"A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME" but...

I did um-and-ah about whether I should blog about the findings reported by Bjarte Stubhaug and colleagues [1] observing that "a brief, concentrated treatment program for CFS/ME might be highly beneficial."

The reasoning behind my reticence was primarily to do with the study design whereby "a 4-day group intervention program, comprised by education, cognitive group therapy sessions, mindfulness sessions, physical activity and writing sessions, within a context of cognitive behavioral therapy, mindfulness, acceptance and commitment model" was delivered to over 300 people diagnosed with Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME) and self-report results plotted "1 week before and 1 week after the intervention program, and at 3 months and 1 year after the intervention" without any control group or any kind of blinding. Even the researchers themselves wrote that their study design make "conclusion of the actual effect of the treatment program [in part or whole] and its impact on the clinical course through the follow-up period difficult." But, here I am...

As you can see from the picture accompanying this post, others are also just a little bit critical of the Stubhaug paper and findings. Although I can't speak for anyone else, I imagine some of the 'criticism' of the study and results rightly follows on from the methodology employed by the authors. I did also wonder if some feeling might also be there because of the subject matter, and specifically, the continuing idea in some quarters that the application of the biopsychosocial (BPS) model to CFS/ME should carry weight. To quote from the authors: "The therapeutic rationale behind the program was to increase the medical knowledge and interpretation of bodily distress, challenge and modify dysfunctional illness perceptions as well as illness behavior, and through acceptance and commitment strategies contribute to behavioral change and clinical improvement." Sounds about as BPS as you can get I reckon.

Focusing for now on the methodological and related side of the Stubhaug paper, the starting point for the study was the authors' observation that: "The most promising treatment so far seem to be cognitive-behavioral treatment programs... and graded exercise." Just before anyone gets angry about this, authors do also highlight how "the effectiveness of interventions and robustness of findings are continuously being questioned" in this area. Yes, yes they are being questioned (see here and see here for examples) and by lots and lots of different people. Nonetheless, researchers decided to test whether their 4-day program, encompassing quite a few elements, might impact on some of the signs and symptoms of CFS/ME in their cohort. Said program included education: an "introduction to stress medicine with focus on physiological and psychological stress", cognitive group therapy, mindfulness and writing experience ("patients were instructed to write for 15 min about positive experiences and emotions"). They also talk about the use of "daily walking sessions of 60–90 min, in low to moderate pace" which, considering other research (see here), sounds pretty 'full on' to me, in light of some of principal issues that define CFS/ME (see here).

Relying on self-report measures such as the Chalder Fatigue Scale and the Short Form Health Survey-36 (SF-36), researchers reported their results as per the timescales already mentioned. The picture that emerged was a fairly positive one as various statistically significant group changes (improvements) were noted across the testing sessions, even when taking into account different ways of diagnosing CFS and across the various instruments used. Most participants also said that they were pretty satisfied with the intervention program and the service they received. In short, the study met it's aims quite successfully.

But... not to pour cold water on the findings, one cannot forget about the 'open study' shortcomings of the study design. So on top of what has already been mentioned: "Many patients with CFS/ME tend to be critical to biopsychosocial interventions, and possibly most of these patients did not accept referral to the clinic, contributing to the possible selection bias." I'd say that this was another quite important *issue* that faced the Stubhaug study. The authors go on to note that their results "clearly represent a CFS population, albeit not representing the total body of CFS/ME patients" so perhaps clarifying the caution needed in this area of science specifically around any sweeping generalisations. And as an example: "At 1 year follow-up, half of the patients completing assessments (56%) still report levels of fatigue representing substantial fatigue." Such an intervention is therefore no panacea for CFS/ME.

What else? Well, the continued focus on subjective questionnaires over and above more objective measures is also apparent in the Stubhaug findings (see here). As I've mentioned on more than one occasion, it's perfectly acceptable to ask patients how they are feeling and about related issues like quality of life for example (see here). But when it comes to a condition or set of conditions like ME/CFS defined by fatigue and other symptoms that very much impact on core issues such as activity, it strikes me that one should really include an objective measure of activity if one wants to study it in its entirety. So yes, actigraphy would have been a good feature to see in this study (with before and after results). Even a pedometer costing a few quid, used a few times a week over a number of different weeks would be something at least. And once again, how about also including some biological parameters into such studies too? Y'know, just on the off-chance that things like mindfulness, minus any grand sweeping claims, for example, could have possible biological effects too [2]?

----------

[1] Stubhaug B. et al. A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME. An Open Study, With 1-Year Follow-Up. Front Psychiatry. 2018;9:720.

[2] Hoge EA. et al. The effect of mindfulness meditation training on biological acute stress responses in generalized anxiety disorder. Psychiatry Res. 2018 Apr;262:328-332.

----------

"Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study"

The quote titling this post - "Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study" - comes from the findings reported by Roxanne Parslow and colleagues [1] during their study designed "to explore outcomes important in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) and what improvements in fatigue and disability are key."

Indeed, this latest study seems to follow a theme of looking at the personal experiences of CFS/ME [2] by members of this authorship team, potentially onward to the development of a PROM (Patient Reported Outcome Measure) [3] specifically with children and adolescents in mind. If this was a goal, I wondered if perhaps this *could* also be linked to some other work from some of the Parslow paper authors that has also been previously discussed on this blog too (see here)?

I specifically wanted to talk about this paper because of the word 'payback' and it's particular use to mean an "increase in fatigue and symptoms following activity." Mentioning it only twice in their article (one of those occasions being the use of a reference), I think the authors mean post-exertional malaise (PEM) (see here and see here for more discussion of this concept). They however, seemed a little reluctant to use that term. In answering one of the reviewers of their paper prior to acceptance for publication, the authors did say: "Payback is defined as a core symptom in NHS guidance, and is used in the clinical setting." They also clarified how "the term ‘payback’ was used instead of exhaustion."

