A Case Study of Successful Application of the Principles of ME/CFS Care to an Individual with Long COVID, 2023, Petracek, Rowe et al

[Sly Saint]

Abstract:
Persistent fatigue is one of the most common symptoms of post-COVID conditions, also termed long COVID. At the extreme end of the severity spectrum, some individuals with long COVID also meet the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), raising the possibility that symptom management approaches for ME/CFS may benefit some long COVID patients. We describe the long-term outcomes of a 19-year-old male who developed profound impairment consistent with ME/CFS after a SARS-CoV-2 infection early in the pandemic.

We evaluated and treated him using our clinic’s approach to ME/CFS. This included a history and physical examination that ascertained joint hypermobility, pathological reflexes, physical therapy maneuvers to look for a range of motion restrictions in the limbs and spine, orthostatic testing, and screening laboratory studies. He was found to have profound postural tachycardia syndrome, several ranges of motion restrictions, and mast cell activation syndrome.

He was treated according to our clinic’s guidelines for managing ME/CFS, which included manual physical therapy maneuvers and both non-pharmacologic measures and medications directed at postural tachycardia syndrome and mast cell activation. He experienced significant improvement in his symptoms over 30 months. His case emphasizes how the application of the principles of treating ME/CFS has the potential to provide a direction for treating long COVID.

https://www.mdpi.com/2227-9032/11/6/865

 

[rvallee]

significant improvement in his symptoms over 30 months

So, time.

Ascribing any effect here is simply not valid. Even at 12 months it should take a huge amount of evidence to give credit to some intervention or another, otherwise this makes as much sense as giving credit to some dance ritual for having solved major flooding, years after it happened. As if there's some kind of... evaporative process happening. We need medicine to respect basic reasoning.

By far the most common factor mentioned in recovery for long haulers is time. It clearly plays a significant role, and this has major implications for what the cause and resolution are.

The most frustrating thing about this is that the fact that time is a major factor is significant, that whatever process is involved has to account for that, but it's barely researched because all medical research on chronic illness uses single points in time.

Because whatever the factors are, there are people who recover spontaneously. They went to sleep feeling horrible and woke up not feeling ill anymore. Not always full resolution, but sometimes. So this factor can work on such a time scale. Sometimes it's slow improvement over days or weeks. Taking months makes no sense here other than natural recovery.

 

[Hutan]

Yep, this paper is not science, it's advertising. Advertising that ignores reality. There's probably a specific word for that.

 

[Denise]

Interesting discussion on this.
The article came across differently to me.
I understood the authors to be saying that appropriate diagnosis and careful, well thought out interventions (that seem to have had some degree of success with PwME), when done early on, have a reasonable chance of making a difference in level of function in those with Long COVID.

 

[bobbler]

Interesting discussion on this.
The article came across differently to me.
I understood the authors to be saying that appropriate diagnosis and careful, well thought out interventions (that seem to have had some degree of success with PwME), when done early on, have a reasonable chance of making a difference in level of function in those with Long COVID.

Agree that that point is one that needs to be noted more. There is no 'cure' currently, but we've gone through a decade where certainly in the UK many/most (?) received nothing on principle. Including for related conditions that began at the same time, trying things that might help in some and don't do terrible harm (and there might have been a clinical guide to help on who/when they tend to work), comorbidities and sometimes basic medical care - until recently (when 'MUS' has spread to other conditions) basically didn't get things those who weren't labelled would have done as standard.

So given that 3 year time period is pretty key, far from taking other solveable issues off the plate/body - no matter how small they might seem - these things were purposefully accumulating in these individuals as a load of illness in a way others didn't have that.

In the current situation that seems to be the best chance people have - decent advice that says that is the time period those around them need to get their head around taking it seriously for if there is to be a chance of any natural improvement/give people the best chance. And that informing future plans if the same people do recover but then end up taking a big dip again.

The authors themselves note some or all of the recovery might have been spontaneous over time. But from reading this none of these ideas were applied without common sense judgement e.g. they looked into the history of allergies and asthma and tried out different things for POTS to see if they helped. And it is a case study rather than a trial and isn't too bad an indicator of how one might approach doing what is worth trying without suggesting this necessarily means he either had ME/CFS or that any of these things were a cure for LC.

