NIH intramural research program update

[Bob]

Have they said categorically the controls are infection free??

I can't remember, but we haven't seen the study design yet.

 

[Bob]

I don't want alternative tests. I think all participants should be subject to the same qualifying tests, and these should be exhaustive.

Oh, I thought you were advocating for tests that aren't recognized by the CDC. So you're advocating that they use only CDC-approved tests?

 

[duncan]

Ok then. Until they state categorically that controls have no infections, particularly on the TBD front, then there may be cause for concern.

CDC-appoved tests are fine by me. It's whose interpreting them that worries me.lol And I would object to the CDC protocol, but I know that is wasted effort on my part. The C6 needs to be one of the tests - it is FDA-approved - and all values of controls must be below normal levels. Want to wager they won't use the C6? Even if they do, it won't pick up all Borrelia.

Look, @Bob, they cannot accurately guarantee what I am asking. This is one reason why a Lyme control group might prove very bad for the study. There are simply too many question marks and unresolved controversies.

 

[Bob]

Look, @Bob, they cannot accurately guarantee what I am asking. This is one reason why a Lyme control group might prove very bad for the study. There are simply too many question marks and unresolved controversies.

It seems simple to me: They are asymptomatic, with unknown levels of latent infection, which is exactly the same as the healthy control group. If either control group (healthies or Lyme) have an undetectable infection and are asymptomatic, then so much the better. I want to know why they are asymptomatic.

 

[duncan]

You show me where the NIH states that is their premise.

 

[Bob]

You show me where the NIH states that is their premise.

Look, you're saying that there are 'unknowns' with regards to Lyme, and I'm saying that (in my opinion) the 'unknowns' are not important, and that the same 'unknowns' apply to the healthy control group.

For the purposes of this study, why does it matter if asymptomatic "post-Lyme" patients have an undetectable simmering infection? In what ways would that hinder the usefulness of the outcomes?

 

[duncan]

First and foremost, that is not how it is being represented. This matters.

Secondly, you need to appreciate the relapsing remitting quality of some Borrelia. Some other TBD's too. What might be latent or stealth today can be full-blown in three months. So in effect, it's an active infection in some cases, potentially. Wouldn't that impact how that control is contrasted and compared with ME/CFS patients?

Don't they need to say up front that we are dealing with immune responses that are mediated or not by infection? Isn't this basic science?

Don't we need a concrete premise with concrete variables to evolve and test a hypothesis?

 

[Bob]

Secondly, you need to appreciate the relapsing remitting quality of some Borrelia. Some other TBD's too. What might be latent or stealth today can be full-blown in three months. So in effect, it's an active infection in some cases, potentially. Wouldn't that impact how that control is contrasted and compared with ME/CFS patients?

That's something that I wasn't aware of. No one has mentioned it before. If that is common then I can see that could be a problem. But, even so, either the patient is asymptomatic or unwell during the study.

Don't they need to say up front that we are dealing with immune responses that are mediated or not by infection? Isn't this basic science?

I think they are saying that there is no detectable infection in ME patients, healthy controls, or post-Lyme controls.
Some would argue that's a false premise for all three groups, but you're arguing that its a false premise only for post-Lyme patients.
By the way, it could equally be a false premise if MS was a control group, if MS is caused by an unknown pathogen.

Don't we need a concrete premise with concrete variables to evolve and test a hypothesis?

Their premise is straight-forward. But you don't agree with their methodology.

 

[duncan]

a) Check out Borrelia Miyamotoi or babesia;
b) I never argued it's a false premise ONLY for post-Lyme;
c) I don't agree with their premise that post-Lyme is a good control group, for all the reasons I've already discussed.

 

[Bob]

I acknowledge that there are 'unknowns' in relation to the post-Lyme group but I can't understand why 'unknowns' necessarily make a control group inappropriate. Unknown factors might give us completely unexpected answers. There are just as many unknowns in a healthy control group. And all the alternative control groups that have been suggested have just as many unknowns, or possibly more. e.g. we know the cause of Lyme but we don't know the cause of MS. If we're factoring out unknowns then that rules out all possible controls, but especially diseases like MS.

The 'knowns' for the Lyme group are that the patients definitely had an infection, and they are now definitely asymptomatic. This is more important than the 'unknowns'in my opinion.

No one has yet explained to me why it would be a problem if differences were detected between the groups. Why are we worried about detecting differences or similarities between ME patients and asymptomatic post-Lyme patients? Why should such differences/similarities be unhelpful?

