Immunoglobulin for chronic fatigue syndrome (CFS/ME): systematic reference list

John Mac · Oct 10, 2018

Key message
The Norwegian Institute of Public Health was commissioned by the Norwegian Myalgic Encephalopathy Association to perform a literature search followed by sorting of relevant research on the effect of immunoglobulin for chronic fatigue syndrome (CFS/ME).

Method
We performed a systematic literature search for randomized controlled trials published up to June 2017 and sorted relevant references according to publication year.

Results

We identified seven randomized controlled trials published between 1986 and 1999

We identified eight relevant systematic reviews.

We did not assess the methodological quality of the studies, nor did we summarize the results. We present references to the studies with links to the studies’ abstracts or fulltext.
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Downloadable pdf file is in Norwegian

https://www.fhi.no/en/publ/2018/Immunoglobulin-for-chronic-fatigue-syndrome-CFS-ME/

Alvin · Oct 10, 2018

Did it successfully treat symptoms?

John Mac · Oct 10, 2018

Alvin said: ↑

Did it successfully treat symptoms?
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nor did we summarize the results
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The English summary suggests they didn't try to, but maybe our Norwegian members could read the pdf for us

Trish · Oct 10, 2018

It looks like it is simply a literature search, and the end result is a list of 7 trials between 1986 and 1999, and 8 systematic reviews.

It seems a bit excessive for 8 reviews to have been done of 7 trials. What am I missing here?

Jonathan Edwards · Oct 10, 2018

Trish said: ↑

It looks like it is simply a literature search, and the end result is a list of 7 trials between 1986 and 1999, and 8 systematic reviews.

It seems a bit excessive for 8 reviews to have been done of 7 trials. What am I missing here?
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None of the reviews are actually of IVIG in ME. They are general reviews of ME treatment or of use of IVIG. Hardly surprising that there are eight in all I guess.

Amw66 · Oct 10, 2018

Nigel Speight used this with some success in paediatric cases . I' m sure I saw this in an interview clip.

Amw66 · Oct 10, 2018

Transcript of Dr. Speight interview
https://www.prohealth.com/library/video-nigel-speight-me-in-children-part-2-32465

Denise · Oct 10, 2018

Kathy Rowe published an article about IVIG in ME(1997). (I don't see it in the references of this review which is why I am pointing to it here.)
Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents
https://www.sciencedirect.com/science/article/pii/S0022395696000477?via%3Dihub

Tom Kindlon · Oct 11, 2018

UK guidelines previously recommended that IVIG not be given for CFS and instead CBT be used.

See 2nd message below

https://www.bmj.com/rapid-response/...t-decided-immunoglobulin-was-not-suitable-cfs

Prescribing intravenous immunoglobulin: summary of Department of Health guidelines
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1831 (Published 20 October 2008)Cite this as: BMJ 2008;337:a1831

On what basis was it decided that Immunoglobulin was not suitable for CFS?
Chronic Fatigue Syndrome (CFS) is included in this document in the relatively short list of conditions for which Immunoglobulin is not recommended. How was this decision reached? Was it because of NICE recommendations? By the criteria they used for their guidance on "CFS/ME", there would be a lot more conditions in the same category as CFS as, in CFS as in many other conditions, there have not been many studies involving Immunoglobulin (although some doctors in the UK and in other countries, who haven't published on the subject, do use it).

How was the positive study by Kerr[1] viewed? Its abstract is short so, rather than try to summarise it, here it is: "Three cases of chronic fatigue syndrome (CFS) that followed acute parvovirus B19 infection were treated with a 5-day course of intravenous immunoglobulin (IVIG; 400 mg/kg per day), the only specific treatment for parvovirus B19 infection. We examined the influence of IVIG treatment on the production of cytokines and chemokines in individuals with CFS due to parvovirus B19. IVIG therapy led to clearance of parvovirus B19 viremia, resolution of symptoms, and improvement in physical and functional ability in all patients, as well as resolution of cytokine dysregulation." These patients had been ill for over 2 years.

Was the decision influenced as it was felt that CBT was "effective" for CFS? The decision makers may be interested to know that a meta- analysis of the efficacy of CBT for CFS was recently published[2]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value. They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study." d was calculated to be 0.48.