I can't see what good leaving someone without treatment for POTS does for ME with all the crashes and exertion of that for example. And whatever views might be on MCAS if someone had allergies and a certain combo of antihistamines helps with symptoms I don't get the issue and particularly if they've raged when their ME has gone on a downward tilt etc. And we know that not only is ME/CFS (and this is LC) probably different types but people who get it have different bodies and comorbidities and severities so until there is a miracle cure we need to get people's minds back around some sort of clinical approach.

And for methodology purposes too - because if some things on that list might have been standard and help a bit and others are 'woo' and it is all put down to that woo thing we've an issue. But I do think that if we had decent clinics that could be making sure any standard things had been tackled that is more 'evening the field' vs leaving people untreated making for it being 'homogenous' sample isn't it? ie any trial has stabilised patients with whatever standard medical care is relevant to them before you see whether 'that one trialled treatment' makes a difference?

 

[Mij]

"He was treated according to our clinic’s guidelines for managing ME/CFS, which included manual physical therapy maneuvers and both non-pharmacologic measures and medications directed at postural tachycardia syndrome and mast cell activation".

How does this apply specifically to M.E? This could apply to many other health conditions.

What type of manual maneuvers help pwME?

 

[Hutan]

We reported his short-term history after infection in an earlier case series [6] and here describe in greater detail his response over 30 months, emphasizing how the application of the lessons learned in managing ME/CFS informed the treatment of his long COVID.

Here's the thread on that earlier case series
Petracek, L.S.; Suskauer, S.J.; Vickers, R.F.; Patel, N.R.; Violand, R.L.; Swope, R.L.; Rowe, P.C. Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19 2021

I wonder if we are going to see similarly detailed case studies for the other two people mentioned in that earlier case series.

 

[Jonathan Edwards]

There's probably a specific word for that.

Yes, misrepresentation.

 

[Hutan]

Because 60% of adolescent and young adult ME/CFS patients in our studies meet the Beighton score criteria for joint hypermobility (defined as a score of 4 or higher), compared to only 24% of healthy controls, we obtain a Beighton score in all patients. The odds ratio for having joint hypermobility in an adolescent or young adult with ME/CFS is 3.5 (95% confidence interval 1.6–7.5) [20].
Other work has shown high rates of biomechanical dysfunction in those with ME/CFS [12,21]. After controlling for the degree of joint hypermobility, ME/CFS patients are more likely to have a restricted range of motion of the limbs and spine than are healthy controls on an 11-point range of motion (ROM) score in which higher scores reflect worse dysfunction [20]. The median ROM score for patients is 5, compared to 2 for healthy controls (p < 0.001). As a result, we include in our physical examination a number of simple measures of range of motion that are usually part of a physical therapist’s evaluation (seated slump testing, ankle dorsiflexion, passive straight leg raise, brachial plexus strain testing, prone knee bend, and prone press up).

That bolded sentence required a bit more of an explanation, I think. On the one hand, the ME/CFS patients have higher than normal range of motion in joints, but some of the joints have lower than normal range of motion? and both things are indicative of ME/CFS pathology?

 

[Jonathan Edwards]

I understood the authors to be saying that appropriate diagnosis and careful, well thought out interventions (that seem to have had some degree of success with PwME), when done early on, have a reasonable chance of making a difference in level of function in those with Long COVID.

That is what they are saying but without a scrap of evidence.
We don't even have evidence for success in PwME, or well thinking out, really.

I have no idea what restriction of movement has to do with it, especially if it supposed to be related to more unrestricted movement - i.e. hypermobility.
I get the impression that this group has lost the plot.

Edit: cross posted with Hutan.
Yes, this is getting a bit topsy-turvy.

