Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection, 2019, Wyller et al

[Andy]

Might be more appropriate in Other Health News and Research sub-forum, especially considering who the authors are, but thought it could start here.

Abstract
Introduction
Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

Materials and methods
A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

Results
The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p=0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 x 106 cells/L, p=0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p=0.01) and plasma epinephrine (363 vs 237 nmol/L, p=0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p=0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p=0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B= 4.5 x 10-4, p<0.001), urine norepinephrine (B=9.6 x 10-2, p=0.044) and high-frequency power of heart rate variability (B= -3.7 x 10-2, p=0.024).

Conclusions
In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

https://www.sciencedirect.com/science/article/pii/S0889159119301333

 

[Trish]

I haven't read it all, but it looks like they did their best to try to find differences between the fatigued after 6 months and not fatigued after 6 months post EBV infection.

BUT - the divided them into the 2 groups purely on the basis of the Chalder Fatigue questionnaire. On the 11 point version, scoring 4 or more was classed as fatigued. And for PEM the only test was “How often do you experience more fatigue the day after an exertion?”.

The minimal between group difference on steps per day suggests to me they were chasing shadows.
mean(SD) fatigued 8710 (3872); not fatigued 9329 (3019)

The fatigued group was nearly half the total group. A much tougher set of criteria for inclusion in the fatigued group might have told them more, I suspect. Maybe they didn't actually have anyone with CFS, but quite a lot with some lingering mild post viral fatigue.

 

[Hoopoe]

In principle, the idea of following patients with EBV infection and taking blood for some tests seems a good one.

They say that

Subgrouping according to different CFS diagnostic criteria did not significantly alter the results.

but I cannot find data on how many met different CFS diagnostic criteria.

It seems plausible that CFS is not the same thing as post-EBV chronic fatigue (which as far as I know tends to resolve within a year). In one study, about 10% of adults developed CFS after an infection. If we assume that this is similar to adolescents with EBV then perhaps 20 will develop CFS, with varying severity. That analysing the results according to case definitions didn't affect the results could be due to a lack of statistical power.

 

[Hoopoe]

BUT - the divided them into the 2 groups purely on the basis of the Chalder Fatigue questionnaire. On the 11 point version, scoring 4 or more was classed as fatigued. And for PEM the only test was “How often do you experience more fatigue the day after an exertion?”.

This is not a validated measure of PEM. Maybe they didn't find differences between diagnostic criteria because they didn't use them properly?

 

[Hoopoe]

The present study failed to replicate previous findings of differences in autonomic cardiovascular responses to orthostatic manoeuvre between chronically fatigued individuals and healthy controls (Wyller et al., 2007a, Wyller et al., 2008a, Wyller et al., 2008b). This result adheres to one previous finding from our group, indicating that differential responses to orthostatic challenge are more related to expectancies than to the gravity per se (Wyller et al., 2014). It is possible that an abnormal orthostatic response is a late characteristic of the CFS condition itself, developing over time. However, we speculate that previous findings might have been confounded by deconditioning due to sedentary behaviour, as several previous studies have included CFS patients with a marked reduction in activity levels.

Or maybe because you're studying mostly people that will get better within a year and never develop CFS.

The comment about expectancies also reveals they're in the school of thought where patients are blamed at every opportunity.

 

[chrisb]

Could they have been CFS patients if they did nothave a marked reduction in activity levels?

 

[Peter]

In principle, the idea of following patients with EBV infection and taking blood for some tests seems a good one.

They say that but I cannot find data on how many met different CFS diagnostic criteria.

It seems plausible that CFS is not the same thing as post-EBV chronic fatigue (which as far as I know tends to resolve within a year). In one study, about 10% of adults developed CFS after an infection. If we assume that this is similar to adolescents with EBV then perhaps 20 will develop CFS, with varying severity. That analysing the results according to case definitions didn't affect the results could be due to a lack of statistical power.

27 out of 91 met criteria, if I remember it right. How many met Fukuda and how many Canada is uncertain.

