CDC: CFS not subject to opportunistic infections?!

[Persimmon]

From what I can gather from the research workers in the ME field I have talked to we do not have reliable evidence of immunodeficiency on laboratory tests...

So I would like to put out an invitation:

If any researcher anywhere in the world can tell me how I can measure an immunodeficiency in ME patients that would mean we should not go ahead I would like to know... I would want to be sure that if I sent 20 ME samples and 20 healthy samples on a blinded label basis there would be a clear difference between the two - say 80% of ME below a line and 80% of normals above. Does anyone think such tests exist?

@ Professor Edwards,
If we're talking about there being a number of different ME's, wouldn't that mean that there could be immunodeficiencies specific to particular forms of ME?
In such circumstances, is it reasonable expect at least 80% of all ME cases to exhibit the same immune abnormalities?

FWIW, I suspect that the disparity of immune test results among ME patients might prove a useful tool in trying to identify sub-groups / different ME's.
For example, some published studies have reported low CD8 numbers; others have reported high CD8 numbers. Mightn't this point to there being some ME patients with consistently elevated CD8 and some with consistently suppressed CD8; and to these sub-groups exhibiting different pathologies?

 

[Alea Ishikawa]

@metalnun and @Hip - Statements in the IACFS/ME Primer:

A number of viruses and/or the antibodies against them have been found more frequently in patients with ME/CFS than in control populations15 (e.g., human herpes viruses, enteroviruses). These studies suggest that virus(es) may play a causative role. Alternatively, the viruses may be opportunistic infections.

Although mild immunological abnormalities (T-cell activation, low natural killer cell function, dysglobulinemias, and auto-antibodies) are common in CFS, subjects are not immunocompromised and are no more susceptible to opportunistic infections than the general population.

So, patients are not medically-explained to be more inclined than the general population to have opportunistic infections, but somehow have more infections vs. controls?


Apparently, that may be due to Rich's explanation - patients are persistently infected, fighting pathogens but not winning the war. There's also more to this mystery.


From the Holtorf Medical Group (emphasis mine):

Numerous studies have demonstrated a high incidence of chronic infections in chronic fatigue syndrome and fibromyalgia. These include viral infections of Epstein bar (EBV), cytomegalovirus (CMV), human herpes virus-
6, (HHV-6), and bacterial infections such as mycoplasma, chlamydia pneumonia (CP) and Borrelia burgdorferi (Lyme disease).
There is controversy regarding the presence of active infection in these conditions because physicians, including infectious disease specialists, do not understand that the standard way to diagnose acute infections, an elevation of IgG and IgM antibodies, is not a sensitive means of detecting chronic infections in these patients . . .

Due to the immune dysfunction seen in CFS, in addition to a lack of IgM antibody formation, there may also be a lack of IgG antibodies present despite the presence of an active infection in CFS patients (22,17,23). This has also been demonstrated to be the case with AIDS patients, as demonstrated in the study published in the New England Journal of Medicine entitled Absence of detectable IgM antibodies during cytomegalovirus disease in patients with AIDS (22).

From the ICC article (emphasis mine):

Immune impairments
. . . Possibly, the initial infection damages part of the CNS and immune system causing profound deregulation and abnormal responses to infections [4]. Publications describe decreased natural killer cell signalling and function, abnormal growth factor profiles, decreased neutrophil respiratory bursts and Th1, with a shift towards a Th2 profile [4–8, 92, 93]. Chronic immune activation [27], increases in inflammatory cytokines, pro-inflammatory alleles [4–8, 94–96], chemokines and T lymphocytes and dysregulation of the antiviral ribonuclease L (RNase L) pathway [62, 97–100] may play a role in causing flu-like symptoms, which aberrantly flare in response to exertion [5, 92].

From D. Berg et al. (emphasis mine):

Because the CFS-FM process may be triggered by a variety of pathogens, we suggest that pathogen-mediated immune activation may induce antibodies, e.g. anti-B2GPI, anti-Annexin V antibodies . . .

