Cytokine signature associated with disease severity in chronic fatigue syndrome patients

[AndyPR]

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

1. Jose G. Montoyaa,b,c,
2. Tyson H. Holmesb,c,d,
3. Jill N. Andersona,b,
4. Holden T. Maeckerc,d,e,
5. Yael Rosenberg-Hassonc,d,
6. Ian J. Valenciab,
7. Lily Chub,
8. Jarred W. Youngerf,1,
9. Cristina M. Tatoc,d, and
10. Mark M. Davis

Abstract
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system.

Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α.

Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Full access at http://www.pnas.org/content/early/2017/07/25/1710519114.full

 

[Kalliope]

STAT: Blood markers of chronic fatigue syndrome could pave the way to a diagnostic test
Overall, people with CSF only had two cytokines that significantly differed in quantity compared to healthy controls. However, when researchers divided people with CSF into mild, moderate, and severe groups, they found that the levels of 17 cytokines increased with increasing severity of the disorder. Thirteen of these cytokines were proinflammatory, meaning they cause inflammation in the body. The results were published Monday in Proceedings of the National Academy of Sciences.

The Telegraph: "Yuppie flu" an inflammatory disease which blood test could easily diagnose, say scientist
Researchers at the Stanford University School of Medicine discovered that people suffering the symptoms of CFS show spikes in 17 proteins produced by the immune system. The bigger the rises, the more severe the condition.

 

[Cheshire]

Miriam Tucker's article:
http://www.npr.org/sections/health-...ign=health&utm_medium=social&utm_term=nprnews

http://www.sciencemag.org/news/2017...une-system-imbalance-chronic-fatigue-syndrome

http://www.medscape.com/viewarticle/883606

http://www.mercurynews.com/2017/07/...iomarkers-linked-to-chronic-fatigue-syndrome/

https://www.newscientist.com/articl...s-may-help-diagnose-chronic-fatigue-syndrome/

 

[notmyself]

i ask in a post earlier about proinflamatory citokines..nobody answers,maybe here i have some more luck..is really no way to lower this pro inflamatory citokines?..literally all my symptoms that i have now are caused by inflamation..i don 't think i ahve any problems with oxygen use,mithocondria or aerobic,anaerobic systems ..i can run longer and faster than most people of my age..So i guess my fatigue and the other symptoms must be caused by chronic inflamation..Doctors in my country are unaware of me/cfs,,When i told him about chronic inflamation he told me that with my normal crp,esr ,fibronogen and complete blood count and immunoglobins all good i will just spend money for nothing doing the citokine panels...cause they will come back normal..

 

[Cheshire]

http://www.ibtimes.co.uk/chronic-fatigue-syndrome-real-disease-driven-by-inflammation-1632755

 

[Simon]

Full free text: Cytokine signature associated with disease severity in chronic fatigue syndrome patients
http://www.pnas.org/content/early/2017/07/25/1710519114.full
Note Mark Davis of Stanford is the senior author, and it's PNAS, which is one of the very top journals, which should help generate interest. Well, the media uptake suggests it has, not least the Science New piece (a v well respected and high profile source of news for researchers). More clues link immune system imbalance with chronic fatigue syndrome | Science | AAAS

And just to make my day, they did it properly, correcting for the fact that they made many comparisons (which makes chance associations much more likely). See below:

P values shown are for the significance of the linear trend. Only statistically significant linear trends adjusted for multiple comparisons (P < 0.05) are shown.

(from powerpoint slide provided by PNAS so presumably fine to show here).

 

[Kalliope]

Stanford Medicine: Blood test: Scientists crack code of chronic fatigue syndrome's inflammatory underpinnings

“I have seen the horrors of this disease, multiplied by hundreds of patients,” Montoya told me in a conversation about the study. “It’s been observed and talked about for 35 years now, sometimes with the onus of being described as a psychological condition. But chronic fatigue syndrome is by no means a figment of the imagination. This is real.”