 

[Peter]

The study was presented in the major newspaper in Norway (Aftenposten) the 27’th of February. Many people know how Wyller sees ME, how he is promoting LP and such things, but I tried to translate some of the article to get an impression of how Wyller look at the study. Hopefully most of the translation is ok.

The headline read something like “Vulnerable EBV-patients more often develops ME”.

Wyller:

- Defines vulnerability as everything from how the immune system and the hormonal system reacts, to the patients thoughts and feelings.He gos on saying, that «this can explain a lot about the underlying causes to ME or severe exhaustion after EBV, who gets it and what the causes may be"

- genetic predispositions and upsetting events earlier in life may also be possible factors of vulnerability.

The newspaper have comments from Kristian Sommerfeldt, doctor at Haukeland and prof. at the university of Bergen. He says the study is thorough, but it is an explorative study that may give room for further investigation/studies.

- The study itself does not show causes to different categories of exhaustion after EBV.
- its a weakness that all registrations/ measurements in the study was done after getting ill, and Sommerfeldt points out that the investigators themself sees this as problem.

The paper also run an anecdote of a «dark room-situation». 10 years later the patient reflects, and find that «one of the causes that he got exhausted after EBV was that he himself was «very sensitive». If you call it sensitive, vulnerable or thin-skinned is not the important. The important thing is that one sees that this is a part of many people personality. The patient think that many that gets severely «exhausted» are highly sensitive. He then explains that he got recovered after LP. After getting recovered I have tried to understand what ME is. To me the research conducted by Wyller seems very important.

Wyller:

- An important discovery is that the severity of the EBV, seems to play a minor part when it comes to who later gets exhausted or develops ME. A large amount of the EBV-virus in the throat and/or in the blood in the start of the disease period is for instance not associated with getting a severe exhaustion later on

- what is important is how bothered you feel that you are. Distress and how concerned you are, could play a part.

Longstanding exhaustion and ME is not only about the body, or only the soul, but about interaction where thoughts, feelings and the immune system, surely also factors we don’t yet know about plays a part, concludes Wyller. He strongly oppose the categorization of ME as either psychiatric or somatic. This is old school and should not be used. ME is a composed state - both psychiatric and somatic. Our study confirms this.

Sommerfeldt:

- problematic that the investigators concludes that it dosent matter how severe the EBV-virus is in relation to who later becomes exhausted.

Sommerfeldt: patients information of symptoms could be at least as important to get hold o in order to understand the severity of the infection as blood samples are.

It is a lot we don’t understand about this. Measuring of distress at the start of illness is related with exhaustion half a year later. The investigators interprets this as distress could increase exhaustion later on. Another likely and reasonable explanation could be, that they who had more explicit disease was more distressed just because they were more ill, thus more exhausted.

Sommerfeldt then stress that the study discuss different levels of exhaustion after EBV, not the prevalence of ME, a diagnosis that just 27 of the 91 with exhaustion qualified for.

 

[Amw66]

Both my son and daughter were ill after glandular fever ( we do not do serology here to know whether EBV/ CMV). Both did not have significant glandular fever ( were not stuck in bed . sore throats mainly, tested afterwards when not getting better was an issue ) but both had issues recovering. My son had severe PVF , my daughter has moderate/ severe ME.

Eldest child ( female) unaffected ( is likely to have had mild glandular fever having gone through school and uni and had similar sore throats). Different blood group.

ETA Also more of her dad' s traits.

 

[Mithriel]

Could they have been CFS patients if they did not have a marked reduction in activity levels?

ME was defined as an abnormal response to exercise not chronic fatigue. The CPET testing shows that cellular respiration is compromised in some way.

Even now I am severely affected (unable to carry out the activities of daily living without help and spend a lot of time lying down) the disease still affects me the same way it did when I was 14. I start to do something then I run out of something needed to carry out the task (could be picking up a cup) I stop for a bit, which varies, and then I can carry on. Of course, if I try to do something more I can be stopped for hours. I don't know if you would call it paralysis but I am unable to move a muscle.

