variability. It is not characterised by PEM/PENE or the same extent of system dysfunction as ME/CFS. Both disorders lack a definitive biomarker as of 2025. Thus, diagnosis remains clinical and supported by objective tests where available.

Main body: Although immune dysregulation is common in patients with each condition, distinct immune signatures have been observed. ME/CFS is characterised by fluctuating pro- and anti-inflammatory cytokine levels and a frequent reduction in natural killer (NK) cell function; this is consistent with immune exhaustion. Patients with FM exhibit elevated IL-6, IL-17 A, and IL-4 levels, and a broader immune imbalance linked to pain amplification rather than immune collapse. Viral infections do not directly cause either condition, but commonly act as triggers. Shared mechanisms, such as spinal reflex arc activation and microglial sensitisation, suggest a common pathway mediated by proprioceptor-induced microglial activation for chronic pain. ME/CFS causes autoimmunity-like processes, whereas evidence of autoimmune drivers for FM is limited. Gut microbiome studies have revealed reduced microbial diversity in patients with ME/CFS. Moreover, the two disorders are characterised by shared, yet distinct, microbial alterations.

Conclusion: Given the chronic and debilitating nature of ME/CFS and FM, prevention and early intervention remain crucial, but understudied. Health education, workplace adaptations, and early diagnostic pathways may substantially reduce the disease burden. Many patients are outside formal healthcare systems. Therefore, digital tools such as symptom-tracking apps, biosensors, remote testing, and assistive technologies are becoming central to disease management and monitoring. These approaches support a transdiagnostic, patient-centred model capable of addressing both conditions and reaching populations that remain underserved.

Source: Murovska M, Krumina A, Araja D, Kujawski S, Zalewski P, Nora-Krukle Z, Berkis U. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights. J Transl Med. 2026 Feb 20. doi: 10.1186/s12967-026-07889-6. Epub ahead of print. PMID: 41715182. https://link.springer.com/article/10.1186/s12967-026-07889-6 (Full text available as PDF file)

An Overview of Severe Myalgic Encephalomyelitis

Abstract:

In this article, we have reviewed the literature on severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a clinical diagnosis in the absence of a diagnostic test. However, in research settings and disability disputes, 2-day cardiopulmonary exercise testing can be used to diagnose and document the abnormal response to exercise. Biomedical research into this disease has been scarce and underfunded for decades. Consequently, there are no effective treatments.

In its most severe form, it is more disabling than many other diseases, and patients are bedbound 24/7, dependent on carers, and spend their days in dark and quiet rooms. Even the soft sound of a human voice can lead to further deterioration. Some of the very severely ill suffer from life-threatening malnutrition and need to be tube-fed. The COVID-19 pandemic has led to a sharp increase in the number of patients with post-infectious diseases, and many of them fulfill ME/CFS criteria.

Dedicated, focused research using advanced medical technologies is needed to gain further understanding of the underlying disease mechanism. This will enable us to find effective pharmacological treatments and address the unmet medical needs of these very ill people.

Source: Vink M, Vink-Niese A. An Overview of Severe Myalgic Encephalomyelitis. J Clin Med. 2026 Jan 19;15(2):805. doi: 10.3390/jcm15020805. PMID: 41598742. https://www.mdpi.com/2077-0383/15/2/805 (Full text)

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities.

Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component.

Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut-brain axis. Neuroendocrine findings such as hypothalamic-pituitary-adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities.

Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise.

Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.

Source: Dudova D, Bozhkova M, Petrov S, Nikolova R, Kalfova T, Ivanovska M, Vaseva K, Nikolova M, Ivanov IN. Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Dec 26;27(1):268. doi: 10.3390/ijms27010268. PMID: 41516145; PMCID: PMC12785471. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785471/ (Full text)

Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies

Introduction:

Fatigue and weariness have been universal experiences throughout human history, coexisting with humanity since its earliest days across all cultures and times. It occurs in ancient stories, including Genesis, in which Adam’s fatigue was linked to the toil imposed upon him as part of the consequences of disobedience, a condition that made sustaining life a laborious task. Acute fatigue, which arises naturally in response to stress or work, is a normal physiological process experienced by all humans regardless of era or place. It signals the body’s need to rest and adapt, playing a vital role in maintaining health and balance.

In contrast, chronic fatigue, as seen in aging populations and conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complex and often debilitating disorder that extends beyond normal tiredness. It involves sustained disruption of metabolic, neurological, and immune functions, resisting typical recovery mechanisms. The 14 papers in this Research Topic collectively explore the multifaceted nature of fatigue, presenting advances in mechanistic research, epidemiology, clinical interventions, rehabilitation techniques, and innovative monitoring technologies aimed at improving diagnosis, treatment, and management of this persistent condition.