No mind, based on interviews with "21 adolescents and their parents (20 mothers and 2 fathers)", most adolescents being female with a mean age of around 14 years, several key themes emerged. To reiterate: "All adolescents with CFS/ME report fatigue, a natural fluctuation of the condition, as well as an increase in fatigue and symptoms after activity (payback)." Several sub-themes also emerged from such reporting including how: "Adolescents and parents reflected on how CFS/ME naturally fluctuates" and "Adolescents and parents recognised patterns of good and bad days" and "Adolescents were limited in the amount of time they could spend on activities, which ranged from minutes, ‘5 min’ to hours, ‘an hour at the most’." These aren't exactly novel findings by any means but it's always useful to see them described in the peer-reviewed research domain.

Heading back to that 'payback' issue, researchers mention how their results are "consistent with previous research where children described the intensity of symptoms fluctuating as well as ‘overextension’ making it worse, resulting in ‘paying the price’." Accepting that such payback or PEM or 'payback exhaustion resulting in fatigue and other symptoms following activity' if you prefer, is widely present in CFS/ME (albeit individual and 'variable' in nature), one might see the Parslow results perhaps as further justification for being slightly critical of the use of something like graded exercise therapy (GET) in relation to CFS/ME (see here). GET relies on the assumption that increasing or grading in physical activity will eventually 'help' facets of CFS/ME. Unfortunately, whilst still expounded in some circles, there is accumulating (peer-reviewed) evidence that many patients with CFS/ME experience GET as more of a hindrance rather than a help for their symptoms (see here). Indeed, allied to terms like 'deconditioning' as part of suite of 'psychobabble' that seems to have enveloped CFS/ME down the years, the idea that CFS/ME is something that can be just 'exercised out of' seems to have been a truly damaging policy that has not seemingly served many patients particularly well.

The Parslow findings are revealing and add something further to the idea that an overhaul of current thinking on CFS/ME in children and adults is perhaps required (see here). Obviously the results are small-scale and require some follow-up, but listening to patients and their parents/caregivers and their collected experiences is a good idea in my book; particularly when it comes to a group of conditions like CFS/ME that have seen more than their fair share of 'assumptions' down the years.

----------

[1] Parslow RM. et al. Adolescent’s descriptions of fatigue, fluctuation and payback in chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): interviews with adolescents and parents. BMJ Paediatr Open. 2018;2(1):e000281.

[2] Parslow RM. et al. Children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review and meta-ethnography of qualitative studies. BMJ Open. 2017 Jan 13;7(1):e012633.

[3] Parslow RM. et al. Important factors to consider when treating children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): perspectives of health professionals from specialist services. BMC Pediatr. 2017 Feb 1;17(1):43.

----------

"by the time ongoing fatigue was established, the immune activation was no longer present"

The quote heading this post - "by the time ongoing fatigue was established, the immune activation was no longer present" - comes from some media coverage of the paper published by Alice Russell and colleagues [1]. Said paper observed some interesting results in relation to the use of interferon-alpha (IFN-α) "used in the treatment of chronic Hepatitis C Virus (HCV) infection" and what this *could* mean in relation to a "proxy model of chronic fatigue syndrome."

The long-and-short of the Russell results and their possible application to chronic fatigue syndrome (CFS) is that for quite a few years now there have been rumblings that at least some cases of CFS (also known as myalgic encephalomyelitis, ME) might be *associated* with a viral hit-and-run encounter. By saying 'hit-and'run' I mean that an initial viral or bacterial infection is experienced which induces the symptoms of CFS. Said infection then eventually disappears for whatever reason(s) but leaves persisting symptoms such as long-term fatigue and more. Further explanation of this hypothesis can be seen in another of my posts on CFS (see here).

So: "Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6–12 months of IFN-α treatment, and at six-months post-treatment." The use of IFN-α is clinically indicated for HCV infection as part of an antiviral therapeutic regime ("IFN-α and ribavirin"). Various biological parameters were assessed in the 55 participants as well as in separate groups of those diagnosed with CFS and so-called "healthy volunteers."

Treatment with IFN-α induced fatigue in quite a few of those being treated for HCV infection. Most cases of fatigue resolved at 6-months post-treatment but for some, fatigue remained and for about 30%, levels of fatigue were "higher six-months post-treatment than at baseline." The authors looked at the biological results obtained for those with 'persistent fatigue' (PF) and compared them with those with 'resolved fatigue' (RF) to see if they could discern some differences.

They came up with a few important group observations: "Subjects who later develop PF have higher fatigue in response to IFN-α", "Subjects who later develop PF have higher IL-10 levels before treatment, and IL-6 and IL-10 levels in response to IFN-α", and "Psychosocial and clinical risk factors do not distinguish PF from RF subjects." What this all amounts to is that within quite a small participant group: "findings from this study support the hypothesis that abnormal immune mechanisms are important in CFS, but only early in the course of the illness, around the time of the trigger, rather than when the syndrome is established." Further the study: "confirms the importance of the acute fatigue response to the trigger, rather than of the recovery period preceding the illness."

There is more to do in this area bearing in mind that CFS is a pretty heterogeneous condition both in terms of symptom onset and the course of the illness. Researchers also admit that they "can only speculate at this stage on whether or not the mechanisms underlying the persistence of fatigue in CFS and IFN-α induced PF are related" and their suggestion of a proxy model. Others who have covered this study have said similar things (see here). This is also important given other results reported by the authors on those diagnosed with CFS compared with those 'healthy' controls/volunteers.

Still, there are some interesting observations made by Russell et al and once again, such results hopefully move CFS further away from the biopsychosocial (BPS) model of old that has seemingly done considerable damage to those diagnosed (see here and see here). Indeed, such post-infective thinking kinda brings CFS back full circle...

----------

[1] Russell A. et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2018 Dec 17.

----------

Is 'escape' the most common function of challenging behaviours in autism?

'Challenging behaviour', 'disruptive behaviour' and 'behavioural crises' are terms that have been used to describe a range of behaviours "that are not culturally or socially acceptable, put the physical safety of the individual and/or others in jeopardy, affect learning, and/or limit access to community setting" in the context of autism and beyond.

