Why has 'persistent enteroviral infection' been dropped as a research strand in ME/CFS? (Jen Brea asking)

Not really. Antibody levels pretty much always peak after infection has been controlled. Antibodies are not in themselves of great value as a protection against a first infection - their production is too slow. They are there to prevent a second infection with the same organism getting hold and to protect newborn babies (maternal antibodies). And antibody levels, once maximal, tend to remain pretty much the same for years. They decline over decades but pretty slowly. I have removed all new production of B cells from people for up to five years - so that they cannot 'restock' antibody production from new B cells in response to antigen. They continue on the antibody production from the old plasma cells they had at the start. For things like tetanus antibodies there is often hardly any fall at all over the period of B cell depletion.

 

'Immune modulator' covers a wide range of drugs, many of which nobody knows much about. I am not sure the term is very helpful. Rituximab might be called an immune modulator. It does not work in ME. Nor do any other drugs that might be called that as far as I am aware.

 

Very cool. Thank you for squaring that for me.

I do not want to detour from this topic, which is enteroviruses, but @Jonathan Edwards, this does not reflect what I know about bacterial antibodies, in particular spirochetal ones. For instance, the VDRL diagnostic used for Syphilis owes much of its utility in that it maps out the 4-fold decline in titres upon successful treatment. Similarily, the C6 embraced in the UK for Borrelia diagnostics is, following successful treatment, either supposed to decline by a 4-fold factor, or drop to normal levels, ie. pre-morbid levels.

Both of these are clearly working on the assumption that antibody levels will drop, albeit with an odd class of pathogens, I will admit.

 

Is there built into this position the assumption that the first infection has resolved? What if it has not?

Also, how would you explain antibiotics being used to see if infection persists, i.e., antibody titres rise during abx use?

 

Spirochaete serological testing is very atypical. The VDRL turned out to detect antibodies to phospholipids, as I understand it of host origin. So VDRL really tests for a peculiar autoantibody response not a test for an antibacterial antibody. Autoantibodies are very often produced by short lived plasma cells so, for instance, when we deplete B cells with rituximab a lot of autoantibodies decline over about 3-6 months, initially quite rapidly.

 

Stated incubation periods do vary slightly from one source to the next, presumably because different sources get their data from different studies.

 

If that is the case, why do ME/CFS patients with high titers to coxsackievirus B see a marked reduction in those titers when treated with interferon alpha, or antivirals such as ribavirin (along with a major improvement in symptoms)?

If those high titers are unrelated to active infection, why is it that antivirals reduce them?

 

I have never seen published documentation of this, @Hip.
Moreover, if you take people with high titres and wait a while there is every likelihood that the next titre will regress to the mean - i.e. be lower. If you treated people with low titres you might well find next time they are higher.

 

This would not square with patterns.

 

So, I have had several infectious disease doctors/researchers tell me the above is actually not true, even though that is the received wisdom. I don't know on the basis of what research they said this. I've had many different viruses in the past, as have all of us. If I have good immunity to CVB4, then why don't I have good immunity to herpesviruses as well? As in, why are my titers to everything I've been infected with in the past low (indicative of past infection) while CVB4 is high?

I do wonder what the purpose of these tests are if they are meaningless. Even if I get a new infection, it will be impossible to tell if I had it in the past unless by coincidence I had a recent, negative test. Unless the idea is that you always test twice, once during the acute phase and once several weeks later.

I suppose my question is the same as the above: if antibody tests are useless to measure recurrent or chronic infection, then how do you then measure that (clinically or in a research setting).

I'm having all of my old onset symptoms from 2012 (right sided numbness, right arm flaccid, walking crooked, stabbing pain in head/chest, feeling flu-ish w/o temp). The worst of it is what I now gather is central apnea. Last night for about 45 minutes, I was almost constantly unable to breathe. I would completely stop breathing automatically, try hard to focus on taking a breath, only when it had been dangerously long would my brain then kick in and I'd gasp for air. And then I'd stop breathing again. Over and over, almost continuously. WTF?

I am trying to get re-tested today/tomorrow for both antibodies and PCR. If high titers are meaningless and PCR unreliable, then I don't know where that leaves me (and all of us). This is not post-exertional malaise. This is not dauer. I am not crashed. Yes, when at baseline I have all of these symptoms, too, but none of the more popular recent understandings of this condition can explain what I experience during acute flares.

Not asking for medical advice. Just saying WTF as it is highly unlikely even if I sought help that I would be able to find it.

EDIT: Sorry, I missed this in your earlier post @Jonathan Edwards. I see that the general application of antibody tests is testing two weeks apart.