Anyway, the point is that when I was first ill (after a coxsackie B infection) I was affected this way along with episodes of vision and speech problems, an inability to maintain homeostasis like temperature control and OI as well as intense pain. But I never missed a day of school, went out dancing and worked in a shop on Saturdays managing to hide the stops for recovery.

I have no doubt now that I damaged my body and if I had been older I would have recognized I was ill but as a 14 year old I kept getting told "wait till you start work then you will know what tiredness really is" As it was I was more concerned with hiding things I could not explain.

I hope the disease is more recognised today so that children like me get help.

 

[ME/CFS Skeptic]

the divided them into the 2 groups purely on the basis of the Chalder Fatigue questionnaire. On the 11 point version, scoring 4 or more was classed as fatigued.

Yes, this doesn't make much sense. An old population study by Wessely and Chalder used that cut-off score of 4 on the CFQ and found that 18% of the patients in primary care had chronic fatigue. So this doesn't seem to be a good cutoff if you want to find "markers of disease mechanisms" in patients who remain ill after an EBV infection. If 18% of the population experiences similar symptoms of fatigue than what kind of disease are they studying? Their results are pretty much meaningless: they should have used a more stringent definition of fatigue. With the Chalder fatigue Scale, If a person feels drowsy, has difficulties concentrating, problems starting things and difficulties finding the right word, then that would be sufficient to put him in the fatigue group...

This is not a validated measure of PEM. Maybe they didn't find differences between diagnostic criteria because they didn't use them properly?

Lily Chu, vicepresident of the IACFS/ME and co-author of the IOM-report already reprimanded the team of Wyller because of their flawed definition of PEM. She wrote:

I wish to re-emphasize that post-exertional fatigue is not equivalent to post-exertional malaise. As described in the NAM report, PEM is not only increased fatigue following activity but also involves exacerbation of other symptoms, like muscle/joint pain, problems sleeping, headaches, cognitive dysfunction, sore throats, tender lymph nodes, and flu-like feelings (1). Furthermore, PEM can be delayed by hours to days relative to the triggering event and last hours, days, and even longer.

But this was in 2018, so after the CEBA-project was completed.

If we assume that this is similar to adolescents with EBV then perhaps 20 will develop CFS, with varying severity. That analysing the results according to case definitions didn't affect the results could be due to a lack of statistical power.

Yes, I also think they lack statistical power, perhaps that's why they focus on fatigue instead of ME/CFS. On page 17 they write that there were 26 patients according to the Fukuda-criteria and only 19 according to the Canadian criteria (with a flawed assessment of PEM). In a different publication on the same study, they wrote:

As relatively few individuals in the EBV infected group adhered to case definitions of CFS at 6 months follow-up, a multiple logistic regression analysis featuring CFS caseness as dependent variable was not statistically feasible.

Something similar may be true for this study, without them willing to admit it.

 

[ME/CFS Skeptic]

The authors write (on page 18):

Participants classified as CFS cases according to the Fukuda-definition or the Canada definition had higher symptoms scores but were otherwise similar to the entire EBV CF+ group for the great majority of variables (Supp Table 2)

I can't seem to find a supp Table 2. Has anyone seen it? Perhaps it still has to be uploaded, because this isn't the final version of the paper yet.

 

[Kalliope]

Front page article about this study on a Norwegian news site about research. Prof. Wyller is interviewed and is still claiming that the study supports his hypothesis that ME is due to a hypersensitivity in the brain. He is sceptical to a purely biomedical approach and says the brain can be changed just as well though conversations as with drugs. The "patient organisation" Recovery Norge (an organisation mainly for people who claim to have recovered from ME by their own effort) is mentioned with their 50 recovery stories, as is the Norwegian ME Association with their survey where the majority of 1 100 responders did not improve by cognitive behavioural therapy.

Paediatrician and neurologist professor Kristian Sommerfelt is also interviewed and says it's unlikely that a disease with such long term and severe symptoms as strictly defined ME, is due to sensitising mechanisms in the brain.

