Research Using Patients Who Fit the Canadian Consensus Criteria and/or Citing the ICC

2022

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome
Patient selection – “Patients with ME/CFS included in this study were diagnosed according to the 2003 Canadian Consensus Criteria”
Apostolou, Rizwan, Moustardas, Sjorgen, Bertilson, Bragee, Polo and Rosen (Sweden) – 20 October 2022 – “Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva…  Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. … This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.”

A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
Patient selection – CCC
Kedor, Freitag, Meyer-Arndt … Bellmann-Strobl & Scheibenbogen (Germany) – 30 August 2022 – “19 post-COVID-19 syndrome patients [out of 42] fulfill the 2003 Canadian Consensus Criteria for ME/CFS. Disease severity and symptom burden is similar in post-COVID-19 syndrome-ME/CFS and non-COVID-19- ME/CFS patients.”
“Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.”

Metabolic Evidence for Peroxisomal Dysfunction in ME/CFS
Patient selection – Fukuda & CCC
Che, Brydges, Yu, Price, Joshi, Roy, Lee, Barupal, Cheng, Palmer, Levine, Peterson, Vernon, Bateman, Hornig, Montoya, Komaroff, Fiehn & Lipkin (USA) – 18 July 2022 – “Our findings indicate a series of interconnected metabolic alterations in people with ME/CFS that may contribute to the pathogenesis of ME/CFS: (i) reduced levels of plasmalogens, unsaturated phospholipid ethers, and carnitines suggest peroxisomal dysfunction; (ii) reductions in levels of PCs indicate dysregulation of CDP-choline pathway, and (iii) elevations in the levels of dicarboxylic acids, particularly the TCA cycle intermediates alpha-ketoglutarate and succinate, consistent with an impairment in the TCA cycle that may contribute to physical and cognitive fatigue.”

Revisiting IgG Reactivity to Epstein-Barr Virus in ME/CFS and Its Potential Application to Disease Diagnosis
Patient selection – CCC
Sepulveda, Malato, Sotzny, Grabowska, Fonseca, Cordeiro, Graca, Biecek, Behrends, Mautner, Westermeier, Lacerda & Scheibenbogen (Poland, Portugal, Germany, Austria, Chile, UK) – 24 June 2022 – “Thus, given the heterogeneous nature of ME/CFS, it is pivotal to stratify patients adequately, based on age, gender, and disease trigger for biomarker discovery…. An implication of having a different antibody profiling between men and women is that analysis of each gender should be performed separately. … In conclusion, this study identified two candidate antigens whose antibodies could be used to identify ME/CFS patients with an infectious trigger. To strengthen our findings, two other cohorts of patients are currently studied, including the well-characterized ME/CFS patients with different disease triggers and healthy controls from the United Kingdom ME/CFS biobank.”

Survey of Anti-Pathogen Antibody Levels in ME/CFS
Patient selection – CCC
O’Neal, Glass, Emig, Vitug, Henry, Shungu, Mao, Levine & Hanson (USA) – 10 June 2022 – “While most of the differences were not significant, the opposite trends between male and female antibody levels indicate it is inappropriate to combine data from the two sexes. … Age-based cohort stratification provides additional insight into humoral immune biology, with a large number of antigens identified with significantly different antibody levels between subjects under 50 and those over 50. … The subtle serological alterations between healthy controls and ME/CFS subjects found here should be interpreted cautiously, but these findings do contribute to the growing body of evidence that the immune system of ME/CFS patients is dysregulated.”

The Pathobiology of ME/CFS: The Case for Neuroglial Failure
Patient selection – CCC
Renz-Polster, Tremblay, Bienzle & Fischer (Germany & Canada) – 09 May 2022 – “From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.”

Diagnosis of ME/CFS Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles
Patient selection – CCC & Fukuda
Gonzalez-Cebrian, Almenar-Perez, Xu, Y, Huang, Gimenez-Orenga, Hutchinson, Lodge, Nathanson, Morten, Ferrer & Oltra (Spain, U.K. & U.S.) – 01 April 2022 – Possible biomarker using extracellular vesicles (EV) – “Strikingly, EV physical features, including EV size and z-potential measures were detected by this model as relevant features for the effective diagnosis of patients indicating a potential important role of EVs in ME/CFS.”

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients
Patient selection – CCC & Fukuda
Rayhan and Baraniuk (Chile, Canada, Austria & Poland) – April 2022 – “In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease. … Study references indicates the following patient selection: “Patients with ME/CFS were diagnosed by a clinician according to the Canadian Consensus and/or CDC-1994 (“Fukuda”) criteria, as determined by the responses on the Symptoms Assessment form to confirm case definition compliance and study eligibility.”

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS
Patient selection – CCC
Germain, Giloteaux, Moore, Levine, Chia, Keller, Stevens, Franconi, Mao, Shungu, Grimson and Hanson (U.S.) – 31 March 2022 – “The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.”

IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS
Patient selection – CCC
Hartwig, Sotzny, Bauer, Heidecke, Riemekasten, Dragun, Meisel, Dames, Grabowski and Scheibenbogen (Germany) – 05 February 2022 – “There is emerging evidence of a network of natural autoantibodies against GPCR [G-protein coupled receptors] which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients. … We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.”

