Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection July 2020 Townsend et al

"The lack of distinct immune signature, coupled with the association with depression, lends credence to the multifactorial aetiology of CFS [59]. It also supports the use of non-pharmacological interventions for fatigue management and provides no basis for the use of immunomodulation in treating post-COVID fatigue."

Above is from the discussion.
 
MEMarge said:
"The lack of distinct immune signature, coupled with the association with depression, lends credence to the multifactorial aetiology of CFS [59]. It also supports the use of non-pharmacological interventions for fatigue management and provides no basis for the use of immunomodulation in treating post-COVID fatigue."

Above is from the discussion.
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:banghead:
 
Townsend et al Nov 2020 said:
CFS may be the end point of a variety of distinct pathways or may be the consequence of pathological changes that are no longer systemically detectable. Despite a lack of distinct immunological findings, it is accepted that CFS can occur in the absence of demonstrable disease [57, 58]. The lack of distinct immune signature, coupled with the association with depression, lends credence to the multifactorial aetiology of CFS [59]. It also supports the use of non-pharmacological interventions for fatigue management and provides no basis for the use of immunomodulation in treating post-COVID fatigue.
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These authors have about as much insight as a brick wall. Did it not occur to them that perhaps the pathology is not in the small number of places where people keep looking?

It's like losing your keys, you look on the table and the couch and then assume they're lost forever, when really you just haven't looked in many places.

Here is the paper they reference with regards to illness-without-demonstrable-disease. It is bad, very bad: potential readers, you have been warned.
https://sci-hub.st/10.1093/clinids/13.Supplement_1.S138
 
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Snow Leopard said:
These authors have about as much insight as a brick wall. Did it not occur to them that perhaps the pathology is not in the small number of places where people keep looking?

It's like losing your keys, you look on the table and the couch and then assume they're lost forever, when really you just haven't looked in many places.

Here is the paper they reference with regards to illness-without-demonstrable-disease. It is bad, very bad: potential readers, you have been warned.
https://sci-hub.st/10.1093/clinids/13.Supplement_1.S138
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This is a thing of beauty (unfortunately not rare beauty):
"Despite a lack of distinct immunological findings, it is accepted that CFS can occur in the absence of demonstrable disease [57, 58]."

Possibly re-phrase as:
Despite a lack of distinct immunological findings [replace "distinct immunological findings" with "any credible evidence"], it is accepted [replace
"it is accepted" with "we accept"] that CFS can occur in the absence of demonstrable disease [57, 58]. "
 
Not the Leighton Cluff who started out with a cohort of 540 men and 60 women from Fort Detrick, whittled them down to 480 men, but produced the same number of positive results, notwithstanding that one of them was originally said to be female.
 
Lest any body take that paper by Cluff too seriously I would just point out one further issue. He says

It was striking that virtually all of those individuals who had CFS following acute influenza had appeared in the clinic complaining of being sick, but fewer than 4 % of those who did not have delayed convalescence came in complaining of being sick.

Despite having the facilities and resources of the biowarfare staff medical provision, and funding from the Chemical Corps, the follow up period for patients was between three and six weeks. There is no indication that any later data were collected. It is therefore not clear upon what basis he was able to make any comments about CFS, or to generalise his findings. It seems a strange omission. It should not have been difficult to arrange to see them again at, say, six months.

 
When the authors uploaded their pre-print to medRxiv on July 30th, I sent the following mail to Dr Townsend:
Dear Dr Townsend,

[xxx]. I would like to thank you for your work on tracking post-COVID19 fatigue in affected patients which you have recently published as a pre-print on medRxiv [1].

I would like to share three major concerns that I have regarding the paper and also some suggestions on how these may be addressed.

1) Discussion: suggestion of graded exercise therapy and cognitive behavioural therapy VS. rest and pacing

A suite of interventions, including graded exercise and cognitive behavioural therapy, are needed to manage CFS and may be relevant to post infectious fatigue (57-59).
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In CFS, thousands of patients have reported harm from graded exercise therapy (GET) and absence of efficacy from CBT [1-3]. However, NHS clinics do not have a mechanism to report harm from GET and as such do not record adverse events from GET [4].

For post-COVID19 fatigue, NICE has stated that GET as in CFS should not be assumed to be a treatment [5]. Indeed, NICE is currently revising its guidelines on CFS and points out that the evidence base on GET is one of the main issues that it will address.

Professor Paul Garner, himself suffering from prolonged COVID19 symptoms including fatigue and post-exertional malaise, has been very vocal about promoting rest and activity management strategies (known as "pacing") [5, 6]. The ME Association has further information and recommendations on post-COVID19 fatigue from their honorary medical advisor, Dr Charles Shepherd [7].