Because this hypercoagulability does not result in a thrombosis, but rather in fibrin deposition, we suggest that an appropriate name for this Antiphospholipid antibody process would be immune system activation of coagulation (ISAC) syndrome . . .

The P value for laboratory diagnosis based on this criterion was < 0.001. . . Twenty-two of the 23 controls were correctly identified. One control was positive in two assays for a false positivity rate of 4%. Of the 54 patients, four had normal values, for a false negative rate of only 7.4%. This shows that greater than 92% of CFS and/or FM patients had a demonstrable hypercoagulable state. What then is the underlying disease process?

 

[WillowJ]

hi, Dr. Edwards,

As the others said, low NK cell function is, as far as I can tell, very well replicated. (It is one of the few things that I think counts as well replicated.) You and Drs. Fluge and Mella would know for sure, but I would not have guessed that would be a contraindication to use of rituxan? (Since this is something found in other autoimmune conditions (this seems a new addition to the link maybe?) and some types of cancers)
http://www.childrensmn.org/Manuals/Lab/Serology/020733.asp

I am not sure what to say about the inconsistencies reported. There are lots of studies, as I think Hip mentioned and linked to a few of them, and I think science doesn't normally expect all of them to be positive, but just to come to a general consensus, right?

OTOH, at one point I heard Dr. Klimas say some of the earlier immune studies were inconclusive due to the limitations of flow cytometry up until the time she was speaking (I cannot recall what year), but that things should improve after that.

Another time I might have something else mentioned, but I forgot what now.

Subgroups is another possibility, of course.

I cannot think of any studies I read (or saw the abstract of) which didn't find that measure in particular (though the ones looking at count variously find normal, high, or low count of NK cells), though I guess I should check the Lorusso review to be sure (as it concluded there were many incosistencies in immune measures), but I don't have my full text handy.

Another problem is that many people being studied under the name of CFS have a different diagnosable condition. (Of course they might have more than one, but in some cases it appears the other was primary.)

We know this because there are studies looking at people who meet Oxford critiera, or the criteria the CDC has been using (we refer to this as the Reeves or Empirical criteria, though CDC claims they have simply operationalized the Fukuda criteria, but they changed the nature and timing of almost every requirement: even a panel of people who are completely unfamiliar with the disease can tell this is not true and said so in the AHRQ draft literature review for P2P), and people who were diagnosed in the USA (presumably under Fukuda or ad hoc criteria) or UK (presumably under NICE, Oxford, or ad hoc criteria) or who generally meet Oxford criteria without the clinical assessment (some "CFS" papers are written this way, albeit probably not biomarker study papers, and in clinical practice conditions, many "fatigue" patients don't actually get clinical assessment--I got exactly one routine general screening and one specific but generic (e.g. to check one of the most common causes of fatigue for my age/gender) blood test and a figurative pat on the head, the first time I went to the doctor with symptoms of ME and dysautonomia).

At any rate, would you think low NK cell function, particularly in the presence of signs of other parts of the immune system being upregulated (like say, high T cell count and positive ANA) to be a contraindication to the use of rituxan?

 

[justy]

There also appears to be a subset of patients with high NK cells, as seen by the Redlabs test for NK cell function, linked to by Hip above which tests Perforin mRNA expression (mine was high).

There appear to be bits and pieces of evidence here and there, but many don't appear to be consistent. I also appear to have an underactive immune response AND an overactive one at the same time, according to testing - I don't know how that can be right??

 

[justy]

Adding to @WillowJ 's account above, ia m also concerned by the high level of misdiagnosis of M.E and the possibility of giving Rituximab to someone who perhaps has an entirely different disease. I believe Julia Newton's team found a 40% misdiagnosis rate?

The NHS needs to start taking patients more seriously, many of us have been medically neglected and could possibly have other, rarer illnesses or just ones that haven't been spotted by a routine GP visit and routine bloods. I have documented my fight to get appropriate testing to rule out other conditions such as Lupus, MS etc elsewhere, but it is a REAL concern in the UK.