2021

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in ME/CFS
Patient selection – CCC
Rayhan and Baraniuk (U.S.) – 15 December 2021 – “TRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.”

Back to the Future? Immunoglobulin Therapy for ME/CFS
Patient selection – CCC
Brownlie and Speight (UK) – November 2021 – “We conclude that: (1) there is a strong case for this area of research to be revived; (2) pending further research, clinicians would be justified in offering a course of IgG [immunoglobulin] to selected ME/CFS patients at the more severe end of the spectrum.”

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in ME/CFS
Patient selection – CCC
Simonato, Dall’Acqua, Zilli, Sut, Tenconi, Gallo, Sfriso, Sartori, Cavallin, Fiocco, Cogo, Agostinis, Aldovini, Bruttomesso, Marcolongo, Comai, and Baritussio (Italy & U.S.) – 19 November 2021 – “Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.”

Complement Component C1q as a Potential Diagnostic Tool for Subtyping
Patient selection – CCC
Castro-Marrero, Zacares, Almenar-Perez, Alegre-Martin and Oltra (Spain) – 15 September 2021 – “The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.”

Potential Therapeutic Benefit of Low Dose Naltrexone in ME/CFS: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment
Patient selection – CCC
Cabanas, Muraki, Eaton-Fitch, Staines and Marshall-Gradisnik (Australia, Japan) – 13 July 2021 – “…this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of [low dose naltrexone hydrochloride] NTX in treating ME/CFS patients.”

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients
Patient selection – CCC & Fukuda
YBlauensteiner, Bertinat, Leon, Riederer, Sepulveda & Westermeier (Austria, Chile & UK) – 19 May 2021 – “In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS. … Patients with ME/CFS were diagnosed by a clinician according to the Canadian Consensus and/or CDC-1994 (“Fukuda”) criteria, as determined by the responses on the Symptoms Assessment form to confirm case definition compliance and study eligibility.”

Discovery of Immune Biomarkers for ME/CFS based on B cell receptor repertoire analysis
Patient selection – CCC
Yamamura et al (Japan) – May 2021 – “Patients, fulfilling the Canadian clinical diagnosis criteria, were recruited from the clinic in the NCNP hospital…
1) They revealed a previously unknown abnormality of B cell receptor repertoire in ME/CFS.
2) B cell receptor repertoire analysis could provide a useful blood diagnostic test for ME/CFS.
It has been reported that B cell depletion therapy and immunoadsorption therapy can be effective for some ME/CFS patients. This method could be utilized to develop such immune-targeted therapy for ME/CFS patients..”

Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS
Patient selection – CCC
Jäkel, Kedor, Grabowski, Wittke, Thiel, Scherbakov, Doehner, Scheibenbogen & Freitag (Germany) – 19 April 2021 – “HGS measurement is a simple diagnostic tool to assess the severity of muscle fatigue in ME/CFS. Repeat HGS assessment further allows to objectively assess fatigability and impaired recovery. Advantages of HGS measurement are easy handling, low cost and the low risk of causing PEM. Thus, it can be implemented easily in both primary care and research as an objective outcome parameter in clinical studies and drug development.”

2020

Changes in DNA methylation profiles of ME/CFS patients reflect systemic dysfunctions
Patient selection – CCC
Helliwell, Sweetman, Stockwell, Edgar, Chatterjee & Ta (New Zealand) – 04 November 2020 – Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls.

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Patient selection – CCC
Sweetman, Kleffmann, Edgar, de Lange, Vallings and Tate (New Zealand) – 24 September 2020

A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques
Patient selection – CCC
Maksoud, du Preez, Eaton-Fitch, Thapaliya, Barnden, Cabanas, Staines, and Marshall-Gradisnik (Australia) – 30 April 2020

Intravenous Cyclophosphamide in ME/CFS. An Open-Label Phase II Study
Patient selection – CCC
Rekeland, Fosså, Lande, Ktoridou-Valen, Sørland, Holsen, Tronstad, Risa, Alme, Viken, Lie, Dahl, Mella and Fluge (Norway) – 29 April 2020

The effect of ME/CFS severity on cellular bioenergetic function
Patient selection – Fukuda & CCC
Thomas, Elson, Straasheim, Newton and Walker (UK, USA) – 10 April 2020

Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS
Patient selection – CCC
Schreiner, Harrer, Scheibenbogen, Lamer, Schlosser, Naviaux and Prusty (Germany, USA) – 23 April 2020

Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in ME/CFS
Patient selection – Fukuda & CCC – severely ill
Almenar-Pérez, Sarría, Nathanson & Oltra (Spain, USA) – 07 February 2020

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients
Patient selection – CCC
Missailidis, Annesley, Allan, Sanislav, Lidbury, Lewis, and Fisher (Australia) – 06 February 2020

Cell-Based Blood Biomarkers for ME/CFS
Patient selection – CCC
Missailidis, Sanislav, Allan, Annesley and Fisher (Australia) – 03 February 2020

2019

ME/CFS patients exhibit altered T cell metabolism and cytokine associations
Patient selection – CCC
Mandarano, Maya, Giloteaux, Peterson, Maynard, Gottschalk & Hanson (U.S.) – 12 December 2019 – “… To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS CD8+ T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.”

