Hornig/Lipkin cytokine study out now - press release

Daffodil

Daffodil

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i cannot read the whole thread so this may have been mentioned, but since they say most CFS patients had IBS before CFS onset, and some believe IBS to be caused by intracellular bacteria, maybe CFS is also caused by this bacteria? Any thoughts?
 
MeSci

MeSci

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Simon said:
IFN-gamma driving fatigue?
The Dubbo studies (ref 29) found that the link with IFN-gamma was in the acute phase of the illness (glandular fever, or whatever), not once people had developed CFS. And @Jonathan Edwards said earlier on this thread he didn't think the cytokine levels generally were high enough to be causing symptoms.

IFN-gamma drives faster tryptophan degradation, causes cognitive problems?

the authors said:
IFNγ may accelerate degradation of tryptophan, resulting in depletion of the neurotransmitters serotonin and melatonin in the central nervous system through activation of indoleamine-2,3-dioxygenase, a rate-limiting enzyme in the kynurenine pathway. Activation of this pathway also results in increased levels of quinolinic acid, a neurotoxic compound that acts as an agonist at glutamatergic [NMDA (N-methyl-d-aspartate)] receptors (30–32). Psychomotor changes, including cognitive problems (deficits of memory and attention) as well as affective disturbances, are correlated with changes in the kynurenine pathway in disorders ranging from Alzheimer’s disease (33) to major depression (34). We hypothesize that IFNγ-mediated lesions in kynurenine metabolism may culminate in the depression and psychomotor retardation that contribute to disability in some patients with ME/CFS (34–36).
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Which is quite dramatic. I wonder if there is a way of testing this?
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A search for 'kynurenine' in PR finds 58 hits. Some involve dietary interventions to try to switch (via the gut) from kynurenine production to serotonin production, and some involve taking 5-HTP.

Also relating to your and other posts, perhaps interferon-gamma levels could also be used to measure progress toward recovery?
 
MeSci

MeSci

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A.B. said:
I also wonder about people who have a gradual onset where symptoms are initially occasional after a particularly busy time but then something like a virus triggers a much worse state where symptoms are much more severe and there all the time.
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I think there may still be an infection involved in gradual onset cases. My mother had an infectious onset CFS that eventually resolved, even though she never fully regained her energy. I was infected by her shortly afterwards, but it cleared without complications. A few years later I had gradual onset CFS without apparent cause. I had actually forgotten about this co-infection and was only reminded of it today. Somewhere between this and the onset I also had a hepatitis B vaccination.
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I was quoting @user9876 in the post you were replying to! (I don't want to take credit for the idea.)
 
U

user9876

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Bob said:
I think it's Byron Hyde who says that gradual onset is actually usually sudden onset but the patient isn't aware of when they first became ill. e.g. when carefully studying the case history, he can usually identify an infection whereby problems started however subtle the symptoms were at the time. Sometimes the infection can be during childhood, with some resulting mild or short-lived ME-like symptoms, but full-blown ME doesn't become apparent until adulthood.

As an alternative possibility, I think that Jonathan Edwards has said that an initial infection might be a red herring e.g. that the patient is unaware that they are already ill with ME (i.e. with no obvious symptoms) when they get the (apparently) precipitating infection. The precipitating infection provokes/amplifies the existing (but previously hidden) ME, such that the ME symptoms suddenly become apparent. (I might be putting words into Jonathan Edwards' mouth - hopefully he'll correct me if I am.)

In both these scenarios, there may be no meaningful distinction between (apparent) gradual or sudden onset ME.
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I was assuming that is what gradual onset was but maybe it needs a different name. With my child I think she had a mild form of ME for a few years before becoming severely affected and diagnosed.

I'm thinking it could be important for this type of work where they are associating measures with illness duration. If some people have a mild condition first then does the clock start there rather than when it gets severe but how easy is this to measure. It could cause confusion with replicating such studies or using the results as part of a diagnostic method.
 
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Bob

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user9876

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Bob said:
This is a very well written and interesting article about the issues surrounding the science media centre, for anyone interested:

UK’s Science Media Centre lambasted for pushing corporate science
Mićo Tatalović
14/05/14
http://www.scidev.net/global/journa...-lambasted-for-pushing-corporate-science.html
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There seems to be a number of non ME based articles criticising the SMC. I wonder if it is worth someone contacting the journalists writing these stories about the distortions in ME coverage.
 
rosie26

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Do we know if 'all' the patients in this study had been through severe ME first? I can't remember if it was stated. I am just wondering what side of severe ME some of these patients were, as in, before severe, during, and after.
 