 

[Sidereal]

We also compared mean cytokine levels in cases with ≤3-y fatigue duration (n = 30) and those with >3-y fatigue duration (n = 156), as per Hornig et al. (17). We did not find any cytokine to be significantly different between these two groups (SI Appendix, Table S3).

Oh dear, yet another promising study fails replication.

 

[Simon]

Oh dear, yet another promising study fails replication.

I'm going to take heart from the fact there was a replication! And with only n=30 it would be harder for the findings to replicate. But still.

 

[Sidereal]

I'm going to take heart from the fact there was a replication! And with only n=30 it would be harder for the findings to replicate. But still.

Yeah, they do acknowledge low power in the Discussion.

Recently, Hornig et al. (17) reported a group of cytokines that inversely correlated with fatigue duration, and in our cytokine assay we investigated the same 51 cytokines. In our study, several cytokines [GRO-α (CXCL-1), IFN-β, IL-15, IL-1A, IL-1RA, IL-2, IL-8, TGF-α, and TGF-β] also inversely correlated with fatigue duration before controlling for potentially confounding variables (age, nonspecific binding, race, and sex). After correction for age (SI Appendix, Fig. S3), nonspecific binding, and race, only one cytokine, CXCL9, inversely correlated with fatigue duration. When analysis was performed for both disease severity and fatigue duration, the findings for disease severity remained statistically significant for most cytokines, whereas those for fatigue duration did not. It is possible that disease duration and severity interact in their association with cytokine expression. To assess that possibility for each cytokine separately, we fit a regression model that allows mean cytokine expression levels to vary flexibly over the 2D distribution of total scores from the Multidimensional Fatigue Inventory (MFI-20) assessment of disease severity (51) and fatigue duration in years (52). This analysis found no evidence that the relationship between mean cytokine expression and disease severity changes with duration of disease (SI Appendix, Table S4). The importance of analyzing ME/CFS data by severity is further supported by the lack of correlation between fatigue duration and disease severity (SI Appendix, Fig. S4). However, the lack of observed correlation between disease (fatigue) duration and cytokine levels may result from the lower statistical power of the current study, because the sizes of both our overall sample of cases (n = 186) and, especially, of cases with ≤3-y fatigue duration (n = 30), were smaller than those studied by Hornig et al. Thus, our failure to discover any differences between short and long duration does not allow us to rule out definitively the possibility that mean serum levels might differ between these two specific fatigue-duration categories (≤3 y vs. >3 y).

 

[notmyself]

Oh dear, yet another promising study fails replication.

so the studies stating that the immune system is overactive in the beggining and become exhausted after around three years is not necesarry real..i'm actually happy about that

 

[Forbin]

They say their inability to confirm changes due to illness duration may be due to that fact that they had fewer patients overall [186 vs 298] and fewer patients ill less than 3 years [30 vs 52].

[The longer than 3 years patients would have been 156 vs 246.]

The importance of analyzing ME/CFS data by severity is further supported by the lack of correlation between fatigue duration and disease severity (SI Appendix, Fig. S4). However, the lack of observed correlation between disease (fatigue) duration and cytokine levels may result from the lower statistical power of the current study, because the sizes of both our overall sample of cases (n = 186) and, especially, of cases with ≤3-y fatigue duration (n = 30), were smaller than those studied by Hornig et al. Thus, our failure to discover any differences between short and long duration does not allow us to rule out definitively the possibility that mean serum levels might differ between these two specific fatigue-duration categories (≤3 y vs. >3 y).

 

[A.B.]

TGF-β keeps coming up.

Wikipedia says

TGF-β has mainly inhibitory effects on B lymphocytes. TGF-β inhibits B cell proliferation.

TGF-β also induces apoptosis of immature or resting B cells

Is elevated TGF-β an attempt to stop autoimmunity?

