Role of infection and neurologic dysfunction in chronic fatigue syndrome - Komaroff

[Dolphin]

Role of infection and neurologic dysfunction in chronic fatigue syndrome.

Semin Neurol. 2011 Jul;31(3):325-37. doi: http://dx.doi.org/10.1055/s-0031-1287654. Epub 2011 Sep 30.

Komaroff AL, Cho TA.

Source
Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. Komaroff@hms.harvard.edu

Abstract*

Chronic fatiguing illnesses following well-documented infections and acute "infectious-like" illnesses of uncertain cause have been reported for many decades.

Chronic fatigue syndrome (CFS) was first formally defined in 1988.

There is considerable evidence that CFS is associated with abnormalities of the central and autonomic nervous systems.

There also is evidence linking several infectious agents with CFS, although no agent has been proven to be a cause of the illness.

Most of the infectious agents that have been linked to CFS are able to produce a persistent, often life-long, infection and thus are a constant incitement to the immune system.

Most also have been shown to be neuropathogens.

The evidence is consistent with the hypothesis that CFS, in some cases, can be triggered and perpetuated by several chronic infections that directly or indirectly affect the nervous system, and that symptoms are a reflection of the immune response to the infection.

Thieme Medical Publishers.

* I gave each sentence its own paragraph.

 

[Dolphin]

I just read the full text of this.

No psychobabble.

Generally doesn't dismiss physical findings mentioned although in some places does also mention studies that didn't back findings up.

But the weight of abnormalities is impressive. 195 refs in all virtually all ME/CFS papers.

 

[*GG*]

Not surprising, Dr. Komaroff is not a denier and does some good research is well respected by most in our arena.

GG

 

[Sean]

Thanks for this, D.

Your link just times out for me.

PMID: 21964849

 

[Firestormm]

Morning,

Was this like a summary/overview or research? Either way it sounds like it might be worth reading. Am guessing one requires a subscription? Might try and hunt it down somewhere later.

Thanks D

 

[Dolphin]

Morning,

Was this like a summary/overview or research?

Summary/overview

Either way it sounds like it might be worth reading. Am guessing one requires a subscription? Might try and hunt it down somewhere later.

Thanks D

Currently isn't free

 

[Dolphin]

Not surprising, Dr. Komaroff is not a denier and does some good research is well respected by most in our arena.

GG

Yes, but still in some papers, if they try to cover everything, will often mention say CBT or GET has been shown to be effective, etc. from the writers trying to show what is currently seen as evidence-based (perhaps nudged by reviewers). But there's none of those sorts of findings listed.

 

[Dolphin]

Some "practical" info:

EVALUATION OF PATIENTS WITH POSSIBLE CFS

[..]

It is our clinical impressionnot tested in a
blinded, controlled study involving non-CFS control
volunteersthat patients with CFS are more likely to
have the following abnormalities on examination: posterior
cervical and posterior auricular adenopathy, persistent
tachycardia when moving from a recumbent to a
standing position, impaired tandem gait, and abnormal
Romberg test.

Although as summarized above, many laboratory
and imaging tests have revealed abnormalities that are
more common in patients with CFS than in various
healthy control and disease comparison groups, none of
these tests has sufficient specificity and sensitivity to
constitute a diagnostic test. A panel convened at NIH
recommended a small and inexpensive battery of laboratory
tests in patients with protracted and severe fatigue,
primarily to rule out other causes of fatigue:
complete blood count with manual differential white
blood cell count, erythrocyte sedimentation rate, chemistry
panel, urinalysis, and thyroid function testing.189
Based on a case-control study that we conducted involving
over 700 cases and controls over 10 years in two
different geographic areas, the following test abnormalities
may be found more often in patients with CFS:
atypical lymphocytosis, circulating immune complexes,
elevated levels of IgG, and antinuclear antibodies.190

[..]

189. Schluederberg A, Straus SE, Peterson P, et al. NIH
conference. Chronic fatigue syndrome research. Definition
and medical outcome assessment. Ann Intern Med 1992;
117(4):325331

190. Bates DW, Buchwald D, Lee J, et al. Clinical laboratory test
findings in patients with chronic fatigue syndrome. Arch
Intern Med 1995;155(1):97103

 

[oceanblue]

I just read the full text of this.

No psychobabble.

Generally doesn't dismiss physical findings mentioned although in some places does also mention studies that didn't back findings up.

But the weight of abnormalities is impressive. 195 refs in all virtually all ME/CFS papers.

I'd be willing to hand this to doctors.

I don't have access to the full text so a couple of questions:

1. Did the authors say how many of these findings had been replicated?
With 195 papers, you might think that by now some consistent findings would have emerged. Hopefully they did.