The main paper cited above is the PACE trial (White et al., 2011). Many issues have been raised concerning the methodology used by the investigators and how they have impacted the results that they published in the Lancet. As a result, more than 100 scientists (clinicians, researchers and academicians) have called for the retraction of the results [8].

Some of the most egregious flaws were:

- unblinded trial with subjective outcomes despite one objective outcome (actimetry) showing no improvement

- overly broad (Oxford) diagnostic criteria, of which the NIH concluded that they may cause harm and should be retired

- post-hoc outcome switching

- sending a newsletter to participants during the trial to share positive results that may have impacted positive bias

- fighting in court against a FOI request to release anonymous information from the clinical trial, on which QMUL (Dr White's institution) spent £220,000, but ultimately lost

- conflicts of interest with insurance companies and DWP

For a summary on the methodology flaws, please see [9] or [10] (a full reanalysis is provided in [11]). Further details on the biases and conflicts of interests are given in [12].

Trials on GET and CBT for CFS have been plagued with the same flaws; reanalyses of the current Cochrane review for GET [13] and CBT [14] in CFS highlight them in great detail. The Cochrane collaboration has appointed an independent advisory group, led by Hilda Bastian, for the upcoming revision of its review on GET [15].

The CDC has stopped recommending GET and CBT for CFS [16] and so has the Dutch Health Council [17]. Instead, the CDC advise pacing activities [18].

The Workwell Foundation, a group of physiotherapists who have been researching CFS for more than 20 years, have stated that they oppose GET [19].

2) Introduction: CFS is not unexplained persistent fatigue lasting more than 6 months, but is characterized by post-exertional malaise

Historically, the consideration of CFS as unexplained persistent fatigue lasting more than 6 months has been popularized by the CDC-1994 (Fukuda) criteria [20]. These criteria have been widely used to conduct research on the condition.

However, they have been criticized for not requiring the hallmark symptom of ME/CFS: post-exertional malaise (PEM). PEM is a serious aggravation of symptoms following physical or cognitive exertion, most often delayed by 24-48h, that can be objectively measured via the 2-day CPET [21, 22]. In this regard, the Fukuda criteria are not very different from the Oxford criteria (cf. 1)) and should thus not be used anymore.

Revised diagnostic criteria were published in 2015 by the National Academy of Medicine (NAM) in their seminal report on CFS [23] and are now endorsed by the CDC [24]. They require not only a substantial reduction of activity levels that is accompanied by a fatigue lasting more than 6 months, but also post-exertional malaise, and cognitive deficiences or orthostatic intolerance.

The stricter criteria from either the Canadian (CCC, [25]) or the International consensus (ICC, [26]), which both require PEM, are used in research and as a routine tool for confirming a diagnosis of CFS by specialists. For example, the NIH intramural study on ME/CFS uses the CCC [27], as did the phase 3 clinical trial for rituximab [28].

Direct links to criteria:
NAM -> https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html
CCC -> https://me-pedia.org/wiki/Canadian_Consensus_Criteria
ICC -> https://me-pedia.org/wiki/International_Consensus_Criteria#Criteria

3) Fatigue Assessment : the Chalder Fatigue Questionnaire is not a reliable measurement of fatigue

The Chalder Fatigue Questionnaire, also used in the PACE trial, has been closely evaluated. A submission detailing its flaws to the NIH and CDC working group on ME/CFS was made and is available here: https://huisartsvink.files.wordpress.com/2018/08/wilshire-mcphee-cfq-cde-critique-for-s4me-final.pdf

I hope you can consider these concerns and hopefully change at least 1) in your paper. Too many CFS patients, who initially presented as having "just" post-viral fatigue with (undiagnosed) PEM, have been harmed by GET. GET should not in any way, shape or form be recommended anymore ; instead, rest and pacing activities are key to improving recovery from a viral infection.

