Neuroendocrine and immune contributors to fatigue (CDC) (mostly on CFS)

Dolphin

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(Despite its title, most of this article is on CFS)

This article is now available for free at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933136/

PM R. 2010 May;2(5):338-46.
Neuroendocrine and immune contributors to fatigue.

Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM.

Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, MD(dagger).
Abstract

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body's stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF).

This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF.

In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF.

Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.

Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation.
Published by Elsevier Inc. All rights reserved.

PMID: 20656615 [PubMed - in process]
 

Dolphin

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Christine Heim and Urs Nater have been heavily involved in the CFS program at the CDC. One gets an insight into their views with this review which is largely on CFS

e.g.
Immune System

Many findings suggest that infectious agents (viral and bacterial infections) and immunologic dysfunction (eg, inappropriate production of pro- and anti-inflammatory cytokines) may play a role in the pathophysiology of at least some cases of patients with CFS (reviewed in [81-83]). Indeed, persistent postinfection fatigue has been well documented [84]. Results of early studies showed that many individuals with CFS had evidence of enhanced antibody responses to Epstein-Barr virus (EBV). However, subsequent reports showed that many patients with CFS lacked evidence of EBV reactivity, although they displayed elevated antibody titers to a number of other viral agents. Interestingly, acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue [85]. Taken together, results of these studies suggest that, although some cases of CFS may be triggered by an infectious agent, the chronic symptoms of this syndrome are unlikely to be caused by an active infection.
[..]

Interestingly, results of a recent and robustly designed study by Raison et al [97] showed that fatigue not only in its severe and chronic form, as in CFS, but also in its milder forms, is associated with increased inflammation, as indexed by elevated plasma C-reactive protein levels and white blood cell count, even after adjusting for depressive status. This study further supports the notion that the symptom of fatigue, rather than a diagnosis of CFS itself, may be what is clinically associated with inflammation. In addition, childhood traumatic experiences appear to be an important risk factor for a hypocortisolemic profile in CFS [54], and adults with a history of childhood trauma exhibit elevated markers of inflammation, even in the absence of depression [98]. Moreover, patients with depression and childhood trauma show even higher levels of inflammation than with either risk factor alone [98,99]. Whether immune status is different in patients with CFS, with or without a history of childhood trauma, remains to be determined.
 
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The lead author is from the NIH, not the CDC. I also note Reeves or Jones aren't co-authors. Otherwise you get this:
http://archpsyc.ama-assn.org/cgi/content/full/66/1/72 (which was cited paper number 54 in the aforementioned paper).


linked paper said:
Our results further substantiate the idea that CFS is part of a spectrum of disorders that are associated with childhood adversity, including depression, anxiety, and other functional somatic disorders.7 Because all of these disorders often manifest or worsen in relation to acute stressors, enhanced stress reactivity as a potential consequence of early adversity may be a central feature common to this spectrum of disorders.
The above does not make sense since they found two pathologically distinct CFS groups (eg ELS + hypocortisolism and no-ELS).
Note that their data was based on weekday cortisol and didn't control for employment status/activity levels. I still find their result of only those with ELS to have decreased cortisol response quite bizarre and believe it must be due to another uncontrolled variable, or due to the controlling of the data that they did do (sex, medication use and race all had an effect on the cortisol measure apparently!).
 

Dolphin

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The lead author is from the NIH, not the CDC. I also note Reeves or Jones aren't co-authors. Otherwise you get this:
http://archpsyc.ama-assn.org/cgi/content/full/66/1/72 (which was cited paper number 54 in the aforementioned paper).
I had to abbreviate as one can only so many characters in the title - maybe I should have made this more clear.

However, it is important to remember that there is a core CDC CFS program (around US$4-5m a year) and team. Only 5-10 people would have been corresponding authors on papers. If one searches PubMed for "reeves wc"[au] cfs one can see the names that keep coming up with Nater and/or Heim involved in a lot of the studies and I don't think they are particularly better papers.
There is not really a NIH program as such.

Silverman the lead author you refer to appears to be more into fatigue research - she has no references for CFS papers in this paper. My guess is she was more responsible for the more general fatigue parts with Heim and Nater having a lot of influence on the CFS part. They certainly signed it so it gives an idea what they are willing to agree to. I'm not particularly interested in what Silverman might agree to as she seems to be a nobody in CFS terms. ETA: I just searched for Silverman and nothing showed up for CFS papers.
 

Dolphin

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The above does not make sense since they found two pathologically distinct CFS groups (eg ELS + hypocortisolism and no-ELS).
Note that their data was based on weekday cortisol and didn't control for employment status/activity levels. I still find their result of only those with ELS to have decreased cortisol response quite bizarre and believe it must be due to another uncontrolled variable, or due to the controlling of the data that they did do (sex, medication use and race all had an effect on the cortisol measure apparently!).
Their Early Life Stress (ELS) papers used the so-called empiric criteria (Reeves et al., 2005) for CFS. I think it's best to regard these as not CFS papers at all. I'm not one to say Fukuda studies are rubbish but this hugely inflated the prevalence rates (around 10-fold) giving an idea how diluted a definition it is.
 