Transient receptor potential melastatin 2 channels are overexpressed in ME/CFS patients
Patient selection – not stated
Balinas, Cabanas, Staines and Marshall-Gradisnik (Australia) – 03 December 2019

Naltrexone [NTX] Restores Impaired Transient Receptor Potential Melestatin 3 Ion Channel Function in Natural Killer Cells From ME/CFS Patients Patient selection – CCC
Cabanas, Muraki, Staines and Marshall-Gradisnik (Australia & Japan) – 31 October 2019 – “… we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.”

Evidence of altered cardiac autonomic regulation in ME/CFS
Patient selection – CCC
M.Nelson, J.Bahl, J.Buckley, R.Thomson & K.Davison (Australia) – 25 October 2019 – “… Meta-analysis revealed significant differences between patients and controls in a number of parameters, including patients having: higher RHR, HRtilt, orthostatic HR response, and LF/HF ratio; and lower HRmax, HRthreshold, HFP and RMSSD. These differences suggest an altered regulation of HR in ME/CFS patients that is suggestive of reduced vagal and increased sympathetic modulation of heart rate. … However, the results of this review suggest that there are quantifiable differences in autonomic HR regulation in ME/CFS patients, and future research in ME/CFS populations should therefore focus on determining if there are additional HR parameters which have diagnostic utility in this group.”
HFP = high frequency power of heart rate variability, HRmax = maximal heart rate, HRmentaltask = heart rate during mental task, HRtilt = heart rate during head-up tilt testing, LF/HF = ratio between low frequency and high frequency power of heart rate variability analysis, RHR = resting heart rate, RMSSD = root mean of the sum of squares of beat to beat deviations

Abnormal blood lactate accumulation during repeated exercise testing in ME/CFS
Patient selection – CCC
Lien, Johansen, Veierød, Haslestad, Bøhn, Melsom, Kardel and Iversen (Norway) – 03 June 2019

2018

Evaluation of four clinical laboratory parameters for the diagnosis of ME
Patient selection – CCC
De Meirleir, Mijatovic, Subramanian, Schlauch and Lombardi (Belgium & US) – 21 November 2018

Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from CFS/ME patients
Patient selection – CCC
Cabanas, Muraki, Eaton, Balinas, Staines and Marshall-Gradisnik (Australia & Japan) – 14 August 2018

Immunoadsorption to remove ß2 adrenergic receptor antibodies in CFS/ME
Patient selection – CCC
Scheibenbogen, Loebel, Freitag, Krueger, Bauer, Antelmann, Doehner, Scherbakov, Heidecke, Reinke, Volk and Grabowski (Germany) – 15 March 2018

2017

Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, CFS and sedentary control subjects
Patient selection – unk
Baraniuk & Shivapurkar (US) – 10 November 2017

Cytokine signature associated with disease severity in CFS patients
Patient selection – unk
Montoya, Holmes, Anderson, Maecker, Rosenberg-Hasson, Valencia, Chu, Younger, Tato & Davis (US) – 28 June 2017

2016

Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS
Patient selection – CCC
Fluge, Melle, Bruland, Risa, Dyrstad, … Dahl & Tronstad (Norway) – 22 December 2016

Impaired calcium mobilization in natural killer cells from CFS/ME patients is associated with transient receptor potential melastatin 3 ion channels
Patient selection – unk
Nguyen, Johnston, Clarke, Smith, Staines & Marshall-Gradisnik (Australia) – 11 October 2016

Extended B cell phenotype in patients with ME/CFS: a cross-sectional study
Patient selection –
Mensah, Bansal, Berkovitz, Sharma, Reddy, Leandro & Cambridge (England) – May 2016

2015

Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS patients
Patient selection – unk
Armstrong, McGregor, Lewis, Butt & Gooley (Australia) – 30 May 2015

Characterisation of cell functions and receptors in CFS/ME
Patient selection – unk
Hardcastle, Brenu, Johnston, Nguyen, Huth, Wong, Ramos, Staines & Marshall-Gradisnik (Australia) – 02 June 2015

2014

Evidence in CFS for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression
Patient selection – unk
Barnden, Crouch, Kwiatek, Burnet & Del Fante (Australia) – 18 December 2014

Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with ME/CFS
Patient selection – unk
Morris & Maes (UK & Australia) – March 2014

Mitochondrial dysfunctions in ME/CFS explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways
Patient selection – unk
Morris & Maes (UK) – March 2014

2013

Discriminative Validity of Metabolic and Workload Measurements for identifying Individuals with CFS
Patient selection – unk
Snell, Stevens, Davenport & Van Ness (US) – November 2013

Note: Some studies use various labels (ME/CFS, CFS, CFS/ME) due to the inconsistent use of these labels worldwide. This list focuses on the research subjects used showing research is applicable to myalgic encephalomyelitis.