Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test

Posted on 08/13/2019 by wames

Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test, by Cara Tomas, Tiffany A Lodge, Michelle Potter, Joanna L Elson, Julia L Newton, Karl J Morten, in Sci Rep. 2019 Aug 7;9(1):11464. doi: 10.1038/s41598-019-47966-z.

 

Research abstract:

The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group.

Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.

Discussion
Given the evidence presented here, we advise that the MES test should not be used as a diagnostic test in its current form as in this study shows there to be no differences between CFS/ME and control results when the MES protocol was followed using fresh blood samples. This is contrary to results from the group who devised the test and offer it to patients.

We explored the impact of delayed sample processing on blood glucose concentration in the collection tube as a possible explanation for the discrepancies in results between our group and the Myhill group. As expected with such high cell numbers the glucose rapidly dropped as the cells utilized the glucose. In addition the neutrophil component on FACS analysis in the white cell fraction showed differences in size and granularity between the 1 hr and 24 hr fractions suggestive of altered properties. Having taken into account a 24 hour delay between blood collection and cell isolation, we have shown decreases in ATP parameters in control cells similar to those seen by the Myhill group in the CFS/ME patients. We suggest that it is potentially the delay between sample collection and cell isolation that is causing the decrease in mitochondrial function previously reported in CFS/ME patients.

While this study used relatively small samples sizes compared with the original study, abnormalities in CFS/ME patients should be reproducible even in small sample sizes given the current use of this test for diagnostic purposes.

The Myhill group have recently altered their protocol to use PBMCs instead of neutrophils, however, this research has not been published and we have no information on the control ranges used and whether they were developed from blood samples processed over 24 hrs. The CFS/ME PBMC study by Tomas et al. did show the utility of using PBMC using the Seahorse extracellular flux analyser to study energetics3. However, the sudden switch to using PBMCs for the MES protocol appears to be as a result of criticism over the use of neutrophils rather than being an evidence lead change. There has been no data published from the Myhill group regarding the suitability of PBMCs with their previously established protocol, or any publication of results with the new cell type. After a diagnosis of CFS/ME is made using the MES test, patients are subsequently sold supplements in order to treat their CFS/ME, despite there being no placebo-controlled trial to show their effectiveness. The first peer-reviewed publication regarding the MES test from the Myhill group came after they had already been using the test and supplement regime with CFS/ME patients despite there being no published evidenced of the effectiveness, reliability, or reproducibility of the test. Additionally, the MES test has not been conducted using other patient groups with fatigue as a core symptom, therefore its specificity for CFS/ME has not been confirmed.

If energetic dysfunction is to be used as a marker of CFS/ME its exact role in the condition needs to be better understood including studying energetic dysfunction in other fatigue groups. Only when we have clearer understanding of the disease process and knowledge of specific factors shown to be different in CFS/ME should we consider developing a diagnostic test to aid in treatment strategies and determining outcome in clinical trials.

Clinicians approached by patients with results from the MES test should be advised to interpret the results with caution, while patients considering paying for the test should be advised of the lack of supporting scientific evidence. The test in its current form does not have the reliability or reproducibility required of a diagnostic test and therefore should not be offered by the NHS or private clinics as a diagnostic test for CFS/ME. Other tests of energetic dysfunction could be developed using the seahorse extracellular flux assay but more research is required as to the meaning of the results in the aetiology of CFS/ME before a test using this approach should be developed.

Comment from the funders of the study, the ME Association: Independent researchers determine mitochondrial test is unreliable and should not be used as test in ME/CFS

Response to the paper ‘Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test’ by Cara Tomas et al

Responding to criticism of their mitochondrial test Myhill & McLaren emphasize that the test has “never been presented as a diagnostic test for CFS/ME.” They query whether the researchers did a true replication as they had offered to do a comparison test in their labs on the same samples but the offer wasn’t accepted. Regarding the technical details, Dr McLaren says he finds it strange that no significant differences were found between fresh & frozen cells, which is at odds with what he & other scientists have found while exploring the test.

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The IDO metabolic trap hypothesis for the etiology of ME/CFS

Posted on 08/12/2019 by wames

The IDO metabolic trap hypothesis for the etiology of ME/CFS, by Alex A Kashi, Ronald W Davis, Robert D Phair in Diagnostics Vol 9, #3, p 82 [July 26, 2019]

 

Research abstract:

Dr Robert Phair

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk.

Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible ! cure.

A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common.

A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation.

This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.

Comment:

The IDO Metabolic Trap July 26, 2019
By Christopher Armstrong, PhD

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Symptom frequency & development of a generic functional disorder symptom scale suitable for use in studies of patients with IBS, FMS, or CFS

Posted on 08/09/2019 by wames

Symptom frequency and development of a generic functional disorder symptom scale suitable for use in studies of patients with irritable bowel syndrome, fibromyalgia syndrome or chronic fatigue syndrome, by Michael E Hyland, Alison M Bacon, Joseph W Lanario, Anthony F Davies in Chronic Diseases and Translational Medicine
Volume 5, Issue 2, June 2019, Pages 129-138 [https://doi.org/10.1016/j.cdtm.2019.05.003]

Research abstract:

Objectives
To describe the extent to which irritable bowel syndrome (IBS), fibromyalgia syndrome (FMS), and chronic fatigue syndrome (CFS) exhibit symptom overlap, and to validate a patient-derived, generic symptom questionnaire.

Methods
A patient-derived 61-item symptom-frequency questionnaire was completed by participants recruited through IBS, FMS and CFS self-help websites. Principal axis factor analysis with oblimin rotation was performed separately for those reporting an IBS, FMS or CFS diagnosis.

Results
Questionnaires were completed by 1751 participants of whom 851 reported more than one of the three diagnoses. Stomach pain on at least a weekly basis was reported by 79% of IBS, 52% of FMS, and 43% of CFS single diagnosis participants. Pain increasing the day after activity was reported by 32% of IBS, 94% of FMS, and 85% of CFS single diagnosis participants. Waking still tired at least once weekly was reported by 75% of IBS, 97% of FMS, and 95% of CFS single diagnosis participants.

Exploratory factor analysis produced consistent results across all three diagnostic groups, the 61 items loading on 12 correlated factors with a single higher order factor on which all items loaded. Frequency analysis led to the rejection of one item (cold sores on or near lips), and freeform reporting by participants of additional symptoms identified an additional five, namely, restless legs, hair loss/brittle hair/thinning, dizziness/balance problems, blurred vision and urination problems.

Conclusions
IBS, FMS and CFS are polysymptomatic spectrum disorders with a wide range of overlapping symptoms, many of which are unrelated to diagnostic criteria. Frequency analysis and factor analysis confirm the validity of using the same questionnaire across different diagnostic categories. The 65-item general symptom questionnaire (GSQ-65) is a valid generic symptom scale suitable for assessing the many different symptoms of people with IBS, FMS and CFS.

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With severe ME, everything is cut off from possibility

Posted on 08/08/2019 by wames

by Greg Crowhurst, Stonebird

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Severe ME: complex, unpredictable symptoms

Posted on 08/08/2019 by wames

Stonebird – the lived experience of severe ME

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The frail teenager set to spend all of her summer holidays in her bedroom

Posted on 08/08/2019 by wames

Wales online blog post: The frail teenager set to spend all of her summer holidays in her bedroom, by Mark Smith, 6 August 2019

Lola Brandrick, 13, from Swansea, is crippled by pain and is constantly exhausted

While all her school mates are out enjoying their summer holidays, poor Lola Brandrick can only dream of joining them.

The 13-year-old is confined to her bed, constantly exhausted and crippled by widespread pain due to a condition which continues to puzzle many doctors.

Even the smallest of tasks can have a devastating impact on the teenager’s energy levels for days, weeks or even months afterwards.

But ever since she was diagnosed with myalgic encephalomyelitis (ME) at the age of seven her family have fought to get her the care and support she desperately needs.

“Having to battle all the time just to be believed has been heartbreaking,” said her mum Victoria Lewis, 45, a fitness instructor and mum-of-two from Swansea.

Read the full article

 

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Severe ME day- 8 August 2019

Posted on 08/08/2019 by wames

Severe ME Day – 8th of August 2019

A day to remember everyone who is suffering or who has ever suffered from severe and very severe Myalgic Encephalomyelitis.

The 25% Group offers support for severe ME.

They have published a 2 page info sheet: How can I help someone with severe ME?