2. Did they discuss publication bias as a possibility?
With lot's of (presumably) small studies with positive findings it's ripe for publication bias where small but negative studies (as opposed to small but positive ones) don't get published. Likewise for attempted replications. Negative results are particularly hard to get published ('I did a small study and found nothing'...) Maybe the authors addressed this.

I can see your point about the impressive weight of abnormalities, but it would be good too to know which of these many findings are reproducible which might throw light on the specific underlying pathophysiology.

The evidence is consistent with the hypothesis that CFS, in some cases, can be triggered and perpetuated by several chronic infections that directly or indirectly affect the nervous system, and that symptoms are a reflection of the immune response to the infection.

Hopefully the planned Lipkin/CFI pathogen studies will start to produce some answers on this.

 

[Dolphin]

I don't have access to the full text so a couple of questions:

1. Did the authors say how many of these findings had been replicated?
With 195 papers, you might think that by now some consistent findings would have emerged. Hopefully they did.

Well some findings had several papers referenced. Although often I think these were reasonably broad areas so not necessarily exactly the same thing that was tested.

2. Did they discuss publication bias as a possibility?
With lot's of (presumably) small studies with positive findings it's ripe for publication bias where small but negative studies (as opposed to small but positive ones) don't get published. Likewise for attempted replications. Negative results are particularly hard to get published ('I did a small study and found nothing'...) Maybe the authors addressed this.

Whether publication bias is such an issue in the ME/CFS field of biological findings, I'm not sure.

I would have thought researchers having difficulty getting published might be more of a problem if there have already been a few negative findings rather than if no negative findings had previously been published; and in the case of ME/CFS, (outside of XMRV) the volumes of studies are usually low so there may not be that many cases where a finding has already been refuted a few times. There have certainly been plenty of negative findings published in the past.

 

[Desdinova]

Not surprising, Dr. Komaroff is not a denier and does some good research is well respected by most in our arena.

That's because Dr. Komaroff approached ME/CFS with true scientific skepticism unlike many who seemingly confuse healthy scientific skepticism with outright cynicism. My understanding has always been when ME/CFS came upon the scene in the 80's breakouts that he was scientifically skeptical. But as he and others did serious research and really looked into it that progressively changed.

 

[oceanblue]

This must have been a huge amount of work, taking in nearly 200 references. 'The authors thank Jessica Erickson for her help in surveying the literature' but it seems harsh not to include her as an author - since the paper is basically a literature survey.

What I particularly liked is that the authors were very honest about the limitations of the evidene and didn't try to force it with unsubstantiated claims:

abstract
...There is considerable evidence that CFS is associated with abnormalities of the central and autonomic nervous systems. There also is evidence linking several infectious agents with CFS, although no agent has been proven to be a cause of the illness

...The evidence is consistent with the hypothesis that CFS, in some cases, can be triggered and perpetuated by several chronic infections that directly or indirectly affect the nervous system, and that symptoms are a reflection of the immune response to the infection.

body
...when it comes to incriminating infectious agents in CFS, this is all no more than circumstantial evidence.

...We recognize that many challenges remain in terms of defining the nature of the correlation (causality) and the specificity of the changes to CFS.

So, a very useful summary of the state of play but no new insights as far as I can see.

 

[Enid]

Of course it is "infection" - aetiology's the big thing now.

 

[oceanblue]

Promise unfulfilled

I found reading the Komaroff review a dispiriting experience - there must have been 150 findings of biological abnormalities in CFS patients but almost of all them were different, with very few replications. A good number of the reports were from the 1990s, suggesting there had been no follow-up or replication for over a decade. It's no wonder there has been so little progress in understanding the pathophysiology of the illness when researchers have apparently failed to follow up on so many promising findings.

Just reading the titles and abstracts of cited papers in the review I was struck by how often I came across words and phrases like 'possible', 'preliminary', 'exploratory', 'suggests' and 'need confirmation' - and how rarely I found words like 'validated', 'confirmed' or 'replicated'. When I did my biochemistry degree, way back in the 80s, there were of course many preliminary and provisional findings in recent papers - it's the nature of science - but these were regularly followed by confirmation (or refutation) of the original findings. The lab where I did my final year project routinely tried to replicate important new findings in their field as soon as they were published.

It's only by confirming interesting findings that there can be progress: each validated finding a building block that other researchers can use to make further progress. Of course, CFS is phenomenally challenging to study as, are many chronic illnesses (all the low-hanging fruit has long gone), but without rigourously following up the leads that do exist to either prove or discount them, it's going to be tough to get anywhere. Meanwhile there is a vast arrary of unconfirmed findings that anyone can pick from to support just about any hypothesis on the illness.

What's needed is robust replication: repeating the findings on an independent sample of patients and controls, with a substantial sample size, and, ideally, by an independent research group.