A recent paper published by Esther Hong and colleagues [1] continued the research interest in this area (see here and see here) specifically focusing on gaining "perspective on what are the most commonly treated topographies of challenging behaviors" and "to identify the most commonly reported functions of those challenging behaviors." I'm assuming use of the word 'topography' in this context means 'profile' in terms of what types of challenging behaviours were noted.

Relying on behavioural data from over 3200 people diagnosed with an autism spectrum disorder (ASD) who were "receiving a minimum of 20 h of ABA [applied behavior analysis] treatment per month", researchers examined data on a range of behaviours falling into the category of 'challenging'. These included: "(a) aggression, (b) disruption, (c) elopement, (d) inappropriate sexual behavior, (e) lying, (f) noncompliance, (g) obsessive behaviors, (h) pica, (i) self-injurious behavior, (j) stealing, (k) stereotypy, (l) tantrums, and (m) teasing/bullying." Accepting that ABA in the context of autism is not everyone's cup of tea (despite some important data emerging [2]), one of the 'benefits' to this study at least, was that behaviour was recorded in some detail as a function of the implementation of ABA using something called The Skills™ database. This also allowed researchers to examine the potential 'function' of such behaviours too: "Skills™ also contains a field denoting the function of the behavior as identified by the supervising behavior analyst at the time of observation. Functions are classified as “attention,” “automatic,” “escape,” or “tangible.”."

Results: "The most commonly treated challenging behaviors were stereotypy, noncompliance, aggression, tantrums, SIB, elopement, disruption, and obsessive behaviors, respectively." Although 'stereotypy' ('the persistent repetition of an act) was the most frequently observed 'challenging behaviour', I'd personally be a little reluctant to put it into this category. I say this because there have been some reports suggesting that such a behaviour serves an important purpose in terms of being calming and aiding coping in certain situations for certain people. The majority of those challenging behaviours were coded most frequently in terms of 'escape' when it came to perceived function by the therapists who were doing the coding. Interestingly, and going back to my point about stereotypy, this behaviour was most frequently coded as 'automatic' alongside another behaviour that probably shouldn't be seen as a challenging behaviour: obsessive behaviours. Automatic, I assume, means just that: involuntary and well, automatic.

Alongside such information, authors also detail some nice Venn diagrams to illustrate how various categories of behaviours (and their specific manifestations) might meet and *correlate* based on their acquired data. Certainly, in the context of aggression and self-injurious behaviour (another important topic), there are some potentially important details to discern.

Although ABA still remains a point of contention among some, in the context of the Hong report, I can see how the quite detailed data collection on behaviour that it accrues holds some important information in the presence of some often, quite distressing behaviours. I'm happy to think that 'escape' could be a quite common function of various challenging behaviour(s), and moves to making 'some controlled escape' from particular situations might perhaps be useful to reduce the presence of such challenging behaviours. I know others will talk about 'demand avoidance' as being important too, but I'm cautious that this might not be an effective strategy in the longer term in helping people to build up 'resilience' to certain situations and environments.

But... I also think that 'escape' is not the whole story when it comes to challenging behaviours. I do still think that issues such as 'frustration' for example, can play a role. Also moving away from a purely 'behavioural' point of view, there is other evidence pointing to biology and physiology as being potentially involved in the presence of certain challenging behaviours. Fatigue? Yep, that's been mentioned (see here). Communication? Yep, that too (see here); particularly when verbal communication might be limited. And I'm also minded to mention that challenging behaviours can also be associated with things like the expression of pain (see here) that probably ties into the communication issue(s) too. In short, it's going to be complicated [3].

----------

[1] Hong E. et al. Topography and Function of Challenging Behaviors in Individuals with Autism Spectrum Disorder. Advances in Neurodevelopmental Disorders. 2018; 2: 206-215.

[2] Makrygianni MK. et al. The effectiveness of applied behavior analytic interventions for children with Autism Spectrum Disorder: A meta-analytic study. Research in Autism Spectrum Disorders. 2018; 51: 18-31.

[3] Rattaz C. et al. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. J Intellect Disabil Res. 2018 May 24.

----------

"CFS symptoms resemble a hypothyroid state" but...

I am a little late getting to the paper published by Begoña Ruiz-Núñez and colleagues [1] observing that, at least for some diagnosed with chronic fatigue syndrome (CFS), clinical findings related to thyroid function might "resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy." But I did get here eventually. Before heading into this paper, I'm gonna link to one of the 'already prepared' discussions on the Ruiz-Núñez findings (see here). My analysis is pretty similar but not entirely the same...

So: "We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males)" was the starting point, as participants provided blood samples and 24-hour urine samples onward to various analyses being carried out. This included: "the measurement of routine hematological parameters [Hb, hematocrit, WBC, red blood cells (RBC), and thrombocytes]" and more specifically: "parameters of thyroid function, low-grade inflammation and gut wall integrity..., together with secondary markers of inflammation." Those 'parameters of thyroid function' included various measures of free and total levels of T3 and T4 required to ascertain the presence of "low-T3 syndrome." I was impressed to see that a measure of gut wall integrity was also on the research menu in the form of plasma zonulin levels being included (albeit analysed via ELISA and bearing in mind the issues that have emerged with that particular method).

Results: "Chronic fatigue syndrome patients exhibited lower FT3, TT4, TT3, %TT3, SPINA-GD, and SPINA-GT, lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4; and higher %rT3 and rT3/TT3 ratio." These findings were based on 'group' comparisons with those sex-matched not-CFS controls, and point to some 'issues' with thyroid function in general. Coupled to other thyroid related findings, the Ruiz-Núñez suggest that lower levels of thyroid hormones were detected but "distinct from thyroidal disease" typical levels of thyroid-stimulating hormone (TSH) were also reported. TSH is the stuff that tells the thyroid gland to make thyroid hormone (thyroxine (T4)), where T4 is, in effect, the starting material for T3 (triiodothyronine). Where there are suitable levels of TSH but lower levels of T4 and/or T3, one gets the impression that it's more about what's 'happening' to T3 and T4 over and above issues with their production. Indeed, the collected findings led authors to talk about that 'low T3 [triiodothyronine]syndrome' as being potentially pertinent to their findings in relation to CFS. Going back to those plasma zonulin findings, and there is just a sentence from Ruiz-Núñez and colleagues: "Zonulin, a parameter of intestinal permeability... was lower in CFS patients as compared to controls" but not much else.