 

[Jonathan Edwards]

What about the TH1 TH2imbalance that researchers/clinicians such as Professor Kenny De Meirleir is finding in his individual patients - is this important?

To be honest I don't think there is such a thing as TH1/TH2 imbalance. People in immunology got excited about this idea, based on T cells in mice, about 15 years ago. It was supposed to explain all known diseases. Then it became clear nobody was quite sure what the imbalance would do, or that humans actually have 'TH1' or 'TH2'
cells rathe than T cells behaving in lots of different ways in different situations. The fashion moved on to TH3, TH17 and TReg. I haven't heard a serious immunologist talk about TH1/TH2 imbalance for nearly a decade. One of the things that worries me about the ME science folklore is that a lot of it is based on ideas we moved on from a long time ago!

I believe he also finds high levels of chronic bacterial intracellular infections in his patient group - I have been diagnosed with chronic Bartonella, chronic Chlamydia Pneumoniae and possible Lyme disease. How do we go about using Rituximab in patients with possible long standing chronic, undiagnosed bacterial infections - is this even a problem?

Trouble is nobody else seems to confirm these infections. If the tests used were reliable then they would have been published and standardised world wide. There still seems to be a problem in ME that people are being diagnosed on the basis of tests that are not generally recognised and standardised. In other diseases this does not happen any more. Everyone accepts a level of quality control is essential before findings are taken seriously.

This is completely anecdotal, but we seem to have at least a subset of patients, like me, who are VERY susceptible to common infections and are constantly ill with one thing and another, but we don't seem to mount a proper immune response - in other words only from experience do I know that if I go near anyone with an illness I will catch it and then I will be ill with it for weeks, until eventually all these illnesses just join up into one long never ending illness. I also don't have the SEVERITY of illness that healthy people around me have.

I don't know how this can be tested for right now in the UK. But I do know that my M.E doctor from outside the UK is concerned enough about my immune system that he is suggesting IVIG for me.

Dr Nigel Speight at his pre dinner speech at Invest In ME this year also mentioned some studies that clearly show the efficacy of IVIG for M.E patients. Why would this help if there was not some sort of immune system issue.

My concern is that researchers wont see your plea for information here, but that doesn't mean they aren't interested in the Immune system in M.E.

Yes, there seems no doubt that a subset of PWME have persistent trouble with symptoms from common infections. But note that a lot of the symptoms we have from infections are due to our immune response rather than the infection itself. It certainly looks as if immune responses are different in ME, but that needs to be distinguished from 'immunocompromised'. IVIG is in fact often used in autoimmunity, where the immune response is excessive. It is hard to see why IVIG would be much use as a 'top up' of antibodies to a current infection in someone with reasonably normal Ig levels. IVIG is pooled from people who will not have themselves seen the infection question recently so are likely to have less antibody than the patient. I have recently had some discussion with Dr Speight and we agree that further study of ICIG would be worthwhile. However, I think if it does work it is likely to be through a more subtle modulatory mechanism.

I realise that a lot of researchers may not look in on PR and I am not suggesting this should be my main route for finding out abut tests. And I already know of many groups interested in the immunology. However, I have so far not come across any reliable tests and I am just interested to see if they can be smoked out via the PR grapevine, which I think is more efficient than might appear on the surface!

 

[Jonathan Edwards]

@ Professor Edwards,
If we're talking about there being a number of different ME's, wouldn't that mean that there could be immunodeficiencies specific to particular forms of ME?
In such circumstances, is it reasonable expect at least 80% of all ME cases to exhibit the same immune abnormalities?

Yes, quite right, I was only quoting that as an example of what might be needed. If 10% of PWME should a level that only occurred in 1% of healthy controls that would also do - etc. etc. But then we would need to check at least 100 normal samples.

 

[Jonathan Edwards]

hi, Dr. Edwards,

As the others said, low NK cell function is, as far as I can tell, very well replicated. You and Drs. Fluge and Mella would know for sure, but I would not have guessed that would be a contraindication to use of rituxan?

