Cytokines do not change after exercise or sleep deprivation in CFS

Firestormm

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http://www.ncbi.nlm.nih.gov/pubmed/24027260

Clin Vaccine Immunol. 2013 Sep 11. [Epub ahead of print]

Cytokines do not change after exercise or sleep deprivation in chronic fatigue syndrome.

Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, Yamamoto Y, Cherniack NS, Klapholz M, Rapoport D, Natelson BH.
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Pain & Fatigue Study Center.
Abstract

A major hypothesis for the cause of chronic fatigue syndrome (CFS) is immune dysregulation, thought to reflect upregulated pro-inflammatory cytokines leading to the symptoms characteristic of this illness.

Because symptoms worsen with physical exertion or sleep loss, we hypothesized we could use these stressors to magnify underlying potential pathogenic abnormalities in the cytokine systems.

We conducted repeated blood sampling for cytokines from healthy subjects and CFS patients during a post-exercise and total sleep deprivation night, and assayed for protein in serum, message in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs.

We found that these environmental manipulations did not produce clinically significant upregulation of pro-inflammatory cytokines.

These data do not support an important role for immune dysregulation in the genesis or stress-induced worsening of this illness.
 

Nielk

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This is a Benjamin Natelson study. It seems like they only looked at Cykotine markers to see if there was any change post stress.
 

Hope123

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Haven't read the article yet but lots of reasons could explain difference:

1) If they selected subjects using Fukuda, did they make sure they had PEM/ sore throat/ enlarged lymph nodes as one of the criteria subjects had? Remember you can fit Fukuda without having any signs/ symptoms of immune dsyfunction. If no immune symptoms, perhaps that's why no cytokine changes seen.

2) What type of exercise did they employ?

3) Which cytokines did they look at and what were the techniques used to test for cytokines? Cytokines fluctuate naturally even in healthy people and the assay technique can affect results.

4) When did they take the cytokine samples and how frequently did they do it? Some people get PEM immediately after an activity, others have more delayed response - like a day or two - before it is felt. Remember, we don't have good studies about the timing and duration of PEM. I've not seen one study where they asked people about PEM AND also drew cytokines at the same time -- which would seem like a pretty simple thing researchers should consider.

5) Did the subjects have any other illnesses? Remember in the Utah Lights' study, people with FM had a different gene profile than people with only CFS or CFS+FM. Often times, I wonder if some FM patients are being classified as having CFS because they qualify due to fatigue and non-immune Fukuda symptoms. If that's the case, these subjects might not have changes with activity; some FM patients get much better with exercise unlike CFS patients.
(I know two people who are related - one has CFS, the other FM; the latter can take aerobics classes and feel good afterwards, the former crashes.)
 
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The results of this must be compared to those of healthy individuals.

A study of men attending a military training course who underwent strenuous exercise, calorie deficiency and sleep deprivation.
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3083.1996.d01-32.x/abstract

There was an increase in neutrophils, but a general suppression of the immune system.
The authors found no changes of interleukin 1, 2 and 4 during the course, but a (12–20%) reduction (P<0.01) of interleukin 6
I'm not really sure what the 'expected' result of the Natelson study would have been.
 
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3) Which cytokines did they look at and what were the techniques used to test for cytokines? Cytokines fluctuate naturally even in healthy people and the assay technique can affect results.
They used three different techniques,

But interestingly,

The major outcome of these studies was our finding inconsistency in results across analytic methods, a result which has been noted by others 29. Patterns of cytokine mRNA expression may not necessarily reflect patterns of cytokine protein production due to posttranscriptional regulation of these genes by mechanisms like mRNA decay, translation, nuclear export, and cytoplasmic localization 30. The variability in results raises questions about just which method future researchers should use to try to define cytokine abnormalities in illness populations.
They did make a series of interesting observations and they noted differences between the CFS&FM group vs the CFS group.

I actually believe the conclusion is quite sound, that changes in symptoms are not caused by stress-induced cytokine changes in serum.

edit: that is not to say that changes in spinal fluid might not be important.
 

Firestormm

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This was a previous study by many of the same authors from 2010:

Toru Nakamura,1,2 Stephan K. Schwander,3,* Robert Donnelly,3 Felix Ortega,3 Fumiharu Togo,4 Gordon Broderick,5 Yoshiharu Yamamoto,6 Neil S. Cherniack,1,3,† David Rapoport,7 and Benjamin H. Natelson1,

Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia
Discussion

A major hypothesis for the cause of CFS is an immune dysfunction characterized by a general upregulation of proinflammatory cytokines.

This hypothesis is based, in part, on clinical reports that administration of proinflammatory cytokines in the treatment of disease in humans produces a flu-like syndrome resembling that of CFS (26). However, there have been few empirical data supporting this hypothesized link between proinflammatory cytokines and CFS, and our own prior studies in CFS patients did not find any cytokine abnormalities (15, 38).

The results of this study using nocturnal samples also do not support the hypothesis of an upregulated inflammatory immune system mediated by cytokines in the genesis of CFS. A similar conclusion has been reached in a study of a sample of patients with postinfectious fatigue (32)...

...In summary, we designed this study to examine two alternative hypotheses: one, that CFS and FM are caused by increases in proinflammatory cytokines, and two, that CFS and FM are caused by disrupted sleep produced by increases in anti-inflammatory cytokines.