I'm not particularly au fait with all the details of low T3 syndrome in the context of CFS or anything else so can't really add too much more. From what I gather, this is not a CFS-exclusive condition but does seemingly tap into talk about CFS being reflective of a "hypometabolic state" (see here). Questions about how to 'treat' such thyroid-related issues in the context of CFS remain unanswered, despite authors talking about "trials with, e.g., T3 and iodide supplements" being potentially indicated. I say this bearing in mind that the focus on biochemistry in the Ruiz-Núñez paper could perhaps, have been complemented by a little more on the presentation of clinical symptoms too.

In short, quite a bit more investigation in this area is indicated...

----------

[1] Ruiz-Núñez B. et al. Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study. Front. Endocrinol. 2018. Mar 20.

----------

KPAX002 for Chronic Fatigue Syndrome part 2: controlled study says no

KPAX002 mentioned in the title of this post refers to "a mitochondrial modulator technology platform" according to the manufacturer that includes a low dose of methylphenidate combined with various nutrients designed to impact on mitochondrial function. Within the context of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) (but not necessarily accurately so!), there is some preliminary research history suggesting that KPAX002 might be something to look at for intervening in some of the disabling characteristics of CFS/ME (see here). This, on the basis that mitochondria in particular, might be something quite important to at least some cases (see here and see here).

The fly in the scientific ointment?

Well the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo. In keeping with the phase 2 label attached to the trial - looking at both initial clinical results and also any side- or adverse effects - authors reported no statistically significant difference in the frequency of reported adverse effects between KPAX002 and a placebo over the 12 weeks of study. First, do no harm and all that.

The Montoya paper is open-access so readers can see for themselves how things were done and the details of the results. I however, want to highlight a few points that I thought were important:

First, the authors acknowledge the "unexpectedly positive results" observed the last time around [2] that led to this more rigorous trial. Personally, I don't think there was anything too unexpected about those pilot study results, given the methodological issues typically associated with a pilot study. Y'know, a small un-blinded participant group taking part in a trial using a preparation that they probably will have been told *might* affect various symptoms they experience or themselves possibly 'exposed' to other anecdotal reports of good effects. That and no control group, no placebo included and importantly, no objective measure of fatigue (a real issue when it comes to quite a bit ME/CFS research) and well, I'd be surprised if something significant didn't come up during the initial findings. And just in case you think I'm being all 'high-and-mighty' about this, I've published using the same type of pilot study methodology before, including some of the same inherent issues (see here).

Second, I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study. I say this on the basis of both the commercial take on the results (see here) and also sentences like: "The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057)." Both those p-values (p being a measure of statistical significance) are above the [currently] recognised threshold for p equal to or less than 0.05, yet are listed as a 'robust response'. Even more, throughout the paper I note the words 'trend in favor of' being used, which some people might translate as being 'well, they were nearly statistically significant results'. I say this also bearing in mind that the final participant numbers - KPAX002 use = 48 and placebo = 57 - are not exactly facets of what one would call an under-powered study. I'm probably being a nit-picker here but like it or not, the [current] rules of science are the [current] rules of science.

Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper. Again, it's a small detail but one that should nevertheless be acknowledged. I would have also like to have seen a little more on who funded the trial too and especially who funded the provision of the KPAX002 supplement for trial purposes. I reiterate that there is no malice is intended in saying that, but readers require such details.

I don't want to come down too hard on these results because it's obvious that quite a bit of work has gone into their production. I'm also not closing the door on the idea that future research with a more targeted group with ME/CFS might not produce something a little more statistically significant with regards to KPAX002. But for now, the answer must be that controlled study of the formulation did not meet clinical endpoints in a statistical sense, and hence KPAX002 cannot be said to be superior to placebo for CFS/ME. With all the setbacks that the label(s) ME/CFS has had to endure down the years with regards to the 'psychobabble' explanations (see here) and other 'eureka' moments (see here), the Montoya findings are bad news for patients yet again. But, they also should represent a further call to re-double research efforts; particularly when it comes to the biology of the condition(s) and onward the acceleration of research for interventions for this quality of life draining condition (see here).

----------

[1] Montoya JG. et al. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900

[2] Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74.

----------

Immunoadsorption and ME/CFS: observations from a small proof of concept study

Immunoadsorption refers to "an alternative blood purification technique... used to eliminate pathogenic antibodies." I'll freely admit that I don't know an awful lot about this procedure, so approach the findings reported by Carmen Scheibenbogen and colleagues [1] with a degree of naivety with regards to 'usefulness' and also important issues such as safety.

Authors report preliminary findings from their 'proof of concept' study, using immunoadsorption (IA) on a small group of adults (N=10) diagnosed with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) who also presented with "infection-triggered disease onset, disease severity according to the Bell scale of ≤ 50 of 100, and elevated levels of ß2 antibodies." The Bell scale by the way, seems to refer to a scale developed by David Bell with scores ranging from 0 to 100 to denote fatigue symptoms, post-exertional malaise (PEM) and 'ability to work full-time'. A lower score denotes more severe symptoms. The description "elevated levels of ß2 antibodies" refers to antibodies against ß2 adrenergic receptors; receptors which are found throughout the body and are involved in various biological tasks including smooth muscle relaxation and regulating certain cardiac functions. As the authors note: "Antibodies to ß2... receptors had been reported in various other diseases including dilatative cardiomyopathy, postural tachycardia, regional pain syndrome, Alzheimer, Sjögren’s syndrome, asthma and others." The 'antibodies' bit implies that the body is failing to recognise these receptors as 'self' and instead wrongly mounts an immune response against them.

Scheibenbogen et al mention that during their other studies on ME/CFS [2] they noted "a sustained decline of pretreatment elevated ß2 antibody levels in clinical responders to rituximab treatment." The rituximab bit refers to some initially encouraging results [3] from the use of this treatment that, unfortunately, do not seem to have weathered more rigorous scientific scrutiny (see here). Authors further hypothesised that IA might be a route to "removing autoantibodies" and specifically those "elevated antibodies against β2."