 

[duncan]

@Bob, if they say a control group is infection-free, and that is a key premise, and that control group is not infection-free, then the study might be askew from the get-go. Perhaps more importantly, they arguably have demonstrated a disconcerting credibility gap.

Neither is good.

 

[Bob]

@Bob, if they say a control group is infection-free, and that is a key premise, and that control group is not infection-free, then the study might be askew from the get-go. Perhaps more importantly, they arguably have demonstrated a disconcerting credibility gap.

You want them to use different standards for the different groups, and I question if that is reasonable. They have to use the same standards across the groups. How can you guarantee that the ME patients are infection free? The post-Lyme patients are asymptomatic, which is the key to the study. It's the thing that makes the group very special in my opinion, whether infected or infection free. Why is there a problem comparing Lyme patients with ME patients? I still don't get it. I want them compared. Why don't you want them compared? Bring on the unknowns, as far as I'm concerned. In fact that's what this study is investigating: the unknowns.

 

[Kati]

You want them to use different standards for the different groups, and I question if that is reasonable. They have to use the same standards across the groups. How can you guarantee that the ME patients are infection free? The post-Lyme patients are asymptomatic, which is the key to the study. It's the thing that makes the group very special in my opinion, whether infected or infection free. Why is there a problem comparing Lyme patients with ME patients? I still don't get it. I want them compared. Why don't you want them compared? Bring on the unknowns, as far as I'm concerned. In fact that's what this study is investigating: the unknowns.

I do not know if it's been done before as i do not follow Lyme research, but have they compared chronic Lyme atients (the symptomatics) to the 'cured Lyme patients' (asymptomatics)? And if not, would that not be the first steps?

In the fruit salad example, it would be best to compare apples to apples and oranges to oranges. Not apples to oranges.

 

[duncan]

@Bob:

Because I fear Lyme patients in that control are being mischaracterized.

Because I fear there is a stigma associated with Lyme that will effect NIH personnel working on the ME/CFS study.

Because it's more than just Lyme in many of these patients. It's also bartonella and miyamotoi and babesia...And testing for THOSE is notoriously unreliable, too.

Because I don't have much faith in the NIH Lyme team, and I wonder why they are involved in the first place. I don't much care how they have favored Lyme researchers that have qualified persistent Lyme symptoms as nothing more than the aches and pains of everyday life.

I've more....

 

[duncan]

@Kati , the NIH doesn't really acknowledge chronic Lyme. They have Lyme, then PTLDS. They don't even much care to discuss the late stage vs early stage distinction.

It would seem sometimes that in the NIH Island, Lyme is reduced to acute, then acute-treated-cured. After that, it's just those nuts who only think they're sick.

 

[jamie]

Just a personal anecdote about lyme to add. My mom got classic Lyme with bullseye and standard treatment a few years ago. She and her doctor consider her cured. But to me it is obvious she went down hill after that both mentally and physically.

She can't follow a conversation well, she's in a lot of pain and tired all the time and started having outbursts on a regular basis is when that were just not her personality before.. She is in her 70s so the docs put it up to aging possible fibro even when I tried to make her go to a lyme literate doc she said she was fine and that old people just lose some of their memory. To me it is a drastic change in a short time following the lyme. She was retested and was negative but not by a lyme specialist.

So she's "cured" as far as she and her doctor are concerned but I think there is a good chance she has chronic lyme but does't have access to a lyme doctor.

Could she make it into the study? Probably not but who knows. Chronic lyme is not seen as a real illness my mainstream medicine.

 

[jamie]

To me it's not even so much a factor that unknown infectious people could be part of controls, it's that the very people who helped discredit a massive and hard fighting group of lymes patients and made them into a joke much like us at the NIH are now showing up in our study.

Pick a disease without the political baggage so similar to ours. how can they possibly say Post lyme is mandatory when there are so many others to chose from?

 

[RustyJ]

As with Lyme, much the same with the label post-infectious me/cfs. I note that it has been the consensus of the CDC and NIH that me/cfs may have been an infection, but is now psychogenic. Walitt's statements have consistently referred to this narrative.

Firstly there is no discrete entity 'post-infectious me/cfs', nor to this point is there any clinical means of verifying that a recognized infection triggers me/cfs in those registering for the study. Only an association. Note, I am not saying that me/cfs is not caused by an infection, just that they may have got the wrong trigger point.

Also we have multiple causes of infection with multiple possible end points - why is it assumed that someone with post acute Q-fever symptoms can be defined the same as someone with post acute EBV or post acute flu or any number of other infections?