Oh and it also suppresses NK cells:
Regulation of NK cell functions by TGF-beta 1.
https://www.ncbi.nlm.nih.gov/pubmed/7636180

That could explain why reduced NK cell function also keeps coming up.

 

[Wonkmonk]

Is this article consistent with Dr Montoya's prior studies of herpes virus and treatment with antivirals like Valcyte?

I.e., does it support the notion that herpes virus infection could be the cause of the disease for some patients and treated effectively with antivirals?

As far as I can see (with very low knowledge of medicine), the article says that you'd expect some of the markers go up in case of infection, but it doesn't directly address Montoya's prior research on herpes virus.

 

[Wonko]

Promising, based on what I've read so far, in common with everything else that seems to have happened today.

Pretty sure it's probably all a dream so looking forward to the cure being released tomorrow.

Come on, PACE debunking, this, in one day......can't be happening

 

[Snow Leopard]

TGF-β keeps coming up.

Indeed it does. It's the sixth study so far and the only consistent cytokine finding. I don't much care for these cytokine studies, but I'm starting to pay more attention to TGF-β!

I don't much care for the severity associations (how did they correct for multiple comparisons...), I don't think many if any of them will replicate.

 

[Forbin]

The Telegraph might want to run this by the proofreader again...

Leptin tells the stomach when the brain is full and is the reason that people lose their appetite when ill.

 

[notmyself]

Indeed it does. It's the sixth study so far and the only consistent cytokine finding. I don't much care for these cytokine studies, but I'm starting to pay more attention to TGF-β!

I don't much care for the severity associations (how did they correct for ltiple comparisons...), I don't think many if any of them will replicate.

so you belive something else is the main cause of symptoms?

 

[me/cfs 27931]

Science Media Centre disagrees. No surprise here.

JULY 31, 2017
expert reaction to cytokines for Chronic Fatigue Syndrome
http://www.sciencemediacentre.org/expert-reaction-to-cytokines-for-chronic-fatigue-syndrome/

Researchers publishing in Proceedings of the National Academy of Sciences (PNAS) report a link between chronic fatigue syndrome and cytokine concentrations that correlate with the disease’s severity.

Prof. Anthony Cleare, Professor of Psychopharmacology & Affective Disorders, King’s College London’s Institute of Psychiatry, Psychology & Neuroscience, said:

“Contrary to the authors’ assertions, the study provides no evidence that inflammation actually causes CFS/ME. Just two out of 51 measures of inflammation were increased in patients, but this could just as easily be a consequence of the illness and its effects on people’s lives. For example, CFS/ME sufferers may have sleep problems or depression, both of which can cause elevated inflammation, and neither of which were measured in this study. They may also take medication that can alter the cytokines measured in the study, and the authors do not state if this was examined.

“Thus, it is premature to assert that CFS is an inflammatory disease. There remains no basis to use cytokines as a diagnostic test.

“Importantly, there is no indication that the course of illness is linked to any measures of inflammation, or that treating inflammation benefits patients, which would be needed to suggest this is an important step in helping patients with this serious and disabling illness.

“What we need are longer term studies that examine the course of CFS/ME over time, to see whether raised inflammation is linked to the course or progression of illness, and studies on whether giving medicines to reduce inflammation improves the illness. Neither this study nor the previous body of research in the field suggest this is the case.”

* ‘Cytokine signature associated with disease severity in chronic fatigue syndrome patients by Montoya et al. published in Proceedings of the National Academy of Sciences on Monday 31st July.

Declared interests

Prof. Cleare: “Professor Cleare has published papers and hold grants investigating links between inflammation and CFS.”

 

[Sidereal]

TGF-β keeps coming up.

Yup. It's also mentioned in the literature as being elevated in worms who are in dauer, for what it's worth.

I don't much care for the severity associations (how did they correct for multiple comparisons...), I don't think many if any of them will replicate.

Same here, I just ignore these sorts of studies. None of them ever seem to replicate.