Results: "Prior to IA all patients had elevated antibodies against β2, in addition 7 patients against ß1 adrenergic receptors and 6 patients against both M3 and M4 acetylcholine receptors." Autoantibodies in many of the participants included for study went beyond just those against β2.

Following quite a few cycles of IA - "IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered" - authors reported that: "Levels of ß2 adrenergic antibodies were low to undetectable in 9 of 10 patients." This is kinda what would be expected following IA (bearing also in mind that: "After the 5th IA cycle all patients received 25 g IgG i.v." also known as IVIG).

Insofar as the clinical course of participants' presented symptoms, well, it was a bit of a mixed bag. So: "A rapid improvement of several symptoms was reported by 7 of these 9 patients during IA. However, none of the patients completely recovered and 5 patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms." I'm happy to report that the authors did utilise the wonderful technology headed under the term actigraphy (activity monitoring) as per their assessing participants step counts "by a Vivofit activity tracker." Such objective activity monitoring is sadly lacking from many other studies on ME/CFS (see here for example). Again however, the step counts reflect an initial 'good start' for IA followed by a not-so-good finish...

"Taken together, this pilot study provides evidence that IA can effectively remove ß2 and M3/M4 autoantibodies in CFS/ME and can result in rapid moderate to marked symptom improvement." I wouldn't disagree with the authors' conclusions but would perhaps suggest that the current results as they stand don't yet provide authoritative evidence for a beneficial effect of IM in the longer term. More [controlled] study is required.

----------

[1] Scheibenbogen C. et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672.

[2] Loebel M. et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016; 52: 32-39.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898.

----------

Mood cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms make up Gulf War Syndrome

The results of the meta-analysis by Alexis Maule and colleagues [1] provide an important addition to the peer-reviewed literature on Gulf War Syndrome / Illness (GWS). Their detailing and combining of results from various studies looking at self-reported health symptoms among deployed troops during the Persian Gulf War of 1990 adds further credence to the range of symptoms reported by returning troops. Also, they provide further clues as to where science should continue to look and intervene to help our veterans.

I've talked about the Persian Gulf War and GWS a few times before on this blog (see here and see here and see here for examples). Described in some quarters as one of the most toxic wars in history, there are still many questions that require answering about why so many veterans returned from theatre in such poor health. Much like another quite nebulous condition very often confused with other diagnoses under the heading 'medically unexplained symptoms' (see here), the relative lack of knowledge about GWS has made the condition / constellation of symptoms fertile ground for various 'psychosomatic explanations'. This, I believe, has done, and continues to do, a real disservice to the veterans of this conflict and their loved ones.

Maule et al settled on some 21 published studies, including nearly 130,000 participants and covering almost 30 years of research (the war itself started in late 1990) where self-reported symptoms were compared "in GW-deployed veterans and GW-era control veterans." GW-deployed veterans were defined as "veterans who deployed to the Gulf area in support of the 1990–1991 GW." Their comparators were described as "non-deployed veterans or veterans serving in the military during the 1990–1991 GW period who deployed to areas other than the Gulf (eg, Germany, Bosnia)." Reported health symptoms were searched for and responses boiled down across the studies.

Results: "A total of 56 distinct health symptoms were reported in three or more studies and included in the meta-analysis." Of the various health symptoms reported, 'lacking energy' topped the frequency chart for deployed veterans, fairly closely followed by related issues such as 'fatigue' and 'unrefreshing sleep'. When classifying reported health symptoms together, the following categories emerged: mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms. Further: "Results of the meta-analysis showed GW-deployed veterans had increased odds of reporting all of the analysed symptoms compared with GW-era controls, indicating that the health problems associated with GW deployment include widespread, multiple body symptoms."

The authors do caution that it is not possible to say that all of these symptoms are cardinal features of GWS insofar as their inability "to assess the effect of some covariates relevant to health symptom reporting (eg, post-traumatic stress disorder and specific deployment exposures)." They also talk about how their meta-analysis approach, similar to other occasions across various different topics, may also be liable to publication bias ("when studies with positive findings are more likely to be published than studies with null and/or negative findings"). They did try and 'correct' for this possible bias and still reported that "42 out of the 56 summary ORs [odds ratios] remained significant." That included all those 'fatigue-related' health items previously reported on.

The work from Maule and colleagues adds to a significant research base observing that poorer health outcomes seem to be an important part of deployment to the Persian Gulf during Operation Desert Storm [2]. It again reminds us that we owe a debt to those veterans and their families, to continue to pursue a research agenda that takes their health issues seriously, and provides them with answers and the relief that many still sorely need.

----------

[1] Maule AL. et al. Meta-analysis of self-reported health symptoms in 1990–1991 Gulf War and Gulf War-era veterans. BMJ Open. 2018; 8: e016086.

[2] Porter B. et al. Health Status of Gulf War and Era Veterans Serving in the US Military in 2000. J Occup Environ Med. 2018 Jan 24.

----------

Is early adolescent physical activity protective against later "chronic disabling fatigue"?

TIE fighter crossing the moon?

One particular detail in the recent paper by Simon Collin and colleagues [1] (open-access available here) talking about higher physical activity potentially being *protective* against subsequent adolescent 'fatigue', immediately caught my attention: "CDF [chronic disabling fatigue], a proxy for clinically diagnosed CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis]."

This is not the first time that this authorship group have used the term CDF and seen it's use 'merging' into meaning something close to or like CFS/ME (see here) and I doubt that it will be the last. Far be it from me to put myself forward as some sort of expert on diagnosing CFS/ME - I'm not - but CDF as representing a proxy for CFS/ME does not mean that CDF is the same as CFS/ME. And that's also bearing in mind that the issue of diagnosis of CFS/ME is still the topic of lots and lots of (continuing) discussion (see here)...