Forskning.no: Norske forskere fant få fysiske forskjeller mellom ME-syke og friske
google translation: Norwegian researchers found few physical differences between ME-patients and healthy people

 

[Snowdrop]

I would very much like to know what goes on in the minds of the BPS people vis a vis how they view what is science in this context. If talk therapy works because it changes the brain then should they not be obliged to show that? And even if they could show brain changes exactly how is it they would be able to show/prove that the particular brain change is a result of the talk?

Edit: fixed spelling

 

[Pondering]

Ug... it is too bad this work wasn't being done by better researchers. The whole point of my tuft cell postings was to speculate as to a new possible mechanism as to how the virus hits a person, leaves and then leaves behind either new or changed tuft cells that then go on to cause CFS (or contribute) in some patients. This type of study could have supported or refuted that idea. Scientists with closed minds or agendas (IMHO) can do so much damage.

I got the idea from the extremely new research showing that H1N1 hit a mouse and left behind tuft cells in the lungs. The tuft cells have then been implicated in autoimmune asthma which they are now looking to prove/disprove as the next step.

So H1N1 --> Tuft Cells in Lungs (H1N1 gone) --> Autoimmune derived Asthma.

In CFS patients I was speculating it would go "one of the viruses implicated in CFS" ---> Tuft cells in the Thymus (virus gone) --> CFS

The way I was thinking this hypothesis could be tested would be to do this exact study. You also could eliminate a number of other possibilities. Put the patients in an MRI and take the measurements for CCI, etc. then check again.

Using my go to example, this is how they proved a bacteria caused ulcers rather than "stress" (which is why I think it is a good metaphor).

 

[Kalliope]

Front page article about this study on a Norwegian news site about research. Prof. Wyller is interviewed and is still claiming that the study supports his hypothesis that ME is due to a hypersensitivity in the brain. He is sceptical to a purely biomedical approach and says the brain can be changed just as well though conversations as with drugs. The "patient organisation" Recovery Norge (an organisation mainly for people who claim to have recovered from ME by their own effort) is mentioned with their 50 recovery stories, as is the Norwegian ME Association with their survey where the majority of 1 100 responders did not improve by cognitive behavioural therapy.

Paediatrician and neurologist professor Kristian Sommerfelt is also interviewed and says it's unlikely that a disease with such long term and severe symptoms as strictly defined ME, is due to sensitising mechanisms in the brain.

Forskning.no: Norske forskere fant få fysiske forskjeller mellom ME-syke og friske
google translation: Norwegian researchers found few physical differences between ME-patients and healthy people

Henrik Vogt has commented the article. Here's a google translation:

The pediatrician Kristian Sommerfelt says that cognitive methods cannot contribute making CFS / ME healthy. This implies a pure denial of both research knowledge that suggests improvement and increased chance of recovery by such methods and stories of people who have experienced getting well again through such methods (such as those published by Recovery Norway).

In order to justify such a denial, Sommerfelt does a manoeuvre that involves pure misinformation: He tries to draw a distinction between a "strictly defined ME" and a "not strictly defined ME" (ie a "real" and a "false" ME) . This he expresses can be done using diagnostic criteria.

As stated in the article: "The pediatrician believes it is likely that some patients with fatigue that fall outside the strict criteria for ME may have symptoms due to causes that can be treated well with cognitive therapy." But here it is important not to mix apples and pears, says Sommerfelt ".

But there are no clues (and Sommerfelt should know this) that some diagnostic criteria are "strict" in the sense that they can distinguish a specific group of ME patients who are more "real" than others. Norwegian researchers have also argued for this in a publication (Case definitions for chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME): a systematic review, (Brurberg et al., BMJ Open, 2014).

The so-called Canada criteria, which are often (also in this article) referred to as "strict", are not particularly specific, scientific or valid. They are not made by professionals who are particularly credible (one of them is alternative medicine Kenny De Meirleir who has traveled around and sold patients expensive and undocumented products for a number of years) and they are not even published in a journal registered at PubMed database (Journal of Chronic Fatigue Syndrome). These criteria, however, were made by a group with an apparently "biomedical" approach, which then used these criteria and which the international ME movement has promoted as more valid than other criteria. But it's not correct.