There are many threads discussing the problems around classifying me/cfs as a post-infectious illness on PR going back ten years or so. Many of those threads ended up with a consensus that the so-called trigger infection may have been secondary, or the consequence of some early pathological event.

Personally, I had a sudden onset of symptoms following CMV, yet I recall I had a number of chronic problems such as bronchitis and severe allergies in the twelve months prior to getting CMV. So it is quite likely I had immune dysfunction prior to sudden onset. I know from participating in those earlier threads that many other patients could recall similar events, not all but many.

It means that those truly getting me/cfs from a currently recognized pathogen may be a much smaller proportion of the patient community.

What this does is water down significantly the current assumptions about post-infectious me/cfs for this study and it weakens the possibility of statistically significant findings coming out of such a small sample.

There were better ways to narrow the focus for the study. They could have selected patients who also had intestinal complaints, or those who featured PEM, or OI for that matter.

 

[Sasha]

@Bob, one thing that worries me about the post-Lyme group is that, biologically speaking, recovering from Lyme might not be the same as recovering from (say) EBV, just as having Lyme doesn't have identical symptoms to having EBV.

 

[Valentijn]

I still don't understand the objections to the post-Lyme control group, despite trying hard to understand.

My main objection is that they weaken the statistical power of the study. A few of the dodgier investigators have engaged in such behavior before, using multiple control groups. The result is that there needs to be a huge difference in a lab result between the patients and a control group for it to have statistic significance. Anything more nuanced or representing a subgroup is completely lost. And depending on the ethics of those investigators, they will gloss over the lack of power and present the study as a straight-forward null result. I do not want them to have the opportunity to do that again.

My other objection is that the Lyme group introduces uncertainty, instead of reducing it. As @duncan has said at some length ... are they cured or in remission? Ticks are notorious for not being picky about the pathogens they acquire and transmit, so past and present co-infections are a very real likelihood. That transforms it from "cured Lyme group" into "a bunch of patients with Lyme + X, Y, and/or Z".

Some of those co-infections, such as Bartonella, make Lyme testing look like a picnic by comparison. Mainstream Bartonella testing is widely acknowledged to have an 80% false negative rate ... on average it takes 5 blood tests to get a positive result in someone who is definitely infected.

When comparing ME to something, it should be compared to something which is very well understood. Otherwise, we don't know what we're comparing it to, or what the similarities and differences mean. Generally I would not be opposed to that happening, but it should not be happening in a preliminary exploratory study, especially when the results could impact on Stage II and Stage III of that study, or on prospects for further studies.

The idea behind a control group is to control for variables. I don't think you can deny that a Lyme group potentially introduces new variables instead.

A reason given against the post-Lyme control is that the bacterial infection might still be present but simmering, but the same could be said for ME (that an infection is simmering) so that seems perfect to me.

Except that you don't come closer to getting an answer in the case of ME by introducing a similar mystery in the form of Lyme. It would be better to have people who recovered completely from post-viral fatigue after 6 months due to EBV, and now have normal EBV titers.

The issue of whether a patient had Lyme or not won't be an issue if they're using officially recognised tests.

The official tests have a huge false negative rate. That's part of the reason they make a crappy control group. Are they asymptomatic and cured, or asymptomatic with the bacteria still hiding out somewhere? We need to know, if we're going to use them as a basis for interpreting results from ME patients. And the state of Lyme testing is not sufficient to provide any definitive answers.

The post-Lyme patients are healthy controls but a more homogeneous cohort than the standard healthy control because they've all had the same infection

It's unlikely that none of them ever had co-infections. Maybe the Lyme antibiotics wiped them out as well, but maybe not.

And nearly all the population is post-mono or post-herpes.

But most are not post-post-viral fatigue from EBV. Or post-Q-fever.

I understand that there may be many false negative diagnoses, but that's irrelevant for this study.

No, it isn't. They tested positive at some point, but due to inaccuracy of all testing methods, it cannot be guaranteed that they are negative now. All that is known is that they were firmly diagnosed with Lyme at some point, and they were treated. Beyond that, all we can do is guess if the infection was cleared, and no others were present.

I'm only interested in why they are asymptomatic. If they are infectious but asymptomatic, then lets find out why.

That's a completely different trial. The purpose of this trial is to answer questions about ME. The very existence of questions about the Lyme group should be a very strong indication that they are not suitable controls.

I acknowledge that there are 'unknowns' in relation to the post-Lyme group but I can't understand why 'unknowns' necessarily make a control group inappropriate. Unknown factors might give us completely unexpected answers.

Again, because the purpose of a control group is to control for variables. A control group should not be capable of doing anything unexpected.