Muscle dysfunction in CFS

Review abstract:

Introduction:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis.

Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level.

Methods:
Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis.

Results:
Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction.

Discussion:
Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.

Understanding muscle dysfunction in Chronic Fatigue Syndrome, by G Rutherford, P Manning, JL Newton in Journal of Aging Research, Feb 2016

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Post Activity Relapse (PAR) or PEM?

Another contribution to the discussion of the key characteristic of ME, Post Exertional Malaise (PEM), comes from Kasper Ezelius of the Sweish patient group ME-föreningen: Suggestion to replace PEM by PAR

Deterioration after mental or physical exertion is often referred as “post exertional malaise” (PEM). But the word malaise, is very far from what it is. In the Swedish medical dictionary malaise is defined as a vague diffuse sense of discomfort and tiredness. But the patients rather experience a crash with an increase of most of the symptoms.

To be clear that the entire symptom complex deteriorates, it would be better to replace the word “malaise” with “relapse”. Relapse also better describes that it takes some days to recover. Post exertional malaise could be interpreted like a few minutes of feeling slightly unwell after running.

The exertion does not need to feel like an exertion at the time the patient is doing it, and it would be better to replace the word “exertion” with “activity”. So an improved term of “post exertional malaise” (PEM) would be “post activity relapse” (PAR). I think post activity relapse is a far better description, and I hope future disease descriptions, clinical guides and research articles use this terminology. I think post activity relapse is short enough in order to use it several times in a text, without being felt as too burdensome, but I think it is important to clarify somewhere in the text that the activity can be both of mental and physical kind.

The term “relapse after mental or physical activity” has the advantage of being clear that:

  • both physical and mental activity create worsening
  • it must not be an exertion in the classical sense, but rather an activity
  • the worsening does not only create malaise, but a whole range of the ME symptoms are worsened (hyperacusis, orthostatic intolerance, need to rest, cognitive difficulties, pain, etc).
  • it takes days to recover

The relapse does not need to occur directly after the exertion, but it may take a few days (1-3 days, sometimes more) before the deterioration starts. This has been described by Dr John L Whiting from Australia in the message list Co-Cure the 9th of December 2015. For the case there is a delay in the relapse, I suggest that the term “delayed post activity relapse” (DPAR) is used, but that it is also clarified that the activity can be both mental and physical.

Example of use:
A patient with ME must have post activity relapse (PAR), which is a relapse after mental or physical activity. A patient may at occations experience a delayed onset of the PAR, and this is called delayed post activity relapse (DPAR).

Summary
Post exertional malaise is proposed to be replaced by “relapse after mental or physical activity”, but for repeated use a shorter form can be used: “post activity relapse” which can be abbreviated “PAR”.

At the occations the onset is delayed the term “relapse with delayed onset after mental or physical activity” is used, but for repeated use a shorter term can be used: “delayed post activity relapse” which can be abbreviated “DPAR”.

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Methods of applying the CDC1994 case definition

Research abstract:

Background:
Multiple case definitions are in use to identify chronic fatigue syndrome (CFS). Even when using the same definition, methods used to apply definitional criteria may affect results.

The Centers for Disease Control and Prevention (CDC) conducted two population-based studies estimating CFS prevalence using the 1994 case definition; one relied on direct questions for criteria of fatigue, functional impairment and symptoms (1997 Wichita; Method 1), and the other used subscale score thresholds of standardized questionnaires for criteria (2004 Georgia; Method 2). Compared to previous reports the 2004 CFS prevalence estimate was higher, raising questions about whether changes in the method of
operationalizing affected this and illness characteristics.

Methods:
The follow-up of the Georgia cohort allowed direct comparison of both methods of applying the 1994 case definition. Of 1961 participants (53% of eligible) who completed the detailed telephone interview, 919 (47%) were eligible for and 751 (81%) underwent clinical evaluation including medical/psychiatric evaluations. Data from the 499 individuals with
complete data and without exclusionary conditions was available for this analysis.

Results:
A total of 86 participants were classified as CFS by one or both methods; 44 cases identified by both methods, 15 only identified by Method 1, and 27 only identified by Method 2 (Kappa 0.63; 95% confidence interval [CI]: 0.53, 0.73 and concordance 91.59%). The CFS group identified by both methods were more fatigued, had worse functioning,
and more symptoms than those identified by only one method. Moderate to severe depression was noted in only one individual who was classified as CFS by both methods. When comparing the CFS groups identified by only one method, those only identified by Method 2 were either similar to or more severely affected in fatigue, function, and symptoms than those only identified by Method 1.