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Fair enough.
Re: Marni Silverman, I hope I am not misunderstanding you. I think being a "nobody" in CFS research has its advantages, given what the "somebodies" are publishing. But I assume you mean that since she is not a part of the regular CFS research group, she could not exactly disagree with some of the questionable stuff that the others wanted to put in the paper.
 

Dolphin

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But I assume you mean that since she is not a part of the regular CFS research group, she could not exactly disagree with some of the questionable stuff that the others wanted to put in the paper.
Yes, something along those lines. The others were the CFS "experts" and what one sees is much more likely to be their views. Or as I said, they signed up to it anyway.

Also, she is unlikely to be called as a CFS expert while the others might. So I think it is of more interest to hear what they are saying. Similarly it might give an idea where the CDC's budget might be spent more than how the NIH budget might be spent (especially as it doesn't have much of an inhouse program and it's unclear that she would be involved if they were doing research).
 

Esther12

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I'm not so sceptical about the childhood trauma thing.

Of the people I know with CFS, childhood trauma doesn't seem to be common, but it does seem (from work on other illnesses as well as CFS) that childhood trauma can mess up people's bodies, immune systems and minds quite badly. If automnic (SP?) stuff is a big part of CFS, then it could play a role through that.

I don't see this as remotely legitimising the abusive way CFS is usually treated by the psycho-socialists though.
 

Dolphin

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I'm not so sceptical about the childhood trauma thing.

Of the people I know with CFS, childhood trauma doesn't seem to be common, but it does seem (from work on other illnesses as well as CFS) that childhood trauma can mess up people's bodies, immune systems and minds quite badly. If automnic (SP?) stuff is a big part of CFS, then it could play a role through that.

I don't see this as remotely legitimising the abusive way CFS is usually treated by the psycho-socialists though.
You are right that it would be different from a lot of what is said which is more about lifestyle e.g. one could get better simply by doing more.

At the same time, it is unclear how treatable trauma is while if there's an infection involved, that could be treated.

But mainly I think the two CDC studies they quote, although they can look impressive as they are randomly done community studies, are junk because of the definition used.
 

Cort

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I think this shows how difficult it is to put the CDC CFS research program into a box or into a tight category...this is not just a psychological interpretation of CFS; it at times attempts to account for symptoms using physiological measures; ie inflammation - low cortisol...

They do not believe that the problems of at least a subset of patients are driven by a chronic infection but they also tie in these other factors. They show that inflammation in CFS is not simply the result of depression or is not simply tied to depression - and they believe that it contributes to the fatigue in the disorder as well. It's an interesting blend of 'psychology' and physiology. I actually think we'll be seeing more of this as researchers look deeper into things like neuro-inflammation and inflammation overall. This is like a demi-Sickness behavior approach.

One problem is that they are very slow - that inflammatory study they talked about just measured two or three factors.....They do not appear to be interested in looking for a herpesvirus subset....they are very conservative but the physiological findings are keeping parts of their feet on the ground.

Many findings suggest that infectious agents (viral and bacterial infections) and immunologic dysfunction (eg, inappropriate production of pro- and anti-inflammatory cytokines) may play a role in the pathophysiology of at least some cases of patients with CFS (reviewed in [81-83]). Indeed, persistent postinfection fatigue has been well documented [84]. Results of early studies showed that many individuals with CFS had evidence of enhanced antibody responses to Epstein-Barr virus (EBV). However, subsequent reports showed that many patients with CFS lacked evidence of EBV reactivity, although they displayed elevated antibody titers to a number of other viral agents. Interestingly, acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue [85]. Taken together, results of these studies suggest that, although some cases of CFS may be triggered by an infectious agent, the chronic symptoms of this syndrome are unlikely to be caused by an active infection.
[..]

Interestingly, results of a recent and robustly designed study by Raison et al [97] showed that fatigue not only in its severe and chronic form, as in CFS, but also in its milder forms, is associated with increased inflammation, as indexed by elevated plasma C-reactive protein levels and white blood cell count, even after adjusting for depressive status.[/B] This study further supports the notion that the symptom of fatigue, rather than a diagnosis of CFS itself, may be what is clinically associated with inflammation. In addition, childhood traumatic experiences appear to be an important risk factor for a hypocortisolemic profile in CFS [54], and adults with a history of childhood trauma exhibit elevated markers of inflammation, even in the absence of depression [98]. Moreover, patients with depression and childhood trauma show even higher levels of inflammation than with either risk factor alone [98,99]. Whether immune status is different in patients with CFS, with or without a history of childhood trauma, remains to be determined.