For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[3].

[1] Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19 -associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6

[2] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[3] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

Competing interests: None declared

Competing interests: No competing interests

24 October 2008 Tom Kindlon Information Officer (voluntary position) Irish ME/CFS Association
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https://www.bmj.com/content/337/bmj.a1831/rapid-responses

CFS is increasingly recognised as a heterogeneous condition

07 October 2009
Tom Kindlon
Information Officer (voluntary position)
Irish ME/CFS Association, Dublin, Ireland

Following on from my last e-letter[1]: I have now located the first edition of these guidelines[2]. This edition by Provan et al[2], when putting Chronic Fatigue Syndrome (CFS) in the "black indications" group, explicitly recommends CBT for CFS. This seems to ignore the fact that CFS is increasingly recognised as being a heterogeneous condition[3]. Also, Price et al. [4] reviewed 15 studies of CBT with a total of 1043 ME/CFS participants. At treatment end, 40% of people in the CBT group showed clinical improvement in contrast to only 26% in usual care, but changes were not maintained at a 1-7-month follow-up when including people who had dropped out, which hardly suggests CBT is a solution for all. Roberts et al[5] recently found that the subgroup of CFS with hypocortisolism had a poor response to CBT.

How many of the "eminent neurologists" that Provan et al. refer to had actually used on IVIg on CFS patients? If any have used it, did it help none of their patients? If none were helped, this would seem to be an unusual group from patients I've heard from. Did the "eminent neurologists" make any attempt to sub-group the patients? From what I have heard, most neurologists in the UK are not that interested in CFS so I feel these are valid points to raise.

At the main international conference for CFS, a poster demonstrated that in South Korean CFS patients IVIg improved kidney function[6]. The same researcher also reported a positive outcome for cognitive function. These are outcome measures that have not generally been used in trials of CBT for CFS.

Was the following study[7] looked at: "Antibodies against Epstein- Barr virus, associated with antibody dependent cytotoxic cell activity, were found to be present in diminished titer in 20 of 22 patients tested with chronic mononucleosis syndrome (CMS). Gamma globulin was shown to improve symptoms in 53% of the patients treated, compared with 32% of placebo injections. 89.5% of 57 patients treated with a gamma globulin treatment program remained in the treatment program because of relief of symptoms, and only four patients dropped out because there was no relief of symptoms or side effects. Four patients experienced complete relief of symptoms following a variable length treatment program. It would appear that intramuscular gamma globulin treatment is efficacious in the treatment of CMS and that the average interval between treatments is three weeks." "Chronic mononucleosis syndrome" would generally be called CFS these days.

I have just been reading the minutes of the last (US) Chronic Fatigue Syndrome Advisory Committee (CFSAC) meeting[8]. The CFSAC is a federal US committee which advises the Health and Human Services Secretary on matters relating to CFS. Dr. James Oleske, chairman of the committee mentioned his experiences of IVIg:

"I got involved with CFS mainly because I was studying very severe EBV patients and post-EBV people who were having some clear and defined immunodeficiencies. I was involved in a clinical trial to see if IV gammoglobulin helped them. The data I have is on a much more infectious disease-driven group than Dr. Jason's."

[..]

"There are a number of investigational therapies that I don't think we've done much with because we haven't had a clinical trial program where we can enroll patients from multiple sites. The numbers game becomes very important. I can tell you that immunoglobulin helps patients who have subclass deficiency and recurring pulmonary infections"

[..]

"I also had analyzed the kids on gammaglobulin. I can't publish this data because when I submitted it, most of the people said, "What are your criteria for diagnosis?"

I thought I would also mention this successful double-blind, placebo- controlled trial[9] which had the following results and conclusions: "RESULTS: At the interview conducted by the physician 3 months after the final infusion, 10 of 23 (43%) immunoglobulin recipients and three of the 26 (12%) placebo recipients were assessed as having responded with a substantial reduction in their symptoms and recommencement of work, leisure, and social activities. The patients designated as having responded had improvement in physical, psychologic, and immunologic measures (p less than 0.01 for each). CONCLUSION: Immunomodulatory treatment with immunoglobulin is effective in a significant number of patients with CFS, a finding that supports the concept that an immunologic disturbance may be important in the pathogenesis of this disorder."