I am not sure what to say about the inconsistencies reported. There are lots of studies, as I think Hip mentioned and linked to a few of them, and I think science doesn't normally expect all of them to be positive, but just to come to a general consensus, right?

At any rate, would you think low NK cell function, particularly in the presence of signs of other parts of the immune system being upregulated (like say, high T cell count and positive ANA) to be a contraindication to the use of rituxan?

The trouble is that even the NK studies seem inconsistent. Moreover, NK function studies are notoriously varibale in results. We have worked with NK function assays at UCL for years and consistency is a huge problem. Moreover, the UK investigators I have talked to who have looked at NK function in ME cannot confirm an abnormality.

There are deeper concerns with these assays now that we know more about the variation in NK receptors. In the genetic NK defects people tend to have no NK cells at all and that does seem to be associated with severe infection, although the gene defect affect a lot more than just NK cells so we do not know it is the absence of NK cells that is the problem. It is much less clear that low numbers or low function in a K562 assay mean very much. I would have no particular qualms about treating someone with low NK function results as it stands because I am not confient that these results tell us anything important in a person who has no history of true opportunistic infection.

Again, I do not think T cell counts tell us anything very important, unless they are extremely low. And ANA is of course a sign of autoimmunity, which is what rituximab is good for, so that would be the opposite of a contraindication maybe. Moreover, dermatomyositis patients have very low NK activity on K562 but dermatomyositis has shown very useful responses to rituximab (and DM patients do not get opportunistic infections as far as I know).

 

[WillowJ]

@Jonathan Edwards Thank you. That's a relief as far as rituximab treatment, but perplexing about the NK cell dysfunction studies.

 

[user9876]

I would have no particular qualms about treating someone with low NK function results as it stands because I am not confient that these results tell us anything important in a person who has no history of true opportunistic infection.

If you are worried about people with opportunistic infections and the effects of Rituximab then could you just exclude those with a history of that from any initial trial or give antibiotics and antifungals along with the Rituximab.

Hematologists use Rituximab of immune compromised patients who have a re-occurrance of EBV after a bone marrow transplant. But they do insist on a very limited lifestyle to avoid infections whilst patients are on anti-rejection drugs.

 

[justy]

justy said: ↑
I believe he also finds high levels of chronic bacterial intracellular infections in his patient group - I have been diagnosed with chronic Bartonella, chronic Chlamydia Pneumoniae and possible Lyme disease. How do we go about using Rituximab in patients with possible long standing chronic, undiagnosed bacterial infections - is this even a problem?

@Jonathan Edwards replied:
Trouble is nobody else seems to confirm these infections. If the tests used were reliable then they would have been published and standardised world wide. There still seems to be a problem in ME that people are being diagnosed on the basis of tests that are not generally recognised and standardised. In other diseases this does not happen any more. Everyone accepts a level of quality control is essential before findings are taken seriously.

I'm a bit confused by your response here - are you saying that the testing I had is not valid? I don't think that can be right as you are not aware of what specific testing I had done. How do we know the tests are not reliable? How do we know they are not standard tests? after all we do Know and the literature widely supports the view that Cpn can become chronic, that it can cause symptoms, and that it can be treated. As I have longstanding chronic lung issues why would we presume I don't really have Cpn.

I agree entirely with your comment about 'M.E folklore' but I am concerned that this can work both ways - there is also a folklore in the UK that M.E patients cannot possibly have these chronic infections because f they did have we would know. Of course that can't be true as I have never been tested by the NHS for Cpn, despite my history of pneumonia and ill health, nobody thought to do it. The NHS seriously under tests patients, so we would never really know if patient A had these infections or not.

I am concerned that the work of many M.E researchers can be put aside as being 'out of date' 'folklore' etc when these are real researchers who do publish their work and have it scrutinised. I'm not saying they are getting it right, but if there are concerns about their approach and testing far better to have the conversation with them about their approaches and tests.

Would it be possible for you to comment on if a patient had a persistent bacterial infection whether or not Rituximab would be suitable?