Keeping all that in mind, I do want to briefly talk about the new paper from Collin et al. The Avon Longitudinal Study of Parents and Children (ALSPAC) was, once again, the data source for their findings, and yet again, this was a study looking at adolescent and young adults. The aim of the study was to: "investigate whether levels and patterns of physical activity at age 11 years are associated with ‘chronic disabling fatigue’... at ages 13 and 16 years."

A strength of the Collin research is that authors looked at more than just subjective 'how much exercise did you do' questionnaire via their use of actigraphy. So: "All ALSPAC children who attended research clinics at age 11 years... were asked to wear an Actigraph AM7164 2.2 accelerometer (Actigraph LLC, Fort Walton Beach, Florida, USA) for 7 days." Further: "Data from children who had worn the accelerometer for at least 10 hours a day for at least 3 days were considered valid" and from such data various calculations were made in terms of sedentary time, total physical activity and the proportion of "moderate-to-vigorous physical activity." Such data was analysed in the context of CDF measurements at ages 13 and 16 using methods previously described in their other research [2].

Results: "Children who had CDF at age 13 years had lower levels of physical activity at age 11 years." The authors translated this into various stats including: "For each additional 1% of monitored time spent in moderate-to-vigorous activity, the odds of CDF were reduced by 16%" and "Each additional hour of sedentary time per day was associated with 35% higher odds of CDF."

But just before anyone thinks that pushing children off the sofa and into some moderate-to-vigorous exercise in early adolescence is some kind of magical shield protecting against CDF, a few words of caution from the authors might also be important. Namely: "the lower levels of physical activity at age 11 years [may be] a consequence of chronic fatigue which is already present or developing and which persists until the child is 13 years old." In other words, there could be an alternative explanation for the lower physical activity (PA) levels *causing* chronic disabling fatigue; those who didn't do much PA were already developing and manifesting CDF...

"The main limitation of our study is that children were not assessed by a doctor, which is why we describe our outcome as ‘chronic disabling fatigue’, a proxy for CFS/ME." Yup, no arguments there; also reiterating why one needs to be quite careful about the terminology used around CFS/ME. The suggestions that lower physical activity might show a *correlation* with CDF also needs to be carefully handled given some continuing conversations about 'exercise therapy' in the context of CFS/ME (see here) and in particular, what various patients have been reporting from interventions in this area (see here)...

----------

[1] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jan 30. pii: archdischild-2017-314138.

[2] Norris T. et al. Natural course of chronic fatigue syndrome/myalgic encephalomyelitis in adolescents. Arch Dis Child. 2017 Jun;102(6):522-528.

----------

"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

----------

[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

----------

FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) - a trial protocol and some questions...

FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) is an initiative discussed in a recent study protocol paper published by Sarah Baos and colleagues [1]. It continues a research interest based on previous published results from a trial undertaken in the Netherlands by Sanne Nijhof and colleagues [2] looking at a possible intervention option for adolescents with chronic fatigue syndrome (CFS) (also referred to as myalgic encephalomyelitis, ME by some).

Said intervention option - Fatigue In Teenagers on the interNET (FITNET) - is "a web-based cognitive-behavioural treatment accessible to patients and both parents, based on the existing face-to-face CBT [cognitive behaviour therapy] protocol for adolescents developed by the ECCF [Expert Centre for Chronic Fatigue (Radboud University Nijmegen Medical Centre, ECCF)]." The previous Nijhof findings concluded that: "FITNET offers a readily accessible and highly effective treatment for adolescents with chronic fatigue syndrome" on the basis of previous (registered) trial results.

The recent Baos paper detailing 'what researchers are going to do' is looking to build on the previous Nijhof findings to determine whether "it is effective in the National Health Service (NHS) or if it is cost-effective." Alongside the descriptions offered by Baos et al, trial authors have also prospectively registered their intention to undertake this study (see here).

I don't want to recite all the study details described by Baos et al (the paper is open-access) but I do think a few points are worth noting and a few questions perhaps need to be asked. I say this on the basis that mention of the letters/words CBT in the context of CFS/ME has some 'history' (see here and see here for a part of that history). Also, at the time of writing this post, some of the premises for implementing the FITNET-NHS trial are also subject to 're-inspection' (see here) in light of fairly recent changes to official CFS/ME management guidance in countries outside of the UK (see here)...

Anyhow, point 1: "This is an RCT comparing FITNET-NHS with Activity Management for paediatric CFS/ME." RCT means randomised-controlled trial and means participants (planned 700+ aged 11-17 years old) will be randomly placed in either the treatment arm of the study or the 'activity management' control group. Actually, the authors mention another important detail in respect of the study progression: "An internal pilot study will be conducted with continuation of the trial based on achieving defined criteria." What this means is that certain criteria need to be met before the trial progresses, following a sort of pseudo-adaptive design. The stop criteria we are told are: "(1) the recruitment rate is substantially below target during the last 6 months of the internal pilot study and if the qualitative data suggests that we cannot improve recruitment by changing recruitment methods or (2) the qualitative data suggests that the interventions are not acceptable to participants." I've talked about recruitment rates in relation to trials run by some of the Baos authors before on this blog (see here). In terms of 'acceptability' of the interventions, well, the findings from Geraghty and colleagues [3] perhaps need airing in line with some of the history around the use of CBT in the context of CFS/ME. Will all of this affect recruitment rates? We'll see.

Point 2: Activity management (the comparator). There are various elements - mandatory, flexible, prohibited - that such activity management will include. Prohibited elements, I think, mean that specialist therapists cannot discuss in detail things like "feelings, beliefs and how they change" nor "feelings and their relationship with behaviour." Mandatory elements by contrast include finding a baseline level of activity, "to record time spent each day doing high-energy cognitive activities" and importantly: "Increasing activity by 10–20% each week." Yes, this is an active comparator that looks like it is expecting quite an increase in activity over the duration of the study. I think they call this graded exercise therapy (GET). All of this will be delivered on-line and participants will "receive treatment for 3 to 6 months." As you can see, things like recording activity levels (the ActiveME app is mentioned) is going to be predominantly (exclusively?) done via "paper/electronic diaries." I'm a little cautious of this method, and once again (see here) need to question why more objective activity trackers such as the wonderful technologies headed under the title of actigraphy are not being fully utilised with CFS/ME research in mind (see here for another example). Given also that the primary outcome measure is: "Disability measured using the Physical Function Scale (SF-36-PFS) at 6 months after randomisation", surely such actigraphic data would provide a really sound comparator to such subjective scoring?