Conclusions:
The two methods demonstrated substantial concordance. While Method 2 classified more participants as CFS, there was no indication that they were less severely ill or more depressed. The classification differences do not fully explain the prevalence increase noted in the 2004 Georgia study. Use of standardized instruments for the major CFS domains
provides advantages for disease stratification and comparing CFS patients to other illnesses.

Methods of applying the 1994 case definition of chronic fatigue syndrome – impact on classification and observed illness characteristics, by E.R. Unger, J.-M.S. Lin, H. Tian, B.M. Gurbaxani, R.S. Boneva, J.F. Jones in Population Health Metrics, December 2016 and March 12, 2016 [Preprint]

Comment from Tom Kindlon: Depression scores in this follow-up study are very different to scores in original study (looking solely at the Reeves et al. (2005) operationalization) Read more

 

 

 

 

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Norwegian researchers call for more research into Lightning process

Article:

The cause of chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) is not well understood and is disputed, and therapeutic options are limited. Many patients who attended the Lightning Process course reported positive effects. This should lead to a randomised controlled intervention trial.

Since 2008 several thousand patients with CFS/ME have attended the Lightning Process (LP) course in Norway (1). The course is a three-day intensive brain rehearsal programme with the option for follow-up. Although what triggers CFS/ME in the individual case may vary, it is assumed that symptoms maintenance and chronification can be attributed to a stress response with elevated state of alertness and persisting activation of the sympathetic nervous system, driven by classic and operant conditioning mechanisms. The Lightning Process is based on these theories of stress.

What is the Lightning Process?
The Lightning Process course is a form of psychoeducation comprising both a theoretical component and exercises which participants practice at home. The course has elements in common with cognitive behavioural therapy, a therapeutic method that has demonstrated results in CFS/ME (2). Both methods take the association between thoughts, feelings and actions as their starting point, and aim at breaking self-reinforcing and inconvenient spirals. However, the Lightning Process differs from cognitive behavioural therapy in certain aspects: The course is designed as a three-day mental brain rehearsal, led by a coach with specific Lightning Process training. Whereas cognitive behavioural therapy addresses the contents of patients’ thoughts, LP places more emphasis on discussing how one relates to the thought patterns (3). Patients are furthermore encouraged to seek out experiences that engender positive emotions, without a fixed plan, instead of analysing negative thoughts and emotions. In addition, considerable attention is paid to the importance of semantics – how words and concepts contribute to negative thought patterns.

Research
To our knowledge, two scientific studies of the Lightning Process have been conducted, both of them qualitative. In one study, seven of nine adolescents reported significant improvement, while two did not experience any effect (4). The second study investigated patients’ experiences and found that higher scores on understanding of one’s own condition, feelings of confidence towards the course leader and positive bodily response distinguished patients who reported a positive effect from patients who reported a negative or no effect (5). Both studies indicate that the course may be beneficial for some patients with CFS/ME. In England a pilot study has also been conducted with children/adolescents which will lead to a randomised controlled trial (6).

A telephone questionnaire survey was conducted in collaboration with Godthaab Health and Rehabilitation of all participants who had attended Lighting Process courses in 2008 (7). The majority reported an improvement in quality of life and activity level. The improvement persisted one year after course participation, and no serious adverse effects were reported. The user survey of course only allows the generation of hypotheses, but indicates that the course can have a positive effect on these conditions.

Need for further knowledge
CFS/ME can be debilitating for the individual and represents a significant societal problem. There is a great need for more research on the effects of various forms of treatment. The Lightning Process has shown promising results, but these need to be reproduced in randomised controlled trials. Before the results of such studies are available, the evidence base is insufficient for recommending that the Lightning Process be systematically used in the health services.

Chronic fatigue syndrome and experience with the Lightning Process, by L Landmark, R M B Lindgren, B Sivertsen, P Magnus, S Conradi, S N Thorvaldsen,J K Stanghelle in Tidsskr Nor Legeforen 2016; 136:396, Nr. 5 – 15. mars 2016

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Natural Killer Cells in CFS/ME & Multiple Sclerosis

Research abstract:

Patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and multiple sclerosis (MS) suffer from debilitating fatigue which is not alleviated by rest.

