Cytokine Study in Moderate and Severe ME Patients

[msf]

http://www.ncbi.nlm.nih.gov/pubmed/26516304

Int J Med Sci. 2015 Sep 5;12(10):764-72. doi: 10.7150/ijms.12399. eCollection 2015.
Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.
Hardcastle SL1, Brenu EW1, Johnston S1, Nguyen T1, Huth T1, Ramos S1, Staines D1, Marshall-Gradisnik S1.
Author information

• 1National Centre for Neuroimmunology and Emerging Diseases, 9.22, G40 Griffith Health Institute, School of Medical Science, Griffith University, Parklands Drive, 4222, Gold Coast, QLD, Australia.

Abstract
Immunological dysregulation is present in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), with recent studies also highlighting the importance of examining symptom severity. This research addressed this relationship between CFS/ME severity subgroups, assessing serum immunoglobulins and serum cytokines in severe and moderate CFS/ME patients. Participants included healthy controls (n= 22), moderately (n = 22) and severely (n=19) affected CFS/ME patients. The 1994 Fukuda Criteria defined CFS/ME and severity scales confirmed mobile and housebound CFS/ME patients as moderate and severe respectively. IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients. This was the first study to show cytokine variation in moderate and severe CFS/ME patients, with significant differences shown between CFS/ME symptom severity groups. This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness.


Wooh! First again! Must have something to do with me checking Pubmed several times a day...

 

[SOC]

This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness.

I'm all for more stringent analysis.

 

[msf]

The fact that they used the Fukuda criteria suggests to me that the severe cases had ME and the moderates had CFS.

 

[SOC]

The fact that they used the Fukuda criteria suggests to me that the severe cases had ME and the moderates had CFS.

Yes, possibly. It's not clear from the abstract if they evaluated patients for PEM. Since Fukuda does not require PEM, it's quite possible they had different disease groups if they had some patients with PEM and some without. I don't know if we have good reason to think that non-PEM CFS (whatever that is) cannot be severe while ME is not moderate. Even if they had an ME group and a non-PEM group, I don't know that they'd split clearly in this relatively small sample into moderate and severe.

I'd be interested to know if there was a correlation between severity (and observed difference in cytokines) and length of illness. If so, the correlation might be between length of illness and cytokines rather than severity and cytokines.

Interesting study. I look forward to further analysis from our gurus-in-residence.

 

[msf]

Sorry, I was speaking loosely, I don´t think they would divide perfectly into the two groups either, just that there would be this tendency. Jason claims that his (and the CCC) criteria identify a smaller group of patients with more severe illness compared with the Fukuda criteria.

 

[Scarecrow]

The group sizes are relatively small. Lots of cytokines measured, some going this way, some going that. Is there a hypothesis?

 

[SOC]

Sorry, I was speaking loosely, I don´t think they would divide perfectly into the two groups either, just that there would be this tendency. Jason claims that his (and the CCC) criteria identify a smaller group of patients with more severe illness compared with the Fukuda criteria.

I'm not really disagreeing with you. I had approximately the same thought you did when I first read the abstract -- that perhaps they had identified ME vs non-PEM CFS per Fukuda. What I posted was then my internal ponderings about whether that could be true or not. It's hard to say without reading the entire paper, and maybe not even then.

 

[msf]

I guess the hypothesis is that severe and moderate ME/CFS patients would differ in terms of their cytokine profiles. And they did.

 

[Scarecrow]

I guess the hypothesis is that severe and moderate ME/CFS patients would differ in terms of their cytokine profiles. And they did.

And would another 20 severe patients and another 20 moderate patients show the same pattern?

I'm not convinced.

Hopefully, someone with access to the full article will come along soon and fill us in. The abstract is sketchy, not even any p values. How significant is significant?

 

[halcyon]

Perhaps they address this in the full paper but no mention of duration of illness? Perhaps their work was done before the Columbia paper came out.

IL-1β was significantly reduced in severe compared with moderate CFS/ME patients

Matches the long but not short duration findings from Columbia.

IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients.

Matches the long but not short duration findings from Columbia.

RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients.

I don't believe there were any statistically significant differences with these cytokines in the Columbia study.

IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients.

Matches the short but not long duration findings from Columbia. I was ready to assume that the patients they were studying were all > 3 years ill before I got to this one.

 

[Sea]

The fact that they used the Fukuda criteria suggests to me that the severe cases had ME and the moderates had CFS.

Their dividing line for severity was homebound = severe, not homebound = moderate. Homebound sufferers samples were taken at home.