Very sincerely,

[xxx]

References

[1] Geraghty, K., Hann, M., & Kurtev, S. (2019). Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. Journal of Health Psychology, 24(10), 1318–1333. https://doi.org/10.1177/1359105317726152

[2] https://www.meaction.net/2019/04/03/get-and-cbt-are-not-safe-for-me-summary-of-survey-results/

[3] https://www.actionforme.org.uk/uploads/images/2020/02/Big-Survey-GET-and-GET-for-people-with-ME.pdf

[4] McPhee, G., Baldwin, A., Kindlon, T., & Hughes, B. M. (2019). Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England. Journal of Health Psychology. https://doi.org/10.1177/1359105319854532

[5] https://www.bmj.com/content/370/bmj.m2912

[6] https://blogs.bmj.com/bmj/2020/06/2...d-cameras-unknown-limits-and-harsh-penalties/

[7] https://meassociation.org.uk/wp-con...-Following-Coronavirus-Infection-30.04.20.pdf

[8] https://www.virology.ws/2018/08/13/trial-by-error-open-letter-to-the-lancet-version-3-0/

[9] https://www.s4me.info/docs/PaceBriefing3.pdf

[10] https://me-pedia.org/wiki/PACE_trial#Criticisms_of_the_study

[11] Wilshire, C.E., Kindlon, T., Courtney, R. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol 6, 6 (2018). https://doi.org/10.1186/s40359-018-0218-3

[12] Geraghty, K. J. (2017). Further commentary on the PACE trial: Biased methods and unreliable outcomes. Journal of Health Psychology, 22(9), 1209–1216. https://doi.org/10.1177/1359105317714486

[13] Vink M, Vink-Niese F. Graded exercise therapy does not restore the ability to work in ME/CFS - Rethinking of a Cochrane review. Work. 2020;66(2):283-308. https://doi.org/10.3233/WOR-203174

[14] Vink, M., & Vink-Niese, A. (2019). Cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective. Re-analysis of a Cochrane review. Health psychology open, 6(1), 2055102919840614. https://doi.org/10.1177/2055102919840614

[15] https://www.cochrane.org/news/appointment-lead-independent-advisory-group

[16] https://www.statnews.com/2017/09/25/chronic-fatigue-syndrome-cdc/

[17] https://www.healthcouncil.nl/documents/advisory-reports/2018/03/19/me-cfs

[18] https://www.cdc.gov/me-cfs/healthca...-mecfs/treating-most-disruptive-symptoms.html

[19] https://workwellfoundation.org/wp-c...T-Letter-to-Health-Care-Providers-v4-30-2.pdf

[20] https://me-pedia.org/wiki/Fukuda_criteria

[21] Stevens S, Snell C, Stevens J, Keller B and VanNess JM (2018) Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Pediatr. 6:242. https://doi.org/10.3389/fped.2018.00242

[22] https://www.dialogues-mecfs.co.uk/films/post-exertional-malaise/

[23] Institute of Medicine. 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press. https://doi.org/10.17226/19012.

[24] https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html

[25] Bruce M. Carruthers, Anil Kumar Jain, Kenny L. De Meirleir, Daniel L. Peterson, Nancy G. Klimas, A. Martin Lerner, Alison C. Bested, Pierre Flor-Henry, Pradip Joshi, A. C. Peter Powles, Jeffrey A. Sherkey & Marjorie I. van de Sande (2003) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Journal of Chronic Fatigue Syndrome, 11:1, 7-115, DOI: 10.1300/J092v11n01_02
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I received a reply within the next hour, in which Dr Townsend said he would "ensure that [the non-necessary inclusion of graded exercise] is clarified following peer review and prior to formal publication":
Dear [xxx],

Many thanks for your detailed feedback. I agree broadly with your points.
Regarding the use of graded exercise: I am sorry that this is interpreted as being globally recommended. We are aware of the literature showing that there are some patient groups that have a good response, but others that have no response and some that have a negative response. We would suggest that all patients with these symptoms are seen by a multidisciplinary team and have individualised treatment plans, which will incorporate a suite of interventions and will not necessarily include graded exercise.
We will ensure that this is clarified following peer review and prior to formal publication.
Regarding the CFS diagnostic criteria: it is important to state that we are not assessing CFS here. Our follow up interval is too short for this. Rather, we are using some elements of CFS assessment to try and describe what we see as a specific post-COVID syndrome.
However, this remains a very new area and will require a lot more research. I have no doubt that this will change rapidly, and I would hope that more research is published to help us understand this better.

Again, I want to thank you for your feedback. This is one of the best aspects of MedRx.

Kind regards

Liam Townsend
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The authors left the text as it was in the pre-print, and it now appears unchanged in the published version of the article. Peer review history on PLoS ONE indicates they did not propose changes during the process.
 
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cassava7 said:
The authors left the text as it was in the pre-print, and it now appears unchanged in the published version of the article. Peer review history on PLoS ONE indicates they did not propose changes during the process.
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Sigh. Not the first time genuine concerns from patients goes completely ignored by researchers...

Given the citation of the aforementioned Leighton Cluff paper which shows clear contempt for patients (not to mention ableist and racist), I'm not overly surprised.
 
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