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Sasha

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G

Gijs

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I am very hapy with this news. I don’t wanne be negative but i don’t think there will be a significant change in the medical community at this point. Also i don’t expect more budget for research. So what did we ‘win’ with this medical campagne? Nothing yet. Paradigma change will only occure with substantial evidence and repliction. This is not the case yet. Cytokines will not lead to objective test because they are not consistent.

For example: il17a is not consistent [1] and Lipkin et al., think it is a very important finding. So his ‘house’ is not build on solid ground.
1. Journal of Translational Medicine 2009, 7:96 Plasma cytokines in women with Chronic Fatigue Syndrome Mary Ann Fletcher* 1,2, Xiao Rong Zeng1,2, Zachary Barnes1, Silvina Levis1,2 and Nancy G Klimas* 1,2 1Department of Medicine, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL USA 2Miami Veterans Health Care Centre, 1201 NW 16th St, Miami, FL USA

Maybe professor Edwards can explain these fluctuations of cytokine?

I have a question for professor Edward: can cytokines flair up or go down by both mental- or physical stress (running)?
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M

msf

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Does anyone know when the pathogen study might be published? I know they already gave a press conference about it, but I would like to see the detail.
 
Kati

Kati

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New article posted by Myriam Tucker on Medscape

http://www.medscape.com/viewarticle/840706

No comments yet. I wonder what will be said about that.

Chronic Fatigue Syndrome: Immune Alterations Seen Early

Patients with recent-onset myalgic encephalomyelitis/chronic fatigue syndrome had distinct alterations in plasma immune signatures in an analysis of data and blood specimens from two large multicenter cohort studies.

The findings were published online February 27 in Scientific Advances by Mady Hornig, PhD, from the Center for Infection and Immunity and the Department of Epidemiology, Columbia University Mailman School of Public Health, New York City, and colleagues.

Patients who were within 3 years of developing the illness, which has now been renamed "systemic exertion intolerance disease" by the Institute of Medicine, had prominent activation of both proinflammatory and anti-inflammatory cytokines and dissociation of intercytokine regulatory networks, suggesting a potential biomarker for diagnosing the condition, the authors say.


"The presence of a specific immune profile early in the course of ME/CFS has important implications for the diagnostic process.... [W]e were able to define a distinctive immune signature that differed from that of healthy controls. Integration of these immune markers with clinical findings will provide clinicians with a stronger framework for establishing an ME/CFS diagnosis, and, possibly, make it easier to rule out other conditions at an earlier time point," Dr Hornig and colleagues write.

For reasons that are not clear, the findings in recent-onset patients contrasted both with those of controls and with those of patients with a longer illness duration.

According to Dr Hornig and colleagues, "the restriction of this pattern of immune disturbances to short-duration as opposed to long-duration cases suggests that both the dysregulation of immune cell interactions...and the opportunities for intervention may be transient. Therapeutic strategies that specifically target abnormalities found in these early immune profiles may present novel but time-limited opportunities not only for remediation but potentially also for staving off the long-term, chronic decline associated with ME/CFS."

William Schaffner, MD, professor of medicine at Vanderbilt University in Nashville, Tennessee, and a noted expert in infectious disease and vaccines, told Medscape Medical News, "This illness has been very difficult to define.... What I like about this paper is they're looking for light at the end of the tunnel. They're not starting etiologically, but defining the pathophysiology. And it does look as though in this one study, there's a biphasic phenomenon, earlier and later, with different immunologic criteria. It's interesting, provocative, and I think lends itself to a hypothesis which is at least consistent with clinical observations. So, it has the attractiveness of coherence. And, it's a study that's replicable."

Such replication, he said, should be conducted by other investigators who "have populations of patients [with] CFS with similar appropriately chosen controls and all the precision that has been done with study.... I think the findings are sufficiently robust and provocative and coherent that they ought to command funding, whether from private or public sources."

Distinct Pattern in Short-Duration Illness

The researchers studied clinical databases from two large multicenter cohort studies assessing the relationship of immune signatures, investigating a total of 51 inflammatory cytokines, with diagnosis and clinical variables One database was funded by the National Institute of Allergy and Infectious Diseases, and the other was from the philanthropically funded Chronic Fatigue Initiative.