Point 3: There are a range of secondary outcomes listed by Boas and colleagues in relation to measuring any effects from intervention and/or comparator. I am happy to see that quality of life (QoL) will be measured via use of the EQ-5D-Y (EuroQoL health-related quality of life questionnaire, Youth version) given some chatter about this previously (see here and see here). But there are some things missing from such an outcome line-up; a primary one seems to be that although fatigue and physical function is kinda (see above) mentioned in an analysis sense, more specific facets of CFS/ME are not seemingly being addressed such as PEM (post-exertional malaise). I note from the study website for example, the authors talk about how "fatigue and other symptoms get worse after exertion" suggesting that they know all about PEM. The question then: why not try and test for it and importantly, assess it before and after intervention? OK, I know that measuring PEM is still more of an art rather than a science [4], but I wonder if it would have been helpful for researchers to also potentially think about examining biochemistry for example, as well as psychology and behaviour throughout their study to aid some further investigation in this important area. Y'know things like immune function for example [5] which seems to be an area of research rising (see here) and could add something extra when it comes to sub-grouping among the CFS/ME population? Oh, and just in case you were thinking 'eh?' when it comes to me talking about CBT potentially affecting immune function, have a look at another trial protocol from Schakel and colleagues [6] and the measures they want to use/are using as part of their study "to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges."

Point 4: Safety. I am happy to see that safety of the intervention(s) is also discussed in the Boas paper. To quote for example: "We will define a serious deterioration in health as: (1) clinician-reported serious deterioration in health, (2) a decrease of ≥ 20 in SF-36-PFS between baseline and 3, 6 or 12 months or scores of ‘much’ or ‘very much’ worse on the Clinical Global Impression Scale or (3) withdrawal from treatment because of feeling worse." Good news indeed, and I assume this covers the comparator arm of the study too. What is perhaps missing from such study safety features however, is a little more detail on what screening will be carried out before participants are allowed on to the study in order to reduce/minimise any potential adverse events or even worse, include those who really shouldn't be included in such a study ('first, do no harm'). So: "Young people will be excluded if any of the following apply: (1) they are not disabled by fatigue (defined in eligibility screening), (2) their fatigue is due to another cause, (3) they are unable to complete video calls or FITNET-NHS online chapters or (4) they report pregnancy at assessment." Under 'their fatigue is due to another cause' I'm a little unsure about what this might mean. Does this for example, infer that all potential participants will be screened for mitochondrial disease in light of other data suggesting overlap with cases of CFS/ME (see here) and a possible/probably connection with some fatigue-related symptoms? How is one able to rule out so many potential causes of fatigue other than CFS? As to the idea that there may be those 'unable to complete video calls or FITNET-NHS chapters', well, I imagine that excludes those who might be at a more severe presentation stage of their illness? This then introduces the issue of representativeness of any trial results subsequently obtained...

I applaud the authors for communicating as much as they did about their intentions to conduct this trial. More research groups need to do this both inside and outside the realms of CFS/ME to make replication easier and allow old farts like me to scrutinise and comment from on high. Relying solely on the cold, objective science in this often contentious area, I can also see the rationale behind their running this trial and the urgent need to improve quality of life for many, many young (and older) people diagnosed with CFS/ME.

But... as things stand with the protocol, particularly the distinct lack of using widely available objective measures to provide data on activity levels, I can't also see how this study is going to significantly add to the existing research base nor wider discussions about the use of something like CBT in the context of CFS/ME. I say that also acknowledging that the original FITNET trial is not without criticism [7], including a section that was titled 'The Actometer Results' that perhaps should be renamed 'What happened to the Actometer Results' given "the results were not reported and the reason for this was not given." One also needs look at the masses of discussions on the PACE trial (see here for example) that included CBT as part of an intervention package, to see how the biopsychosocial (BPS) model on which such research rest is, at best, disliked by many suffering with CFS/ME (see here). Said discussions now even reaching the House of elected officials here in Blighty (see here). The glaring lack of any biochemical measures also accompanying this new study adds to the feeling that despite recognition from the authors that "common symptoms in children and young people are unrefreshing sleep, problems with memory and concentration, headaches, nausea (feeling sick), dizziness, muscle and joint pain, and sore throats" psychosomatic ideas still prevail regarding the nature of such symptoms and the continuing rationale for studying CBT in the context of CFS/ME.

I'll hopefully come back to this topic as and when any study results are forthcoming ("Overall trial end date 30/10/2021").

----------

[1] Baos S. et al. Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial. Trials. 2018; 19: 136.

[2] Nijhof SL. et al. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet. 2012 Apr 14;379(9824):1412-8.

[3] Geraghty K. et al. 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. J Health Psychol. 2017 Aug 1:1359105317726152.

[4] McManimen SL. & Jason LA. Differences in ME and CFS Symptomology in Patients with Normal and Abnormal Exercise Test Results. International journal of neurology and neurotherapy. 2017; 4(1): 066.

[5] Nijs J. et al. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis⁄chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1b. J Intern Med. 2010 Apr;267(4):418-35.

[6] Schakel L. et al. The effects of a psychological intervention directed at optimizing immune function: study protocol for a randomized controlled trial. Trials. 2017 May 26;18(1):243.

[7] Ghatineh S. & Vink M. FITNET's Internet-Based Cognitive Behavioural Therapy Is Ineffective and May Impede Natural Recovery in Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. A Review. Behav Sci (Basel). 2017 Aug 11;7(3). pii: E52.

----------

One percent of Chinese middle school students "met the definition of CFS"

CFS mentioned in the title of this post refers to chronic fatigue syndrome otherwise known as myalgic encephalomyelitis (ME). The question of how prevalent CFS/ME might be in various groups - particularly young people - was tackled in the paper published by Jieyao Shi and colleagues [1] (open-access available here). This continues some previous research chatter on this topic (see here) including the important differentiation of chronic fatigue syndrome from just 'chronic fatigue' (see here)...