In my last reply[1], I included information on the successful trial by Kerr and colleagues[10] on the CFS subgroup associated with Parvovirus B-19. A case-study[11] also found IVIg to be successful for a case of CFS associated with Parvovirus B19.

Given this information, I hope for the next edition of the guidelines, serious consideration will be given as to whether it would be better to put CFS in the grey indications group, rather than the black indications group. ["Grey indications are those for which the evidence base is weak, in many cases because the disease is rare; IVIg treatment should be considered on a case-by-case basis, prioritised against other competing demands." Black indications: "Indications for which IVIg is not recommended - The prescription of IVIg is not appropriate for the following conditions."]

References:

[1] Kindlon T. On what basis was it decided that Immunoglobulin was not suitable for CFS? http://www.bmj.com/cgi/eletters/337/oct20_2/a1831#203678

[2] Provan D et al. Clinical guidelines for the use of intravenous immunoglobulin. (1st edition) http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/di... [Last accessed: 2 Oct 2009]

[3] Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev. 2005 Mar;15(1):29-58. Review. PMID: 15929497

[4] Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database of Systematic Reviews Issue 2. Art No.: CD001027. doi:10.1002/14651858. CD001027.pub2.

[5] Roberts AD, Charler ML, Papadopoulos A, Wessely S, Chalder T, Cleare AJ. Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome? Psychol Med. 2009 Jul 17:1-8. [Epub ahead of print] PMID: 19607750

[6] Park T. Improved renal function in CFS patients with IV immunoglobulin treatment. Poster Presentation, 9th International IACFS/ME Research and Clinical Conference, March 2009.

[7] Dubois RE. Gamma globulin therapy for chronic mononucleosis syndrome. AIDS Research 1986; 2(1): 191-5.

[8] Minutes of the CFSAC Meeting, May 2009. US Dept of Health & Human Services website: http://www.hhs.gov/advcomcfs/meetings/minutes/cfsac052709min.pdf [Last accessed: 2 Oct 2009]

[9] Lloyd A, Hickie I, Wakefield D, Boughton CR. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. American Journal of Medicine 1990; 89: 561-68.

[10] Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19 -associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6

[11] Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clin Infect Dis. 1997 Jun;24(6):1048-51.

Competing interests: None declared

Competing interests: No competing interests
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Jonathan Edwards · Oct 11, 2018

Denise said: ↑

Kathy Rowe published an article about IVIG in ME(1997). (I don't see it in the references of this review which is why I am pointing to it here.)
Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents
https://www.sciencedirect.com/science/article/pii/S0022395696000477?via%3Dihub
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This is one of the 7 papers. In fact two of the papers refer to this study.

inox · Oct 11, 2018

John Mac said: ↑

The English summary suggests they didn't try to, but maybe our Norwegian members could read the pdf for us
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It's only a list of possible relevant papers - studies and systematic reviews. The result of a systematic litterature search, nothing more. And that doesn't include actually reading the papers either, selection is based on title and abstract only:

(google translate: )

We took only based on the publication title and summary for selecting and sorting
tere references. That means we may have included references by reading the full text
proves to be irrelevant to the inclusion criteria and that we may have omitted relay
habitual references. We have not assessed the studies' methodological quality or assembled re-
sult.
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Not really sure how usefull such litrature seaches are, but they are a thing.

Edit:

Larun has given expert input on this, as senior researcher.
Kjetil Brurberg has signed the foreword, as head of the department.

Alvin · Oct 11, 2018

Tom Kindlon said: ↑

UK guidelines previously recommended that IVIG not be given for CFS and instead CBT be used.
Click to expand...

Dear god, withhold treatment and tell people their illness doesn't exist while they keep deteriorating
Who is protecting these people from a medical ethics hearing?

adambeyoncelowe · Oct 11, 2018

So how strong is the evidence for IVIg? Is this another weak area?

kendonoghue · Oct 29, 2018

Here's Google Doc's English translation.

https://docs.google.com/document/d/1QKjkFFmgnVArPKyDgoXSaRObIg48Rh-rcpbbsfLgTVQ/edit?usp=sharing

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Immunoglobulin for chronic fatigue syndrome (CFS/ME): systematic reference list

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