Excerpts:

Even severe illness may not be instantly apparent – for example your friend/relative may be able to walk to the toilet, yet be too ill to go out in a wheelchair, watch TV or even sit up in bed for more than a few minutes.

They may spend most of their energy on something as basic as eating. They may look remarkably well for half an hour or an hour, but then spend the rest of the day in pain in a darkened room.

Flare up of symptoms after activity or stimuli is a key feature of the illness. The activity may be tiny by healthy standards and stimuli things you probably don’t even notice (such as light, movement, or background noise).

Here are a few ways to help: shut doors (to reduce noise), use headphones if watching TV nearby, be aware that talking uses energy – ask your friend/relative how long the conversation needs to be and try to stick to that. If they seem particularly energetic, ironically this may be a sign that they are doing too much (and running on adrenaline!) – ask if they need a rest.

Stonebird: the lived experience of severe ME – a website with information and help for and about people with severe ME, such as Severe ME: notes for carers

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Metabolic features of Gulf War illness [similarities & differences to CFS]

Posted on 08/06/2019 by wames

Metabolic features of Gulf War illness, by Robert K Naviaux, Jane C Naviaux, Kefeng Li, Lin Wang, Jonathan M Monk, A Taylor Bright, Hayley J Koslik, Janis B Ritchie, Beatrice A Golomb in PLoS ONE 14(7): e0219531 [Published: July 26, 2019] https://doi.org/10.1371/journal.pone.0219531

Research abstract:

Background
More than 230,000 veterans—about 1/3 of US personnel deployed in the 1990–1991 Persian Gulf War—developed chronic, multi-symptom health problems now called “Gulf War illness” (GWI), for which mechanisms and objective diagnostic signatures continue to be sought.

Methods
Targeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. 40 male participants, included 20 veterans who met both Kansas and CDC diagnostic criteria for GWI and 20 nonveteran controls without similar symptoms that were 1:1 matched to GWI cases by age, sex, and ethnicity. Serum samples were collected and archived at -80° C prior to testing. 358 metabolites from 46 biochemical pathways were measured by hydrophilic interaction liquid chromatography and tandem mass spectrometry.

Metabolic similarities & differences between Gulf War illness & CFS

Results
Veterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Lipid abnormalities accounted for 78% of the metabolic impact. Fifteen ceramides and sphingomyelins, and four phosphatidylcholine lipids were increased.

Five of the 8 pathways were shared with the previously reported metabolic phenotype of males with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, 4 of the 5 shared pathways were regulated in opposite directions; key pathways that were up-regulated in GWI were down-regulated in ME/CFS. The single pathway regulated in the same direction was purines, which were decreased.

Conclusions
Our data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Metabolomic differences between GWI and ME/CFS show that common clinical symptoms like fatigue can have different chemical mechanisms and different diagnostic implications. Larger studies will be needed to validate these findings.

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CFS – an illness without disease?

Posted on 08/05/2019 by wames

CFS – an illness without disease?

In a recent paper psychologist Prof Michael Sharpe and sociologist Monica Greco discuss CFS as an ‘illness without disease’ in comparison to cancer, a known disease, and argued that, while illness-focused treatments like CBT and GET can ameliorate the symptom of fatigue, there is also a need to address the paradoxical predicament of illness-without-disease that patients find themselves in.

Chronic fatigue syndrome and an illness-focused approach to care: Controversy, morality and paradox, by Michael Sharpe and Monica Greco in Medical humanities 2019; 45: 183-187.

Responses to this paper:

More science and less philosophy needed, by Susanna Agardy, Retired due to ME/CFS

At the heart of Sharpe and Greco’s article lies the complaint that while cancer patients accept CBT/GET treatments for their fatigue, ME/CFS patients reject these treatments. Of course they do! ME/CFS patients have a different disease, the main feature of which makes them unable to increase exertion.

The article contains several omissions and misinterpretations…

The argument provides a rationale for a science-denying approach to ME/CFS and endangers patient welfare. It is a departure from the previous model of more directly trying to correct patients’ ‘dysfunctional thinking’ and consequent ‘deconditioning’. This version of the Emperor’s New Clothes is also unacceptable…

Science, physiology and clarification of misleading terms, by Adi C Wood, Scientist ME

The view held by these authors that chronic fatigue syndrome is an illness without disease is at odds with the findings of the National Academy of Science, physiological and bio-medical researchers worldwide…

Sharp & Greco want us to abandon science, by Michael N Dyson, Computer Technician

Sharp & Greco state: “This new approach assumes that the reality of illness has a complex and indeterminate character”.