 

[Sea]

Matches the short but not long duration findings from Columbia. I was ready to assume that the patients they were studying were all > 3 years ill before I got to this one.

I am classified as moderate by their standards (ie can travel to their centre for a blood draw). I have been ill for 29 years.

It would be interesting to know whether the exertion of having to travel for the blood draw actually makes a difference to the profile, so they could be comparing travelers vs non-travelers rather than (or as well as) moderate vs severe

 

[allyann]

Full Study here - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615236/

 

[SOC]

Their dividing line for severity was homebound = severe, not homebound = moderate. Homebound sufferers samples were taken at home.

I see their logic in that dividing line and I applaud their efforts to see if there's a difference in cytokines among severity levels, but it still seems rather arbitrary. It's not like homebound/not is a black and white dividing line. One could be homebound from POTS symptoms but have much less immune dysfunction than someone with less severe POTS but major immune dysfunction, pain, and cognitive dysfunction and who gets out of the house to go grocery shopping because they don't eat if they don't shop. There might have been clearer differences if they'd compared severe (housebound) to mild (able to work).

It would be nice if we had a more sophisticated way of evaluating severity that included more objective measures than housebound/not.

I guess we gotta start somewhere and this is as good a place as any. This study gives us some leads that can be followed up with further, more sophisticated studies when the funding finally becomes available.

It would be interesting to know whether the exertion of having to travel for the blood draw actually makes a difference to the profile, so they could be comparing travelers vs non-travelers rather than (or as well as) moderate vs severe

In hindsight, it would have made more sense to collect all the samples at home in order to eliminate the confounding factor of the extra exertion involved in traveling for the blood draw.

 

[alex3619]

I guess the hypothesis is that severe and moderate ME/CFS patients would differ in terms of their cytokine profiles. And they did.

They established the principle that studies that do not differentiate might be unreliable. They are moving toward more specific subgroup analysis I think.

There appear to be three axes, all separate, but this might be wrong: duration of illness, severity of illness, and typicality of illness. Typicality directly addresses disease definitions.

 

[allyann]

The CFS/ME patients were classified as either mobile or housebound and these severities were translated to 'moderate' and 'severe' subgroups respectively. Moderate CFS/ME patients were those who were mobile, initially identified as those who were able to regularly leave the house unassisted and who had the potential to maintain a job, even with reduced hours. Severe CFS/ME patients were those who were initially identified as housebound, unable to sustain a job due to the constraints of their symptoms and those who were not able to leave the house unassisted. These severity subgroups were then confirmed through the use of an extensive questionnaire The CFS/ME patients were classified as either mobile or housebound and these severities were translated to 'moderate' and 'severe' subgroups respectively. Moderate CFS/ME patients were those who were mobile, initially identified as those who were able to regularly leave the house unassisted and who had the potential to maintain a job, even with reduced hours. Severe CFS/ME patients were those who were initially identified as housebound, unable to sustain a job due to the constraints of their symptoms and those who were not able to leave the house unassisted. These severity subgroups were then confirmed through the use of an extensive questionnaire containing routinely used severity scales in CFS/ME: the Fatigue Severity Scale (FSS), Dr Bell's Disability Scale, the FibroFatigue Scale and the Karnofsky Performance Scale (KPS) 9.

 

[M Paine]

Each of these studies is a new step towards sub-categorizing this illness. It's good to see a group taking a more 'inclusive' approach towards categorizing the illness. The same perhaps can't be said of other Australian publications recently, which seemed to go on a bit of a tangent.

 

[jimells]

The study says they excluded autoimmune disease patients from the study. I guess they must mean "known" autoimmune disease, since the research in Norway suggests some of us *do* have an autoimmune disease, if I am understanding their work correctly.

If some of the cohort have the autoantibodies identified by Fluge and Mella, and some don't, how would that affect this study's results? (I'm guessing the answer is, there's no way to know)

Can anybody make any sense out of all the various differences between healthy/moderate/severe groups? In spite of my complete ignorance of this stuff and inability to properly evaluate research, for some reason I get a feeling that the differences are kinda random, and that's why their conclusions seem a little vague.

I find it encouraging that *finally* someone is taking a serious look at severe patients.

 

[jimells]

The application of the 1994 Fukuda diagnostic criteria was then used in combination with an extensive questionnaire delineating each patient's diagnosis, history and symptoms

Since they have detailed history and symptoms, then it should be possible to do a follow-up analysis by length of illness?

 

[Sea]

The study says they excluded autoimmune disease patients from the study. I guess they must mean "known" autoimmune disease

Yes, only excluded by questionnaire not by testing.