Source: Kujawski S, Hodges L, Morten KJ, Zalewski P. Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies. Front Neurosci. 2025 Dec 10;19:1751667. doi: 10.3389/fnins.2025.1751667. PMCID: PMC12728026. https://pmc.ncbi.nlm.nih.gov/articles/PMC12728026/ (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)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available.

Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances.

This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Source: Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180809/ (Full text)

Interdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

in English, German

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, chronic multisystemic disease which, depending on its severity, can lead to considerable physical and cognitive impairment, loss of ability to work and the need for nursing care including artificial nutrition and, in very severe cases, even death.

The aim of this D-A-CH (Germany, Austria, Switzerland) consensus statement is 1) to summarize the current state of knowledge on ME/CFS, 2) to highlight the Canadian Consensus Criteria (CCC) as clinical criteria for diagnostics with a focus on the leading symptom post-exertional malaise (PEM) and 3) to provide an overview of current options and possible future developments, particularly with regard to diagnostics and therapy. The D-A-CH consensus statement is intended to support physicians, therapists and valuer in diagnosing patients with suspected ME/CFS by means of adequate anamnesis and clinical-physical examinations as well as the recommended clinical CCC, using the questionnaires and other examination methods presented.

The overview of the two pillars of therapy for ME/CFS, pacing and symptom-relieving therapy options, is intended not only to provide orientation for physicians and therapists, but also to support decision-makers from healthcare policy and insurance companies in determining which therapy options should already be reimbursable by them at this point in time for the indication ME/CFS.

Source: Hoffmann K, Hainzl A, Stingl M, Kurz K, Biesenbach B, Bammer C, Behrends U, Broxtermann W, Buchmayer F, Cavini AM, Fretz GS, Gole M, Grande B, Grande T, Habermann-Horstmeier L, Hackl V, Hamacher J, Hermisson J, King M, Kohl S, Leiss S, Litzlbauer D, Renz-Polster H, Ries W, Sagelsdorff J, Scheibenbogen C, Schieffer B, Schön L, Schreiner C, Thonhofer K, Strasser M, Weber T, Untersmayr E. Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-Syndrom [Interdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome]. Wien Klin Wochenschr. 2024 Aug;136(Suppl 5):103-123. German. doi: 10.1007/s00508-024-02372-y. Epub 2024 May 14. PMID: 38743348. https://pubmed.ncbi.nlm.nih.gov/38743348/

Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities.

Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.

Source: Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW. Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies. Trends Mol Med. 2024 Mar 4:S1471-4914(24)00028-5. doi: 10.1016/j.molmed.2024.02.003. Epub ahead of print. PMID: 38443223. https://www.sciencedirect.com/science/article/pii/S1471491424000285 (Full text)

Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions

Abstract:

Post-viral pain syndrome, also known as post-viral syndrome (PVS), is a complex condition characterized by persistent pain, fatigue, musculoskeletal pain, neuropathic pain, neurocognitive difficulties, and sleep disturbances1,2 that can occur after an individual has recovered from a viral infection. Much remains unknown regarding the pathophysiology of post-viral syndromes and few studies have provided a comprehensive summary of the condition, agents that cause it, and successful treatment modalities.

With the COVID-19 pandemic continuing to affect millions of people worldwide, the need for understanding the etiology of post-viral illness and how to help individuals cope with the sequalae is paramount.2 This narrative review provides a summary of the sequelae of post-viral syndromes, viral agents that cause it, the pathophysiology, treatment, and future considerations for research and targeted therapies.

Source: Caleb Tackey, P. Maxwell Slepian, Hance Clarke & Nimish Mittal (2023) Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions, Canadian Journal of Pain, DOI: 10.1080/24740527.2023.2272999 https://www.tandfonline.com/doi/full/10.1080/24740527.2023.2272999 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Me/Cfs): The Biology of a Neglected Disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with debilitating symptoms that impact all aspects of life. The diverse symptom presentation indicates that ME/CFS is likely to have a multifactorial origin. However, it is an extremely understudied disease with no standardised diagnostic criteria or proven treatment avenues. It is hypothesised that environmental insults (such as acute infection, mainly viral) or stress in genetically susceptible individuals may trigger the development of ME/CFS.

These insults result in acute inflammatory responses, along with aberrant immune activation. A spiralling disruption of homeostasis promotes subsequent patho-mechanisms including gut dysbiosis and systemic inflammation, and eventually a pathological clotting system, chronic endothelialitis, vasoconstriction, and hypoxia. Additionally, dysfunctional energy metabolism including oxidative stress is also present in the development of ME/CFS. Since the exact pathophysiology of ME/CFS remains unclear, additional research is required to reveal further insight into this “neglected” disease.

Source: Arron, Hayley and Marsh, Benamin and Khan, M. Asad and Jaeger, Beate and Kell, Douglas and Pretorius, Etheresia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Me/Cfs): The Biology of a Neglected Disease. Available at SSRN: https://ssrn.com/abstract=4622074 or http://dx.doi.org/10.2139/ssrn.4622074 (Full text available as PDF file)