In addition to the fatigue-related symptoms suffered by patients with CFS/ME and MS, dysfunction of the immune system and, in particular, reduced natural killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS.

The purpose of this pilot study was to compare NK cellular mechanisms in patients with CFS/ME and MS to investigate potential dysfunctions in the NK cell activity pathway.

Flow cytometry protocols assessed CD56dimCD16+ and CD56brightCD16+/- NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins.

All participants in this study were female and included 14 patients with CFS/ME, nine patients with MS and 19 non-fatigued controls.

The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune-enhancing medications.

In the MS cohort, KIR2DL5 was significantly increased on CD56brightCD16+/- NK cells and expression of CD94 was significantly increased on CD56dimCD16+ NK cells in comparison with the controls.

Co-expression of CD57 and perforin was significantly increased on CD56dimCD16+ NK cells from patients with CFS/ME compared to the MS and non-fatigued control participants.

The results from this pilot study suggest that NK cells from patients with CFS/ME and MS may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.

Introduction:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with disabling levels of fatigue.

Patients suffer from a state of permanent exhaustion which is also accompanied by a myriad of symptoms associated with autonomic, neurological, endocrine
and immune systems [1, 2].

Symptom severity may vary on a daily or weekly basis and is not alleviated by rest [3, 4].

Persistent fatigue is a characteristic of CFS/ME and approximately 65-95% of patients with multiple sclerosis (MS) also experience unremitting fatigue [5, 6].

Exacerbation of symptoms following physical or cognitive activity has been described in both CFS/ME and MS, as have memory and cognitive difficulties, gastrointestinal disturbances and irregular sleep patterns [5].

The symptoms suffered by patients with CFS/ME and MS may present as a relapsing-remitting course, and both CFS/ME and MS share a significant female preponderance [7, 8].

Approximately six females are affected to every one male for CFS/ME and 2.3–3.5 females to every one male for MS [7, 9].

Dysfunction of the immune system may contribute to the pathogenesis of CFS/ME and MS.

In particular, reduced natural killer (NK) cell cytotoxic activity is a consistent finding in CFS/ME and relapsing-remitting patients with MS [10-12].

CD56dimCD16+ NK cells elicit cytotoxic activity to remove target cells infected by viruses, bacteria orcells that have been malignantly transformed [13].

NK cell cytotoxic activity is a tightly regulated process which consists of a number of ordered steps including adhesion to the target cell, NK cell activation by surface receptors and release of lytic proteins to induce apoptosis of the target cell [14-16].

Whilst the consequences of reduced NK cell activity may be attributed to the persistence of viral infections reported in some patients with CFS/ME, contrasting evidence in MS suggests that the activity of NK cells can either exacerbate or attenuate disease activity [3, 7, 17].

The opposing effects of NK cells reported in patients with MS may be mediated by the different subsets of NK cells eliciting either cytotoxic or cytokine effector functions [18].

Reduced cytotoxic activity of peripheral NK cells from patients with MS has been correlated with clinical exacerbations of disease activity [12].

This finding has been replicated in the experimental autoimmune encephalomyelitis (EAE) mouse model where depletion of NK cells was associated with increased disease activity [19].

It has also been suggested that NK cells have an immunoregulatory role that promotes the remission state in relapsing-remitting MS [12, 20].

Through cytotoxic activity and the production of type 2 cytokines such as IL-5 and IL-13, NK cells may lyse and suppress T helper 1 autoimmune cells which mediate the inflammatory process in the CNS of patients with MS [20, 21].

The potential immunoregulatory role of NK cells in MS maintaining the remission state highlights the importance of optimal NK cell effector function.

As reduced NK cell cytotoxic activity has previously been reported in both CFS/ME and MS, the aim of this pilot study was to investigate cellular mechanisms required for NK cell effector function.

Adhesion molecules, surface receptors and lytic proteins were measured to determine whether mechanisms which may contribute to reduced NK cell cytotoxic activity are similar or different in female patients with CFS/ME and MS.

Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis, by Huth TK, Brenu EW, Ramos, Nguyen T, Broadley S, Staines D, Marshall-Gradisnik S in Scand J Immunol. 2016 Jan; 83(1):44-51.

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Major proposed US study acknowledges CFS is physical, not mental

Blog article: CDC study finds CFS is physical, not mental, by  Russell Logan 7 March 2016
Also the NIH has dropped the FMD component of its clinical study of post-infectious ME/CFS:

Despite decades of suggesting otherwise, the CDC has just determined that CFS patients have normal mental health function and severe physical impairments.