 

[justy]

Sorry if I am not being clearer in my argument - as I have said before I am a humanities gal and the scientific arena is not my thing, but what I am essentially getting at is that testing cannot just be dismissed off the bat with no evidence to back it up.

I am happy to be proven wrong and be shown that I do not have two intracellular infections that are adding to my illness levels and that could possibly be treated and hopefully result in some improvement in symptoms. I would rather not have them and not have to go through the treatments which are costly and difficult to tolerate

But I would like us to have a real discussion, amongst patients and researchers and clinicians about the validity or otherwise of various testing and for it not to be dismissed in one sentence with no evidence to back it up - I believe that we are attempting to be more rigorous and that has to cut both ways.

I hope this isn't coming across as confrontational, that is certainly not my aim and I am aware that typed conversations don't have the nuance of 'live' ones.

 

[Valentijn]

@justy - The Lyme test used by Infectolab has been tested and verified against samples known to be positive or negative serologically. It showed 89.4% sensitivity and 98.7% specificity, when using a positive threshold of 3 or greater. Which is extremely good, when compared to Western Blot, etc.

Those results haven't been replicated yet, but nor has anyone demonstrated any problem with that study, or produced any contradiction of the results.

 

[Jonathan Edwards]

If you are worried about people with opportunistic infections and the effects of Rituximab then could you just exclude those with a history of that from any initial trial or give antibiotics and antifungals along with the Rituximab.

Hematologists use Rituximab of immune compromised patients who have a re-occurrance of EBV after a bone marrow transplant. But they do insist on a very limited lifestyle to avoid infections whilst patients are on anti-rejection drugs.

Yes, I think one would definitely exclude people who have had unusual infections from rituximab treatment at least at this stage. I also had a rule not to use rituximab in people with significant pre-existing lung disease because rituximab can probably occasionally produce a form of pneumonitis. We used to interpret that flexibly depending on how severe the autoimmune problem was.

I would not be inclined to use rituximab and add antibiotics as a 'prop-up' partly because antibiotics are in themselves one of the commonest causes of opportunistic infection, particularly clostridium difficile (and of course a cause of candida infection).

 

[Sushi]

Just another patient-testing anecdote: I was diagnosed with Bartonella by a positive PCR test.

Sushi

 

[Jonathan Edwards]

I'm a bit confused by your response here - are you saying that the testing I had is not valid? I don't think that can be right as you are not aware of what specific testing I had done. How do we know the tests are not reliable?

How do we know they are not standard tests? after all we do Know and the literature widely supports the view that Cpn can become chronic, that it can cause symptoms, and that it can be treated. As I have longstanding chronic lung issues why would we presume I don't really have Cpn.

Don't worry, Justy, you are coming across totally non confrontational. If anyone is being confrontational it's me and I am only doing it because I would like to get just this sort of honest discussion in a situation where none of us
is quite sure what we should believe. My comment about reliability of diagnostic tests for infection was in relation to the general situation. I try to steer clear of advising on an individual basis as you know but I do have a sense that you have a specific problem, at least with your chest, that is likely to involve persistent infection of some kind.

But there remains the fact that some private ME practitioners seem to diagnose multiple cryptic infections on almost everyone and yet someone like Julia Newton, who is doing a detailed study of all aspects of her patients and cannot be accused of not taking things seriously, makes no mention of this at all.

I do not know what tests you have had but they are likely either to be cultures of organisms or tests of immune response - either antibody or T cell. Positive cultures are fairly straightforward but my understanding is that these are rarely feasible for the infections we are talking about. There is a lot of talk about antibody tests. I have spent my life studying antibodies and antibody tests and in general they are not very reliable at diagnosing ongoing infection. T cell tests are probably not validated for anything except tuberculosis and even there there are problems.

So when you ask how I know tests are not reliable, I have to say I do not know. However, on a general basis tests are unreliable until they have been proven reliable, not the other way around. And unreliable tests and treatments are historically the norm in medicine. It is only rather recently that medicine has become more than witch-doctoring. In hypertension that happened in about 1970. In rheumatology it happened about 1985. For ME, which as we all agree has been ignored, I think it is only happening just now.

