Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome (2017) Wyller et al.

hixxy · Dec 6, 2017

J Transl Med. 2017 Dec 4;15(1):245. doi: 10.1186/s12967-017-1350-1.

Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome.

Wyller VB, Nguyen CB, Ludviksen JA, Mollnes TE.

Abstract

BACKGROUND:
Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-β) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-β isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-β levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group.

METHODS:
CFS patients aged 12-18 years (n = 120) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18).

RESULTS:
Plasma levels of all three isoforms of TGF-β were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-β were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-β3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5.

CONCLUSIONS:
Plasma levels of all TGF-β isoforms were not altered in adolescent CFS. However, the TGF-β isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-β3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.

KEYWORDS:
Adolescent; Chronic fatigue syndrome; Inflammation; Transforming growth factor beta
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https://www.ncbi.nlm.nih.gov/pubmed/29202780
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1350-1

Marco · Dec 7, 2017

There's some useful demographic data included in this study but while Wyller continues to promote his 'sustained arousal' theory (fair enough - it has some face validity) his own previous work suggests that sympathetic inhibition not only doesn't work but may also exacerbate objective impairments in physical activity :

Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial.

https://www.ncbi.nlm.nih.gov/pubmed/24493300

Valentijn · Dec 7, 2017

Only 38% met CCC criteria, and 73% Fukuda. This study would have been more interesting if they'd studied ME or even CFS. They recruited with Oxford:

A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary.
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Average CFQ score for patients was 19.3 (8.7 for controls), which seems pretty low. Steps walked per day was 4,662 versus 10,293 for healthy controls. Some patients had been sick for as little as 4 months.

For TGF-B1 and B3 comparisons between CFS subgroups (Oxford, Fukuda, CCC) they switched from using mean (average) to using median (middle value) with no explanation. Another group did this in the past with stimulants to hide a big deterioration resulting from the drug.

And here comes the babble:

Taken together, the results of the present study seem to suggest that underlying disease mechanisms of CFS are more related to altered immunological control than to altered levels of immune markers per se. Similar observations have been reported in a study of neuroendocrine regulatory systems [29], and are also in line with findings of a relationship between HPA axis dynamics and clinical symptoms [50, 51].

On a more general level, the findings of the present study seem to comply with the “sustained arousal” model of CFS [30]. In this model, a maladaptive stress response is considered a central pathophysiological element, eliciting autonomic and neuroendocrine alterations which in turn are responsible for subtle immunological alterations.
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They have TGF data for individual patients and controls at https://static-content.springer.com.../MediaObjects/12967_2017_1350_MOESM2_ESM.xlsx but not with subgrouping of patients according to criteria they meet, which is what would be needed to do the calculations for the means where they only showed medians.

Adrian · Dec 7, 2017

Valentijn said: ↑

For TGF-B1 and B3 comparisons between CFS subgroups (Oxford, Fukuda, CCC) they switched from using mean (average) to using median (middle value) with no explanation.
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I would generally favor the median as it is more robust to outliers and makes less assumptions about linearity of any scale.

Valentijn · Dec 7, 2017

Adrian said: ↑

I would generally favor the median as it is more robust to outliers and makes less assumptions about linearity of any scale.
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In which case they're still using the mean for TGF-B2. The lack of consistency itself is the red flag.

Adrian · Dec 7, 2017

Valentijn said: ↑

In which case they're still using the mean for TGF-B2. The lack of consistency itself is the red flag.
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Yes and I don't see why they can't quote both.

Sometimes differences between the mean and median are informative in terms of the distribution but it would be better if they gave scatter plots. I thought this was becoming common. That lets the reader see the distribution of the data.

Snow Leopard · Dec 12, 2017

Didn't this group disprove the "sustained arousal" hypothesis with several of their studies including a drug trial. Why are they still talking about it?

Esther12 · Dec 12, 2017

Snow Leopard said: ↑

Didn't this group disprove the "sustained arousal" hypothesis with several of their studies including a drug trial. Why are they still talking about it?
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Hard to prove a negative. They tested their theory, and failed to find support for it.... but why give up on it just because of that!!

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