Biomedical research findings in ME/CFS that were replicated by multiple groups - discussion thread

ME/CFS Skeptic

ME/CFS Skeptic

Senior Member (Voting Rights)
I'm hoping to get an overview of biomedical abnormalities found in ME/CFS that were replicated by multiple groups. I realize that, due to the paucity of research, most of the findings are unimportant and non-specific with some inconsistencies in the findings but I still think it would be useful to have an overview.

I was thinking of:

Low Natural Killer Cell Cytotoxicity
https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-019-1202-6

increase heart rate at rest, lower at peak - chronotropic intolerance
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824690/
https://www.frontiersin.org/articles/10.3389/fped.2019.00082/full

Decrease in workload at the ventilatory threshold during 2-day CPET.
https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.14138
https://pubmed.ncbi.nlm.nih.gov/24755065/
https://content.iospress.com/articles/work/wor203170
https://www.scirp.org/journal/paperinformation.aspx?paperid=98389
https://pubmed.ncbi.nlm.nih.gov/28782878/
https://academic.oup.com/ptj/article/93/11/1484/2735315
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1836-0

Reduced VOpeak on singular CPET
https://pubmed.ncbi.nlm.nih.gov/30557887/

Reduced cerebral blood flow?
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x
http://europepmc.org/article/med/1491843
https://pubmed.ncbi.nlm.nih.gov/8542261/
https://www.sciencedirect.com/science/article/abs/pii/S0022510X10005666

Increase prevalence of POTS
https://www.frontiersin.org/articles/10.3389/fped.2018.00349/full
https://pubmed.ncbi.nlm.nih.gov/24206536/
https://pubmed.ncbi.nlm.nih.gov/18805903/

...​

Any other suggestions or things that I should look at? Does anyone know what the situation is with hypocortisolism and a attenuated morning response? Are the findings consistent?
 
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Very low ESR

https://ashpublications.org/blood/article/132/Supplement 1/4874/262252/Erythrocyte-Deformability-As-a-Potential-Biomarker

To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.
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https://www.consultant360.com/content/chronic-fatigue-syndrome-update-diagnosis-primary-care

The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0 to 3 mm/h. A normal ESR or one that is in the upper reference range suggests another diagnosis.
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These studies found a reduced Left Ventricle though mainly done by Miwa.

2003
Peckerman
Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome
https://pubmed.ncbi.nlm.nih.gov/12920435/

2008
Miwa
Small Heart Syndrome in Patients withChronic Fatigue Syndrome
https://onlinelibrary.wiley.com/doi/epdf/10.1002/clc.20227

2009
Miwa
Cardiovascular Dysfunction with Low Cardiac Output
Due to a Small Heart in Patients with Chronic Fatigue Syndrome
https://www.jstage.jst.go.jp/article/internalmedicine/48/21/48_21_1849/_pdf

2011
Miwa
Small Heart With Low Cardiac Output for Orthostatic Intolerance in Patients With Chronic Fatigue Syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652296/

2012
Julia Newton
Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging
https://pubmed.ncbi.nlm.nih.gov/21793948/
substantially reduced left ventricular mass (reduced by 23%), end-diastolic volume (30%), stroke volume (29%) and cardiac output (25%).

2015
Miwa
Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle
https://pubmed.ncbi.nlm.nih.gov/24736946/

2016
Olimulder
Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging
https://link.springer.com/article/10.1007/s12471-016-0885-8
"In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function."



ETA:
1994
Dworkin, Lawrie, Lerner
Abnormal left ventricular myocardial dynamics in eleven patients with chronic fatigue syndrome.
https://europepmc.org/article/med/7955743

ETA:
2016
Newton
Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study
https://openheart.bmj.com/content/3/1/e000381

ETA: There are also several studies by van Campen that mention cardiac problems.
 
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Neuroinflammation? Referring to VanElzakker's paper [1] (esp. Table 1) for studies that found significant differences between ME/CFS vs. control groups (not listing others).

[1] VanElzakker MB, Brumfield SA and Lara Mejia PS (2019) Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front. Neurol. 9:1033. https://doi.org/10.3389/fneur.2018.01033

PET

Nakatomi, Y., Mizuno, K., Ishii, A., Wada, Y., Tanaka, M., Tazawa, S., Onoe, K., Fukuda, S., Kawabe, J., Takahashi, K., Kataoka, Y., Shiomi, S., Yamaguti, K., Inaba, M., Kuratsune, H., & Watanabe, Y. (2014). Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(6), 945–950. https://doi.org/10.2967/jnumed.113.131045

There might be older PET or SPECT studies.

MRS -- all show increased ventricular lactate

Mueller, C., Lin, J.C., Sheriff, S. et al. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging and Behavior 14, 562–572 (2020). https://doi.org/10.1007/s11682-018-0029-4
(Lactate levels correlated with levels of fatigue)

Benjamin H. Natelson, Diana Vu, Jeremy D. Coplan, Xiangling Mao, Michelle Blate, Guoxin Kang, Eli Soto, Tolga Kapusuz & Dikoma C. Shungu (2017) Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia, Fatigue: Biomedicine, Health & Behavior, 5:1, 15-20, https://doi.org/10.1080/21641846.2017.1280114

Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, et al. Increased ventricular lactate in chronic fatigue syndrome. III relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology NMR Biomed. (2012) 25:1073–87. https://doi.org/10.1002/nbm.2772

Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, et al. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed. (2010) 23:643–50. https://doi.org/10.1002/nbm.1512
(Lactate levels correlated with levels of fatigue)

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The following ME/CFS research summaries and reviews may be helpful:

General summaries and reviews

Komaroff AL. Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome. JAMA. 2019;322(6):499–500. https://doi.org/10.1001/jama.2019.8312

Cortes Rivera, M., Mastronardi, C., Silva-Aldana, C., Arcos-Burgos, M., & Lidbury, B. (2019). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics, 9(3), 91. https://doi.org/10.3390/diagnostics9030091

ME Association's research summary with links to reports on some consistent findings, e.g. NK cells (May 2020): https://meassociation.org.uk/wp-content/uploads/MEA-M.E.-Research-Summary.pdf

ME Action's research summary (June 2019): https://www.meaction.net/wp-content/uploads/2019/06/19_MEA_Revised_2019_Research_Summary_190610.pdf

Wasn't a research review conducted for the IOM report too? Although now a bit old (2015), it could list some of the older but consistent studies.
EDIT: the IOM report does contain a research review (Chapters 4 & 5, pp. 71-180), but it doesn't exclusively focus on objective findings of abnormalities in ME/CFS. Rather, it goes into great detail about the prevalence and the assessment of ME/CFS symptoms (and then they try to link them to evidence of biological abnormalities when possible).

Specific systematic reviews

Maksoud R, du Preez S, Eaton-Fitch N, Thapaliya K, Barnden L, et al. (2020) A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques. PLOS ONE 15(4): e0232475. https://doi.org/10.1371/journal.pone.0232475

Up to Aug 2019 only, so it doesn't include the recent results on cerebral blood flow from van den Campen et al. and the MRS study by Younger.
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown.
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Huth, T.K., Eaton-Fitch, N., Staines, D. et al. A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID). J Transl Med 18, 198 (2020). https://doi.org/10.1186/s12967-020-02356-2
Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent.

The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ME/SEID.
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Holden, S., Maksoud, R., Eaton-Fitch, N. et al. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease. J Transl Med 18, 290 (2020). https://doi.org/10.1186/s12967-020-02452-3
Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies.
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