 

[Hutan]

His Beighton score was 3/9. He had 2+ symmetrical deep-tendon reflexes but a bilaterally positive Hoffman sign. Examination of his range of motion revealed limitations in several areas. On seated slump testing, which involves neck and spinal flexion followed by unilateral leg extension, he lacked 30 degrees of full leg extension on the right and 60 degrees on the left. His passive straight leg raise reached end-range at 35 degrees bilaterally which was restricted for his degree of overall flexibility.

Upper limb neurodynamic testing with a median nerve bias elicited stretch across the antecubital fossa at 130 degrees of elbow extension on the left and 140 degrees on the right (normal is >170 degrees of elbow extension). A cervical spine MRI showed no cervical stenosis or cerebellar tonsillar descent below the foramen magnum.

A Beighton score of 3/9 is normal.

I'm not a physiotherapist, and I'm not sure what is being said about these other tests. But, as an example, that elbow extension test isn't saying that the man's range of motion at the elbow was 130 or 140 degrees - when, give or take a few degrees, 180 degrees would be normal. Instead, the authors seem to be saying that there was reported stretch at that joint at 130/140 degrees of elbow extension. Isn't there some subjectivity in that measure? A difference between a sensation of stretch at 130/140 degrees and 170 degrees, especially when assessed by another person, seems rather subtle to me. But perhaps I'm not interpreting that correctly? Can anyone interpret that bolded sentence for me?

 

[Jonathan Edwards]

Instead, the authors seem to be saying that there was reported stretch at that joint at 130/140 degrees of elbow extension. Isn't there some subjectivity in that measure? A difference between a sensation of stretch at 130/140 degrees and 170 degrees, especially when assessed by another person, seems rather subtle to me. But perhaps I'm not interpreting that correctly? Can anyone interpret that bolded sentence for me?

I think this is a median nerve stretch test. You probably put the hand into a position that already tightens the nerve - maybe wrist extension - and then extend the elbow. It would be a median nerve version of what is known as the sciatic stretch test - straight leg raise with dorsiflexion of the foot at the ankle.

These tests produce discomfort and pins and needles in most people at some point. I had physios doing them on me when I had sciatica and carpal tunnel syndrome and coming out with 'expert advice' on my neurodynamics. Except that what they said didn't fit what I actually knew was the case from the images and my symptom pattern. Physios love these tests but they are pretty dubious. There is another one called the slump test for spinal nerve stretching in general. In an acute prolapsed disc the sciatic stretch test can be dramatically clear - able to raise the good leg to 70 degrees and the bad one to twenty with a yell of pain.

I don't know who the authors on this are but I suspect at least one is a physio and this is typical of the sort of self-fulfilling work-up procedures they love to go through.

 

[Hutan]

The man's plasma histamine at 3.5 ng/mL was high (normal range <1.8 ng/mL). Histamine at that level sounds as though it could cause all sorts of symptoms. That is interesting. I wonder how common that is in ME/CFS and how many people benefit from various anti-histamines.

And very mildly high chromagranin.

High chromogranin a levels can be a sign of cancer, among other things, and yet this case study makes no mention of that possibility, or any tests done to rule that out.
(Incidentally, as I googled chromogranin, there's a case study of a youngish man with high chromogranin who had what was initially diagnosed as functional dyspepsia - for which CBT is often prescribed - he turned out to have pancreatic cancer. Another example where dismissal with a 'oh, you just need to think about your symptoms differently and calm down' would not lead to a good outcome.)

 

[Hutan]

Laboratory testing on several occasions during the first year of post-COVID illness confirmed an elevated plasma histamine (3.5 ng/mL, 3.2 ng/mL, 2.0 ng/mL, with a normal range of ≤1.8), as well as a mild elevation in chromogranin A (144 ng/mL, with a normal range of 25–140), which can be released by mast cells [30]. We interpreted these results as consistent with mast cell activation syndrome, using the “consensus-2 definition” [30,39]. This definition requires the presence of symptoms of increased mast cell activity along with one of the following minor criteria: (1) multifocal or disseminated infiltrates of mast cells in marrow and/or extracutaneous organ(s), (2) abnormal spindle-shaped morphology in >25% of mast cells in marrow or other extracutaneous organs, (3) abnormal mast cell expression of CD2 and/or CD25, (4) genetic changes shown to increase mast cell activity, (5) above-normal levels of tryptase, histamine or its metabolites, heparin, chromogranin A, or other mast cell mediators, (6) symptomatic response to inhibitors of mast cell activation or mast cell mediator production or action.