So, what was done? "This cross-sectional survey enrolled 18,420 middle-school students aged 10 to 18 years (mean 14.9 ± 1.68) who were selected randomly between September 2010 and January 2011 from 25 junior- and senior-middle schools in Suzhou, China at a ratio of 1:1 with respect to the gender and grade." That's quite a big starting participant group in anyone's book; although eventually whittled down ever so slightly to 18,190 after dropping those who did not complete the study instruments properly for example.

As to the question of defining CFS (a *real issue* down the years), we are told that two schedules were used: "the US CDC-94 definition of CFS" otherwise known as the Fukuda criteria, and the "Chaldea fatigue scale (CFQ)" which is an error;  it should read the Chalder Fatigue Scale. A diagnosis of CFS was decided on the basis of both schedules yielding a positive result and "at the same time the school health workers excluded the fatigue symptoms that may be associated with other medical conditions after reviewing their yearly routine physical examination records." Where CFS criteria were not fully met, a diagnosis of chronic fatigue (CF) was given.

Results: "The prevalence of CFS and CF in this study was 0.9% and 12.0%, respectively." Nothing particularly novel there given other data that has discussed similar CFS frequency figures present in similar age-groups (see here). The idea that chronic fatigue not CFS is present in around 1 in 10 young adults is rather startling...

I was also quite interested in another observation made by Shi et al: "Other than fatigue, muscle pain, joint pain, difficulty in concentration, headache, and sore throat as specified in the CDC-94, despondency, irritability and being afraid of going to school were the most important symptoms of CFS in the middle-school students investigated in this study." Despondency, irritability and being afraid to go to school are again, probably not unexpected when it comes to CFS/ME in this age-group. I'm minded to suggest that such characteristics are likely 'reactive' symptoms to the presence of CFS/ME over and above having any significant aetiological input. If for example, you've been bed-bound, struck down by months or years of not being able to do all the things that teenagers and young adults like and want to do, it's very possible that you probably wouldn't feel your best and could, in the longer-term, be prone to developing something approaching depressive symptoms. That doesn't mean that depressive symptoms or actual depression caused your CFS/ME or even that depression is a core part of your CFS/ME; merely that depression joins the clinical presentation as per other instances in medicine [2]. As for the observation about being afraid to go to school, well, one only needs to look at other conditions where school refusal has been noted (see here) to perhaps understand some important hows-and-whys.

"Our study shows that CFS is prevalent among Chinese teenagers, and requiring proper intervention and treatment." That was the conclusion reached by Shi and colleagues, and with it the next obstacle to face: what is 'proper intervention and treatment'? Importantly too, will this manage to leave out the psychobabble explanations that have pervaded Western ideas on CFS/ME? Will it instead concentrate on the idea that CFS/ME is a multi-faceted organic illness - with probably more than one aetiology [3] - displaying both physiological and psychological side-effects?

----------

[1] Shi J. et al. Chronic fatigue syndrome in Chinese middle-school students. Medicine (Baltimore). 2018 Jan;97(4):e9716

[2] Tang PL. et al. A Systematic Review and Meta-Analysis of Demoralization and Depression in Patients With Cancer. Psychosomatics. 2015 Nov-Dec;56(6):634-43.

[3] Mørch K. et al. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterology. 2013;13:28.

----------

"patients with CFS/ME do not exhibit insufficient concentrations of circulating total 25(OH)D"

The title heading this post comes from the findings reported by Kate Earl and colleagues [1] (open-access available here), where '25(OH)D' refers to calcifediol, a compound typically used to estimate how much vitamin D is present in the body and CFS/ME refers to Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

After assaying some 92 people with CFS/ME and an almost equal number of 'age-matched healthy controls' (HCs) for plasma total 25(OH)D and individual vitamin D metabolites - "25(OH)D2 and 25(OH)D3" - researchers concluded that vitamin D deficiency was not rife in their cohort. Indeed we are told that: "total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively)." The authors were also able to report that vitamin D supplementation by the CFS/ME group seemed to be a primary reason for their findings.

There are a few important strengths to the Earl results that are worth mentioning. Not least that vitamin D metabolites were measured by mass spectrometric methods similar to other independent research occasions (see here for example). Mass spectrometry seems to have quite a few advantages over other methods of vitamin D analysis; now labelled as a gold-standard technique. Added to their use of a deuterated standard ("hexadeuterated (OH)D3") and one has some degree of confidence in the analytical results; albeit, as the authors acknowledge: "that only the main marker of vitamin D status, that is, 25(OH)D, was measured" and how "there is a need to assess all of the vitamin D metabolites" of which there are quite a few [2].

At first glance, the Earl findings seem pretty unremarkable. Supplementation with vitamin D, as everyone is being encouraged to do these days (see here), means higher levels of circulating vitamin D. I would be surprised if they didn't. This is also not the first time that vitamin D levels in relation to CFS/ME have been talked about in the peer-reviewed domain either (see here) albeit not always with the same results but again with that caveat about supplementation in mind.

Given however that a measure of fatigue - "the Chalder Fatigue Questionnaire" - was also included for all participants in the Earl study, and how nothing very much seemed to be present when looking at any connection between fatigue scores and vitamin D status, this provides a possible clue that vitamin D is probably not a big player specifically in relation to the presentation of fatigue in most cases of CFS/ME. Such a questionnaire does not rule out other potential associations (e.g. post-exertional malaise, PEM) nor that other, potential comorbidity appearing alongside CFS/ME might not have a stronger vitamin D link (see here for example). But for now, it adds to the literature (see here) casting doubt on any direct role for vitamin D in relation to CFS/ME.

----------

[1] Earl KE. et al. Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. BMJ Open. 2017 Nov 8;7(11):e015296.

[2] Abu Kassim NS. et al. Simultaneous determination of 12 vitamin D compounds in human serum using online sample preparation and liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2017 Dec 6. pii: S0021-9673(17)31772-7.

----------