Diagnostic criteria were stricter for the National Institutes of Health cohort, which required patients (aged 18 - 70 years) to meet both the 1994 Centers for Disease Control and Prevention's CFS criteria and the 2003 Canadian Consensus criteria for ME/CFS, and all had to have had a viral-like prodrome. With the Chronic Fatigue Initiative cohort (aged 18 - 65 years), subjects only had to meet one or the other definition.

In all, there were 52 adult patients with illness onset (not diagnosis) within 3 years, 246 with illness duration longer than 3 years, and 348 controls matched for age, sex, and variables known to affect immune status, including season of sampling and geographic site. Plasma samples were collected at the same time of day under controlled conditions of mild stress (completing study forms).

When all the cases were combined, there were few major differences in inflammatory cytokine levels between cases and controls.

However, the researchers found significant differences in more than half of the 51 cytokines when the patients with short-duration and longer-duration ME/CFS were compared individually with the controls (with and without adjustment for sex and age).

Overall, the short-duration patients had higher levels of both proinflammatory and anti-inflammatory cytokine levels compared with the controls, including the proinflammatory cytokines interleukin 1a (IL-1a; P = .0178), IL-8 (P = .0112), IL-12p40 (P = .0009), IL-17A (P = .0243), and TNF-α (P = .0261) and the anti-inflammatory cytokines IL-1RA (P = .0105), IL-4 (P = .0028), and IL-13 (P = .0198). Two of the 51 cytokines were reduced in the short-duration ME/CFS group compared with controls: CD40 ligand (P = .0037) and platelet-derived growth factor BB (P = .0004).

Patterns were similar when comparing the short-duration with the long-duration patient groups. With logistic regression modeling, two proinflammatory cytokines were notably elevated in the short-duration group compared with the longer-duration group: Interferon gamma (odds ratio, 104.77) and IL-12p40 (odds ratio, 1.501).

Dr Hornig and colleagues say this marked association with interferon gamma in the early phase of illness is consistent with a viral trigger or disrupted immune regulatory networks. Interferon gamma can disrupt immune cell homeostasis, resulting in greater vulnerability toward developing certain types of autoimmune responses.

Network diagrams of intercytokine correlations revealed another difference between the short-duration ME/CFS group and both the long-duration group and the controls: CD40 was not only reduced, but its action was related to only five other cytokines, whereas in the longer-duration and control groups, it drove most of the inverse relationships with other immune molecules.

The finding of both decreased and dissociated CD40 is "intriguing," the authors say, noting that although the transmembrane protein is essential for the regulation of B-cell maturation and other functions, abnormally high levels have been linked to adverse neurovascular events, mild cognitive impairment, and Alzheimer's disease.

Moreover, they add, constitutive CD40L deficiency is associated with both susceptibility to recurrent infections and neurocognitive decline that is unexplained by the presence of any known pathogen or clear signs of encephalitis.

Cytokine alterations were more closely correlated with illness duration than with global illness severity measures, "suggesting that the immunopathology of ME/CFS is not static," they write.

The reason for the lack of findings in the longer-duration group is not clear, but might represent an "exhaustion" phenomenon similar to that seen in pancreatic beta cell production in people with long-duration type 2 diabetes. "We can only speculate," Dr Hornig and colleagues remark.

Indeed, Dr Schaffner called the biphasic aspect of the data "intriguing and bothering" and said it needs to be investigated further.

He told Medscape Medical News, "Many of us have over the years hoped for an etiologic agent [for ME/CFS]. We still don't have one, but now we may have some insights into the pathophysiology. I'm optimistic, but I've been optimistic in the past so my optimism is guarded.... I wish these investigators well."

The study was funded by the Hutchins Family Foundation. Dr Schaffner serves on data safety monitoring boards for experimental vaccines studies for Pfizer and Merck.

Sci Adv. Published online February 27, 2015. Full text
 
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msf

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RE: Interferon-gamma interfering with serotonin production, I found this article to be an excellent (although somewhat dense) summary:

http://ceri.com/fftrypto.htm

If the author is right it might not be a good idea simply to supplement tryptophan, since this will also increase quinolinic acid, which is already raised because of overexpression of IDO. The author then suggests supplementing with 5-HTP, since this will not be catabolized by IDO.
 
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