Our patient met the major criterion as well as minor criteria 5 and 6. We did not test for the other criteria as these were deemed unnecessary due to the cost and time involved, especially since he already clearly met the diagnosis.

Just further on the mast cell diagnosis. To a man with a hammer, the world looks like a nail. Perhaps this clinic did consider a range of alternative causes for the histamine and chromogranin A levels, but this case study does not report that. There are a number of other diagnoses that would also fit. I think people going to specialist clinics need to be aware of the possibility that other diagnoses may not be sufficiently considered - a bit of confirmatory bias may be applied.

We added escitalopram to address the increase in sensory overstimulation that had appeared after COVID, with a background of personal and family history of mild anxiety.

I feel really uneasy about this. The young man is a bit worried about being so sick, and he has postural orthostatic tachycardia, which won't be helping with feeling calm. So, fair enough, he feels a bit anxious (the level of anxiety is only ever referred to as 'mild'). His symptoms seem to improve over time, so why leap into giving him escitalopram? Table 4 notes that he had 'improvement in response to stressors and response to sensory stimuli at a dose of 5 mg/day, but an increase in fatigue at 10 mg/day'.

Escitalopram has some unpleasant or even dangerous side effects:

Commonly reported side effects of escitalopram include: diarrhea, drowsiness, ejaculatory disorder, headache, insomnia, nausea, and delayed ejaculation. Other side effects include: anorgasmia, constipation, dizziness, dyspepsia, fatigue, decreased libido, diaphoresis, and xerostomia.

Rare side effects: Coma, confusion, decreased urine output, dizziness, fast or irregular heartbeat, headache, increased thirst, muscle pain or cramps, nausea or vomiting, seizures, swelling of the face, ankles, or hands, trouble breathing, unusual tiredness or weakness

Is masking what is probably a very normal and probably manageable level of anxiety really worth the risk of those side effects, some of which are also his existing symptoms? I doubt it.

 

[Hutan]

On low dose naltrexone:

We added naltrexone, which has some utility for addressing symptoms in both fibromyalgia and ME/CFS [40,41,42]. This was associated with an improvement in energy and overall function (Table 4 and Figure 4).
3.3. Comment: Naltrexone
In a retrospective study of 218 patients with ME/CFS, naltrexone was associated with self-reported improvement of symptoms in 73.9%, most commonly in alertness, physical performance, and cognitive dysfunction [40]. Cabanas and colleagues found that the impaired function of Transient Receptor Potential Melastatin 3 (TRPM3)—nociceptor channels thought to be involved in the pathophysiology of ME/CFS—was restored by naltrexone [41].

Reference 40 - the 218 patients study:

Polo, O.; Pesonen, P.; Tuominen, E. Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 2019

We have a thread on it that is worth a read:Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 2019, Polo et al.
It was an open label retrospective study; the clinic with the medical records that this paper was based on has since been closed down.

Reference 41

Cabanas, H.; Muraki, K.; Staines, D.; Marshall-Gradisnik, S. Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Forum thread here:
Potential therapeutic benefit of Low Dose Naltrexone in [ME/CFS]: Role of Transient Receptor Potential Melastatin 3 ion channels, 2021, Cabanas et al
Again, well worth a read. There were only 9 patients, they were recruited after having been on LDN for at least 4 weeks. So these patients had already demonstrated their willingness to consider the possibility that LDN was helpful. There were some rather random self-reported benefits - but given the open-label and framing, these mean little. The researchers found that the TRPM3 ion channels in the 9 patients were functioning like the TRPM3 ion channels in the 9 controls. But they didn't measure TRPM3 channels function in this study before the LDN was started.

Citing these papers as evidence to justify prescribing any drug, especially to young people, should be unacceptable. Even the authors of the papers called for randomised controlled trials. We need better from people that are held up to be expert ME/CFS clinicians.