Since disparate results have come from studies sampling the blood once during the daytime, we decided to sample blood several times during the nighttime while subjects slept. We reduced variability by studying women with CFS alone or with CFS plus FM, at the same menstrual phase, and after excluding any subjects with current major depression.

Despite using these “pure” patient groups, we found evidence for a rather small elevation of one anti-inflammatory cytokine, IL-10, only in those patients with CFS alone, and in only one of three assays, the one quantifying cytokines in plasma. Obvious limitations of this study are the relatively small sample size and our focus on female patients only.

These data provide additional experimental evidence against the hypothesis that CFS is a manifestation of an upregulated proinflammatory state and leave open the role for anti-inflammatory cytokines in the genesis of CFS.
 

Hope123

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This is bias on my part but I would take those Natelson studies with a grain of salt because he has said publicly before that he thinks the cause of CFS is the brain and not in the immune system. So if his studies confirm what he believes, I'm not surprised. :)

As most people know already anyway, the literature on cytokines has been inconsistent in the past.

My bias of course is the opposite. Part of this is I feel sick each and every day, like I have the flu.And I have the data to back it up in myself -- I have extremely elevated cytokines taken at different time points by my immunologist. In some case, 10X normal range.

But also because I think it's too premature to conclude brain or immune system -- I think it's probably both and the way they interact. In addition, it appears to date that the people who do get substantially better do so because of medications that affect the immune system -- antivirals, IVIG, rituximab, etanercept, etc.I've not heard of brain-directed meds that have substantially improve CFS for people; some drugs like Provigil may help with alertness but others report it gives them perception of (rather than true) energy only to crash later.
 

Hope123

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The results of this must be compared to those of healthy individuals.

A study of men attending a military training course who underwent strenuous exercise, calorie deficiency and sleep deprivation.
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3083.1996.d01-32.x/abstract

There was an increase in neutrophils, but a general suppression of the immune system.


I'm not really sure what the 'expected' result of the Natelson study would have been.
The effects of exercise on the immune system can vary a lot depending on duration/ intensity etc. I did a little reading on this in the past and it seems like a "moderate" degree of exercise is best. Too little and the immune system doesn't get stimulated enough (e.g. "practice" for when the bugs invade); too much and it can become suppressed (e.g. triatheletes, some of whom regularly get mild colds). In fact these "practice" sessions are one theory why moderate exercise can decrease colds and flus in people.
 

ukxmrv

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What would be the point of a sleep deprivation night on subjects who may have circadian rhythm problems?

I may be wrong about this and need to read the full paper of course. If they deprived subjects of sleep for one night and these are people who get their best sleep during the day (like I do) then I'd question that as a choice of ordeal.

Also there was another thread on this forum for people who felt better after not sleeping. I'm one of these odd ones who feels as if some sort of "switch" turns if I sleep from say midnight to 8am. I awake feeling wretched.
 

Dolphin

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I just read this paper quickly. Unfortunately I don't have the supplemental tables - they showed the nonsignificant results which might have helped give context. There were plenty of examples of different patterns within any one analytic method e.g. a statistical significant result within either the controls or the patients before/after exercise or sleep, and with the other group even going in the opposite direction, but this didn't reach significance.

For example:

qRT-PCR Assay [Mean cytokine level (relative quantity)]

IL-4

Control (n=13)

Normal: 0.76 +/- 0.33
Sleep Deprivation: 0.29 +/- 0.11*


CFS (n=15)

Normal: 0.42 +/- 0.13
Sleep Deprivation: 1.34 +/- 0.92

* significant difference from normal night within group
I think a big problem is the sample sizes: when there are big variances, it seems likely a lot of these samples would be underpowered.

Also the point Hope123 brings up could be relevant: people not having exertion-related CFS but just satisfying four of the other 7 minor Fukuda criteria.

Also, looking at Table 3 ["VAS scores before and after the nights"], for sleepiness, pain, blue, anxiety & fatigue, it's far from clear to me that the patients were "hit" hard enough to find effects
 

Dolphin

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I recall that one of the Dubbo studies found very large numerical differences (e.g. 10 vs 140 - a vague impression from one scale that comes to mind) but because they weren't statistically significant (as large variances and very small sample sizes e.g. less than 10 I think) they said no evidence for immune dysfunction/similar. That seemed very premature and so does this, although to a lesser extent (the differences here weren't as big the Dubbo study I had in mind, as I recall).
 

cigana

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This is bias on my part but I would take those Natelson studies with a grain of salt because he has said publicly before that he thinks the cause of CFS is the brain and not in the immune system. So if his studies confirm what he believes, I'm not surprised. :)

As most people know already anyway, the literature on cytokines has been inconsistent in the past.

My bias of course is the opposite. Part of this is I feel sick each and every day, like I have the flu.And I have the data to back it up in myself -- I have extremely elevated cytokines taken at different time points by my immunologist. In some case, 10X normal range.

But also because I think it's too premature to conclude brain or immune system -- I think it's probably both and the way they interact. In addition, it appears to date that the people who do get substantially better do so because of medications that affect the immune system -- antivirals, IVIG, rituximab, etanercept, etc.I've not heard of brain-directed meds that have substantially improve CFS for people; some drugs like Provigil may help with alertness but others report it gives them perception of (rather than true) energy only to crash later.
It is interesting, I had highly raised cytokines across the board (one of them I think 100's times the norm). After treatment with nexavir and antibiotics, they all normalized...but I did not feel any different.