There is no "strictly defined ME" or "not strictly defined ME". It is not possible to create specific specific criteria when one does not initially understand the disease and its delimitation. One may decide to define a smaller group of patients with several criteria, but that does not mean that one has blinked out a more "real" group. This is not only unsustainably scientific to claim that some criteria blink out a "strictly defined ME group", it is ethically problematic as it implies that a group of patients does not have "the real problem". This is especially unfortunate in a context where patients have had difficulty in being taken seriously.

There is evidence for treatment / strategies that work both research-wise and from healthy stories.

In addition, several of Recovery Norway's recovery stories from people who have been among the most sick in the country (bed-ridden in dark rooms over time) and / or who have been ill according to all criteria, including the Canada criteria.
In one story, for instance, one of our female members received ME diagnosis according to the Canada criteria from the cancer doctors Fluge and Mella in Bergen (participated in the rituximab study) - before she recovered with a cognitive approach and stress management at the Clinic for Stress Medicine. on Fitjar.
Should the members of Recovery Norway believe Sommerfelt in that cognitive techniques do not work against "strictly defined ME", they would logically have been hindered from becoming healthy.

Henrik Vogt
Head of Recovery Norway, doctor, PhD

 

[Hoopoe]

Vogt: your science is unreliable but we know LP works. How? Just look at this outcome switched uncontrolled study and these anecdotes.

 

[rvallee]

I would very much like to know what goes on in the minds of the BPS people vis a vis how they view what is science in this context. If talk therapy works because it changes the brain then show they not be obliged to show that? And even if they could show brain changes exactly how is it they would be able to show/prove that the particular brain change is a result of the talk?

You're expecting too much from a belief system. It's an ideology, reality does not factor in. I'm not even convinced they believe that it actually works, they just say it does and aren't bothered with being shown wrong because they have no clue about how disastrous reality is. They think all it amounts to is some vague complaints while we are perfectly capable of having a normal life and secretly manage to do while also complaining.

It's like "lifting a curse" when you don't believe curses are real. It doesn't matter what you do in the end since curses being imaginary means they don't have any actual consequences. The details are irrelevant. You just keep on trying until the "accursed" accepts they never were cursed in the first place.

The science here is irrelevant, it's not at all what it's about at all. The role of science here is like spells or rituals, it's only a means of influence. It's the same mechanism as snake oil salesmen, the content of the "medicine" is entirely irrelevant, what matters is the show and the sale.

 

[inox]

Yes, I also think they lack statistical power, perhaps that's why they focus on fatigue instead of ME/CFS. On page 17 they write that there were 26 patients according to the Fukuda-criteria and only 19 according to the Canadian criteria (with a flawed assessment of PEM). In a different publication on the same study, they wrote:

Wyller have always used unexplained fatigue for at least 6 months as his proxy for ME. He often rerefers to this review by Larun et al to justify this - see comments - there are claims about widest possible criteria is the best for research etc.
https://bmjopen.bmj.com/content/4/2/e003973

His been much criticized for this, and have since startet to include numbers for patients according to Fukuda and Canada-criteria. He also used to have no mention of PEM i his studies, and now seems to have made his own proxy for that as well.

I mostly read this as prepering to have counter-arguments ready, that are harder to explain why doesn't hold up/isn't good enough in the public debate we have here.

 

[Mithriel]

A common theme with "recovery" treatments is that they have worked for the "sickest" patients but this is actually meaningless in the context. People who are very ill from the start usually have epstein barr. Herpes viruses can retreat into the nervous system after a prolonged period leading to remission. (I am not saying they are not ill or that it can't become ME just in the context of how good a treatment is).

A treatment that works would affect the less ill just as much. We need something that prevents the mildly affected becoming severely affected. These quack nostrums are more likely to do the opposite.