 

John Chia finds high enterovirus IgG titers in his ME/CFS patients are routinely decreased when using interferon alpha, ribavirin and oxymatrine treatments, which all fight enterovirus. Moreover, when these treatments are discontinued, titers increase again, along with a relapse in ME/CFS symptoms (so the subsequent increase in titers tends to rule out the possibly that the initial decrease was due to a natural reduction in titers over time).

There's not much published material of this phenomenon, but one of Chia's published papers does document it:

 

It is the exact opposite for Borrelia, that is, in the absence of abx therapy, Bb titres often decrease in late stage, with abx, titres often rise.

The thing they appear to have in common is treatment impacts immune response.

 

So not exactly robust evidence then?

 

There's not much robust evidence of anything. That's why we need to go do the work.

 

Yes but you can’t clutch at every straw. At some point you need to prioritise...especially when there are limited funds.

You also need to consider risk as well...so tackling the low hanging fruit first makes more sense than chasing all the dreams and ideas.

In my world, innovation is curtailed to around 20% of your budget and the 80% goes to what is the most likely to succeed.

We seem to have very little to go on from the reactivated/smouldering virus theory. Just saying “then we should investigate it” when all the available evidence suggests it’s a non starter seems strange to me, especially while the basics haven’t been done yet.

 

The relapsing-remitting quality might, coupled with its frequently idiosyncratic character/manifestation.

This is small consolation, even if it fits.

 

@JenB
It is hard not to sound like giving medical advice but you realise that and I will try to respond in general terms.

I am open to being proved wrong. However, the received wisdom never changed in the 35 years I was a physician. My mother was a senior member of the UK Virus Reference Laboratory until she retired. Her lab monitored thousands upon thousands of samples. She is too old now to advise but this was the sort of work she published on and she went on going to meetings into her eighties. I never heard the basic principles change. My own research involved switching off B cell responses over periods of years and monitoring antibody levels so I have my own personal data that is in keeping with what I said above. So I would be interested to know what research might say otherwise. From what I have read so far there is nothing in relation to ME/CFS that would go against the standard principles.

What worries me about all this is that there are clearly physicians out there who make a living out of treating people as if they have long term infections without good evidence. In the UK by and large they often get struck off the medical register but in other countries that does not seem to apply. Even in the UK a few treat ME/CFS with anti-virals but I think fewer and fewer now.

A key point is that viral antibody titres vary widely between people, so it would be pretty impossible to diagnose ongoing infection by titre level. There would have to be clinical evidence of a site of viral replication. As far as I know in ME there is no such evidence that is reasonably convincing.

Because the assays do not give levels that can be compared between one person and another very meaningfully. Everything is based on the way the level changes in the individual. All you need is for your immune system to produce a clone of B cells by chance that is particularly good at binding a Coxsackie protein in the assay substrate and you will have higher levels than a lot of other people. It is not that the tests are meaningless, it is just that the bit that is meaningful is change for the specific individual.

If there are specific neurological symptoms then they should be assessed by formal neurological examination. As I mentioned before, neurological exam is remarkably precise at pinning down any specific nerve lesion. It takes about a year of specific neurology training to get to that level of precision so a lot of physicians are not able to deal with subtle problems but a neurologist should be. Specific neurological problems due to local virus infection are in general pretty easy to identify by a neurologist. It is pretty much the same as an electrician doing a circuit check on a house wiring. The recurrent neurological symptoms described by people with ME in general do not show up on exam and nobody knows why that is, but it makes local viral infection pretty unlikely.

 

Oh, I don't know. Today autoantibodies are in favor in some camps, or some kind of immune dysfunction. Three to five years down the line, who knows? Something is causing all that cytokine/chemokine activity.

 

I think what's hard is that there are many people who have high antibody titers, treat the purported infection, feel better, have drop in titers. This idea hasn't not been sufficiently researched, but here is a reflection of the general model:

Persistently high antibody titers and deficient specific cellular immunity to varicella-zoster virus in a retarded patient after varicella infection
https://www.ncbi.nlm.nih.gov/pubmed/1329433

In my case, my improvement on herpes antivirals didn't require anything as phantasmagorical as antibody titers to perceive. HSV-1 was constantly reactivating in the form of blisters on my mouth. Every time it would, I'd have a flare of specific neurological symptoms + intracranial pressure. When I started taking antivirals, the HSV-1 reactivations stopped, I had a clear increase in overall capacity and a resolution of those symptoms. Every time I stop, these symptoms come back. Every time I resume, they recede. We need to find a way/do the research to square what people are observing clinically.

CVB4 unfortunately doesn't carrying anything as overt as a blister outbreak or shingles to convey to the third party observer "yes, this is really happening."

 

Which cytokine activity is that @duncan? Studies I have seen so far show no consistent difference from normals, except possibly a rise in TGFbeta, which is anti-inflammatory by and large.