Replications... sort of
The Komaroff paper, which was a perfectly good as a review, did include a few at least partial replications:

Low cortisol in CFS patients
A small 1998 study found that CFS patients (n=21) had, on average, lower free urinary cortisol levels than healthy controls, while depressed patients had higher cortisol levels than controls. Then a 2001 study by Wessely & Cleare confirmed the low cortisol levels in CFS patients in a large sampe (n=121, p<0.0005), though it didn't look at depressed patients.

However, a later paper by the same authors (not in the Komaroff review) again found lower free urinary cortisol levels, but noted this wasn't corroborated by correspondingly lower levels of cortisol metabolites. (If urinary cortisol levels are reduced, cortisol metabolites in urine should be reduced too - but they weren't.)

>> Verdict: Urinary cortisol is lower in CFS patients but circulating cortisol in the body might not be - so low cortisol in patients has not yet been convincingly established.​

Natural Killer Cell Cytotoxicity
The review cites several mall studies with evidence of reduced Natural Killer Cell Cytotoxicity (NKCC), though oddly omits the ultimate bioabnormality paper, in 2010 by Fletcher and Klimas, which convincingly demonstrates lower average NKCC in CFS patients (n=176, p<0.0005). There was also a later confirming paper by Brenu (n=95, p<0.05).

>> Verdict: :victory: Mean NKCC is lower in CFS patients than in healthy controls.
However, it's worth noting that there is still substantial overlap on NKCC levels between individual CFS patients and healthy controls.​

Symptoms of autonomic dysfunction
This single study from Julia Newton in 2007 gets a mention as it uses one patient sample (n=40) for an inital exploratory phase then a separate sample for the validation phase (n=30). This is a much better approach than the usual one in CFS papers where there isa single sample, and after reviewing the data a threshold that is set to give the maximum difference between patients and controls in that particular sample. The Newton study uses a global measure of ANS, the Composite Autonomic Symptom Scale, 'COMPASS':

Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.860.99)

>> Verdict: Great approach but awaits confirmation by further, larger studies.​

Higher levels of lactate in brain ventricles
An initial study in 2010 found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in CFS compared with controls (n=17), confirmed by two further small studies, the latest last month. High levels of lactate could represent problems with energy metabolism in the brains of CFS patients. All of these studies are quite small, presumably because the technology (Magnetic Resonance Spectroscopic Imagining, if you're interested) is expensive and hard to access. However, the authors have consistently pursued an important finding (elevated lactate) and found the same result each time.

>> Verdict: Needs larger studies to confirm, but as given the first finding was in 2010 this is as good as could be hoped for.​

Promising Future?
What I find encouraging is that there seems to be a shift towards replication in the field. The three most important findings in recent years are probably XMRV, Rituximab and the Lights' gene expression on moderate exercise studies. There have already been numerous attempt to replicate the XMRV findings with the Mother of All Replication Studies (Lipkin) underway. Fluge & Mella, the authors of the amazing but small Rituximab study, are planning a large multi-centre trial to attempt replication of their initial findings, while Drs Enlander and Bell are planning a replication study in the US too. And the Lights are being funded by the NIH to validate the results of the old study with new patients. Hopefully attempts to replicate of important findings will become the norm in CFS research.

 

[OverTheHills]

Komaroff may disappoint you, but reading your post, Oceanblue, is an uplifting experience.
Clear evidence of critical thought, and an even-handed rather than ideological perspective. If only more of the researchers could manage working to the same standard.

Some of us patients manage to do a fine job getting rebuttal letters published in journals. I am beginning to wonder whether we (the mass of scientifically untrained patients) could support them to get original papers published. I would be happy to chip in some small scale funding, proof reading etc if it would help.

OTH

 

[Firestormm]

Ocean, I have still not read this one through properly. Not been up to reading much in the past few weeks, but I did start a thread on another forum about my 'disillusionment' with research over the years and a seeming lack of replication.

It was this paper - at a cursory glance - and a couple of others recently that led me to start that thread. The replies though, like yours above, did actually curtail my frustrations a little.

I do rate this paper from Komaroff as I do most papers that provide a synopsis of other research across a spectrum. It helps me to better understand the situation - it's easier for me with my limitations now to read. And I will make time to properly read it through.

Just wish sometimes they weren't so many 'new' papers hitting the journals so often lol! Hard for anyone with this condition to keep up let alone understand them and that's why it's so cool having a 'community' that can do the job when we aren't at our individual best and break things down even more.

Anyhoo... as you were

 

[oceanblue]

Thanks, OTH!

@OTH/Firestormm: I thought the Komaroff review itself was pretty good and very fair about the limits of the evidence. It was the low quality of evidence available that bugged me, particularly as it reflected the quality of research I'd come across in other areass of biological abnormality not covered by Komaroff's paper.

Agreed there is something of a deluge of papers: fewer, better studies would be good for patients' brains as well as progress in research.