If by this they mean that the cause of any given illness cannot in principle be determined – as I suspect they are – then it is clear that they are abandoning the scientific enterprise. We ask Sharp and Greco: do they say illness is an effect? If they do then ipso facto they concede it has a cause or causes, and it is the task of science, in the broadest sense, to elucidate those causes…

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MAGENTA trial comment: ‘Targeting activity levels in ME/CFS

Posted on 08/02/2019 by wames

Michiel Tack queries some conclusions of the recently published MAGENTA trial paper.

Physical activity patterns among children and adolescents with mild-to-moderate chronic fatigue syndrome/myalgic encephalomyelitis, by Emma Solomon-Moore, Russell Jago, Lucy Beasant, Amberly Brigden, Esther Crawley in BMJ Paediatrics Open Volume 3, Issue 1, 2019

The study concludes:

  • Children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are less active than the general child population, but not all are inactive. 9.4% of participants met physical activity recommendations.
  • Compared with being ‘inactive’, ‘active’ children reported greater physical function but increased anxiety, while ‘lightly’ active children reported greater physical function and reduced fatigue.
  • Paediatricians need to recognise that physical activity varies between patients with CFS/ME when they recommend treatment.

Comment: Targeting activity levels in ME/CFS,  by Michiel Tack in BMJ Paediatrics Open [Published on: 15 July 2019]

Contrary to what is claimed by Solomon-Moore et al., [1] the study by Van der Werf et al., (reference 17) [2] found little evidence of a boom and bust activity pattern in adult patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The Dutch researchers measured physical activity using actimeters worn for 12 consecutive days. There was no significant difference in day-to-day fluctuations in physical activity between ME/CFS patients and controls. The peak amplitude and peak duration of physical activity were larger in controls than in ME/CFS patients while the latter had longer rest duration after an activity peak. Another actimeter study [3] found no supporting evidence of a more fluctuating activity pattern in patients with ME/CFS compared to controls, during the day, nor during consecutive days.

Now, Solomon-Moore et al. report that in children and adolescents with ME/CFS, no fluctuating active or boom-bust physical activity pattern could be identified.

It would be helpful if the authors could clarify how the actimeter data impacted the treatments in the MAGENTA trial. According to the trial protocol [4], one of the interventions aimed to “convert a boom–bust pattern of activity (lots 1 day and little the next) to a baseline with the same daily amount”. Was this aspect removed from the intervention now that participants showed little indication of a boom–bust activity pattern? Or were young ME/CFS patients instructed to correct illness behavior they did not display when tested objectively?

Solomon-Moore et al., [1] also report that 9.4% of participants achieved government recommended levels of physical activity for children and adolescents, namely a minimum of 60 minutes of moderate to vigorous physical activity per day. This is of interest given that approximately half of healthy children and adolescents do not reach this target. [1] These results indicate that activity patterns are unlikely to be a key factor in perpetuating ME/CFS symptoms, at least for this subgroup. Nonetheless, one of the interventions in the MAGENTA trial aims for a gradual increase in physical activity by prescribing exercise targets. Were ME/CFS patients who already met government health recommendations for physical activity also instructed to increase their amount of exercise by 10-20% a week or were they exempted?

I look forward to reading the authors’ response to these questions.

References

[1] Solomon-Moore E, Jago R, Beasant L, Brigden A, Crawley E. Physical activity patterns among children and adolescents with mild-to-moderate chronic fatigue syndrome/myalgic encephalomyelitis. BMJ Paediatr Open. 2019 May 2;3(1):e000425. 2019.

[2] van der Werf SP, Prins JB, Vercoulen JH, et al. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000;49:373–9.

[3] Meeus M, van Eupen I, van Baarle E, De Boeck V, Luyckx A, Kos D, et al. Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011 Nov;92(11):1820-6.

[4] Brigden A, Beasant L, Hollingworth W, et al. Managed activity graded exercise iN teenagers and pre-Adolescents (magenta) feasibility randomised controlled trial: study protocol. BMJ Open 2016;6:e011255.

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