Even in a research lab in a UK teaching hospital may main task in training young scientists was in persuading them not to try to get the results they thought I wanted but to get whatever results turned up. Most young scientists throw away results if they do not fit with the theory they think they are supposed to confirm for the boss. And in the private sector the pressure is even greater. You say you are a humanities gal. My first degree was actually in Art History, although I had signed up to being a scientist before that. Art History taught me how to gather reliable evidence - because in Art History if you get an attribution wrong your client is $10million worse off. In contrast medicine seemed to me slap dash. Nobody really cared if the results were meaningless as long as they could be published. Things are improving, but tests are still unreliable until proved otherwise.

Would it be possible for you to comment on if a patient had a persistent bacterial infection whether or not Rituximab would be suitable?

I guess you are thinking of your own situation here. It reminds me of a woman I got to know very well, as we spent several years together trying to get her back to some sort of health from perhaps the worst RA I have seen in twenty years. I inherited her from a retiring colleague who seemed to think that his most difficult patient better go to Jo Edwards to sort out! She had chronic lung disease from smoking, bronchiectasis and lung nodules. Rituximab was the only thing left to try. Things were not easy but she found an outstanding chest physician (NHS) at the Brompton Hospital who took her chest problem seriously and got it under control. She had rituximab early on in our studies and now that we know more we could have done things better, but it got her disease under control for several years. I think it is just a matter of being totally systematic about all aspects and weighing up the risks carefully. Oncologists like Dr Fluge and Dr Mella deal with much more difficult combinations of problems than I ever have and that sort of expertise is now generally available in a large teaching centre.

Put another way, if infection is known to be present it can generally be worked around. What I think is more difficult is treating people who have a past history of genuinely opportunistic infection like pneumocystis or systemic cytomegalovirus, which may indicate an increased risk of further problems if rituximab is given.

 

[A.B.]

But there remains the fact that some private ME practitioners seem to diagnose multiple cryptic infections on almost everyone and yet someone like Julia Newton, who is doing a detailed study of all aspects of her patients and cannot be accused of not taking things seriously, makes no mention of this at all.

I believe Dr Meirleir has said that about half his patients have some sort of (chronic?) infection. It would be a good idea to get in touch with him.

 

[lansbergen]

I also had a rule not to use rituximab in people with significant pre-existing lung disease because rituximab can probably occasionally produce a form of pneumonitis.

Would be barely able to breath qualify for that?

People with the ouvert disease of the infection I suspect usely die of what is called lung complications. Time between infection and ouvert disease can run from 3 to 40/50 years and even longer.

 

[heapsreal]

Its all about subsets. Some show inflammatory markers and also have other autoimmune issues,
some have the low nk function and or numbers(this could probably be broken down further into bright nk cells),
some have low cd8 t cells function,
some have low t cells subsets and some have high t cell subsets,
some have low total lymphocytes and others have high,
some have elevated RNaseL,
some have low neutrophils and other have elevated neutrophils.
Some seem to have very low immunoglobulins and require IVIG and some have high immunoglobulins.

Take your pic, mix and match them etc etc and that can give you some sub groups. confuse things some more and add a few infections.

I believe my sinus infections are opportunistic and increased as my neutrophil count slowly dropped over tiime. I believe my elevated T cell subsets are an indicator of ongoing ebv/cmv and that my low nk function and bright nk function is one reason why these infections have been hard to control. My iga and igg subclasses have been elevated probably indicates my immune system is trying to fight something??

All of us seem to have a unique immune profile. I think we are all going to have to be treated individually. Theres going to be no one magic bullet, probably more like a few bullets depending on your subset?

I think immune dysfunction is a better way to describe the immune system of those with cfs/me as some parts seem to be overactive and others underactive.

 

[lansbergen]

I think immune dysfunction is a better way to describe the immune system of those with cfs/me as some parts seem to be overactive and others underactive.

I agree