The findings coincide with the NIH’s decision to drop a key component of its clinical study of post-infectious ME/CFS, amid patient concerns about serious and potentially crippling methodological problems with the study, highlighted in a review by MEAdvocacy.org.

The CDC Multi-site Clinical Assessment of CFS, which began in 2012, collected data from 450 patients at seven clinical centers in the US.

According to the CDC, the aim of the study was “to characterize patients with CFS or myalgic encephalomyelitis (ME) in clinical practices of clinicians with expertise in CFS/ME.”

Dr Elizabeth Unger, head of the CDC’s Chronic Viral Diseases Branch, announced the early findings of the multi-site study at a CDC Grand Rounds event on ME/CFS in February.

‘Those preliminary and as yet unpublished findings reveal that functional status in CFS patients is severely impaired, except for mental and emotion function.’

The CDC used standardized questionnaires to measure the major domains or characteristics of the illness, including pain, function, fatigue, type and severity of symptoms, and sleep.

Data on medical history, family history, physical examination results, medications and results of laboratory tests was also collected.

One of the tools the CDC used in their assessment was the SF-36 Health survey which defines mental function as psychological distress and psychological wellbeing.

The study showed that mental and emotional function of patients was close to normal, despite the serious nature and often lengthy term of the illness.

The copy of Dr Unger’s slide from the Grand Rounds event shown below has red markers indicating normal values for healthy people and blue boxes representing the range for study participants. The diamonds indicate the study participants’ average score.

FMD control group dropped from new NIH study
Coincidentally, it has been announced that the NIH will drop the controversial functional (psychogenic) movement disorder (FMD) control group from its upcoming clinical study.

The inclusion of the FMD control group and the addition of FMD and behavioral experts to the study ignited patient concerns about whether the study was contrived to validate a psychological basis to the illness.

You can read more about the problems associated with the FMD group here.

UPDATE: Link to NIH study details has been updated – NIH has updated their information [9/3/16]

In the video of the CDC Grand Rounds event, Dr Elizabeth Unger’s presentation begins at the 17:40 mark.

 

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Potential diagnostic biomarkers in Natural Killer cells of patients with CFS/ ME

Research abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population. Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis.

We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that can be detected in the peripheral blood of CFS/ME patients.

METHODS: miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1.miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort. The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene targets.

RESULTS: Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR. Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B-cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME pathology.

CONCLUSION: This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets consistent with cellular activation and altered effector function.

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME), by RD Petty, NE McCarthy, R Le Dieu, J R Kerr in PLoS One. 2016 Mar 11;11(3):e0150904

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Human placental extract as a treatment for CFS?

ME research UK article, 9 March 2016: Human placental extract

In Korea, human placental extract (HPE) is apparently used to treat various illnesses. In most other countries, it is considered an alternative and complementary therapy as there is little formal evidence to support its use, and this may be why the FDA in the US keeps a watching brief (read more).

HPE is extracted from human placentas collected at full-term delivery, using heat and acid hydrolysis, and is said to consist of proteins, minerals, amino acids, and steroid hormones. The rationale for its use seems to lie in traditional Chinese medicine, and in the belief that dysfunction in a part of the body can be treated by eating the equivalent part of the body of animal, for example, eating animal kidneys as a treatment for kidney disease. In illnesses of unknown cause associated with a range of symptoms, however, it can be difficult to identify an appropriate animal part to consume, and it seems that extracts of placenta are suitable in these cases, on the basis that they may include basic nutrients.

A new paper in the Biological and Pharmaceutical Bulletin (read more) reports on a randomised clinical trial of HPE – manufactured by GCJBP Corporation of Korea which also provided funding for the study – in patients with chronic fatigue, some fulfilling the Fukuda criteria for CFS (ME/CFS group) and some not (idiopathic chronic fatigue group; ICF). In total, 78 patients with fatigue were recruited; 40 with ME/CFS and 38 with ICF. All were randomly assigned to receive a subcutaneous injection of either HPE or normal saline (placebo) three times a week for 6 weeks. The patients had a variety of clinical outcomes measured, including three different measures of fatigue (Fatigue Severity Scale; Visual Analog Scale; and Multidimensional Fatigue Inventory).

The results can be simply stated. Compared with the start of the study, the ME/CFS patients’ fatigue scores were reduced in both the HPE and placebo groups after 6 weeks, but the reduction in fatigue (on all three measures) was significantly greater (albeit modest; around 10% more) after HPE than after placebo. This effect was not seen in ICF patients; HPE had no greater effect on their fatigue than placebo after 6 weeks. Other measures such as blood pressure and serum biochemistry variables were unchanged, and adverse events were similar in both groups.

The researchers’ conclusion was that HPE was more effective than placebo in reducing fatigue in people with ME/CFS but not in patients with ‘simple’ chronic fatigue. They suggest that the anti-inflammatory properties of HPE may be improving the chronic inflammation underlying ME/CFS, and/or that cytokines present in HPE may be improving the immune function.

The same researchers at Ajou University have previously reported health improvements after subcutaneous injections of HPE in elderly Koreans (read more) and in in middle-aged Korean women with menopausal symptoms (read more), so they have something of a track record in studying the effect of HPE within a Korean culture that accepts placental products. Whether the modestly positive effects reported for HPE in this study would translate to other cultures in a moot point, and there remains the burning question of the underlying mechanism of action of a shallow injection of HPE under the skin – could it have the anti-inflammatory effects claimed, and if so, how?

ME Research UK sometimes gets phone calls from patients asking what to make of smallish, one-off and often unusual reports, like this one from Korea. Sadly, very little can be concluded about effectiveness from any single study, particularly as the scientific literature is replete with one-off smallish studies that overwhelmingly report positive outcomes for various interventions in various illnesses.

For instance, a quick look at the ME/CFS literature on complementary and alternative therapies (see review) alone reveals small studies showing ‘beneficial’ outcomes for qigong plus meditation (fatigue); massage (fatigue, pain and insomnia); tuina and tai chi (general symptoms); NADH (various symptoms); acetyl-L-carnitine (fatigue, pain and concentration); essential fatty acids (symptoms and general heath), and so on….

Are they all reporting true therapeutic effects? Were they published because their outcomes were positive, while the ‘negative’ studies were kept in a file drawer? No-one will ever know unless other researchers try to replicate the findings. Independent replication by other groups at other institutions is where the rubber meets the road; it’s a vital part of the scientific process, and without it the meaning of an isolated finding is anyone’s guess, particularly where the ‘treatment’ is unusual.

Human Placental Extract as a Subcutaneous Injection is effective in Chronic Fatigue Syndrome.

 

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Mitochondrial myopathy – differential diagnosis of CFS

Article abstract:

Introduction: Symptoms of mitochondrial diseases and chronic fatigue syndrome (CFS) frequently overlap and can easily be mistaken.

Methods: We report the case  of a patient diagnosed with CFS and during follow-up was finally diagnosed with mitochondrial myopathy by histochemical study of muscle biopsy, spectrophotometric analysis of the complexes of the mitochondrial respiratory chain, and genetic studies.

Results: The results revealed 3% fiber-ragged blue and a severe deficiency of complexes I and IV and several mtDNA variants. Mother, sisters, and nephews showed similar symptoms, which strongly suggests a possible  maternal inheritance. The patient and his family responded to treatment with high doses of riboflavin and thiamine with a remarkable and sustained fatigue and muscle symptoms improvement.

Conclusions: This case illustrates that initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS, and  in these patients a regular reassessment and monitoring of symptoms is recommended to reconfirm or change the diagnosis.

Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue
Syndrome, by F Galán, I de Lavera, D Cotán, JA Sánchez-Alcázar in J Investig Med High Impact Case Rep. 2015 Sep 24;3(3)

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Illness progression in CFS: immune signature changes

Research abstract:

Background: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness.

Methods: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18–50 years of age, ill for 7 years (n = 22), and  (iii) age 50 years or older (n  = 28), ill for 11 years on average.

Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori.

Results: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75–88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration.

While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years.

Conclusions: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.

Illness progression in chronic fatigue syndrome: a shifting immune baseline, by Lindsey Russell, Gordon Broderick, Renee Taylor, Henrique Fernandes, Jeanna Harvey, Zachary Barnes, AnneLiese Smylie, Fanny Collado, Elizabeth G. Balbin, Ben Z. Katz, Nancy G. Klimas and Mary Ann Fletcher in BMC Immunology 2016 17:3, 10 March 2016

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